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Intellectual disability v9.371 LRRC32 Ida Ertmanska Added comment: Comment on list classification: There are now 3 unrelated individuals with 3 different homozygous LRRC32 variants and syndromic ID/GDD. Hence, this gene should be promoted to Green on Intellectual disability at the next update.
Intellectual disability v9.370 LRRC32 Ida Ertmanska reviewed gene: LRRC32: Rating: GREEN; Mode of pathogenicity: None; Publications: 40721351, https://doi.org/10.1016/j.rare.2025.100101; Phenotypes: Cleft palate, proliferative retinopathy, and developmental delay, OMIM:619074; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v9.366 MYCBP2 Ida Ertmanska changed review comment from: PMID: 36200388 AlAbdi et al., 2023
Eight patients (7 male, 1 female) with de novo MYCBP2 variants. Phenotypic spectrum: ID (4/8, moderate to severe), GDD (7/8), corpus callosum thinning / dysgenesis / agenesis (4/5). 2 patients had seizures and 1 had abnormal EEG; 1 patient diagnosed with cone dystrophy, one with retinopathy; 2 patients had hearing loss.

PMID: 41200582 Kostovska et al., 2025
Family with three affected members (mother and 2 sons aged 3yrs and 9 mo) carrying a novel heterozygous MYCBP2 variant NM_015057.5 c.7311del, p.(Leu2438Trpfs*3). Phenotypes: mild intellectual disability, dev delay, speech impairment, facial dysmorphism, microcephaly, seizures (only in the mother). Brain MRI not done.

PMID: 41543631 Pham et al., 2026
Proband with a maternally inherited c.4409dup (p.Leu1470Phefs*7), presented with global developmental delay, autism spectrum disorder (ASD), chronic constipation, sleep disturbances, and aggressive behaviors. Brain MRI showed normal corpus callosum. Mother had generally intact cognition (FSIQ = 103).

MYCBP2 is not yet associated with disease in OMIM (accessed 1st Apr 2026).; to: PMID: 33875846 Bertoli-Avella et al., 2021
Large WES/WGS cohort. Study detected three de novo variants (one likely affecting splicing and two missense) in three patients with NDD, microcephaly, and seizures. One case presented bilateral bifid thumbs, talipes, and scoliosis, without vaginal or uterine anomalies. No variants details.

PMID: 36200388 AlAbdi et al., 2023
Eight patients (7 male, 1 female) with de novo MYCBP2 variants. Phenotypic spectrum: ID (4/8, moderate to severe), GDD (7/8), corpus callosum thinning / dysgenesis / agenesis (4/5). 2 patients had seizures and 1 had abnormal EEG; 1 patient diagnosed with cone dystrophy, one with retinopathy; 2 patients had hearing loss.

PMID: 41200582 Kostovska et al., 2025
Family with three affected members (mother and 2 sons aged 3yrs and 9 mo) carrying a novel heterozygous MYCBP2 variant NM_015057.5 c.7311del, p.(Leu2438Trpfs*3). Phenotypes: mild intellectual disability, dev delay, speech impairment, facial dysmorphism, microcephaly, seizures (only in the mother). Brain MRI not done.

PMID: 41543631 Pham et al., 2026
Proband with a maternally inherited c.4409dup (p.Leu1470Phefs*7), presented with global developmental delay, autism spectrum disorder (ASD), chronic constipation, sleep disturbances, and aggressive behaviors. Brain MRI showed normal corpus callosum. Mother had generally intact cognition (FSIQ = 103).

MYCBP2 is not yet associated with disease in OMIM (accessed 1st Apr 2026).
Intellectual disability v9.365 MYCBP2 Ida Ertmanska Added comment: Comment on list classification: There are now more than 10 unrelated patients with heterozygous MYCBP2 variants and a neurodevelopmental disorder, with ID/GDD being the most consistent feature. Hence, this gene should be promoted to Green at the next update.
Intellectual disability v9.364 MYCBP2 Ida Ertmanska changed review comment from: PMID: 36200388 AlAbdi et al., 2023
Eight patients (7 male, 1 female) with de novo MYCBP2 variants. Phenotypic spectrum: ID (4/8, moderate to severe), GDD (7/8), corpus callosum thinning / dysgenesis / agenesis (4/5). 2 patients had seizures and 1 had abnormal EEG; 1 patient diagnosed with cone dystrophy, one with retinopathy; 2 patients had hearing loss.

PMID: 41200582 Kostovska et al., 2025
Family with three affected members (mother and 2 sons aged 3yrs and 9 mo) carrying a novel heterozygous MYCBP2 variant NM_015057.5 c.7311del, p.(Leu2438Trpfs*3). Phenotypes: mild intellectual disability, dev delay, speech impairment, facial dysmorphism, microcephaly, seizures (only in the mother).

PMID: 41543631 Pham et al., 2026
Proband with a maternally inherited c.4409dup (p.Leu1470Phefs*7), presented with global developmental delay, autism spectrum disorder (ASD), chronic constipation, sleep disturbances, and aggressive behaviors. Brain MRI showed normal corpus callosum. Mother had generally intact cognition (FSIQ = 103).

MYCBP2 is not yet associated with disease in OMIM (accessed 1st Apr 2026).; to: PMID: 36200388 AlAbdi et al., 2023
Eight patients (7 male, 1 female) with de novo MYCBP2 variants. Phenotypic spectrum: ID (4/8, moderate to severe), GDD (7/8), corpus callosum thinning / dysgenesis / agenesis (4/5). 2 patients had seizures and 1 had abnormal EEG; 1 patient diagnosed with cone dystrophy, one with retinopathy; 2 patients had hearing loss.

PMID: 41200582 Kostovska et al., 2025
Family with three affected members (mother and 2 sons aged 3yrs and 9 mo) carrying a novel heterozygous MYCBP2 variant NM_015057.5 c.7311del, p.(Leu2438Trpfs*3). Phenotypes: mild intellectual disability, dev delay, speech impairment, facial dysmorphism, microcephaly, seizures (only in the mother). Brain MRI not done.

PMID: 41543631 Pham et al., 2026
Proband with a maternally inherited c.4409dup (p.Leu1470Phefs*7), presented with global developmental delay, autism spectrum disorder (ASD), chronic constipation, sleep disturbances, and aggressive behaviors. Brain MRI showed normal corpus callosum. Mother had generally intact cognition (FSIQ = 103).

MYCBP2 is not yet associated with disease in OMIM (accessed 1st Apr 2026).
Intellectual disability v9.363 COQ5 Ida Ertmanska Phenotypes for gene: COQ5 were changed from AUTOSOMAL RECESSIVE MENTAL RETARDATION; cerebellar ataxia and static encephalomyopathy due to COQ5 C-methyltransferase deficiency to ?Coenzyme Q10 deficiency, primary, 9, OMIM:619028; mitochondrial disease, MONDO:0044970
Intellectual disability v9.362 COQ5 Ida Ertmanska Added comment: Comment on list classification: There are now 6 individuals from 3 unrelated families with intellectual disability and developmental delay, harbouring biallelic variants in COQ5. Hence, this gene can be promoted to Green at the next GMS update.
Intellectual disability v9.361 COQ5 Ida Ertmanska reviewed gene: COQ5: Rating: GREEN; Mode of pathogenicity: None; Publications: 29044765, 36266294, 37599337, 41199775; Phenotypes: ?Coenzyme Q10 deficiency, primary, 9, OMIM:619028, mitochondrial disease, MONDO:0044970; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v9.361 RDH11 Ida Ertmanska Added comment: Comment on list classification: There are more than 3 unrelated individuals reported in literature with biallelic variants in RDH11 and syndromic Intellectual disability. Hence, this gene should be promoted to Green at the next update.
Intellectual disability v9.360 RDH11 Ida Ertmanska gene: RDH11 was added
gene: RDH11 was added to Intellectual disability. Sources: Literature
Q2_26_promote_green tags were added to gene: RDH11.
Mode of inheritance for gene: RDH11 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RDH11 were set to 24916380; 34988992; 41459630; 41904678
Phenotypes for gene: RDH11 were set to ?Retinal dystrophy, juvenile cataracts, and short stature syndrome, OMIM:616108; Neurodevelopmental delay, HP:0012758; Juvenile cataract, HP:0001118
Review for gene: RDH11 was set to GREEN
Added comment: PMID: 41904678 Radio et al., 2026
Report of 16 affected individuals from 9 unrelated families with biallelic LoF RDH11 variants, frequently showing juvenile-onset progressive myopathy with vacuolar degeneration and prodromic asymptomatic hyperCKemia. Common features included: neurodevelopmental impairment (16/16), microcephaly (10/16), retinitis pigmentosa (8/16), juvenile-onset cataracts (11/16), myopathy (8/15), progressive night blindness (9/16), hypoplasia of corpus callosum (8/10 assessed by MRI). Microcephaly and distinct craniofacial traits were also recurrent. Short stature was reported in 4/16 patients.
Muscle weakness was reported as slowly progressive, associated with myopathic facies and exercise intolerance with onset in the first or second decade of life.

PMID: 41459630 Stephenson et al., 2025
Report of a visually asymptomatic 7-year-old boy carrying a homozygous null variant in RDH11 [NM_016026.4:c.216C>A:p.(Cys72*)] with autism, dysmorphic features, oligodontia, microcephaly (<3rd centile) and a novel inherited retinal dystrophy. This retinopathy consisted of yellow deposits and hyperpigmentation within the RPE with absent autofluorescence and a normal electroretinogram.

PMID: 34988992 Liu et al., 2022
Chinese patient with retinitis pigmentosa (RP), juvenile cataracts, intellectual disability, and myopathy. No microcephaly. Trio WES identified variants in RDH11: c.938T>C (p.Leu313Pro) and c.75-3C>A - confirmed in trans. Splice variant shown to cause exon 2 skipping resulting in (p.Lys26Serfs*38) change. Using immunofluorescence, authors found mislocalization of RDH11 protein in muscle cells of the patient.

PMID: 24916380 Xie et al., 2014
3 sibs aged 8-19 years (Italian-American family) with juvenile cataracts (onset at 8-10 years old), issues with night vision, and retinitis pigmentosa, as well as other syndromic features: facial dysmorphologies, psychomotor developmental delays, learning disabilities and short stature. WES detected comp het RDH11 mutations c.C199T:p.R67* and c.C322T:p.R108*. No mention of muscle weakness or microcephaly.

RDH11 is putatively associated in OMIM with AR Retinal dystrophy, juvenile cataracts, and short stature syndrome, OMIM:616108 (accessed 1st Apr 2026).
Sources: Literature
Intellectual disability v9.359 ATG12 Ida Ertmanska changed review comment from: Comment on list classification: There are 5 unrelated families reported in literature with individuals harbouring biallelic ATG12 variants and presenting with intellectual disability / psychomotor delay. Hence, this gene should be upgraded to Green for Intellectual disability.; to: Comment on list classification: There are 5 unrelated families reported in literature with individuals harbouring biallelic ATG12 variants and presenting with intellectual disability / psychomotor delay. This association is supported by a zebrafish model, where atg12 knockout results in developmental delay and impaired brain funciton. Hence, this gene should be upgraded to Green for Intellectual disability.
Intellectual disability v9.359 ATG12 Ida Ertmanska changed review comment from: PMID: 41895291 Lambton et al, 2026
Homozygous and compound heterozygous variants in ATG12 reported in 6 individuals from five unrelated families with neurodevelopmental disorder with hypotonia, seizures (all 6 individuals with variable severity), ataxia, developmental delay and / or intellectual disability (seen in all 5 families), corpus callosum hypoplasia (4/5 individuals) and hypoplasia of the cerebellar vermis (5/5 individuals assessed). Other less consistent MRI findings: reduced white and gray matter, polymicrogyria, cerebellocerebral atrophy, thinning of pons, brainstem hypomyelination, and more. 4/6 individuals died before age 5 years.

Family 1: 2 sibs with ATG12 variants c.359A>C, p.Tyr120Ser and c.363+3A>T (demonstrated to cause exon 3 skipping)
Family 2: proband with a homozygous variant c.413C>T, p.Ala138Val
Family 3 : proband with a homozygous variant c.359A>C p.Tyr.120Ser
Family 4: proband S5 comp het for ATG12 variants c.235C>T (p.Arg79∗) & c.359A>C p.Tyr.120Ser
Family 5: proabdn with homozygous missense variant c.324T>G (p.Phe108Leu)

This gene has no disease association in OMIM (accessed 1st Apr 2026).
Sources: Literature; to: PMID: 41895291 Lambton et al, 2026
Homozygous and compound heterozygous variants in ATG12 reported in 6 individuals from five unrelated families with neurodevelopmental disorder with hypotonia, seizures (all 6 individuals with variable severity), ataxia, developmental delay and / or intellectual disability (seen in all 5 families), corpus callosum hypoplasia (4/5 individuals) and hypoplasia of the cerebellar vermis (5/5 individuals assessed). Other less consistent MRI findings: reduced white and gray matter, polymicrogyria, cerebellocerebral atrophy, thinning of pons, brainstem hypomyelination, and more. 4/6 individuals died before age 5 years.

Family 1: 2 sibs with ATG12 variants c.359A>C, p.Tyr120Ser and c.363+3A>T (demonstrated to cause exon 3 skipping)
Family 2: proband with a homozygous variant c.413C>T, p.Ala138Val
Family 3 : proband with a homozygous variant c.359A>C p.Tyr.120Ser
Family 4: proband S5 comp het for ATG12 variants c.235C>T (p.Arg79∗) & c.359A>C p.Tyr.120Ser
Family 5: proband with homozygous missense variant c.324T>G (p.Phe108Leu)

Functional: Loss of atg12 function in zebrafish causes developmental delay, impaired brain function, and pre-adult lethality.

This gene has no disease association in OMIM (accessed 1st Apr 2026).
Sources: Literature
Intellectual disability v9.359 ATG12 Ida Ertmanska Added comment: Comment on list classification: There are 5 unrelated families reported in literature with individuals harbouring biallelic ATG12 variants and presenting with intellectual disability / psychomotor delay. Hence, this gene should be upgraded to Green for Intellectual disability.
Intellectual disability v9.358 ATG12 Ida Ertmanska gene: ATG12 was added
gene: ATG12 was added to Intellectual disability. Sources: Literature
Q2_26_promote_green tags were added to gene: ATG12.
Mode of inheritance for gene: ATG12 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ATG12 were set to 41895291
Phenotypes for gene: ATG12 were set to neurodevelopmental disorder, MONDO:0700092; Hypoplasia of the corpus callosum, HP:0002079; Cerebellar hypoplasia, HP:0001321
Review for gene: ATG12 was set to GREEN
Added comment: PMID: 41895291 Lambton et al, 2026
Homozygous and compound heterozygous variants in ATG12 reported in 6 individuals from five unrelated families with neurodevelopmental disorder with hypotonia, seizures (all 6 individuals with variable severity), ataxia, developmental delay and / or intellectual disability (seen in all 5 families), corpus callosum hypoplasia (4/5 individuals) and hypoplasia of the cerebellar vermis (5/5 individuals assessed). Other less consistent MRI findings: reduced white and gray matter, polymicrogyria, cerebellocerebral atrophy, thinning of pons, brainstem hypomyelination, and more. 4/6 individuals died before age 5 years.

Family 1: 2 sibs with ATG12 variants c.359A>C, p.Tyr120Ser and c.363+3A>T (demonstrated to cause exon 3 skipping)
Family 2: proband with a homozygous variant c.413C>T, p.Ala138Val
Family 3 : proband with a homozygous variant c.359A>C p.Tyr.120Ser
Family 4: proband S5 comp het for ATG12 variants c.235C>T (p.Arg79∗) & c.359A>C p.Tyr.120Ser
Family 5: proabdn with homozygous missense variant c.324T>G (p.Phe108Leu)

This gene has no disease association in OMIM (accessed 1st Apr 2026).
Sources: Literature
Intellectual disability v9.357 OLA1 Ida Ertmanska Added comment: Comment on list classification: There are 14 individuals reported from 9 unrelated families with biallelic variants in OLA1 and syndromic intellectual disability / psychomotor delay. Hence, this gene should be promoted to Green at the next update.
Intellectual disability v9.356 OLA1 Ida Ertmanska gene: OLA1 was added
gene: OLA1 was added to Intellectual disability. Sources: Literature
Q1_26_promote_green tags were added to gene: OLA1.
Mode of inheritance for gene: OLA1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: OLA1 were set to 41887223
Phenotypes for gene: OLA1 were set to Ehlers-Danlos syndrome, hypermobility type, MONDO:0007523; neurodevelopmental disorder,MONDO:0700092; microcephaly, MONDO:0001149
Review for gene: OLA1 was set to GREEN
Added comment: PMID: 41887223 Alabdi et al., 2026
14 individuals from 9 families reported with homozygous loss of function variants in OLA1 with a phenotype characterised by a neurodevelopmental condition with connective tissue disorder.
All 14 individuals presented with intellectual disability / psychomotor delay. Seizures were reported in unrelated 6 individuals. Joint hypermobility was noted in 13/13 patients, 5 of them had skin laxity. 6 individuals had scoliosis or kyphoscoliosis. Several patients were diagnosed with Ehlers-Danos syndrome.
Microcephaly was noted in 4 individuals from unrelated families (severity details: -4.49 SD, -3SD, -4.6SD, and "HC 45cm at 9 years")

Functional evidence: C. elegans model with knock-in protein-truncating variants showed behavioural abnormalities (reduced bending, no response to touch), and reduced axon numbers in GABAergic neurons.
Variant in family 1 (p.Arg143Ter) was shown to cause complete loss of OLA1 protein on Western blot; RT-PCR was supportive of NMD taking place. Splice variant seen in Family 8 (c.728+5G>A) was demonstrated to cause exon 7 skipping.
Sources: Literature
Intellectual disability v9.355 BRF2 Ida Ertmanska changed review comment from: PMID: 40229899 Mattioli et al., 2025
Report of six families (3 Icelandic, 1 Iranian, 1 Pakistani, 1 of unknown ancestry) with bi-allelic variants in BRF2 presenting with early mortality, brain, and craniofacial anomalies and/or neurodevelopmental disorders (NDD). Patients had phenotypes ranging from perinatal death to Treacher-Collins and craniosynostosis with radial defects and immunodeficiency or global developmental delay, hearing, and vision impairment.
Families 1-3 = Icelandic families with founder BRF2 variant c.214 + 1G > A, not much detail provided on phenotype beyond "early lethality". Genotyping was not done for the affected fetuses, it was inferred from living family members.

Family 4 - female proband with Treacher-Collins syndrome, presented with hearing impairment, soft cleft palate, microcephaly, and facial dysmorphism. She was homozygous for BRF2 c.481G > T; p.(Gly161*).

Family 5 - 2 sibs compound het for BRF2 c.782C > T ; p.(Pro261Leu) & c.404_409delinsA; p.(Met135Asnfs*15);
Patient II:1 female, presented with coronal synostosis, microcephaly, hypertelorism, a small beaked, nose, retrognathia, shortened right radius, and absent left radius, with radial deviation of the hands and contractures of all fingers. She was found to have anemia, leukocytosis, marked eosinophilia, and thrombocytopenia, and developed a significant rash by 1 month of age; she died at 2 mo from bacterial infection.
Patient II:2, male - presented with frontal bone hypoplasia with bilateral coronal synostosis, micrognathia, small orbits, low-set ears, downward slanting palpebral fissures, and significantly decreased B-cell CD19 subsets. He subsequently developed ichthyosiform erythroderma and eosinophilic myeloid hyperplasia. He had developmental and speech delays.

Family 6 - 4 affected sibs with moderate ID, and delays in motor and speech development; 2 sibs had mild hearing and vision impairment. 2 sibs confirmed homozygous for BRF2 c.31G > A; p.(Gly11Ser).

Zebrafish knocked down for the orthologous brf2 presented with abnormal escape response, reduced swimming velocity and head size, and craniofacial malformations. Phenotype was rescued by human BRF2, but not by isoforms with patients variants.

PMID: 40781771 Yoon et al., 2025
Case report of a girl, presumed Korean born to non-consanguineous parents, with multiple congenital anomalies: polydactyly of the right fifth toe, duplex kidney on the right side, hypodontia, and dysmorphic facial features. She had recurrent infections in the neonatal period, and was diagnosed with primary immunodeficiency at 4 months. Mild ID (IQ=60) was diagnosed at age 16 yrs. She harboured comp het BRF2 variants: c.379C>T, p.Arg127Ter & c.782C>T, p.Pro261Leu. Older sister was similarly affected; she died of infection at 19 months.
Single-cell RNA-seq analysis of the patient sample revealed transcriptional abnormalities in PBMCs from the patient harboring BRF2 mutations. BRF2 mutations disrupt RNA Pol III activity specifically at type III promoters, leading to transcriptional dysregulation of critical noncoding RNAs

BRF2 is not yet associated with a phenotype in OMIM (accessed 27 Mar 2026).
Sources: Literature
Sources: Literature; to: PMID: 40229899 Mattioli et al., 2025
Report of six families (3 Icelandic, 1 Iranian, 1 Pakistani, 1 of unknown ancestry) with bi-allelic variants in BRF2 presenting with early mortality, brain, and craniofacial anomalies and/or neurodevelopmental disorders (NDD). Patients had phenotypes ranging from perinatal death to Treacher-Collins and craniosynostosis with radial defects and immunodeficiency or global developmental delay, hearing, and vision impairment.
Families 1-3 = Icelandic families with founder BRF2 variant c.214 + 1G > A, not much detail provided on phenotype beyond "early lethality". Genotyping was not done for the affected fetuses, it was inferred from living family members.

Family 4 - female proband with Treacher-Collins syndrome, presented with hearing impairment, soft cleft palate, microcephaly, and facial dysmorphism. She was homozygous for BRF2 c.481G > T; p.(Gly161*).

Family 5 - 2 sibs compound het for BRF2 c.782C > T ; p.(Pro261Leu) & c.404_409delinsA; p.(Met135Asnfs*15);
Patient II:1 female, presented with coronal synostosis, microcephaly, hypertelorism, a small beaked, nose, retrognathia, shortened right radius, and absent left radius, with radial deviation of the hands and contractures of all fingers. She was found to have anemia, leukocytosis, marked eosinophilia, and thrombocytopenia, and developed a significant rash by 1 month of age; she died at 2 mo from bacterial infection.
Patient II:2, male - presented with frontal bone hypoplasia with bilateral coronal synostosis, micrognathia, small orbits, low-set ears, downward slanting palpebral fissures, and significantly decreased B-cell CD19 subsets. He subsequently developed ichthyosiform erythroderma and eosinophilic myeloid hyperplasia. He had developmental and speech delays.

Family 6 - 4 affected sibs with moderate ID, and delays in motor and speech development; 2 sibs had mild hearing and vision impairment. 2 sibs confirmed homozygous for BRF2 c.31G > A; p.(Gly11Ser).

Zebrafish knocked down for the orthologous brf2 presented with abnormal escape response, reduced swimming velocity and head size, and craniofacial malformations. Phenotype was rescued by human BRF2, but not by isoforms with patients variants.

PMID: 40781771 Yoon et al., 2025
Case report of a girl, presumed Korean born to non-consanguineous parents, with multiple congenital anomalies: polydactyly of the right fifth toe, duplex kidney on the right side, hypodontia, and dysmorphic facial features. She had recurrent infections in the neonatal period, and was diagnosed with primary immunodeficiency at 4 months. Mild ID (IQ=60) was diagnosed at age 16 yrs. She harboured comp het BRF2 variants: c.379C>T, p.Arg127Ter & c.782C>T, p.Pro261Leu. Older sister was similarly affected; she died of infection at 19 months.
Single-cell RNA-seq analysis of the patient sample revealed transcriptional abnormalities in PBMCs from the patient harboring BRF2 mutations. BRF2 mutations disrupt RNA Pol III activity specifically at type III promoters, leading to transcriptional dysregulation of critical noncoding RNAs

BRF2 is not yet associated with a phenotype in OMIM (accessed 27 Mar 2026).
Sources: Literature
Intellectual disability v9.355 BRF2 Ida Ertmanska Added comment: Comment on list classification: There are 3 unrelated families with biallelic BRF2 variants and syndromic congenital anomalies, including intellectual disability and developmental delay. Hence, this gene can be promoted to Green at the next udpate, which also ensures inclusion on R27 Paediatric disorders.
Intellectual disability v9.354 BRF2 Ida Ertmanska gene: BRF2 was added
gene: BRF2 was added to Intellectual disability. Sources: Literature
Q1_26_promote_green tags were added to gene: BRF2.
Mode of inheritance for gene: BRF2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BRF2 were set to 40229899; 40781771
Phenotypes for gene: BRF2 were set to multiple congenital anomalies/dysmorphic syndrome, MONDO:0019042; intellectual disability, MONDO:0001071
Review for gene: BRF2 was set to GREEN
Added comment: PMID: 40229899 Mattioli et al., 2025
Report of six families (3 Icelandic, 1 Iranian, 1 Pakistani, 1 of unknown ancestry) with bi-allelic variants in BRF2 presenting with early mortality, brain, and craniofacial anomalies and/or neurodevelopmental disorders (NDD). Patients had phenotypes ranging from perinatal death to Treacher-Collins and craniosynostosis with radial defects and immunodeficiency or global developmental delay, hearing, and vision impairment.
Families 1-3 = Icelandic families with founder BRF2 variant c.214 + 1G > A, not much detail provided on phenotype beyond "early lethality". Genotyping was not done for the affected fetuses, it was inferred from living family members.

Family 4 - female proband with Treacher-Collins syndrome, presented with hearing impairment, soft cleft palate, microcephaly, and facial dysmorphism. She was homozygous for BRF2 c.481G > T; p.(Gly161*).

Family 5 - 2 sibs compound het for BRF2 c.782C > T ; p.(Pro261Leu) & c.404_409delinsA; p.(Met135Asnfs*15);
Patient II:1 female, presented with coronal synostosis, microcephaly, hypertelorism, a small beaked, nose, retrognathia, shortened right radius, and absent left radius, with radial deviation of the hands and contractures of all fingers. She was found to have anemia, leukocytosis, marked eosinophilia, and thrombocytopenia, and developed a significant rash by 1 month of age; she died at 2 mo from bacterial infection.
Patient II:2, male - presented with frontal bone hypoplasia with bilateral coronal synostosis, micrognathia, small orbits, low-set ears, downward slanting palpebral fissures, and significantly decreased B-cell CD19 subsets. He subsequently developed ichthyosiform erythroderma and eosinophilic myeloid hyperplasia. He had developmental and speech delays.

Family 6 - 4 affected sibs with moderate ID, and delays in motor and speech development; 2 sibs had mild hearing and vision impairment. 2 sibs confirmed homozygous for BRF2 c.31G > A; p.(Gly11Ser).

Zebrafish knocked down for the orthologous brf2 presented with abnormal escape response, reduced swimming velocity and head size, and craniofacial malformations. Phenotype was rescued by human BRF2, but not by isoforms with patients variants.

PMID: 40781771 Yoon et al., 2025
Case report of a girl, presumed Korean born to non-consanguineous parents, with multiple congenital anomalies: polydactyly of the right fifth toe, duplex kidney on the right side, hypodontia, and dysmorphic facial features. She had recurrent infections in the neonatal period, and was diagnosed with primary immunodeficiency at 4 months. Mild ID (IQ=60) was diagnosed at age 16 yrs. She harboured comp het BRF2 variants: c.379C>T, p.Arg127Ter & c.782C>T, p.Pro261Leu. Older sister was similarly affected; she died of infection at 19 months.
Single-cell RNA-seq analysis of the patient sample revealed transcriptional abnormalities in PBMCs from the patient harboring BRF2 mutations. BRF2 mutations disrupt RNA Pol III activity specifically at type III promoters, leading to transcriptional dysregulation of critical noncoding RNAs

BRF2 is not yet associated with a phenotype in OMIM (accessed 27 Mar 2026).
Sources: Literature
Sources: Literature
Intellectual disability v9.353 RHOBTB2 Ida Ertmanska changed review comment from: As there are now more than 3 individuals reported with both mono- and bi-allelic variants in RHOBTB2 with epilepsy, the mode of inheritance should be changed to BOTH monoallelic and biallelic, autosomal or pseudoautosomal at the next update.; to: As there are now more than 3 individuals reported with both mono- and bi-allelic variants in RHOBTB2 with syndromic ID/DD, the mode of inheritance should be changed to BOTH monoallelic and biallelic, autosomal or pseudoautosomal at the next update.
Intellectual disability v9.352 RHOBTB2 Ida Ertmanska Phenotypes for gene: RHOBTB2 were changed from Epileptic encephalopathy, early infantile, 64, 618004; Global developmental delay; Intellectual disability; Seizures; Postnatal microcephaly to Developmental and epileptic encephalopathy 64, OMIM:618004; developmental and epileptic encephalopathy, 64, MONDO:0033373
Intellectual disability v9.351 RHOBTB2 Ida Ertmanska changed review comment from: PMID: 37165955 Langhammer et al., 2023
Report of 13 individuals from 9 families with bilallelic loss of function RHOBTB2 variants with a variable neurodevelopmental disorder including intellectual disability and seizures. 7/9 families were confirmed as consanguineous. Phenotypic spectrum: DD/ID ranging from learning difficulties to moderate ID (11/13 individuals), epilepsy, seizures, and/or abnormal EEG (11/13), microcephaly (5/9 individuals assessed, 2 with more than -3 SD), ataxia & gait disturbances (7/13), MRI anomalies seen in 2 patients. Study also reported 6 new cases with de novo heterozygous missense variants in RHOBTB2.; to: PMID: 37165955 Langhammer et al., 2023
Report of 13 individuals from 9 families with bilallelic loss of function RHOBTB2 variants with a variable neurodevelopmental disorder including intellectual disability and seizures. 7/9 families were confirmed as consanguineous. Phenotypic spectrum: DD/ID ranging from learning difficulties to moderate ID (11/13 individuals), epilepsy, seizures, and/or abnormal EEG (11/13), microcephaly (5/9 individuals assessed, 2 with more than -3 SD), ataxia & gait disturbances (8/10), MRI anomalies seen in 2 patients. Study also reported 6 new cases with de novo heterozygous missense variants in RHOBTB2.
Intellectual disability v9.351 RHOBTB2 Ida Ertmanska changed review comment from: PMID: 37165955 Langhammer et al., 2023
Report of 13 individuals from 9 families with bilallelic loss of function variants with a variable neurodevelopmental disorder including intellectual disability and seizures. 7/9 families were confirmed as consanguineous. Phenotypic spectrum: DD/ID ranging from learning difficulties to moderate ID (11/13 individuals), epilepsy, seizures, and/or abnormal EEG (11/13), microcephaly (5/9 individuals assessed, 2 with more than -3 SD), ataxia & gait disturbances (7/13), MRI anomalies seen in 2 patients. Study also reported 6 new cases with de novo heterozygous missense variants.; to: PMID: 37165955 Langhammer et al., 2023
Report of 13 individuals from 9 families with bilallelic loss of function RHOBTB2 variants with a variable neurodevelopmental disorder including intellectual disability and seizures. 7/9 families were confirmed as consanguineous. Phenotypic spectrum: DD/ID ranging from learning difficulties to moderate ID (11/13 individuals), epilepsy, seizures, and/or abnormal EEG (11/13), microcephaly (5/9 individuals assessed, 2 with more than -3 SD), ataxia & gait disturbances (7/13), MRI anomalies seen in 2 patients. Study also reported 6 new cases with de novo heterozygous missense variants in RHOBTB2.
Intellectual disability v9.351 RHOBTB2 Ida Ertmanska commented on gene: RHOBTB2: As there are now more than 3 individuals reported with both mono- and bi-allelic variants in RHOBTB2 with epilepsy, the mode of inheritance should be changed to BOTH monoallelic and biallelic, autosomal or pseudoautosomal at the next update.
Intellectual disability v9.351 PTPN1 Ida Ertmanska changed review comment from: Comment on list classification: There are 11 unrelated individuals reported with heterozygous PTPN1 variants, presenting with loss of previously acquired skills, spasticity/dystonia, cerebral atrophy, and white matter changes. There is a high degree of non-penetrance, as 9/12 reported patients have inherited the PTPN1 variants from their asymptomatic parents. Hence, this gene is recommended for Green with expert review to determine if the non-penetrance is in scope of testing.; to: Comment on list classification: There are 11 unrelated individuals reported with heterozygous PTPN1 variants, presenting in childhood with loss of previously acquired skills, spasticity/dystonia, cerebral atrophy, and white matter changes. There is a high degree of non-penetrance, as 9/12 reported patients have inherited the PTPN1 variants from their asymptomatic parents. Hence, this gene is recommended for Green with expert review to determine if the non-penetrance is in scope of testing.
Intellectual disability v9.351 PTPN1 Ida Ertmanska commented on gene: PTPN1: Comment on list classification: There are 11 unrelated individuals reported with heterozygous PTPN1 variants, presenting with loss of previously acquired skills, spasticity/dystonia, cerebral atrophy, and white matter changes. There is a high degree of non-penetrance, as 9/12 reported patients have inherited the PTPN1 variants from their asymptomatic parents. Hence, this gene is recommended for Green with expert review to determine if the non-penetrance is in scope of testing.
Intellectual disability v9.351 PTPN1 Ida Ertmanska Phenotypes for gene: PTPN1 were changed from Encephalopathy, HP:0001298 to Encephalopathy, HP:0001298; dystonia, early-onset, and/or spastic paraplegia, MONDO:0859215
Intellectual disability v9.350 PTPN1 Ida Ertmanska edited their review of gene: PTPN1: Changed phenotypes to: Encephalopathy, HP:0001298, dystonia, early-onset, and/or spastic paraplegia, MONDO:0859215
Intellectual disability v9.347 PTPN1 Ida Ertmanska changed review comment from: PMID: 39986310 Zhu et al., 2025
Reported heterozygous PTPN1 variants in 12 patients from 11 families. 2/10 were canonical splice variants, 2 were missense variants, and 6 were STOP-gain. 3 cases were de novo, 9 individuals inherited the variant from an asymptomatic parent. Sequencing method: WES + Sanger.

Phenotype: 12/12 individuals experienced subacute loss of skills (age range 15 months to 8 years) after initial normal development in 11 of 12 (one patient had mild motor delay); weakness (12/12), spasticity (initially manifesting as a hemiparesis in seven patients and then becoming bilateral) +/- dystonia, bulbar involvement (dysphagia and/or dysphasia) in 11/12 patients; absence of seizures. In 4/12 patients, fever and raised liver enzymes were noted around the time of presentation.
Some patients demonstrated stabilisation / recovery of neurological function in the absence of treatment, while in others the disease appeared to respond to immune suppression.

PTPN1 is associated with {Insulin resistance, susceptibility to}, MIM:1258539 in OMIM. It is not associated with disease in ClinGen or Gene2Phenotype (resources accessed 24 Mar 2026).
Probability of loss-of-function intolerance (pLI) score = 1.00 (predicted to be highly intolerant to LoF).
Sources: Literature; to: PMID: 39986310 Zhu et al., 2025
Reported heterozygous PTPN1 variants in 12 patients from 11 families. 2/10 were canonical splice variants, 2 were missense variants, and 6 were STOP-gain. 3 cases were de novo, 9 individuals inherited the variant from an asymptomatic parent. Sequencing method: WES + Sanger.

Phenotype: 12/12 individuals experienced subacute loss of skills (age range 15 months to 8 years) after initial normal development in 11 of 12 (one patient had mild motor delay); weakness (12/12), spasticity (initially manifesting as a hemiparesis in seven patients and then becoming bilateral) +/- dystonia, bulbar involvement (dysphagia and/or dysphasia) in 11/12 patients; absence of seizures. In 4/12 patients, fever and raised liver enzymes were noted around the time of presentation.

Brain MRI findings: Cerebral atrophy (9/12 patients), non-specific white matter changes (8/12), intracranial calcification (2/12). In 8 cases, the brain abnormalities resolved.Some patients demonstrated stabilisation / recovery of neurological function in the absence of treatment, while in others the disease appeared to respond to immune suppression.

Functional evidence: PMID: 10066179 Elchebly et al., 1999 - Ptpn1 knock-out (KO) mice are both viable and healthy, demonstrating enhanced insulin sensitivity and resistance to metabolic syndrome.

PTPN1 is associated with {Insulin resistance, susceptibility to}, MIM:1258539 in OMIM. It is not associated with disease in ClinGen or Gene2Phenotype (resources accessed 24 Mar 2026).
Probability of loss-of-function intolerance (pLI) score = 1.00 (predicted to be highly intolerant to LoF).
Sources: Literature
Intellectual disability v9.347 PTPN1 Ida Ertmanska gene: PTPN1 was added
gene: PTPN1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: PTPN1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PTPN1 were set to 39986310
Review for gene: PTPN1 was set to AMBER
Added comment: PMID: 39986310 Zhu et al., 2025
Reported heterozygous PTPN1 variants in 12 patients from 11 families. 2/10 were canonical splice variants, 2 were missense variants, and 6 were STOP-gain. 3 cases were de novo, 9 individuals inherited the variant from an asymptomatic parent. Sequencing method: WES + Sanger.

Phenotype: 12/12 individuals experienced subacute loss of skills (age range 15 months to 8 years) after initial normal development in 11 of 12 (one patient had mild motor delay); weakness (12/12), spasticity (initially manifesting as a hemiparesis in seven patients and then becoming bilateral) +/- dystonia, bulbar involvement (dysphagia and/or dysphasia) in 11/12 patients; absence of seizures. In 4/12 patients, fever and raised liver enzymes were noted around the time of presentation.
Some patients demonstrated stabilisation / recovery of neurological function in the absence of treatment, while in others the disease appeared to respond to immune suppression.

PTPN1 is associated with {Insulin resistance, susceptibility to}, MIM:1258539 in OMIM. It is not associated with disease in ClinGen or Gene2Phenotype (resources accessed 24 Mar 2026).
Probability of loss-of-function intolerance (pLI) score = 1.00 (predicted to be highly intolerant to LoF).
Sources: Literature
Intellectual disability v9.346 MYCBP2 Ludmila Volozonoka gene: MYCBP2 was added
gene: MYCBP2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: MYCBP2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MYCBP2 were set to 41200582; 36200388; 41543631
Review for gene: MYCBP2 was set to GREEN
Added comment: PMID: 36200388 reports eight de novo MYCBP2 variants (two loss-of-function and six missense) in patients presenting with dysmorphism, global developmental delay, varying degrees of intellectual disability, language delay, and ASD. Less common features include corpus callosum dysgenesis and epilepsy.

PMID: 41200582 describes a loss-of-function MYCBP2 variant identified in a mother and her two sons, all exhibiting similar clinical features as in PMID: 36200388.

PMID: 41543631 demonstrates another loss-of-function variant in a proband with NDD, inherited from a mother with mild features (notably subtle executive dysfunction).
The gene is highly constrained of LOF variants in a general population (pLI = 1).
Sources: Literature
Intellectual disability v9.346 UNC13A Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated 23 Mar 2026.
Intellectual disability v9.343 MARK2 Ida Ertmanska Added comment: Comment on phenotypes: Phenotype updated 20 Mar 2026.
Intellectual disability v9.343 MARK2 Ida Ertmanska Phenotypes for gene: MARK2 were changed from neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071 to Intellectual developmental disorder, autosomal dominant 76, OMIM:621285; intellectual developmental disorder, autosomal dominant 76, MONDO:0979575
Intellectual disability v9.342 MARK2 Ida Ertmanska Tag gene-checked was removed from gene: MARK2.
Intellectual disability v9.342 LRRC7 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated 20 Mar 2026.
Intellectual disability v9.341 LMBRD2 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated 20 Mar 2026.
Intellectual disability v9.341 LMBRD2 Ida Ertmanska Phenotypes for gene: LMBRD2 were changed from Global developmental delay; Intellectual disability; Microcephaly; Seizures; Abnormality of nervous system morphology; Abnormality of the eye to Developmental delay with variable neurologic and brain abnormalities, OMIM:619694
Intellectual disability v9.340 KLHL20 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated 20 Mar 2026.
Intellectual disability v9.340 KLHL20 Ida Ertmanska Phenotypes for gene: KLHL20 were changed from developmental disorder with intellectual disability, epilepsy, and autism spectrum disorder to Neurodevelopmental disorder with early-onset seizures, facial dysmorphism, and behavioral abnormalities, OMIM:621390
Intellectual disability v9.338 KDM2B Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated 20 Mar 2026.
Intellectual disability v9.338 KDM2B Ida Ertmanska Phenotypes for gene: KDM2B were changed from neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071 to Neurodevelopmental disorder with congenital cardiac defects and variable renal and ocular abnormalities, OMIM:621474
Intellectual disability v9.337 WDR37 Arina Puzriakova Phenotypes for gene: WDR37 were changed from Global developmental delay; Intellectual disability; Seizures; Abnormality of the eye; Abnormality of nervous system morphology; Hearing abnormality; Abnormality of the cardiovascular system; Abnormality of the skeletal system; Abnormality of the genitourinary system; Neurooculocardiogenitourinary syndrome, OMIM:618652 to Neurooculocardiogenitourinary syndrome, OMIM:618652
Intellectual disability v9.335 TMEM63C Arina Puzriakova Phenotypes for gene: TMEM63C were changed from hereditary spastic paraplegia, MONDO:0019064 to Spastic paraplegia 87, autosomal recessive, OMIM:619966
Intellectual disability v9.333 FRYL Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype added 20 Mar 2026.
Intellectual disability v9.331 RNU7-1 Arina Puzriakova Phenotypes for gene: RNU7-1 were changed from Aicardi–Goutières syndrome-like; Type I interferonopathy to Aicardi-Goutieres syndrome 9, OMIM:619487; Type I interferonopathy
Intellectual disability v9.330 FEM1B Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated 19 Mar 2026.
Intellectual disability v9.330 FEM1B Ida Ertmanska Phenotypes for gene: FEM1B were changed from neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071 to Neurodevelopmental disorder with behavioral, ear, and skeletal abnormalities, OMIM:621263; neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Intellectual disability v9.328 SMARCA1 Arina Puzriakova Tag gene-checked tag was added to gene: SMARCA1.
Intellectual disability v9.327 WARS Ida Ertmanska commented on gene: WARS
Intellectual disability v9.326 WARS Ida Ertmanska Tag new-gene-name tag was added to gene: WARS.
Intellectual disability v9.318 ISCA-37448-Loss Ida Ertmanska Variant type for ISCA-37448-Loss was changed from small to cnv_loss.
Intellectual disability v9.309 WDR83 Ida Ertmanska changed review comment from: PMID: 41381792 Tabata et al., 2025
7yo Japanese female patient presenting with global developmental delay, intellectual disability, microcephaly, and dysmorphic features. Brain MRI at 7 months showed enlarged bilateral ventricles. WES detected a de novo heterozygous WDR83 variant [NM_001099737; c.653 T > C,p.(L218P)].

Functional: Overexpression of WDR83-L218P in mice via in utero electroporation led to reduced proliferation of neural stem cells. Suggested GOF mechanism of disease.

PMID: 28332277 Kim et al., 2017
ADHD proband with de novo heterozygous WDR83 p.Gly127Arg variant (MAF = 0.000002542 in gnomAD v4)

PMID: 37509073 Wulf et al., 2023 - Homozygous Wdr83 knockout (KO) mice die around embryonic day 11 due to severe defects in cell proliferation and massive apoptosis.
PMID: 19726548 Hammerschmidt, Loeffler & Wolf, 2009 - Heterozygous Wdr83+/- mice display a normal phenotype, with no apparent abnormalities in brain structure or cerebral vascular architecture
Sources: Literature; to: PMID: 41381792 Tabata et al., 2025
7yo Japanese female patient presenting with global developmental delay, intellectual disability, microcephaly, and dysmorphic features. Brain MRI at 7 months showed enlarged bilateral ventricles. WES detected a de novo heterozygous WDR83 variant [NM_001099737; c.653 T > C,p.(L218P)].

Functional: Overexpression of WDR83-L218P in mice via in utero electroporation led to reduced proliferation of neural stem cells. Suggested GOF mechanism of disease.

PMID: 28332277 Kim et al., 2017
ADHD proband with de novo heterozygous WDR83 p.Gly127Arg variant (MAF = 0.000002542 in gnomAD v4)

PMID: 37509073 Wulf et al., 2023 - Homozygous Wdr83 knockout (KO) mice die around embryonic day 11 due to severe defects in cell proliferation and massive apoptosis.
PMID: 19726548 Hammerschmidt, Loeffler & Wolf, 2009 - Heterozygous Wdr83+/- mice display a normal phenotype, with no apparent abnormalities in brain structure or cerebral vascular architecture

WDR83 is not yet associated with disease in OMIM, ClinGen, or G2P (accessed 17 Mar 2026).
Sources: Literature
Intellectual disability v9.309 WDR83 Ida Ertmanska changed review comment from: Comment on list classification: There is 1 patient reported with GDD/ID, and 1 with ADHD - both individuals had heterozygous de novo variants in WDR83. There is some limited functional evidence in mice supporting WDR83 missense variants as causal in proliferation of neural stem cells. Based on available evidence, this gene can only be rated Amber at this time.; to: Comment on list classification: There is 1 patient reported with GDD/ID, and 1 with ADHD - both individuals had heterozygous de novo missense variants in WDR83. There is some limited functional evidence in mice supporting WDR83 missense variants as causal in proliferation of neural stem cells. Based on available evidence, this gene can only be rated Amber at this time.
Intellectual disability v9.308 WDR83 Ida Ertmanska changed review comment from: Comment on list classification: There is 1 patient reported with GDD/ID and 1 with ADHD - both individuals had heterozygous de novo variants in WDR83. There is some limited functional evidence in mice supporting WDR83 missense variants as causal in proliferation of neural stem cells. Based on available evidence, this gene can only be rated Amber at this time.; to: Comment on list classification: There is 1 patient reported with GDD/ID, and 1 with ADHD - both individuals had heterozygous de novo variants in WDR83. There is some limited functional evidence in mice supporting WDR83 missense variants as causal in proliferation of neural stem cells. Based on available evidence, this gene can only be rated Amber at this time.
Intellectual disability v9.308 WDR83 Ida Ertmanska Added comment: Comment on list classification: There is 1 patient reported with GDD/ID and 1 with ADHD - both individuals had heterozygous de novo variants in WDR83. There is some limited functional evidence in mice supporting WDR83 missense variants as causal in proliferation of neural stem cells. Based on available evidence, this gene can only be rated Amber at this time.
Intellectual disability v9.307 WDR83 Ida Ertmanska gene: WDR83 was added
gene: WDR83 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: WDR83 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: WDR83 were set to 28332277; 41381792
Phenotypes for gene: WDR83 were set to neurodevelopmental disorder, MONDO:0700092
Review for gene: WDR83 was set to AMBER
Added comment: PMID: 41381792 Tabata et al., 2025
7yo Japanese female patient presenting with global developmental delay, intellectual disability, microcephaly, and dysmorphic features. Brain MRI at 7 months showed enlarged bilateral ventricles. WES detected a de novo heterozygous WDR83 variant [NM_001099737; c.653 T > C,p.(L218P)].

Functional: Overexpression of WDR83-L218P in mice via in utero electroporation led to reduced proliferation of neural stem cells. Suggested GOF mechanism of disease.

PMID: 28332277 Kim et al., 2017
ADHD proband with de novo heterozygous WDR83 p.Gly127Arg variant (MAF = 0.000002542 in gnomAD v4)

PMID: 37509073 Wulf et al., 2023 - Homozygous Wdr83 knockout (KO) mice die around embryonic day 11 due to severe defects in cell proliferation and massive apoptosis.
PMID: 19726548 Hammerschmidt, Loeffler & Wolf, 2009 - Heterozygous Wdr83+/- mice display a normal phenotype, with no apparent abnormalities in brain structure or cerebral vascular architecture
Sources: Literature
Intellectual disability v9.306 TYW1 Ida Ertmanska changed review comment from: PMID: 34077496 Li et al., 2021
2 Chinese sibs (non-consanguineous parents) reported with comp het TYW1 variants: NM_018264: c.616C>T, p.R206C & c.1166G>A, p. R389Q.
Proband CP_012_1, male - Wechsler Preschool and Primary Scale of Intelligence IQ = 40 at 7 years old (moderate ID);
CP_012_2, older sister - diagnosed with mixed type cerebral palsy (spasticity, dyskinesia), IQ <50 (moderate ID).
Parents confirmed heterozygous for 1 variant each. TYW1:c.616C>T - MAF in gnomADv4 = 0.0004900, including 1 homozygote. TYW1:c.1166G>A MAF in gnomAD v4 = 0.0001559, no homozygotes.

Functional evidence: TYW1 protein levels dramatically reduced in proband compared to controls; tyw1 deficiency in zebrafish resulted in ectopic neuronal cell migration in the brain and undifferentiated motor neuronal cells in the spinal cord - this was rescued by WT human and zebrafish tyw1 mRNA, but not by mRNA with patients' mutations. In addition, tyw1 knockdown zebrafish showed recuded swimming capacity. Kncokout tyw1-/- mice showed impaired motor function and reduced cognition in behavioural tests.

PMID: 38706838 Sun et al., 2024
Fucntional evidence: Study used brain organoid model and human embryonic stem cells to show that translation efficiency of UUU codon was compromised in TYW1−/− cells. Also, neuron differentiation was impaired when TYW1 was depleted.
Sources: Literature; to: PMID: 34077496 Li et al., 2021
2 Chinese sibs (non-consanguineous parents) reported with comp het TYW1 variants: NM_018264: c.616C>T, p.R206C & c.1166G>A, p. R389Q.
Proband CP_012_1, male - Wechsler Preschool and Primary Scale of Intelligence IQ = 40 at 7 years old (moderate ID);
CP_012_2, older sister - diagnosed with mixed type cerebral palsy (spasticity, dyskinesia), IQ <50 (moderate ID).
Parents confirmed heterozygous for 1 variant each. TYW1:c.616C>T - MAF in gnomADv4 = 0.0004900, including 1 homozygote. TYW1:c.1166G>A MAF in gnomAD v4 = 0.0001559, no homozygotes.

Functional evidence: TYW1 protein levels dramatically reduced in proband compared to controls; tyw1 deficiency in zebrafish resulted in ectopic neuronal cell migration in the brain and undifferentiated motor neuronal cells in the spinal cord - this was rescued by WT human and zebrafish tyw1 mRNA, but not by mRNA with patients' mutations. In addition, tyw1 knockdown zebrafish showed recuded swimming capacity. Kncokout tyw1-/- mice showed impaired motor function and reduced cognition in behavioural tests.

PMID: 38706838 Sun et al., 2024
Fucntional evidence: Study used brain organoid model and human embryonic stem cells to show that translation efficiency of UUU codon was compromised in TYW1−/− cells. Also, neuron differentiation was impaired when TYW1 was depleted.

TYW1 is not yet associated with a phenotype in OMIM, ClinGen or G2P (accessed 17 Mar 2026).
Sources: Literature
Intellectual disability v9.306 TYW1 Ida Ertmanska Added comment: Comment on list classification: There is one pedigree reported in literature linking biallelic TYW1 variants to cerebral palsy with intellectual disability. There is also good functional evidence in zebrafish, mouse, and human brain organoids supporting TYW1 role in motor function and cognition. Based on available evidence, this gene can only be rated Amber for now.
Intellectual disability v9.305 TYW1 Ida Ertmanska gene: TYW1 was added
gene: TYW1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: TYW1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TYW1 were set to 34077496
Phenotypes for gene: TYW1 were set to cerebral palsy, MONDO:0006497
Review for gene: TYW1 was set to AMBER
Added comment: PMID: 34077496 Li et al., 2021
2 Chinese sibs (non-consanguineous parents) reported with comp het TYW1 variants: NM_018264: c.616C>T, p.R206C & c.1166G>A, p. R389Q.
Proband CP_012_1, male - Wechsler Preschool and Primary Scale of Intelligence IQ = 40 at 7 years old (moderate ID);
CP_012_2, older sister - diagnosed with mixed type cerebral palsy (spasticity, dyskinesia), IQ <50 (moderate ID).
Parents confirmed heterozygous for 1 variant each. TYW1:c.616C>T - MAF in gnomADv4 = 0.0004900, including 1 homozygote. TYW1:c.1166G>A MAF in gnomAD v4 = 0.0001559, no homozygotes.

Functional evidence: TYW1 protein levels dramatically reduced in proband compared to controls; tyw1 deficiency in zebrafish resulted in ectopic neuronal cell migration in the brain and undifferentiated motor neuronal cells in the spinal cord - this was rescued by WT human and zebrafish tyw1 mRNA, but not by mRNA with patients' mutations. In addition, tyw1 knockdown zebrafish showed recuded swimming capacity. Kncokout tyw1-/- mice showed impaired motor function and reduced cognition in behavioural tests.

PMID: 38706838 Sun et al., 2024
Fucntional evidence: Study used brain organoid model and human embryonic stem cells to show that translation efficiency of UUU codon was compromised in TYW1−/− cells. Also, neuron differentiation was impaired when TYW1 was depleted.
Sources: Literature
Intellectual disability v9.304 FBXO31 Ida Ertmanska changed review comment from: Monoallelic cases:

PMID: 32989326 Jin et al., 2020
Report of 2 unrelated patients with the same de novo FBXO31 mutation 16:87367889:C:T, p.Asp334Asn.
F218-003 - Female, European, presented with spastic diplegia, as well as Esotropia, ID, dysarthria, mixed receptive/expressive language disorder, ADHD, cleft palate, intestinal malrotation and midgut volvulus.
F699-003 - Male, European, presented with spastic paraplegia, as well as Ventricular dilation and thin corpus callosum, ID, attention deficit, anxiety, language impairments, strabismus, severe constipation

PMID: 33675180 Dzinovic et al., 2021
Report of a 9yo boy of Slovakian descent, with a de novo FBXO31 variant c.1000G>A (p.Asp334Asn) - trio WES. He presented with complex, non‐progressive movement‐disorder syndrome dominated by spasticity and dystonia. Brain MRI showed bilateral occipital and parietal white‐matter volume reduction, irregular white‐matter dysmyelination.

FBXO31 p.Asp334Asn is not reported in gnomAD v4.1.0. Revel prediction is Uncertain (0.46).; to: Monoallelic cases:

PMID: 32989326 Jin et al., 2020
Report of 2 unrelated patients with the same de novo FBXO31 mutation 16:87367889:C:T, p.Asp334Asn. Disease onset was under age two years.
F218-003 - Female, European, presented with spastic diplegia, as well as Esotropia, ID, dysarthria, mixed receptive/expressive language disorder, ADHD, cleft palate, intestinal malrotation and midgut volvulus.
F699-003 - Male, European, presented with spastic paraplegia, as well as Ventricular dilation and thin corpus callosum, ID, attention deficit, anxiety, language impairments, strabismus, severe constipation.

PMID: 33675180 Dzinovic et al., 2021
Report of a 9yo boy of Slovakian descent, with a de novo FBXO31 variant c.1000G>A (p.Asp334Asn) - trio WES. He presented with complex, non‐progressive movement‐disorder syndrome dominated by spasticity and dystonia. Brain MRI showed bilateral occipital and parietal white‐matter volume reduction, irregular white‐matter dysmyelination. Intellectual disability estimated at Moderate severity (no IQ assessment; loss of speech at the age of 1.5 years, receptive language disorder)

FBXO31 p.Asp334Asn is not reported in gnomAD v4.1.0. Revel prediction is Uncertain (0.46).
Intellectual disability v9.304 PPP2R1A Ida Ertmanska changed review comment from: PMID: 33106617 Lenaerts et al., 2021
Report of 30 individuals with 16 different de novo variants in PPP2R1A. Shared phenotype: developmental delay (97%), hypotonia (93%), hypermobile joints (58%), CC hypoplasia/agenesis (56%), epilepsy (38%), macrocephaly (38%). Macrocephaly and epilepsy were mutually exclusive. Intellectual disability ranged from mild to severe, based on functional effects of each variant.

Functional evidence: HEK293T cells transfected with PPP2R1A mutants - variants from patients with less severe ID, no seizures, and sometimes macrocephaly typically showed normal B55α and STRN3 binding, while more severe ID, seizures, and sometimes microcephaly correlated with lost B55α binding and increased STRN3 binding.

PPP2R1A is now associated with AD Houge-Janssens syndrome 2, OMIM:616362 (OMIM accessed 13th Mar 2026). PPP2R1A is Definitve in ClinGen for an AD complex neurodevelopmental disorder (Nov 2022).; to: PMID: 33106617 Lenaerts et al., 2021
Report of 30 individuals with 16 different de novo variants in PPP2R1A. Shared phenotype: developmental delay (97%), hypotonia (93%), hypermobile joints (58%), CC hypoplasia/agenesis (56%), epilepsy (38%), macrocephaly (38%). Macrocephaly and epilepsy were mutually exclusive. Intellectual disability ranged from mild to severe, based on functional effects of each variant.

Functional evidence: HEK293T cells transfected with PPP2R1A mutants - variants from patients with less severe ID, no seizures, and sometimes macrocephaly typically showed normal B55α and STRN3 binding, while more severe ID, seizures, and sometimes microcephaly correlated with lost B55α binding and increased STRN3 binding.

PPP2R1A is now associated with AD Houge-Janssens syndrome 2, OMIM:616362 (OMIM accessed 13th Mar 2026). PPP2R1A is Definitve in ClinGen for an AD complex neurodevelopmental disorder (Nov 2022).
Intellectual disability v9.303 CDC42BPB Ida Ertmanska changed review comment from: Comment on list classification: There are several individuals reported in literature with a neurodevelopmental syndrome. In a 2020 report of 14 patients, 12 individuals had syndromic DD and/or ID (PMID: 32031333). Since the initial report, several studies have linked the gene to a neurodevelopmental disorder, though clinical details are limited. Based on available evidence, this gene should be promoted to Green for Intellectual disability with MOI MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted.; to: Comment on list classification: There are several individuals reported in literature with a neurodevelopmental syndrome. In a 2020 report of 14 patients, 12 individuals had syndromic DD and/or ID (PMID: 32031333). Since the initial report, several studies have linked the gene to a neurodevelopmental disorder and ASD, though clinical details are limited. Based on available evidence, this gene should be promoted to Green for Intellectual disability with MOI MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted.
Intellectual disability v9.303 CDC42BPB Ida Ertmanska changed review comment from: Further reports (few clinical details):

PMID: 36344539, Al Kasbi et al., 2022
4 yo male with hypotonia, global developmental delays and seizures, who had two homozygous variants: homozygous frameshift p.Ala1314GlyfsTer35 in CDC42BPB and homozygous missense p.Phe1306Val in SCN10A.

PMID: 35586607 French et al., 2022
Trio WGS cohort. Case 190 (suppl data): heterozygous for c.2605dup, p.Gln869ProfsTer85, de novo; phenotype described as 'CDC42BPB-related disease'.

PMID: 31785789 Turner et al., 2019
Cohort of 8000+ parent-child trios with NDDs. Cases from suppl data table S2, all variants are de novo:
NDAR_INVAZ651VGG_wes1 - patient with autism, het for CDC42BPB:c.4951G>A, p.Val1651Met - 18 alleles reported in gnomAD v4.1.0
13934.p1 - patient with autism, het for CDC42BPB:c.4805A>G, p.Gln1602Arg - not in gnomAD v4.1.0
13606.p1 - patient with autism, het for CDC42BPB:c.2290C>T, p.Arg764* - 2 alleles in gnomAD v4.1.0
14338.p1 - patient with autism, het for CDC42BPB:c.1891_1893dup, p.Ala631dup - not in gnomAD v4.1.0
DDD4K.04028 - patient with a developmental disorder, het for CDC42BPB:c.3349G>A, p.Ala1117Thr - 32 alleles in gnomAD v4.1.0
DDD4K.02790 - patient with a developmental disorder, het for CDC42BPB:c.1067dup, p.Tyr357Leufs*4 - not in gnomAD v4.1.0

PMID: 28263302 Yuen et al., 2017
Reported a de novo frameshift deletion in exon 11 of the CDC42BPB gene (Chr14:103442072_103442075delCTTT) in an individual with autism spectrum disorder by trio genome sequencing (sample AU079605; Supplementary Table 4).; to: Further reports (few clinical details):

PMID: 36344539, Al Kasbi et al., 2022
4 yo male with hypotonia, global developmental delays and seizures, who had two homozygous variants: homozygous frameshift p.Ala1314GlyfsTer35 in CDC42BPB and homozygous missense p.Phe1306Val in SCN10A.

PMID: 35586607 French et al., 2022
Trio WGS cohort. Case 190 (suppl data): heterozygous for c.2605dup, p.Gln869ProfsTer85, de novo; phenotype described as 'CDC42BPB-related disease'.

PMID: 31785789 Turner et al., 2019
Cohort of 8000+ parent-child trios with NDDs. Cases from suppl data table S2, all variants are de novo:
NDAR_INVAZ651VGG_wes1 - patient with autism, het for CDC42BPB:c.4951G>A, p.Val1651Met - 18 alleles reported in gnomAD v4.1.0
13934.p1 - patient with autism, het for CDC42BPB:c.4805A>G, p.Gln1602Arg - not in gnomAD v4.1.0
13606.p1 - patient with autism, het for CDC42BPB:c.2290C>T, p.Arg764* - 2 alleles in gnomAD v4.1.0
14338.p1 - patient with autism, het for CDC42BPB:c.1891_1893dup, p.Ala631dup - not in gnomAD v4.1.0
DDD4K.04028 - patient with a developmental disorder, het for CDC42BPB:c.3349G>A, p.Ala1117Thr - 32 alleles in gnomAD v4.1.0
DDD4K.02790 - patient with a developmental disorder, het for CDC42BPB:c.1067dup, p.Tyr357Leufs*4 - not in gnomAD v4.1.0

PMID: 28263302 Yuen et al., 2017
Reported a de novo frameshift deletion in exon 11 of the CDC42BPB gene (Chr14:103442072_103442075delCTTT) in an individual with autism spectrum disorder by trio genome sequencing (sample AU079605; Supplementary Table 4).

CDC42BPB is included in G2P with limited confidence (monoallelic CDC42BPB-related neurodevelopmental disorder). It is rated Green on Intellectual disability syndromic and non-syndromic panel in PA Australia.
Intellectual disability v9.303 CDC42BPB Ida Ertmanska changed review comment from: Further reports (few clinical details):
PMID: 35586607 French et al., 2022
Trio WGS cohort. Case 190 (suppl data): heterozygous for c.2605dup, p.Gln869ProfsTer85, de novo; phenotype described as 'CDC42BPB-related disease'.

PMID: 31785789 Turner et al., 2019
Cohort of 8000+ parent-child trios with NDDs. Cases from suppl data table S2, all variants are de novo:
NDAR_INVAZ651VGG_wes1 - patient with autism, het for CDC42BPB:c.4951G>A, p.Val1651Met - 18 alleles reported in gnomAD v4.1.0
13934.p1 - patient with autism, het for CDC42BPB:c.4805A>G, p.Gln1602Arg - not in gnomAD v4.1.0
13606.p1 - patient with autism, het for CDC42BPB:c.2290C>T, p.Arg764* - 2 alleles in gnomAD v4.1.0
14338.p1 - patient with autism, het for CDC42BPB:c.1891_1893dup, p.Ala631dup - not in gnomAD v4.1.0
DDD4K.04028 - patient with a developmental disorder, het for CDC42BPB:c.3349G>A, p.Ala1117Thr - 32 alleles in gnomAD v4.1.0
DDD4K.02790 - patient with a developmental disorder, het for CDC42BPB:c.1067dup, p.Tyr357Leufs*4 - not in gnomAD v4.1.0; to: Further reports (few clinical details):

PMID: 36344539, Al Kasbi et al., 2022
4 yo male with hypotonia, global developmental delays and seizures, who had two homozygous variants: homozygous frameshift p.Ala1314GlyfsTer35 in CDC42BPB and homozygous missense p.Phe1306Val in SCN10A.

PMID: 35586607 French et al., 2022
Trio WGS cohort. Case 190 (suppl data): heterozygous for c.2605dup, p.Gln869ProfsTer85, de novo; phenotype described as 'CDC42BPB-related disease'.

PMID: 31785789 Turner et al., 2019
Cohort of 8000+ parent-child trios with NDDs. Cases from suppl data table S2, all variants are de novo:
NDAR_INVAZ651VGG_wes1 - patient with autism, het for CDC42BPB:c.4951G>A, p.Val1651Met - 18 alleles reported in gnomAD v4.1.0
13934.p1 - patient with autism, het for CDC42BPB:c.4805A>G, p.Gln1602Arg - not in gnomAD v4.1.0
13606.p1 - patient with autism, het for CDC42BPB:c.2290C>T, p.Arg764* - 2 alleles in gnomAD v4.1.0
14338.p1 - patient with autism, het for CDC42BPB:c.1891_1893dup, p.Ala631dup - not in gnomAD v4.1.0
DDD4K.04028 - patient with a developmental disorder, het for CDC42BPB:c.3349G>A, p.Ala1117Thr - 32 alleles in gnomAD v4.1.0
DDD4K.02790 - patient with a developmental disorder, het for CDC42BPB:c.1067dup, p.Tyr357Leufs*4 - not in gnomAD v4.1.0

PMID: 28263302 Yuen et al., 2017
Reported a de novo frameshift deletion in exon 11 of the CDC42BPB gene (Chr14:103442072_103442075delCTTT) in an individual with autism spectrum disorder by trio genome sequencing (sample AU079605; Supplementary Table 4).
Intellectual disability v9.303 CDC42BPB Ida Ertmanska edited their review of gene: CDC42BPB: Added comment: Comment on list classification: There are several individuals reported in literature with a neurodevelopmental syndrome. In a 2020 report of 14 patients, 12 individuals had syndromic DD and/or ID (PMID: 32031333). Since the initial report, several studies have linked the gene to a neurodevelopmental disorder, though clinical details are limited. Based on available evidence, this gene should be promoted to Green for Intellectual disability with MOI MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted.; Changed rating: GREEN
Intellectual disability v9.303 WARS Arina Puzriakova Tag Q3_25_promote_green was removed from gene: WARS.
Intellectual disability v9.303 POLRMT Achchuthan Shanmugasundram Added comment: Comment on phenotypes: OMIM phenotype was last accessed on 12 March 2026.
Intellectual disability v9.301 TARS2 Arina Puzriakova Tag Q1_25_ promote_green was removed from gene: TARS2.
Intellectual disability v9.301 SMARCA1 Arina Puzriakova Tag Q2_25_ promote_green was removed from gene: SMARCA1.
Intellectual disability v9.301 HCN2 Ida Ertmanska Added comment: Comment on list classification: In a cohort of 21 patients with HCN2 variants (mono- and bi- allelic), 17 presented with syndromic ID/DD, often severe. Hence, this gene should be promoted to Green on Intellectual disability with MOI BOTH monoallelic and biallelic, autosomal or pseudoautosomal.
Intellectual disability v9.300 HCN2 Ida Ertmanska gene: HCN2 was added
gene: HCN2 was added to Intellectual disability. Sources: Literature
Q1_26_promote_green tags were added to gene: HCN2.
Mode of inheritance for gene: HCN2 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: HCN2 were set to 40468825
Phenotypes for gene: HCN2 were set to Generalized epilepsy with febrile seizures plus, type 11, OMIM:602477; neurodevelopmental disorder, MONDO:0700092
Review for gene: HCN2 was set to GREEN
Added comment: PMID: 40468825 Houdayer et al., 2025
21 individuals with HCN2 variants from 15 unrelated families - 13 monoallelic cases and 8 biallelic. The phenotypic spectrum included developmental delay/intellectual disability (DD/ID, 17/21), epilepsy (10/21), language disorders (16/21), movement disorders (12/21), and axial hypotonia (10/21).
Movement disorders included dystonia, tremor, cerebellar signs, stereotypies. Muscle tone abnormalities included axial hypotonia, hypertonia, pyramidal signs and spasticity. Biallelic LOF cases uniformly presented with severe intellectual disability, while monoallelic cases showed mild to moderate ID (IQ 40-60) with evidence of skill regression. Heterozygous GOF variants resulted in borderline ID and milder epilepsy phenotype.
Thirteen pathogenic HCN2 variants (12 new and 1 already described) were identified: 11 missense, 1 recurrent inframe deletion, and 1 frameshift.

Functional evidence: electrophysiology with Xenopus laevis oocytes and membrane trafficking investigated in HEK cells - p.(Arg324His) variant showed a strong increase of HCN2 conductance; p.(Ala363Val) and p.(Met374Leu) exhibited dominant negative effects. The p.(Leu377His), p.(Pro493Leu), and p.(Gly587Asp) variants rendered HCN2 electrophysiologically silent and impaired membrane trafficking. Structural 3D-analysis revealed that, except for p.(Arg324His), all variants altered HCN2 stability.

HCN2 is associated with several AD phenotypes in OMIM: Generalized epilepsy with febrile seizures plus, type 11 602477; Febrile seizures, familial, 2 602477; {Epilepsy, idiopathic generalized, susceptibility to, 17} 602477 - all same MIM number (accessed 12th Mar 2026). Not yet added to ClinGen or Gene2Phenotype.
Sources: Literature
Intellectual disability v9.299 CELF4 Arina Puzriakova changed review comment from: After NHS Genomic Medicine Service consideration, the rating of this gene has not been changed and remains amber. Additional comments from reviewing GLHs: GnomAD data would make this difficult to classify variants. All ClinVar variants are VUS.; to: After NHS Genomic Medicine Service consideration, the rating of this gene has not been changed and remains amber. Additional comments from reviewing GLHs: gnomAD data would make this difficult to classify variants. All ClinVar variants are VUS.
Intellectual disability v9.299 WARS Arina Puzriakova reviewed gene: WARS: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Intellectual disability v9.299 TARS2 Arina Puzriakova reviewed gene: TARS2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Intellectual disability v9.299 SMARCA1 Arina Puzriakova reviewed gene: SMARCA1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Intellectual disability v9.298 WARS Arina Puzriakova Source NHS GMS was added to WARS.
Source Expert Review Green was added to WARS.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v9.298 TARS2 Arina Puzriakova Source NHS GMS was added to TARS2.
Source Expert Review Green was added to TARS2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v9.298 SMARCA1 Arina Puzriakova Source NHS GMS was added to SMARCA1.
Source Expert Review Green was added to SMARCA1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v9.296 GABRA3 Ida Ertmanska Added comment: Comment on list classification: There are numerous patients reported in literature with variants in GABRA3 and syndromic intellectual disability. GOF variants cause a more severe, X-linked dominant phenotype (severe ID, nonverbal), while LOF variants usually result in a milder phenotype (mild to moderate ID, language impairment) and an X-linked recessive inheritance pattern. Based on available evidence, GABRA3 should be promoted to Green with MOI X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males).
Intellectual disability v9.295 GABRA3 Ida Ertmanska gene: GABRA3 was added
gene: GABRA3 was added to Intellectual disability. Sources: Literature
Q1_26_promote_green tags were added to gene: GABRA3.
Mode of inheritance for gene: GABRA3 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: GABRA3 were set to 41289009
Phenotypes for gene: GABRA3 were set to Epilepsy, X-linked 2, with or without impaired intellectual development and dysmorphic features, OMIM:301091
Review for gene: GABRA3 was set to GREEN
Added comment: PMID: 41289009 Johannesen et al., 2025
Cohort of 43 individuals (18 males and 25 females) with GABRA3 variants - some reported previously. Detailed genotype–phenotype analyses showed that pathogenic GABRA3 variants can cause either dominant or recessive X-linked disorders. GOF variants caused severe phenotypes and followed X-linked dominant inheritance, while LOF variants resulted in milder phenotypes and followed an X-linked recessive pattern. 30 individuals are described in detail, others excluded due to family history or neutral impact of variant.

Among the 20 individuals with GOF variants, 85% (17/20) had epilepsy with a median age of onset at 33 months (range 2–252 months). In contrast, only 10% (1/10) with LOF variants had epilepsy, with onset at 4 months. Individuals with GOF variants were more likely to have severe ID (8/20 vs. 0/10 in LOF group). Female carriers of LOF variants were unaffected.

GABRA3 is linked to Epilepsy, X-linked 2, with or without impaired intellectual development and dysmorphic features, OMIM:301091 (OMIM accessed 10th Mar 2026).
Sources: Literature
Intellectual disability v9.293 NRDC Ida Ertmanska changed review comment from: Comment on list classification: There are more than 3 individuals reported with biallelic NRDC variants and intellectual disability. Hence, this gene should be promoted to Green at the next update.; to: Comment on list classification: There are more than 3 individuals reported with biallelic NRDC variants and syndromic intellectual disability. Hence, this gene should be promoted to Green at the next update.
Intellectual disability v9.292 NRDC Ida Ertmanska Added comment: Comment on list classification: There are more than 3 individuals reported with biallelic NRDC variants and intellectual disability. Hence, this gene should be promoted to Green at the next update.
Intellectual disability v9.291 NRDC Ida Ertmanska changed review comment from: PMID: 41734767 Pehlivan et al., 2026
Report of 14 individuals from nine unrelated families carrying homozygous NRDC pathogenic variants. Common clinical features include severe to profound developmental delay/intellectual disability (12/12), microcephaly (13/13), prematurity (5/13), lethality in the first 3 years of life (9/14), seizures (7/11), joint contractures (4/8), eye/visual abnormalities (5/7 - 3 with optic atrophy, 1 with nystagmus, and 1 case of visual inattentiveness), and abnormal brain imaging studies ranging from diffuse atrophy to lissencephaly (8/11). The identified variants include two splice, three frameshift, and three missense variants.

NRDC is not yet associated with a phenotype in OMIM (accessed 9th Mar 2026).
Sources: Literature; to: PMID: 41734767 Pehlivan et al., 2026
Report of 14 individuals from nine unrelated families carrying homozygous NRDC pathogenic variants (some reported previously). Common clinical features include severe to profound developmental delay/intellectual disability (12/12), microcephaly (13/13), prematurity (5/13), lethality in the first 3 years of life (9/14), seizures (7/11), joint contractures (4/8), eye/visual abnormalities (5/7 - 3 with optic atrophy, 1 with nystagmus, and 1 case of visual inattentiveness), and abnormal brain imaging studies ranging from diffuse atrophy to lissencephaly (8/11). The identified variants include two splice, three frameshift, and three missense variants.

NRDC is not yet associated with a phenotype in OMIM (accessed 9th Mar 2026).
Sources: Literature
Intellectual disability v9.291 NRDC Ida Ertmanska gene: NRDC was added
gene: NRDC was added to Intellectual disability. Sources: Literature
Q1_26_promote_green tags were added to gene: NRDC.
Mode of inheritance for gene: NRDC was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NRDC were set to 41734767
Review for gene: NRDC was set to GREEN
Added comment: PMID: 41734767 Pehlivan et al., 2026
Report of 14 individuals from nine unrelated families carrying homozygous NRDC pathogenic variants. Common clinical features include severe to profound developmental delay/intellectual disability (12/12), microcephaly (13/13), prematurity (5/13), lethality in the first 3 years of life (9/14), seizures (7/11), joint contractures (4/8), eye/visual abnormalities (5/7 - 3 with optic atrophy, 1 with nystagmus, and 1 case of visual inattentiveness), and abnormal brain imaging studies ranging from diffuse atrophy to lissencephaly (8/11). The identified variants include two splice, three frameshift, and three missense variants.

NRDC is not yet associated with a phenotype in OMIM (accessed 9th Mar 2026).
Sources: Literature
Intellectual disability v9.290 FSD1L Ida Ertmanska Added comment: Comment on list classification: Comment on list classification: There are more than 3 families reported in literature with affected individuals presenting with a severe neurodevelopmental disorder, including severe intellectual disability. There is enough evidence to promote FSD1L to Green at the next update.
Intellectual disability v9.289 FSD1L Ida Ertmanska gene: FSD1L was added
gene: FSD1L was added to Intellectual disability. Sources: Literature
Q1_26_promote_green tags were added to gene: FSD1L.
Mode of inheritance for gene: FSD1L was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FSD1L were set to 41720098; 41720099
Phenotypes for gene: FSD1L were set to neurodevelopmental disorder, MONDO:0700092
Review for gene: FSD1L was set to GREEN
Added comment: PMID: 41720098 Serpieri et al., 2026
Report of eleven individuals (including five fetuses) from six unrelated families harbouring biallelic FSD1L variants. Seq method: exome sequencing. Consanguinity was confirmed in 4/6 families, and suspected in the fifth.
Phenotype spectrum: severe intellectual disability (5/5 assessed from 3 families), epilepsy (5 individuals from 3 families), severe hydrocephalus (3 families), vision deficit due to optic nerve hypoplasia/atrophy (3 families), spastic tetraparesis (2 families) corpus callosum hypoplasia/agenesis on MRI (5/5 families assessed),

Variants detected - largely nonsense type:
Family A - homozygous c.409T>G (p.Leu137Val);
Family B - 3 affected fetuses homozygous for c.1411C>T (p.Gln471Ter);
Family C - sibs compound het for c.1228T>G (p.Phe410Val) and c.1251_1252insTAA (p.Thr418Ter);
Family D - affected individuals (1 fetal case) homozygous for c.1366G>C (p.Asp456His) - shown to impact splicing (r.406_442del), resulting in predicted p.Ser136LeufsTer19 change;
Family E - affected child with homozygous c.835C>T (p.Arg279Ter) change;
Family F - fetus homozygous for c.1260G>A (p.Trp420Ter);

Functional evidence: Fsd1l depletion in mouse embryos recapitulated the ventricular dilation observed in affected fetuses.

PMID 41720099 Lin et al., 2026
Report of 6 affected individuals from 4 families with retinitis pigmentosa. One individual underwent a full neurological evaluation, including brain neuroimaging, which revealed no evidence of central nervous system involvement.
FSD1L variants detected:
Family A: 2 sibs compound het for c.1049G>A (p.Arg350Gln) and c.1428del (p.Phe476Leufs∗22)
Family B: individual comp het for c.488G>A (p.Arg163His), c.488G>A & c.745C>T (p.Arg249∗)
Family C: 2 sibs compound het for c.488G>A (p.Arg163His) & c.226_227del (p.Ser77Argfs∗4)
Family D: individual compound het for c.1037_1038delinsT (p.Pro346Leufs∗8) and c.1025+624_1025+649del
Sibs from family A had mild neurological involvement (mild ID, spastic diplegia in one sibling).
Authors note that "specific combination and functional severity of the two alleles likely determines the clinical outcome", with non-LoF variants causing a milder effect (e.g., isolated retinal phenotype).

FSD1L is not yet associated with a phenotype in OMIM or Gene2Phenotype.
Sources: Literature
Intellectual disability v9.287 PHF5A Arina Puzriakova Added comment: Comment on list classification: At least 10 unrelated individuals have been reported with de novo variants in the PHF5A gene. Syndromic developmental delay is reported in at least 9 of those cases, with five individuals developing intellectual disability later in life. Inclusion on this panel would also enable inclusion of the R27 Paediatric disorders super panel which appears relevant to the presentation. Therefore, this gene should be promoted to Green at the next GMS panel update.
Intellectual disability v9.286 PHF5A Arina Puzriakova gene: PHF5A was added
gene: PHF5A was added to Intellectual disability. Sources: Literature
Q1_26_promote_green tags were added to gene: PHF5A.
Mode of inheritance for gene: PHF5A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PHF5A were set to 33811463; 37422718
Phenotypes for gene: PHF5A were set to PHF5A-related neurodevelopmental disorder with congenital malformations
Review for gene: PHF5A was set to GREEN
Added comment: PMID: 33811463 - de novo nonsense variant c.162C>A / p.(Tyr54*) in PHF5A was reported in a patient with left microtia and bilateral absence of 12th ribs

PMID: 37422718 - 9 unrelated individuals with congenital malformations, including preauricular tags and hypospadias, short stature, subtle skeletal features, craniofacial dysmorphism. All had developmental delay, and five individuals developed ID later in life (1 severe, 4 mild). All harboured de novo heterozygous PHF5A variants, including 4 nonsense, 3 missense, 1 splice, and 1 start-loss variant.
Sources: Literature
Intellectual disability v9.282 ABI2 Ida Ertmanska Added comment: Comment on list classification: This gene will be recommended for a promotion to Green once the pre-print article is published.
Intellectual disability v9.280 KCNT2 Ida Ertmanska Phenotypes for gene: KCNT2 were changed from ?Epileptic encephalopathy, early infantile 57, 617771 to Developmental and epileptic encephalopathy 57, OMIM:617771 developmental and epileptic encephalopathy, 57, MONDO:0033366
Intellectual disability v9.279 CDC42BPB Ida Ertmanska changed review comment from: Further reports:
PMID: 35586607 French et al., 2022
Trio WGS cohort. Case 190 (suppl data): heterozygous for c.2605dup, p.Gln869ProfsTer85, de novo; phenotype described as 'CDC42BPB-related disease'.

PMID: 31785789 Turner et al., 2019
Cohort of 8000+ parent-child trios with NDDs. Cases from suppl data table S2, all variants are de novo:
NDAR_INVAZ651VGG_wes1 - patient with autism, het for CDC42BPB:c.4951G>A, p.Val1651Met - 18 alleles reported in gnomAD v4.1.0
13934.p1 - patient with autism, het for CDC42BPB:c.4805A>G, p.Gln1602Arg - not in gnomAD v4.1.0
13606.p1 - patient with autism, het for CDC42BPB:c.2290C>T, p.Arg764* - 2 alleles in gnomAD v4.1.0
14338.p1 - patient with autism, het for CDC42BPB:c.1891_1893dup, p.Ala631dup - not in gnomAD v4.1.0
DDD4K.04028 - patient with a developmental disorder, het for CDC42BPB:c.3349G>A, p.Ala1117Thr - 32 alleles in gnomAD v4.1.0
DDD4K.02790 - patient with a developmental disorder, het for CDC42BPB:c.1067dup, p.Tyr357Leufs*4 - not in gnomAD v4.1.0; to: Further reports (few clinical details):
PMID: 35586607 French et al., 2022
Trio WGS cohort. Case 190 (suppl data): heterozygous for c.2605dup, p.Gln869ProfsTer85, de novo; phenotype described as 'CDC42BPB-related disease'.

PMID: 31785789 Turner et al., 2019
Cohort of 8000+ parent-child trios with NDDs. Cases from suppl data table S2, all variants are de novo:
NDAR_INVAZ651VGG_wes1 - patient with autism, het for CDC42BPB:c.4951G>A, p.Val1651Met - 18 alleles reported in gnomAD v4.1.0
13934.p1 - patient with autism, het for CDC42BPB:c.4805A>G, p.Gln1602Arg - not in gnomAD v4.1.0
13606.p1 - patient with autism, het for CDC42BPB:c.2290C>T, p.Arg764* - 2 alleles in gnomAD v4.1.0
14338.p1 - patient with autism, het for CDC42BPB:c.1891_1893dup, p.Ala631dup - not in gnomAD v4.1.0
DDD4K.04028 - patient with a developmental disorder, het for CDC42BPB:c.3349G>A, p.Ala1117Thr - 32 alleles in gnomAD v4.1.0
DDD4K.02790 - patient with a developmental disorder, het for CDC42BPB:c.1067dup, p.Tyr357Leufs*4 - not in gnomAD v4.1.0
Intellectual disability v9.278 ATOH1 Ida Ertmanska changed review comment from: Comment on list classification: There are 4 individuals from 3 unrelated families reported in literature with biallelic ATOH1 variants and an associated neurodevelopmental syndrome. All patients presented with severe GDD/ID. Based on available evidence, this gene should be promoted to Green for Intellectual disability.; to: Comment on list classification: There are 4 individuals from 3 unrelated families reported in literature with biallelic ATOH1 variants and an associated neurodevelopmental syndrome. All patients presented with severe GDD/ID. Individuals with heterozygous ATOH1 variants present with hearing loss and mild cerebellar signs, without intellectual disability. Hene, based on available evidence, this gene should be promoted to Green for Intellectual disability with MOI set to BIALLELIC, autosomal or pseudoautosomal.
Intellectual disability v9.278 ATOH1 Ida Ertmanska Added comment: Comment on list classification: There are 4 individuals from 3 unrelated families reported in literature with biallelic ATOH1 variants and an associated neurodevelopmental syndrome. All patients presented with severe GDD/ID. Based on available evidence, this gene should be promoted to Green for Intellectual disability.
Intellectual disability v9.277 ATOH1 Ida Ertmanska gene: ATOH1 was added
gene: ATOH1 was added to Intellectual disability. Sources: Literature
Q1_26_promote_green tags were added to gene: ATOH1.
Mode of inheritance for gene: ATOH1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ATOH1 were set to 9367153; 21146598; 33111345; 35518571; 41592563
Phenotypes for gene: ATOH1 were set to ?Deafness, autosomal dominant 89 , OMIM:620284; hearing loss, autosomal dominant 89, MONDO:0859528; pontocerebellar hypoplasia, MONDO:0020135
Review for gene: ATOH1 was set to GREEN
Added comment: PMID: 41592563 Bertola et al., 2026
Report of 5 unrelated families with heterozygous frameshift variants in ATOH1 associated with hearing loss (7/7, mild to severe), cerebellar symptoms (4/6), and a pattern of brainstem malformations (7/7). Cerebellar symptoms are noted to be subtle: motor delay, balance issues, mild ataxia, tremor, and other cerebellar signs. Intellectual disability ascertained in 1/7 individuals - this patient also carried a RNU4-2 variant, thought to be responsible for ID in this case.
Authors also report a homozygous early-truncating variant c.102dup, (p.Pro35AlafsTer18), causing a distinct neurodevelopmental syndrome with severe pontocerebellar hypoplasia, severe ID, and profound hearing loss. Heterozygous parents were asymptomatic.

PMID: 35518571 Višnjar et al., 2022
A homozygous missense variant NM_005172.1:c.481C>G, p.(Arg161Gly) in the ATOH1 gene was identified in the proband and his affected sister, segregating with apparently recessive pontocerebellar hypoplasia (PCH), severe global developmental delay, intellectual disability, and hearing loss.
Brain MRI findings were: posteriorly thin corpus callosum, small posterior fossa with the upward displacement of the tentorium, small cerebellum with more severely hypoplastic vermis than hemispheres, and small brainstem.

PMID: 33111345 Brownstein et al., 2020
Family HL263: Mizrahi Jewish family, affected individuals heterozygous for ATOH1 c.1030delC, p.His344fs17Ter (affects C-terminus). Variant co-segregated over five generations with progressive non-syndromic hearing loss, with onset at birth or early childhood. Method: WES.
Western analysis revealed a significantly slower rate of degradation for mutant ATOH1 protein compared to wild-type ATOH1. Increased protein stability = untimely expression leading to hearing loss.

PMID: 27431290 Anazi et al., 2017
Cohort of ID patients. Patient 15DG1898 was homozygous for ATOH1: c.212del, p.(Gly71Alafs*36); clinical presentation: ID, generalised hypotonia, nystagmus, pontocerebellar hypoplasia, brain atrophy (frontal lobe). No mention of hearing loss (not assessed?).

Functional evidence:
Loss of Atoh1 in mice causes hearing impairment, cerebellar and cochlear malformations, and death (PMID: 9367153, Ben-Arie et al., 1997. ATOH1 previously known as MATH1).
Conditional deletion of Atoh1 leads to lack of differentiated inner ear hair cells (PMID: 21146598 Pan et al., 2010).

ATOH1 is putatively linked to ?Deafness, autosomal dominant 89, MIM:620284 in OMIM (accessed 23rd Feb 2026).
Sources: Literature
Intellectual disability v9.275 BORCS5 Ida Ertmanska gene: BORCS5 was added
gene: BORCS5 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: BORCS5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BORCS5 were set to 27435318; 40385417; 40621786
Phenotypes for gene: BORCS5 were set to arthrogryposis multiplex congenita, MONDO:0015168; neurodevelopmental disorder, MONDO:0700092
Review for gene: BORCS5 was set to GREEN
Added comment: PMID: 40621786 Fisher et al., 2025
Report of 2 fetal cases in a consanguineous Pakistani family. Exome seq revealed a homozygous nonsense variant c.283C>T, p.(Arg95Ter) in BORCS5 (NM_058169.4). Individuals showed neuroaxonal dystrophy with osteopetrosis.

PMID: 40385417 Mencacci et al., 2025 - pre-print
Report of 12 individuals from 7 unrelated families with biallelic BORCS5 variants (NM_058169.4): two missense variants (c.284G>A, p.R95Q; c.296A>C, p.H99P) and four LoF alleles (c.203–1G>T, p.?; c.316delG, p.A106Pfs*20; c.382_383delAG, p.L128Vfs*86; c.417C>G, p.Y139*).
Table 1 = phenotypic spectrum of 6 individuals from families 1-4: profound ID (6/6), severe spasticity (6/6), seizures (6/6), hyperreflexia (6/6), Parkinsonism/dystonia (3/6), limb contractures (5/6), optic atrophy (5/6), abnormal brain MRI including cerebral atrophy and/or corpus callosum agenesis (5/6), microcephaly (6/6 - severity not stated), muscle atrophy (5/6). Infantile onset.
Neuroimaging in 5 cases showed cerebral atrophy, white matter loss, hypomyelination, small T2-hypointense thalami, thin brainstem, and optic nerve atrophy.

PMID: 27435318 Charng et al., 2016
Patient BAB6775 homozygous for NM_058169.4 BORCS5: c.203-1G>T, with DD, microcephaly, seizures, cortical malformations, polymicrogyria, agenesis of corpus callosum. Also reported with more details in PMID:40385417 (do not count).

Additional functional evidence: Zebrafish borcs5 knockout leads to neurodevelopmental defects:microcephaly, ventriculomegaly, movement disorders and epilepsy.

BORCS5 is not yet associated with a disease in OMIM (accessed 20th Feb 2026).
Sources: Literature
Intellectual disability v9.273 CCT8 Ida Ertmanska gene: CCT8 was added
gene: CCT8 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: CCT8 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CCT8 were set to 39480921
Phenotypes for gene: CCT8 were set to CCT8-related neurodevelopmental disorder with brain abnormalities
Review for gene: CCT8 was set to AMBER
Added comment: PMID: 39480921 Kraft et al., 2024
Report of 2 individuals (20yo male and 79yo male) with heterozygous CCT7 variants: c.925_929del p.(Asn309Hisfs*16) - de novo & c.1166_1169delAAAG, p.(Glu389Glyfs*3) - inheritance not known. Patients presented with DD/ID (2/2), cerebral/pyramidal signs (1), seizures (2/2) and MRI abnormalities: Polymicrogyria (2/2).

CCT8 is not yet associated with a disease entity in OMIM (accessed 20th Feb 2026).
Sources: Literature
Intellectual disability v9.272 CCT7 Ida Ertmanska gene: CCT7 was added
gene: CCT7 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: CCT7 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CCT7 were set to 39480921
Phenotypes for gene: CCT7 were set to CCT7-related neurodevelopmental disorder with brain abnormalities
Review for gene: CCT7 was set to RED
Added comment: PMID: 39480921 Kraft et al., 2024
Report of 1 individual (5yo male) with a de novo heterozygous CCT7 variant: c.1135G>A, p.(Glu379Lys), presenting with DD/ID, cerebral/pyramidal signs, and MRI abnormalities:Inferior vermis hypoplasia, corpus callosum hypoplasia.

CCT7 is not yet associated with a disease entity in OMIM (accessed 20th Feb 2026).
Sources: Literature
Intellectual disability v9.270 CCT5 Ida Ertmanska reviewed gene: CCT5: Rating: RED; Mode of pathogenicity: None; Publications: 16333315, 39480921; Phenotypes: ?Neuropathy, hereditary sensory, with spastic paraplegia, OMIM:256840; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v9.270 CCT3 Ida Ertmanska Added comment: Comment on list classification: There are 4 unrelated individuals reported with severe ID/DD and heterozygous CCT3 variants - tagged for promotion to Green at the next update.
Intellectual disability v9.269 CCT3 Ida Ertmanska gene: CCT3 was added
gene: CCT3 was added to Intellectual disability. Sources: Literature
Q1_26_promote_green tags were added to gene: CCT3.
Mode of inheritance for gene: CCT3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CCT3 were set to 39480921
Phenotypes for gene: CCT3 were set to Neurodevelopmental disorder with speech or visual impairment and brain hypomyelination, OMIM:621034; neurodevelopmental disorder with speech or visual impairment and brain hypomyelination, MONDO:0976125
Review for gene: CCT3 was set to GREEN
Added comment: PMID: 39480921 Kraft et al., 2024
4 individuals aged 2-8 yo, reported with heterozygous CCT3 variants (frameshift, missense, stop gain - all 4 confirmed de novo). Patients presented with ID, seizures, visual impairment and brain malformations. Phenotype spectrum: DD/ID (4/4, severe), seizures (2/4), visual impairment (3/4), pyramidal/cerebellar signs (4/4), brain MRI abnormalities (3/3). MRI findings included cerebellar atrophy, hypomyelination of white matter, hypoplasia of corpus callosum, and atrophy of optic tract, chiasm and optic nerves.

CCT3 is associated with Neurodevelopmental disorder with speech or visual impairment and brain hypomyelination, OMIM:621034 (OMIM accessed 20th Feb 2026).
Sources: Literature
Intellectual disability v9.267 TCP1 Ida Ertmanska Added comment: Comment on list classification: There are more than 3 unrelated individuals reported with syndromic intellectual disability and heterozygous TCP1 variants - tagged for promotion to Green at the next update.
Intellectual disability v9.266 TCP1 Ida Ertmanska gene: TCP1 was added
gene: TCP1 was added to Intellectual disability. Sources: Literature
Q1_26_promote_green tags were added to gene: TCP1.
Mode of inheritance for gene: TCP1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TCP1 were set to 39480921
Phenotypes for gene: TCP1 were set to Intellectual developmental disorder with polymicrogyria and seizures, OMIM:621021
Review for gene: TCP1 was set to GREEN
Added comment: PMID: 39480921 Kraft et al., 2024
8 individuals reported with heterozygous TCP1 (CCT1) variants (frameshift, missense, stop gain - 5 confirmed de novo). Patients presented with ID, seizures, and brain malformations. Phenotype spectrum: DD/ID of variable severity (6/6 assessed), seizures (6/7), visual impairment (2/7), pyramidal signs (4 individuals), brain MRI abnormalities (7/8). MRI findings included polymicrogyria, heterotopia, ventriculomegaly and white matter hyperintensities, hypoplasia of corpus callosum.

TCP1 is associated with Intellectual developmental disorder with polymicrogyria and seizures, OMIM:621021 (OMIM accessed 20th Feb 2026).
Sources: Literature
Intellectual disability v9.265 SLC12A9 Ida Ertmanska changed review comment from: PMID: 38334070 Accogli et al., 2024
3 unrelated patients with biallelic LoF variants. Common features included intellectual disability/GDD, skeletal defects (fusion and segmentation vertebral defects) and brain structural abnormalities (thin corpus callosum, hypoplasia of the pons and inferior cerebellar vermis), congenital heart defects, and hypopigmented hair.
Patient 1 was homozygous for SLC12A9 nonsense variant p.(Arg615∗), patient 2 was compound heterozygous for SLC12A9 p.(Ser109Lysfs∗20) and a de novo large deletion, and proband 3 was compound heterozygous for SLC12A9 p.(Glu290Glyfs∗36) and p.(Asn552Lys).
Method: trio exome / genome seq + Sanger seq segregation confirmation.

Functional evidence (rescue): Fibroblasts from proband 1 contained enlarged lysosomes that were corrected by wild-type SLC12A9 cDNA. Patient variant p.(Asn552Lys) failed to correct the lysosomal defect.

This gene is not yet associated with a phenotype in OMIM (accessed 17th Feb 2026).
Sources: Literature; to: PMID: 38334070 Accogli et al., 2024
3 unrelated patients with biallelic LoF variants. Common features included intellectual disability/GDD, skeletal defects (fusion and segmentation vertebral defects) and brain structural abnormalities (thin corpus callosum, hypoplasia of the pons and inferior cerebellar vermis), congenital heart defects, and hypopigmented hair.
Patient 1 was homozygous for SLC12A9 nonsense variant p.(Arg615∗), patient 2 was compound heterozygous for SLC12A9 p.(Ser109Lysfs∗20) and a de novo large deletion 2.1 Mb ((98,261,637-100,363,719)x1 [GRCh37]) on chromosome 7q22.1 that fully encompasses SLC12A9, and proband 3 was compound heterozygous for SLC12A9 p.(Glu290Glyfs∗36) and p.(Asn552Lys).
Method: trio exome / genome seq + Sanger seq segregation confirmation.

Functional evidence (rescue): Fibroblasts from proband 1 contained enlarged lysosomes that were corrected by wild-type SLC12A9 cDNA. Patient variant p.(Asn552Lys) failed to correct the lysosomal defect.

This gene is not yet associated with a phenotype in OMIM (accessed 17th Feb 2026).
Sources: Literature
Intellectual disability v9.265 SLC12A9 Ida Ertmanska Added comment: Comment on list classification: There are 3 unrelated individuals reported in PMID:38334070 with biallelic SLC12A9 variants and a syndromic neurodevelopmental disorder with lysosome defects. ID/GDD was present in all 3 individuals. Hence, this gene should be promoted to Green for Intellectual disability.
Intellectual disability v9.264 SLC12A9 Ida Ertmanska gene: SLC12A9 was added
gene: SLC12A9 was added to Intellectual disability. Sources: Literature
Q1_26_promote_green tags were added to gene: SLC12A9.
Mode of inheritance for gene: SLC12A9 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC12A9 were set to 38334070
Phenotypes for gene: SLC12A9 were set to SLC12A9-related syndromic neurodevelopmental disorder with lysosome defects; neurodevelopmental disorder, MONDO:0700092
Review for gene: SLC12A9 was set to GREEN
Added comment: PMID: 38334070 Accogli et al., 2024
3 unrelated patients with biallelic LoF variants. Common features included intellectual disability/GDD, skeletal defects (fusion and segmentation vertebral defects) and brain structural abnormalities (thin corpus callosum, hypoplasia of the pons and inferior cerebellar vermis), congenital heart defects, and hypopigmented hair.
Patient 1 was homozygous for SLC12A9 nonsense variant p.(Arg615∗), patient 2 was compound heterozygous for SLC12A9 p.(Ser109Lysfs∗20) and a de novo large deletion, and proband 3 was compound heterozygous for SLC12A9 p.(Glu290Glyfs∗36) and p.(Asn552Lys).
Method: trio exome / genome seq + Sanger seq segregation confirmation.

Functional evidence (rescue): Fibroblasts from proband 1 contained enlarged lysosomes that were corrected by wild-type SLC12A9 cDNA. Patient variant p.(Asn552Lys) failed to correct the lysosomal defect.

This gene is not yet associated with a phenotype in OMIM (accessed 17th Feb 2026).
Sources: Literature
Intellectual disability v9.263 PPFIA3 Ida Ertmanska changed review comment from: Comment on list classification: There are 17 unrelated individuals with heterozygous PPFIA3 variants and 1 patient with biallelic PPFIA3 variants, presenting with a syndromic neurodevelopmental disorder. Intellectual disability and/or developmental delay were the presenting features in 18/20 cases. Based on available evidence this gene should be promoted to Green for Intellectual disability.; to: Comment on list classification: There are 17 unrelated individuals with heterozygous PPFIA3 variants and 1 patient with biallelic PPFIA3 variants, presenting with a syndromic neurodevelopmental disorder. Intellectual disability and/or developmental delay were the presenting features in majority of cases. Based on available evidence this gene should be promoted to Green for Intellectual disability.
Intellectual disability v9.263 PPFIA3 Ida Ertmanska changed review comment from: PMID: 38181735 Paul et al., 2024
20 individuals from 18 families with rare PPFIA3 variants (19 heterozygous and 1 compound heterozygous) presenting with developmental delay, intellectual disability, hypotonia, dysmorphisms, microcephaly or macrocephaly, autistic features, and epilepsy. ID/GDD was a presenting feature in 18/20 individuals; 6/20 individuals had epilepsy (see suppl data).
Sources: Literature; to: PMID: 38181735 Paul et al., 2024
20 individuals from 18 families with rare PPFIA3 variants (19 heterozygous and 1 compound heterozygous) presenting with developmental delay, intellectual disability, hypotonia, dysmorphisms, microcephaly or macrocephaly, autistic features, and epilepsy. ID/GDD was a presenting feature in 18/20 individuals; 6/20 individuals had epilepsy (see suppl data).
Sources: Literature
Intellectual disability v9.263 PPFIA3 Ida Ertmanska Added comment: Comment on list classification: There are 17 unrelated individuals with heterozygous PPFIA3 variants and 1 patient with biallelic PPFIA3 variants, presenting with a syndromic neurodevelopmental disorder. Intellectual disability and/or developmental delay were the presenting features in 18/20 cases. Based on available evidence this gene should be promoted to Green for Intellectual disability.
Intellectual disability v9.262 PPFIA3 Ida Ertmanska gene: PPFIA3 was added
gene: PPFIA3 was added to Intellectual disability. Sources: Literature
Q1_26_promote_green tags were added to gene: PPFIA3.
Mode of inheritance for gene: PPFIA3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PPFIA3 were set to 38181735
Phenotypes for gene: PPFIA3 were set to Paul-Chao neurodevelopmental syndrome, OMIM:621122
Review for gene: PPFIA3 was set to GREEN
Added comment: PMID: 38181735 Paul et al., 2024
20 individuals from 18 families with rare PPFIA3 variants (19 heterozygous and 1 compound heterozygous) presenting with developmental delay, intellectual disability, hypotonia, dysmorphisms, microcephaly or macrocephaly, autistic features, and epilepsy. ID/GDD was a presenting feature in 18/20 individuals; 6/20 individuals had epilepsy (see suppl data).
Sources: Literature
Intellectual disability v9.261 SPTAN1 Arina Puzriakova Phenotypes for gene: SPTAN1 were changed from Developmental and epileptic encephalopathy 5, OMIM:613477; developmental and epileptic encephalopathy, 5, MONDO:0013277 to Developmental and epileptic encephalopathy 5, OMIM:613477; Developmental delay with or without epilepsy, OMIM:620540; Spastic paraplegia 91, autosomal dominant, with or without cerebellar ataxia, OMIM:620538
Intellectual disability v9.257 SLITRK2 Ida Ertmanska Added comment: Comment on list classification: There are 8 unrelated individuals reported in literature with monoallelic variants in SLITRK2 and intellectual developmental disorder (7/8 are males). Several male patients inherited variants from unaffected heterozygous mothers. However, there is one heterozygous female reported with a de novo variants and a severe phenotype (severe ID, absent speech, seizures - PMID: 35840571). Thus, the MOI should be set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males).
Intellectual disability v9.254 PHF12 Ida Ertmanska Added comment: Comment on list classification: There are numerous individuals reported in literature in large cohort studies of intellectual disability, ASD, and developmental disorders patients, harbouring heterozygous de novo variants in PHF12. The association between PHF12 and a complex neurodevelopmental disorder was classified as Definitive by the Intellectual Disability and Autism ClinGen Expert Panel (Feb 2025). Based on available evidence this gene should be promoted to Green for Intellectual disability.
Intellectual disability v9.253 PHF12 Ida Ertmanska changed review comment from: The below publication information is taken from ClinGen evidence summary: https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_329aa190-d20e-4f6b-9c85-58242a8a2d33-2025-02-19T110000.000Z?page=1&size=25&search=

Lelieveld SH, et al., 2016, PMID: 27479843
Cohort (Radboud University Medical Center) with unexplained intellectual disability, no detailed clinical information available. Exome seq revealed de novo heterozygous NM_001033561.2(PHF12):c.425C>A (p.Ser142Ter).

Deciphering Developmental Disorders Study, 2017, PMID: 28135719
DDD Study cohort with severe undiagnosed developmental disorders, no detailed clinical information available. Exome seq revealed de novo heterozygous NM_001033561.2(PHF12):c.2645del (p.Pro882GlnfsTer30).

C Yuen RK, et al., 2017, PMID: 28263302
ASD cohort (MSSNG), no detailed clinical information available. Method: Whole genome shotgun sequencing. Het for de novo NM_001033561.2(PHF12):c.1091dup (p.Asn365Ter).

Kaplanis J, et al., 2020, PMID: 33057194
31,058 parent-offspring trios of individuals with developmental disorders.
Cohort (GeneDx) with developmental disorders, no detailed clinical information available: GDX 15850 het for de novo NM_001033561.2(PHF12):c.2360-1G>A
DDD Study cohort: DDD13k.08251 - het for de novo NM_001033561.2(PHF12):c.1970C>G (p.Ser657Ter)
DDD Study cohort: DDD13k.05315 - het for de novo NM_001033561.2(PHF12):c.862C>T (p.Gln288Ter)
Cohort (Radboud University Medical Center) with unexplained intellectual disability: de novo heterozygous NM_001033561.2(PHF12):c.2542-2A>C

PHF12 is not yet linked to a disease entity in OMIM (accessed 10th Feb 2026). The gene-disease association between PHF12 and AD complex neurodevelopmental disorder (MONDO:0100038) was classified as Definitive by the Intellectual Disability and Autism ClinGen Expert Panel (Feb 2025). Gene2Phenotype rated its association with PHF12-related developmental disorder as Strong.; to: The below publication information is taken from ClinGen evidence summary: https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_329aa190-d20e-4f6b-9c85-58242a8a2d33-2025-02-19T110000.000Z?page=1&size=25&search=

Lelieveld SH, et al., 2016, PMID: 27479843
Cohort (Radboud University Medical Center) with unexplained intellectual disability, no detailed clinical information available. Exome seq revealed de novo heterozygous NM_001033561.2(PHF12):c.425C>A (p.Ser142Ter).

Deciphering Developmental Disorders Study, 2017, PMID: 28135719
DDD Study cohort with severe undiagnosed developmental disorders, no detailed clinical information available. Exome seq revealed de novo heterozygous NM_001033561.2(PHF12):c.2645del (p.Pro882GlnfsTer30).

C Yuen RK, et al., 2017, PMID: 28263302
ASD cohort (MSSNG), no detailed clinical information available. Method: Whole genome shotgun sequencing. Het for de novo NM_001033561.2(PHF12):c.1091dup (p.Asn365Ter).

Kaplanis J, et al., 2020, PMID: 33057194
31,058 parent-offspring trios of individuals with developmental disorders.
Cohort (GeneDx) with developmental disorders, no detailed clinical information available: GDX 15850 het for de novo NM_001033561.2(PHF12):c.2360-1G>A
DDD Study cohort: DDD13k.08251 - het for de novo NM_001033561.2(PHF12):c.1970C>G (p.Ser657Ter)
DDD Study cohort: DDD13k.05315 - het for de novo NM_001033561.2(PHF12):c.862C>T (p.Gln288Ter)
Cohort (Radboud University Medical Center) with unexplained intellectual disability: de novo heterozygous NM_001033561.2(PHF12):c.2542-2A>C

Functional evidence:
PMID: 27956701 Graveline et al., 2017 - Phf12 (Pf1) -/- mouse embryos had global growth retardation and impaired development of skeleton, associated skeletal muscle, and brain. They died mid- to late-gestation due to developmental defects including edema and internal hemorrhage. Heterozygous Pf1+/- mice developed normally.

PHF12 is not yet linked to a disease entity in OMIM (accessed 10th Feb 2026). The gene-disease association between PHF12 and AD complex neurodevelopmental disorder (MONDO:0100038) was classified as Definitive by the Intellectual Disability and Autism ClinGen Expert Panel (Feb 2025). Gene2Phenotype rated its association with PHF12-related developmental disorder as Strong.
Intellectual disability v9.253 PHF12 Ida Ertmanska changed review comment from: The below publication information is taken from ClinGen evidence summary: https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_329aa190-d20e-4f6b-9c85-58242a8a2d33-2025-02-19T110000.000Z?page=1&size=25&search=

Lelieveld SH, et al., 2016, PMID: 27479843
Cohort (Radboud University Medical Center) with unexplained intellectual disability, no detailed clinical information available. Exome seq revealed de novo heterozygous NM_001033561.2(PHF12):c.425C>A (p.Ser142Ter).

Deciphering Developmental Disorders Study, 2017, PMID: 28135719
DDD Study cohort with severe undiagnosed developmental disorders, no detailed clinical information available. Exome seq revealed de novo heterozygous NM_001033561.2(PHF12):c.2645del (p.Pro882GlnfsTer30).

C Yuen RK, et al., 2017, PMID: 28263302
ASD cohort (MSSNG), no detailed clinical information available. Method: Whole genome shotgun sequencing. Het for de novo NM_001033561.2(PHF12):c.1091dup (p.Asn365Ter).

Kaplanis J, et al., 2020, PMID: 33057194
31,058 parent-offspring trios of individuals with developmental disorders.
Cohort (GeneDx) with developmental disorders, no detailed clinical information available: GDX 15850 het for de novo NM_001033561.2(PHF12):c.2360-1G>A
DDD Study cohort: DDD13k.08251 - het for de novo NM_001033561.2(PHF12):c.1970C>G (p.Ser657Ter)
DDD Study cohort: DDD13k.05315 - het for de novo NM_001033561.2(PHF12):c.862C>T (p.Gln288Ter)
Cohort (Radboud University Medical Center) with unexplained intellectual disability: de novo heterozygous NM_001033561.2(PHF12):c.2542-2A>C

PHF12 is not yet linked to a disease entity in OMIM (accessed 10th Feb 2026). The gene-disease association between PHF12 and AD complex neurodevelopmental disorder (MONDO:0100038) was classified as Definitive by the Intellectual Disability and Autism ClinGen Expert Panel (Feb 2025). Gene2Phenotype rated its association with PHF12-related developmental disorder as Strong.; to: The below publication information is taken from ClinGen evidence summary: https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_329aa190-d20e-4f6b-9c85-58242a8a2d33-2025-02-19T110000.000Z?page=1&size=25&search=

Lelieveld SH, et al., 2016, PMID: 27479843
Cohort (Radboud University Medical Center) with unexplained intellectual disability, no detailed clinical information available. Exome seq revealed de novo heterozygous NM_001033561.2(PHF12):c.425C>A (p.Ser142Ter).

Deciphering Developmental Disorders Study, 2017, PMID: 28135719
DDD Study cohort with severe undiagnosed developmental disorders, no detailed clinical information available. Exome seq revealed de novo heterozygous NM_001033561.2(PHF12):c.2645del (p.Pro882GlnfsTer30).

C Yuen RK, et al., 2017, PMID: 28263302
ASD cohort (MSSNG), no detailed clinical information available. Method: Whole genome shotgun sequencing. Het for de novo NM_001033561.2(PHF12):c.1091dup (p.Asn365Ter).

Kaplanis J, et al., 2020, PMID: 33057194
31,058 parent-offspring trios of individuals with developmental disorders.
Cohort (GeneDx) with developmental disorders, no detailed clinical information available: GDX 15850 het for de novo NM_001033561.2(PHF12):c.2360-1G>A
DDD Study cohort: DDD13k.08251 - het for de novo NM_001033561.2(PHF12):c.1970C>G (p.Ser657Ter)
DDD Study cohort: DDD13k.05315 - het for de novo NM_001033561.2(PHF12):c.862C>T (p.Gln288Ter)
Cohort (Radboud University Medical Center) with unexplained intellectual disability: de novo heterozygous NM_001033561.2(PHF12):c.2542-2A>C

PHF12 is not yet linked to a disease entity in OMIM (accessed 10th Feb 2026). The gene-disease association between PHF12 and AD complex neurodevelopmental disorder (MONDO:0100038) was classified as Definitive by the Intellectual Disability and Autism ClinGen Expert Panel (Feb 2025). Gene2Phenotype rated its association with PHF12-related developmental disorder as Strong.
Intellectual disability v9.252 RSF1 Ida Ertmanska changed review comment from: PMID: 41606215 Jost et al., 2026
Report of 11 unrelated individuals harboring de novo or inherited from a symptomatic parent heterozygous variants in RSF1 (only 7 with detailed information). All individuals had an NDD: intellectual disability, autism spectrum disorder or developmental delay. Seq method: Exome seq / Genome Seq. 6 variants de novo, one inherited from mosaic mother. Phenotypic spectrum: ID 4/7 (3 mild and 1 moderate-severe), educational difficulties 7/7, seizures 2/7, ASD 3/7, extremities anomalies 4/7, variable skin defects 5/7, variable ophthalmological anomalies 3/7, and other.

RSF1 is linked to AD Neurodevelopmental disorder with dysmorphic facies and behavioral abnormalities, MIM:620489 in OMIM (accessed 10th Feb 2026). It is not yet listed in ClinGen or Gene2Phenotype.
Sources: Literature; to: PMID: 41606215 Jost et al., 2026
Report of 11 unrelated individuals harboring de novo or inherited from a symptomatic parent heterozygous variants in RSF1 (only 7 with detailed information). All individuals had an NDD: intellectual disability, autism spectrum disorder or developmental delay. Seq method: Exome seq / Genome Seq. 6 variants de novo, one inherited from mosaic mother. Phenotypic spectrum: ID 4/7 (3 mild and 1 moderate-severe), educational difficulties 7/7, seizures 2/7, ASD 3/7, extremities anomalies 4/7, variable skin defects 5/7, variable ophthalmological anomalies 3/7, and other.

RSF1 is not yet linked to disease in OMIM, ClinGen or Gene2Phenotype (resources accessed 10th Feb 2026).
Sources: Literature
Intellectual disability v9.252 RSF1 Ida Ertmanska Added comment: Comment on list classification: There are more than 3 individuals reported in literature with heterozygous RSF1 variants and syndromic intellectual disability / developmental delay. Based on available evidence, this gene should be promoted to Green for Intellectual disability.
Intellectual disability v9.251 RSF1 Ida Ertmanska gene: RSF1 was added
gene: RSF1 was added to Intellectual disability. Sources: Literature
Q1_26_promote_green tags were added to gene: RSF1.
Mode of inheritance for gene: RSF1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RSF1 were set to 41606215
Phenotypes for gene: RSF1 were set to Neurodevelopmental disorder with dysmorphic facies and behavioral abnormalities, OMIM:620489
Review for gene: RSF1 was set to GREEN
Added comment: PMID: 41606215 Jost et al., 2026
Report of 11 unrelated individuals harboring de novo or inherited from a symptomatic parent heterozygous variants in RSF1 (only 7 with detailed information). All individuals had an NDD: intellectual disability, autism spectrum disorder or developmental delay. Seq method: Exome seq / Genome Seq. 6 variants de novo, one inherited from mosaic mother. Phenotypic spectrum: ID 4/7 (3 mild and 1 moderate-severe), educational difficulties 7/7, seizures 2/7, ASD 3/7, extremities anomalies 4/7, variable skin defects 5/7, variable ophthalmological anomalies 3/7, and other.

RSF1 is linked to AD Neurodevelopmental disorder with dysmorphic facies and behavioral abnormalities, MIM:620489 in OMIM (accessed 10th Feb 2026). It is not yet listed in ClinGen or Gene2Phenotype.
Sources: Literature
Intellectual disability v9.250 ASTN1 Ida Ertmanska commented on gene: ASTN1: Comment on list classification: There are more than 3 unrelated individuals reported with biallelic ASTN1 variants and a neurodevelopmental disorder. All reported individuals presented with developmental delay and/or intellectual disability, with variable severity. Based on available evidence, this gene should be promoted to Green for Intellectual disability.
Intellectual disability v9.248 JKAMP Ida Ertmanska Added comment: Comment on list classification: There are 14 affected individuals from 10 unrelated families reported in literature with biallelic JKAMP variants and a neurodevelopmental disorder. All individuals presented with syndromic developmental delay / regression and intellectual disability. The human phenotype was partially recapitulated by knockout studies in zebrafish. Based on available evidence, JKAMP should be promoted to Green for Intellectual disability at the next update.
Intellectual disability v9.247 JKAMP Ida Ertmanska gene: JKAMP was added
gene: JKAMP was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: JKAMP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: JKAMP were set to 41643666
Phenotypes for gene: JKAMP were set to neurodevelopmental disorder, MONDO:0700092
Review for gene: JKAMP was set to GREEN
Added comment: PMID: 41643666 Chacon-Millan et al., 2026
Report of 14 affected individuals from 10 unrelated families with biallelic JKAMP variants and a neurodevelopmental disorder. Individuals came from European and Arab backgrounds; age range 18mo - 25yrs. Several frameshift, missense and splice variants reported (homozygous and compound heterozygous states). Phenotype spectrum: moderate-profound neurodevelopmental delay and ID (14/14), neurodevelopmental regression (5/14), early onset epilepsy (14/14, median age of onset 6.5 months), hypotonia (13/14), microcephaly (5/14, severity not stated), various ocular manifestations (5/14), genitourinary malformations (3/14), and other (less common).
MRI findings: cortical and or cerebral atrophy (11/14), delayed myelination (6/14).
Additional functional evidence: Knockout jkamp-/- zebrafish were generated using CRISPR. Roughly half of the knockout fish had a mild phenotype, and half a 'severe' phenotype - similar to variable severity seen in patient cohort. Morphant phenotype consisted of smaller eyes and heads, and reduced expression of a myelin marker mbpa, partially recapitulating the human phenotype.

JKAMP is not yet linked to a disease entity in OMIM, Gene2Phenotype, or ClinGen (resources accessed 10th Feb 2026).
Sources: Literature
Intellectual disability v9.246 MORC2 Arina Puzriakova Phenotypes for gene: MORC2 were changed from Developmental delay; Intellectual disability; Growth retardation; Microcephaly; Craniofacial dysmorphism; Charcot-Marie-Tooth disease, axonal, type 2Z, OMIM:616688 to Charcot-Marie-Tooth disease, axonal, type 2Z, OMIM:616688; Developmental delay, impaired growth, dysmorphic facies, and axonal neuropathy, OMIM:619090
Intellectual disability v9.243 CRNKL1 Ida Ertmanska Phenotypes for gene: CRNKL1 were changed from Microcephaly, progressive, with simplified gyral pattern and cerebellar hypoplasia, OMIM:621436; complex neurodevelopmental disorder, MONDO:0100038 to Microcephaly, progressive, with simplified gyral pattern and cerebellar hypoplasia, OMIM:621436; complex neurodevelopmental disorder, MONDO:0100038
Intellectual disability v9.241 CRNKL1 Ida Ertmanska Phenotypes for gene: CRNKL1 were changed from complex neurodevelopmental disorder, MONDO:0100038 to Microcephaly, progressive, with simplified gyral pattern and cerebellar hypoplasia, OMIM:621436; complex neurodevelopmental disorder, MONDO:0100038
Intellectual disability v9.240 AIMP2 Eleanor Williams Phenotypes for gene: AIMP2 were changed from Leukodystrophy, hypomyelinating, 17, 618006; leukodystrophy, hypomyelinating, 17, MONDO:0054817; neurodevelopmental disorder with microcephaly, seizures, and spastic quadriparesis to Leukodystrophy, hypomyelinating, 17,OMIM:618006; leukodystrophy, hypomyelinating, 17, MONDO:0054817; neurodevelopmental disorder with microcephaly, seizures, and spastic quadriparesis
Intellectual disability v9.238 AIMP2 Eleanor Williams Phenotypes for gene: AIMP2 were changed from Leukodystrophy, hypomyelinating, 17, 618006; neurodevelopmental disorder with microcephaly, seizures, and spastic quadriparesis to Leukodystrophy, hypomyelinating, 17, 618006; leukodystrophy, hypomyelinating, 17, MONDO:0054817; neurodevelopmental disorder with microcephaly, seizures, and spastic quadriparesis
Intellectual disability v9.236 AIMP2 Ida Ertmanska edited their review of gene: AIMP2: Added comment: Comment on list classification: There are 6 unrelated individuals reported in literature with biallelic AIMP2 variants and a complex neurodevelopmental phenotype. 5/6 presentations included syndromic ID/DD. Based on the available evidence, this gene should be promoted to Green for Intellectual disability.; Changed rating: GREEN; Changed publications to: 26795593, 35140751, 35568357, 38374194; Changed phenotypes to: Leukodystrophy, hypomyelinating, 17, OMIM:618006; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v9.236 AIMP2 Ida Ertmanska changed review comment from: Additional cases:
PMID: 38374194 Abolhassani et al., 2024
Patient 925, 3yo Iranian female, with NM_006303.4(AIMP2):c.34_35delinsC (p.Gly12ProfsTer?). She presented with: Preterm birth; Low birth weight; Microcephaly; Mild learning difficulty; Developmental delay, speech & motor; Epilepsy; Hypertonia; Limb atrophy & spasticity; Muscle weakness; Strabismus; Ophthalmoplegia; Visual impairment; Anemia. Also homozygous for a VUS SBF1 variant p.Met524Arg (SBF1 is associated with recessive CMT).

PMID: 35140751 Mazaheri et al., 2022
Iranian proband - 7-month-old infant with a progressive neurological disorder characterized by lack of development, weight loss, severe anemia, skeletal abnormalities, microcephaly and MR imaging features of leukodystrophy. WES revealed a homozygous AIMP2 c.670A>T (p.Lys224Ter) variant, confirmed het in each parent. No mention of seizures. Variant predicted to escape NMD.

PMID: 35568357 Masih et al., 2022
Patient F32.1 - 5yo Indian male - homozygous for NM_006303.4(AIMP2):c.74A>G (p.Tyr25Cys). Clinical presentation: severe DD/ID, generalised tonic-clonic seizures, dysmorphic features, short stature, feeding difficulties, spastic quadriparesis, thin corpus callosum on MRI. Diagnosed with Leukodystrophy, hypomyelinating, 17.

This gene is associated with AR Leukodystrophy, hypomyelinating, 17, MIM:618006 (OMIM accessed 19th Jan 2025). The association between AIMP2 and AR leukodystrophy, hypomyelinating, 17 has been classified as Definitive in ClinGen (Leukodystrophy and Leukoencephalopathy Expert Panel, Sept 2025).; to: Additional cases:
PMID: 38374194 Abolhassani et al., 2024
Patient 925, 3yo Iranian female, with NM_006303.4(AIMP2):c.34_35delinsC (p.Gly12ProfsTer?). She presented with: Preterm birth; Low birth weight; Microcephaly; Mild learning difficulty; Developmental delay, speech & motor; Epilepsy; Hypertonia; Limb atrophy & spasticity; Muscle weakness; Strabismus; Ophthalmoplegia; Visual impairment; Anemia. Also homozygous for a VUS SBF1 variant p.Met524Arg (SBF1 is associated with recessive CMT).

PMID: 35140751 Mazaheri et al., 2022
Iranian proband - 7-month-old infant with a progressive neurological disorder characterized by lack of development, weight loss, severe anemia, skeletal abnormalities, microcephaly and MR imaging features of leukodystrophy. WES revealed a homozygous AIMP2 c.670A>T (p.Lys224Ter) variant, confirmed het in each parent. No mention of seizures. Variant predicted to escape NMD.

PMID: 35568357 Masih et al., 2022
Patient F32.1 - 5yo Indian male - homozygous for NM_006303.4(AIMP2):c.74A>G (p.Tyr25Cys). Clinical presentation: severe DD/ID, generalised tonic-clonic seizures, dysmorphic features, short stature, feeding difficulties, spastic quadriparesis, thin corpus callosum on MRI. Diagnosed with Leukodystrophy, hypomyelinating, 17.

PMID: 26795593 Helbig et al., 2016
Proband with Epileptic encephalopathy. Compound het for AIMP2 c.575-2A>G and c.72_73del (p.Met24IlefsTer25). Patient also has alteration in LRFN2 (not associated with disease in OMIM).

This gene is associated with AR Leukodystrophy, hypomyelinating, 17, MIM:618006 (OMIM accessed 19th Jan 2025). The association between AIMP2 and AR leukodystrophy, hypomyelinating, 17 has been classified as Definitive in ClinGen (Leukodystrophy and Leukoencephalopathy Expert Panel, Sept 2025).
Intellectual disability v9.236 WASHC5 Ida Ertmanska changed review comment from: Comment on list classification: There are two unrelated families reported in literature with biallelic variants in WASHC5 and Ritscher-Schinzel syndrome, including intellectual disability. In addition, washc5 knockout studies in zebrafish recapitulated the human phenotype and showed disrupted nervous development. Based on available evidence, this gene should be promoted to Green for Intellectual disability.; to: Comment on list classification: Evidence for this gene disease association includes a Caucasian family with four affected siblings, eight individuals from a first nations Canadian cohort, and a functional animal model. Individuals reported in literature with biallelic variants in WASHC5 were diagnosed with Ritscher-Schinzel syndrome, which includes intellectual disability. In addition, washc5 knockout studies in zebrafish recapitulated the human phenotype and showed disrupted nervous development. Based on available evidence, this gene should be promoted to Green for Intellectual disability.
Intellectual disability v9.236 WASHC5 Ida Ertmanska changed review comment from: PMID: 24065355 Elliot et al., 2013
8 patients with Ritscher-Schinzel syndrome from a first nations cohort in Canada. All homozygous for a novel splice site mutation c.3335+2T>A in WASHC5. 60% reduction in protein levels was shown in affected patients - demonstrated LoF effect.

PMID: 36130690 Neri et al., 2022
4 siblings carried compound heterozygous variants in WASHC5: c.232C>T, p.Gln78* & c.2489G>A, p.Arg830Gln. Patient 1, a 5yo live born female, and 3 fetal cases (terminated early based on elevated nuchal transluscency). Parents were confirmed as heterozygous for a variant each. All individuals presented with craniofacial dysmorphism, ID/DD, ataxic gait. Family 1: Patient 1 had severe intellectual disability. Cerebellar hypoplasia was noted on brain MRI.

Functional: PMID: 39988189 Wei et al., 2025 - washc5 knockout zebrafish showed disrupted maxillofacial, cardiovascular, and nervous development.

WASHC5 is associated with AR Ritscher-Schinzel syndrome 1, MIM:220210 and Spastic paraplegia 8, autosomal dominant, MIM:603563 (OMIM accessed 9th Jan 2025). Ritscher-Schinzel syndrome is associated with biallelic LoF variants, while Spastic paraplegia arises from GoF monoallelic variants in WASHC5.; to: PMID: 24065355 Elliot et al., 2013
8 patients with Ritscher-Schinzel syndrome from a first nations cohort in Canada. All homozygous for a novel splice site mutation c.3335+2T>A in WASHC5 (KIAA0196). 60% reduction in protein levels was shown in affected patients - demonstrated LoF effect.

PMID: 36130690 Neri et al., 2022
4 siblings carried compound heterozygous variants in WASHC5: c.232C>T, p.Gln78* & c.2489G>A, p.Arg830Gln. Patient 1, a 5yo live born female, and 3 fetal cases (terminated early based on elevated nuchal transluscency). Parents were confirmed as heterozygous for a variant each. All individuals presented with craniofacial dysmorphism, ID/DD, ataxic gait. Family 1: Patient 1 had severe intellectual disability. Cerebellar hypoplasia was noted on brain MRI.

Functional: PMID: 39988189 Wei et al., 2025 - washc5 knockout zebrafish showed disrupted maxillofacial, cardiovascular, and nervous development.

WASHC5 is associated with AR Ritscher-Schinzel syndrome 1, MIM:220210 and Spastic paraplegia 8, autosomal dominant, MIM:603563 (OMIM accessed 9th Jan 2025). Ritscher-Schinzel syndrome is associated with biallelic LoF variants, while Spastic paraplegia arises from GoF monoallelic variants in WASHC5.
Intellectual disability v9.236 CELSR3 Achchuthan Shanmugasundram changed review comment from: PMID:38429302 (2024) reported the identification of biallelic variants in CELSR3 gene in 12 individuals from 11 unrelated families. Six of 12 patients presented with homozygous missense and five with compound heterozygous missense CELSR3 variants, while one individual carried a heterozygous missense variant and an in-frame-deletion in trans.

Affected individuals presented with an overlapping phenotypic spectrum comprising central nervous system (CNS) anomalies (7/12), combined CNS anomalies and congenital anomalies of the kidneys and urinary tract (CAKUT) (3/12) and CAKUT only (2/12).

Individuals with predominant CNS or combined CNS and CAKUT phenotypes presented with intellectual disability and/or developmental delay (ID/DD), hypotonia, seizures, brain malformations, NTDs, macro- or microcephaly. ID was present in five patients, GDD in one and DD alone in 2 patients.

There is also functional evidence available from zebrafish, where transient suppression of CELSR3 ortholog Celsr3 leads to anomalies in the developing CNS and urinary system.
Sources: Literature; to: PMID:38429302 (2024) reported the identification of biallelic variants in CELSR3 gene in 12 individuals from 11 unrelated families. Six of 12 patients presented with homozygous missense and five with compound heterozygous missense CELSR3 variants, while one individual carried a heterozygous missense variant and an in-frame-deletion in trans.

Affected individuals presented with an overlapping phenotypic spectrum comprising central nervous system (CNS) anomalies (7/12), combined CNS anomalies and congenital anomalies of the kidneys and urinary tract (CAKUT) (3/12) and CAKUT only (2/12).

Individuals with predominant CNS or combined CNS and CAKUT phenotypes presented with intellectual disability and/or developmental delay (ID/DD), hypotonia, seizures, brain malformations, NTDs, macro- or microcephaly. ID was present in five patients, GDD in one and DD alone in 2 patients.

There is also functional evidence available from zebrafish, where transient suppression of CELSR3 ortholog Celsr3 leads to anomalies in the developing CNS and urinary system.

This gene has not yet been associated with relevant phenotypes in OMIM (last accessed 13 January 2026) or ClinGen, but biallelic CELSR3 variants have been associated with 'limited' rating on the DD panel of Gene2Phenotype.
Sources: Literature
Intellectual disability v9.235 CELSR3 Achchuthan Shanmugasundram gene: CELSR3 was added
gene: CELSR3 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: CELSR3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CELSR3 were set to 38429302
Phenotypes for gene: CELSR3 were set to neurodevelopmental disorder, MONDO:0700092
Review for gene: CELSR3 was set to GREEN
Added comment: PMID:38429302 (2024) reported the identification of biallelic variants in CELSR3 gene in 12 individuals from 11 unrelated families. Six of 12 patients presented with homozygous missense and five with compound heterozygous missense CELSR3 variants, while one individual carried a heterozygous missense variant and an in-frame-deletion in trans.

Affected individuals presented with an overlapping phenotypic spectrum comprising central nervous system (CNS) anomalies (7/12), combined CNS anomalies and congenital anomalies of the kidneys and urinary tract (CAKUT) (3/12) and CAKUT only (2/12).

Individuals with predominant CNS or combined CNS and CAKUT phenotypes presented with intellectual disability and/or developmental delay (ID/DD), hypotonia, seizures, brain malformations, NTDs, macro- or microcephaly. ID was present in five patients, GDD in one and DD alone in 2 patients.

There is also functional evidence available from zebrafish, where transient suppression of CELSR3 ortholog Celsr3 leads to anomalies in the developing CNS and urinary system.
Sources: Literature
Intellectual disability v9.234 PHF12 Sophie Ellis gene: PHF12 was added
gene: PHF12 was added to Intellectual disability. Sources: ClinGen
Mode of inheritance for gene: PHF12 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Penetrance for gene: PHF12 were set to unknown
Mode of pathogenicity for gene: PHF12 was set to Other
Review for gene: PHF12 was set to GREEN
gene: PHF12 was marked as current diagnostic
Added comment: ClinGen Definitive Classification - 02/19/2025
Sources: ClinGen
Intellectual disability v9.234 WASHC4 Ida Ertmanska Phenotypes for gene: WASHC4 were changed from Mental retardation, autosomal recessive 43, 615817 to Intellectual developmental disorder, autosomal recessive 43, OMIM:615817
Intellectual disability v9.233 WASHC5 Ida Ertmanska changed review comment from: PMID: 24065355 Elliot et al., 2013
8 patients with Ritscher-Schinzel syndrome from a first nations cohort in Canada. All homozygous for a novel splice site mutation c.3335+2T>A in WASHC5. 60% reduction in protein levels was shown in affected patients - demonstrated LoF effect.

PMID: 36130690 Neri et al., 2022
4 siblings carried compound heterozygous variants in WASHC5: c.232C>T, p.Gln78* & c.2489G>A, p.Arg830Gln. Patient 1, a 5yo live born female, and 3 fetal cases (terminated early based on elevated nuchal transluscency). Parents were confirmed as heterozygous for a variant each. All individuals presented with craniofacial dysmorphism, ID/DD, ataxic gait. Family 1: Patient 1 had severe intellectual disability. Cerebellar hypoplasia was noted on brain MRI.

Functional: PMID: 39988189 Wei et al., 2025 - washc5 knockout zebrafish showed disrupted maxillofacial, cardiovascular, and nervous development.

WASHC5 is associated with AR Ritscher-Schinzel syndrome 1, MIM:220210 and Spastic paraplegia 8, autosomal dominant, MIM:603563 (OMIM accessed 9th Jan 2025).; to: PMID: 24065355 Elliot et al., 2013
8 patients with Ritscher-Schinzel syndrome from a first nations cohort in Canada. All homozygous for a novel splice site mutation c.3335+2T>A in WASHC5. 60% reduction in protein levels was shown in affected patients - demonstrated LoF effect.

PMID: 36130690 Neri et al., 2022
4 siblings carried compound heterozygous variants in WASHC5: c.232C>T, p.Gln78* & c.2489G>A, p.Arg830Gln. Patient 1, a 5yo live born female, and 3 fetal cases (terminated early based on elevated nuchal transluscency). Parents were confirmed as heterozygous for a variant each. All individuals presented with craniofacial dysmorphism, ID/DD, ataxic gait. Family 1: Patient 1 had severe intellectual disability. Cerebellar hypoplasia was noted on brain MRI.

Functional: PMID: 39988189 Wei et al., 2025 - washc5 knockout zebrafish showed disrupted maxillofacial, cardiovascular, and nervous development.

WASHC5 is associated with AR Ritscher-Schinzel syndrome 1, MIM:220210 and Spastic paraplegia 8, autosomal dominant, MIM:603563 (OMIM accessed 9th Jan 2025). Ritscher-Schinzel syndrome is associated with biallelic LoF variants, while Spastic paraplegia arises from GoF monoallelic variants in WASHC5.
Intellectual disability v9.233 WASHC5 Ida Ertmanska changed review comment from: PMID: 24065355
8 patients with Ritscher-Schinzel syndromefrom a first nations cohort in Canada. All homozygous for a novel splice site mutation c.3335+2T>A in WASHC5. 60% reduction in protein levels was shown in affected patients - demonstrated LoF effect.

PMID: 36130690 Neri et al., 2022
4 siblings carried compound heterozygous variants in WASHC5: c.232C>T, p.Gln78* & c.2489G>A, p.Arg830Gln. Patient 1, a 5yo live born female, and 3 fetal cases (terminated early based on elevated nuchal transluscency). Parents were confirmed as heterozygous for a variant each. All individuals presented with craniofacial dysmorphism, ID/DD, ataxic gait. Family 1: Patient 1 had severe intellectual disability. Cerebellar hypoplasia was noted on brain MRI.

Functional: PMID: 39988189 Wei et al., 2025 - washc5 knockout zebrafish showed disrupted maxillofacial, cardiovascular, and nervous development.

WASHC5 is associated with AR Ritscher-Schinzel syndrome 1, MIM:220210 and Spastic paraplegia 8, autosomal dominant, MIM:603563 (OMIM accessed 9th Jan 2025).
; to: PMID: 24065355 Elliot et al., 2013
8 patients with Ritscher-Schinzel syndrome from a first nations cohort in Canada. All homozygous for a novel splice site mutation c.3335+2T>A in WASHC5. 60% reduction in protein levels was shown in affected patients - demonstrated LoF effect.

PMID: 36130690 Neri et al., 2022
4 siblings carried compound heterozygous variants in WASHC5: c.232C>T, p.Gln78* & c.2489G>A, p.Arg830Gln. Patient 1, a 5yo live born female, and 3 fetal cases (terminated early based on elevated nuchal transluscency). Parents were confirmed as heterozygous for a variant each. All individuals presented with craniofacial dysmorphism, ID/DD, ataxic gait. Family 1: Patient 1 had severe intellectual disability. Cerebellar hypoplasia was noted on brain MRI.

Functional: PMID: 39988189 Wei et al., 2025 - washc5 knockout zebrafish showed disrupted maxillofacial, cardiovascular, and nervous development.

WASHC5 is associated with AR Ritscher-Schinzel syndrome 1, MIM:220210 and Spastic paraplegia 8, autosomal dominant, MIM:603563 (OMIM accessed 9th Jan 2025).
Intellectual disability v9.233 WASHC5 Ida Ertmanska commented on gene: WASHC5: Comment on list classification: There are two unrelated families reported in literature with biallelic variants in WASHC5 and Ritscher-Schinzel syndrome, including intellectual disability. In addition, washc5 knockout studies in zebrafish recapitulated the human phenotype and showed disrupted nervous development. Based on available evidence, this gene should be promoted to Green for Intellectual disability.
Intellectual disability v9.233 WASHC5 Ida Ertmanska changed review comment from: PMID: 24065355
8 patients with Ritscher-Schinzel syndromefrom a first nations cohort in Canada. All homozygous for a novel splice site mutation c.3335+2T>A in WASHC5. 60% reduction in protein levels was shown in affected patients - demonstrated LoF effect.

PMID: 36130690 Neri et al., 2022
4 siblings carried compound heterozygous variants in WASHC5: c.232C>T, p.Gln78* & c.2489G>A, p.Arg830Gln. Patient 1, a 5yo live born female, and 3 fetal cases (terminated early based on elevated nuchal transluscency). Parents were confirmed as heterozygous for a variant each. All individuals presented with craniofacial dysmorphism, ID/DD, ataxic gait. Family 1: Patient 1 had severe intellectual disability. Cerebellar hypoplasia was noted on brain MRI.

Functional: PMID: 39988189 Wei et al., 2025 - washc5 knockout zebrafish showed disrupted maxillofacial, cardiovascular, and nervous development.; to: PMID: 24065355
8 patients with Ritscher-Schinzel syndromefrom a first nations cohort in Canada. All homozygous for a novel splice site mutation c.3335+2T>A in WASHC5. 60% reduction in protein levels was shown in affected patients - demonstrated LoF effect.

PMID: 36130690 Neri et al., 2022
4 siblings carried compound heterozygous variants in WASHC5: c.232C>T, p.Gln78* & c.2489G>A, p.Arg830Gln. Patient 1, a 5yo live born female, and 3 fetal cases (terminated early based on elevated nuchal transluscency). Parents were confirmed as heterozygous for a variant each. All individuals presented with craniofacial dysmorphism, ID/DD, ataxic gait. Family 1: Patient 1 had severe intellectual disability. Cerebellar hypoplasia was noted on brain MRI.

Functional: PMID: 39988189 Wei et al., 2025 - washc5 knockout zebrafish showed disrupted maxillofacial, cardiovascular, and nervous development.

WASHC5 is associated with AR Ritscher-Schinzel syndrome 1, MIM:220210 and Spastic paraplegia 8, autosomal dominant, MIM:603563 (OMIM accessed 9th Jan 2025).
Intellectual disability v9.233 WASHC5 Ida Ertmanska Phenotypes for gene: WASHC5 were changed from Spastic paraplegia 8, autosomal dominant, 603563; Ritscher-Schinzel syndrome, 220210 to Ritscher-Schinzel syndrome, OMIM:220210, Ritscher-Schinzel syndrome, MONDO:0019078
Intellectual disability v9.232 WASHC4 Ida Ertmanska changed review comment from: Comment on list classification: Based on new guidance from our clinical team, syndromic intellectual disability cases should be included on this panel. There are 3 unrelated families with individuals affected by syndromic ID, harbouring biallelic variants in WASHC4. Hence, WASHC4 should be promoted to Green for Intellectual disability at the next GMS update.; to: Comment on list classification: Based on new guidance from our clinical team, syndromic intellectual disability cases should be included on this panel - regardless of severity. There are 3 unrelated families with individuals affected by syndromic ID, harbouring biallelic variants in WASHC4. Hence, WASHC4 should be promoted to Green for Intellectual disability at the next GMS update.
Intellectual disability v9.231 KDM2A Achchuthan Shanmugasundram changed review comment from: PMID:41468891 (2025) reported a cohort of 18 unrelated individuals including one foetus with heterozygous de novo variants in KDM2A gene and with a neurodevelopmental disorder.

All individuals, excluding the foetus, exhibited developmental delay and/or intellectual disability, with the severity of developmental delay or intellectual disability ranging from learning disabilities to severe intellectual disability. The majority of individuals were affected by mild developmental delay/intellectual disability (11/17) or learning disabilities (2/17), while four individuals presented with severe developmental delay/intellectual disability.

Thew other reported phenotypes include microcephaly (six individuals including the foetus), seizures (five), hypotonia (four), IUGR (eight), short stature (nine), feeding difficulties (six) and dysmorphic facial features (twelve).

The study proposed dual mechanism of pathogenicity: loss of nuclear function for some variants tested and additional cytoplasmic gain-of-function toxicity for c.704C>T (p.Pro235Leu), as eliminating endogenous Drosophila Kdm2 did not produce noticeable neurodevelopmental phenotypes.

This gene has not yet been associated with relevant phenotypes in OMIM (last accessed 09 January 2026), Gene2Phenotype or ClinGen.
Sources: Literature; to: PMID:41468891 (2025) reported a cohort of 18 unrelated individuals including one foetus with heterozygous de novo variants in KDM2A gene and with a neurodevelopmental disorder.

All individuals, excluding the foetus, exhibited developmental delay and/or intellectual disability, with the severity of developmental delay or intellectual disability ranging from learning disabilities to severe intellectual disability. The majority of individuals were affected by mild developmental delay/intellectual disability (11/17) or learning disabilities (2/17), while four individuals presented with severe developmental delay/intellectual disability.

The other reported phenotypes include microcephaly (six individuals including the foetus - none of them had OFC beyond -3 SD), seizures (five), hypotonia (four), IUGR (eight), short stature (nine), feeding difficulties (six) and dysmorphic facial features (twelve).

The study proposed dual mechanism of pathogenicity: loss of nuclear function for some variants tested and additional cytoplasmic gain-of-function toxicity for c.704C>T (p.Pro235Leu), as eliminating endogenous Drosophila Kdm2 did not produce noticeable neurodevelopmental phenotypes.

This gene has not yet been associated with relevant phenotypes in OMIM (last accessed 09 January 2026), Gene2Phenotype or ClinGen.
Sources: Literature
Intellectual disability v9.230 KDM2A Achchuthan Shanmugasundram gene: KDM2A was added
gene: KDM2A was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: KDM2A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KDM2A were set to 41468891
Phenotypes for gene: KDM2A were set to neurodevelopmental disorder, MONDO:0700092
Review for gene: KDM2A was set to GREEN
Added comment: PMID:41468891 (2025) reported a cohort of 18 unrelated individuals including one foetus with heterozygous de novo variants in KDM2A gene and with a neurodevelopmental disorder.

All individuals, excluding the foetus, exhibited developmental delay and/or intellectual disability, with the severity of developmental delay or intellectual disability ranging from learning disabilities to severe intellectual disability. The majority of individuals were affected by mild developmental delay/intellectual disability (11/17) or learning disabilities (2/17), while four individuals presented with severe developmental delay/intellectual disability.

Thew other reported phenotypes include microcephaly (six individuals including the foetus), seizures (five), hypotonia (four), IUGR (eight), short stature (nine), feeding difficulties (six) and dysmorphic facial features (twelve).

The study proposed dual mechanism of pathogenicity: loss of nuclear function for some variants tested and additional cytoplasmic gain-of-function toxicity for c.704C>T (p.Pro235Leu), as eliminating endogenous Drosophila Kdm2 did not produce noticeable neurodevelopmental phenotypes.

This gene has not yet been associated with relevant phenotypes in OMIM (last accessed 09 January 2026), Gene2Phenotype or ClinGen.
Sources: Literature
Intellectual disability v9.227 PRMT9 Achchuthan Shanmugasundram edited their review of gene: PRMT9: Added comment: PMID:41260215 (2025) reported the identification of biallelic loss-of-function variants in PRMT9 gene in 35 individuals from 26 unrelated families primarily presenting with a neurodevelopmental disorder characterised by global developmental delay, learning disabilities, mild to severe intellectual disability, autism spectrum disorder, epilepsy, and hypotonia.

There were 26 different variants identified in total which included frameshifting indels, nonsense variants, missense variants, and two copy-number variants.

Global developmental delay was present un 33 individuals and mild - severe intellectual disability was present in 29 individuals (moderate and above in 11 patients, where ID was mild-moderate or severity not reported in others).

Functional evidence available from skin fibroblasts derived from affected individuals showed reduced expression at the RNA and/or protein level and subsequent aberrant methylation activity. Transcriptomic analysis of fibroblasts from affected individuals indicated differential expression of genes related to intellectual disability, autism, and cilia, suggesting a role of PRMT9 during ciliogenesis. Under ciliogenesis conditions, the skin-derived fibroblasts exhibited anomalies in the length of primary cilia but normal amounts of cilia. In addition, a prmt9 knockout zebrafish model displayed abnormal social preference in adult animals.

This gene has not yet been associated with relevant phenotypes in OMIM (last accessed 09 January 2026), but has been associated with 'Limited' rating on the DD panel in Gene2Phenotype.; Changed publications to: 21937992, 38561334, 41260215
Intellectual disability v9.227 GLUL Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: There are >10 unrelated individuals reported with developmental and epileptic encephalopathy, including global developmental delay and monoallelic GLUL variants. Hence, the MOI should be updated to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' in the next GMS update.
Intellectual disability v9.224 EIPR1 Achchuthan Shanmugasundram changed review comment from: PMID:41058046 (2025) reported the identification of five EIPR1 homozygous missense variants (c.835C>G/ p.Arg279Gly, c.813C>G/ p.His271Gln, c.694C>T/ p.Arg232Trp, c.47G>A/ p.Arg16His and c.419T>A/ p.Val140Asp) in eight individuals from six unrelated families with a neurological disorder featuring a spectrum of global neurodevelopmental delay, microcephaly, ataxia, spasticity, delayed myelination, callosal hypoplasia, cerebellar atrophy, walking and speech impairments, dysmorphic facies, and neutropenia. All had global developmental delay, with significant motor delay (5/8 never attained walking). Severe or profound intellectual disability was present in 3 individuals from two unrelated families.

There is also functional evidence available from cellular studies using a heterologous transfection system, kin fibroblasts from one of the Arg279Gly affected individuals and zebrafish knockout model. Knockout of the orthologous eipr1 in zebrafish resulted in neurodevelopmental and locomotor defects consistent with the clinical phenotype of the human patients.

This gene has not yet been associated with any phenotypes in OMIM (last accessed 05 December 2025), Gene2Phenotype or ClinGen.
Sources: Literature; to: PMID:41058046 (2025) reported the identification of five EIPR1 homozygous missense variants (c.835C>G/ p.Arg279Gly, c.813C>G/ p.His271Gln, c.694C>T/ p.Arg232Trp, c.47G>A/ p.Arg16His and c.419T>A/ p.Val140Asp) in eight individuals from six unrelated families with a neurological disorder featuring a spectrum of global neurodevelopmental delay, microcephaly, ataxia, spasticity, delayed myelination, callosal hypoplasia, cerebellar atrophy, walking and speech impairments, dysmorphic facies, and neutropenia. All had global developmental delay, with significant motor delay (5/8 never attained walking). Severe or profound intellectual disability was present in 3 individuals from two unrelated families.

There is also functional evidence available from cellular studies using a heterologous transfection system, kin fibroblasts from one of the Arg279Gly affected individuals and zebrafish knockout model. Knockout of the orthologous eipr1 in zebrafish resulted in neurodevelopmental and locomotor defects consistent with the clinical phenotype of the human patients.

This gene has not yet been associated with any phenotypes in OMIM (last accessed 05 January 2026), Gene2Phenotype or ClinGen.
Sources: Literature
Intellectual disability v9.224 GTF2I Achchuthan Shanmugasundram changed review comment from: PMID:40962490 (2025) reported the identification of heterozygous de novo variants in GTF2I gene (two non-sense, two splice-site, one missense, one indel and one intragenic deletion) via whole genome/ exome sequencing in seven unrelated individuals with a neurodevelopmental disorder. They all presented with global developmental delay and facial dysmorphic features, with speech delay and/or autistic features in six of them. GDD was severe and moderate in one each, and was mild in the rest. The effect of the two splice-site variants was confirmed by RNA sequencing.

This gene has not yet been associated with relevant phenotypes in OMIM (last accessed 05 January 2026), Gene2Phenotype or ClinGen.
Sources: Literature; to: PMID:40962490 (2025) reported the identification of heterozygous de novo variants in GTF2I gene (two non-sense, two splice-site, one missense, one indel and one intragenic deletion) via whole genome/ exome sequencing in seven unrelated individuals with a neurodevelopmental disorder. They all presented with global developmental delay/ intellectual disability and facial dysmorphic features, with speech delay and/or autistic features in six of them. GDD was severe and moderate in one each, and was mild in the rest. The effect of the two splice-site variants was confirmed by RNA sequencing.

This gene has not yet been associated with relevant phenotypes in OMIM (last accessed 05 January 2026), Gene2Phenotype or ClinGen.
Sources: Literature
Intellectual disability v9.224 LSM1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are six unrelated families reported with biallelic LSM 1 variants (c.231+4A>C in five families and p.Asn40Tyr in one family) and with FICUS syndrome (which includes global developmental delay/ intellectual disability). Hence, this gene can be promoted to green rating in the next GMS update.
Intellectual disability v9.223 LSM1 Achchuthan Shanmugasundram gene: LSM1 was added
gene: LSM1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: LSM1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LSM1 were set to 31010896; 36100156; 40204357
Phenotypes for gene: LSM1 were set to FICUS syndrome, OMIM:621193; FICUS syndrome, MONDO:0978296
Review for gene: LSM1 was set to GREEN
Added comment: PMID:31010896 (2019) reported two siblings with global developmental delay, and multiple congenital anomalies affecting the cardiac, genitourinary, and skeletal systems, and abnormal eye movements. They were identified with a homozygous non-canonical splice variant in LSM1 gene (c.231+4A>C) through whole-genome sequencing. There is also functional evidence available from expression studies and mouse model. Lsm1 knockout mice had a partially overlapping phenotype that affected the brain, heart, and eye.

PMID:36100156 (2022) reported the identification of a homozygous missense variant (p.Asn40Tyr) in LSM1 gene via whole-exome in two similarly affected siblings with global neurodevelopmental delay and intellectual disability.

PMID:40204357 (2025) reported six paediatric patients from four unrelated families with homozygous c.231+4A>C variant. They presented with dysmorphic facial features, global developmental delay/ intellectual disability and multisystemic involvement, including urological, cardiac and skeletal manifestations. This variant was identified in Muslim Arab and Ashkenazi Jewish populations and determined as representing a hotspot variant through haplotype analysis. RT-qPCR functional validation demonstrated exon 3 skipping and elevated mutant isoform. The variant was classified as 'Pathogenic' according to the ACMG classification.

This gene has been associated with relevant phenotypes in OMIM (MIM #621193, OMIM record last accessed 06 January 2026), but not yet in Gene2Phenotype.
Sources: Literature
Intellectual disability v9.220 GTF2I Achchuthan Shanmugasundram gene: GTF2I was added
gene: GTF2I was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: GTF2I was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: GTF2I were set to 40962490
Phenotypes for gene: GTF2I were set to neurodevelopmental disorder, MONDO:0700092
Review for gene: GTF2I was set to GREEN
Added comment: PMID:40962490 (2025) reported the identification of heterozygous de novo variants in GTF2I gene (two non-sense, two splice-site, one missense, one indel and one intragenic deletion) via whole genome/ exome sequencing in seven unrelated individuals with a neurodevelopmental disorder. They all presented with global developmental delay and facial dysmorphic features, with speech delay and/or autistic features in six of them. GDD was severe and moderate in one each, and was mild in the rest. The effect of the two splice-site variants was confirmed by RNA sequencing.

This gene has not yet been associated with relevant phenotypes in OMIM (last accessed 05 January 2026), Gene2Phenotype or ClinGen.
Sources: Literature
Intellectual disability v9.218 EIPR1 Achchuthan Shanmugasundram gene: EIPR1 was added
gene: EIPR1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: EIPR1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EIPR1 were set to 41058046
Phenotypes for gene: EIPR1 were set to neurodevelopmental disorder, MONDO:0700092
Review for gene: EIPR1 was set to GREEN
Added comment: PMID:41058046 (2025) reported the identification of five EIPR1 homozygous missense variants (c.835C>G/ p.Arg279Gly, c.813C>G/ p.His271Gln, c.694C>T/ p.Arg232Trp, c.47G>A/ p.Arg16His and c.419T>A/ p.Val140Asp) in eight individuals from six unrelated families with a neurological disorder featuring a spectrum of global neurodevelopmental delay, microcephaly, ataxia, spasticity, delayed myelination, callosal hypoplasia, cerebellar atrophy, walking and speech impairments, dysmorphic facies, and neutropenia. All had global developmental delay, with significant motor delay (5/8 never attained walking). Severe or profound intellectual disability was present in 3 individuals from two unrelated families.

There is also functional evidence available from cellular studies using a heterologous transfection system, kin fibroblasts from one of the Arg279Gly affected individuals and zebrafish knockout model. Knockout of the orthologous eipr1 in zebrafish resulted in neurodevelopmental and locomotor defects consistent with the clinical phenotype of the human patients.

This gene has not yet been associated with any phenotypes in OMIM (last accessed 05 December 2025), Gene2Phenotype or ClinGen.
Sources: Literature
Intellectual disability v9.217 RPS6KC1 Achchuthan Shanmugasundram changed review comment from: PMID:41130203 (2025) reported the identification of biallelic RPS6KC1 variants (both homozygous and compound heterozygous) in 12 individuals from seven independent families and an unrelated 19-week old foetus through whole-exome sequencing. There were 10 different variants identified in total.

The patients presented with a spectrum of conditions including neurodevelopmental delay, subsequent intellectual impairment, hypotonia, spastic paraplegia, brain white matter loss, and dysmorphic features overlapping with Coffin-Lowry syndrome. The affected foetus had hydrops fetalis and prenatal lethality. Moderate intellectual disability was reported in nine individuals rom four unrelated families.

Functional evidence is available from peripheral blood mononuclear cells (PBMCs), HAP1 RPS6KC1-knockdown cells and from Drosophila melanogaster model recapitulated the defects observed in individuals with RPS6KC1 variants.

This gene has been associated with relevant phenotypes in Gene2Phenotype (with 'moderate' rating on the DD panel), but not yet in OMIM (accessed on 05 January 2026).
Sources: Literature; to: PMID:41130203 (2025) reported the identification of biallelic RPS6KC1 variants (both homozygous and compound heterozygous) in 12 individuals from seven independent families and an unrelated 19-week old foetus through whole-exome sequencing. There were 10 different variants identified in total.

The patients presented with a spectrum of conditions including neurodevelopmental delay, subsequent intellectual impairment, hypotonia, spastic paraplegia, brain white matter loss, and dysmorphic features overlapping with Coffin-Lowry syndrome. The affected foetus had hydrops fetalis and prenatal lethality. Moderate intellectual disability was reported in nine individuals rom four unrelated families.

Functional evidence is available from peripheral blood mononuclear cells (PBMCs), HAP1 RPS6KC1-knockdown cells and from Drosophila melanogaster model, which recapitulated the defects observed in individuals with RPS6KC1 variants. Functional studies on PBMCs from the different individuals indicated diminished expression and phosphorylation of RPS6, impacting ribosomal protein synthesis, and a decrease in the known interactors PRDX3 and SPHK1, accompanied by marked repression of the mTOR/PI3K pathway. The study also detected a dysregulation of phosphoinositides and sphingoid base levels in plasma samples from the different individuals. Studies in HAP1 RPS6KC1-knockdown cells suggested that RPS6KC1 may regulate PRDX3 and SPHK1 activities by facilitating their endosome anchoring. In Drosophila melanogaster, the knockdown of CG7156, the RPS6KC1 ortholog, resulted in locomotor dysfunction, defective neuromuscular junctions, reduced lifespan, and decreased mTOR activity. Overexpression of mTOR in this model improved motor function and lifespan.

This gene has been associated with relevant phenotypes in Gene2Phenotype (with 'moderate' rating on the DD panel), but not yet in OMIM (accessed on 05 January 2026).
Sources: Literature
Intellectual disability v9.216 RPS6KC1 Achchuthan Shanmugasundram gene: RPS6KC1 was added
gene: RPS6KC1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: RPS6KC1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RPS6KC1 were set to 41130203
Phenotypes for gene: RPS6KC1 were set to neurodevelopmental disorder, MONDO:0700092
Review for gene: RPS6KC1 was set to GREEN
Added comment: PMID:41130203 (2025) reported the identification of biallelic RPS6KC1 variants (both homozygous and compound heterozygous) in 12 individuals from seven independent families and an unrelated 19-week old foetus through whole-exome sequencing. There were 10 different variants identified in total.

The patients presented with a spectrum of conditions including neurodevelopmental delay, subsequent intellectual impairment, hypotonia, spastic paraplegia, brain white matter loss, and dysmorphic features overlapping with Coffin-Lowry syndrome. The affected foetus had hydrops fetalis and prenatal lethality. Moderate intellectual disability was reported in nine individuals rom four unrelated families.

Functional evidence is available from peripheral blood mononuclear cells (PBMCs), HAP1 RPS6KC1-knockdown cells and from Drosophila melanogaster model recapitulated the defects observed in individuals with RPS6KC1 variants.

This gene has been associated with relevant phenotypes in Gene2Phenotype (with 'moderate' rating on the DD panel), but not yet in OMIM (accessed on 05 January 2026).
Sources: Literature
Intellectual disability v9.215 UNC13A Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: As there is sufficient evidence available for the association of both monoallelic and biallelic UNC13A variants with GDD/ ID, the MOI should be updated to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' in the next GMS update.
Intellectual disability v9.213 UNC13A Achchuthan Shanmugasundram edited their review of gene: UNC13A: Added comment: PMID:41125872 (2025) identified a neurodevelopmental syndrome caused by variants in the UNC13A gene. Systematic patient and variant characterisation enabled classification of three disease subtypes.

A first group of six patients (18 months to ~15 years old) presented with severe-to-profound global developmental delay (GDD) or intellectual disability (ID), hypotonia and seizures of different types (largely controllable with medication) or death in early childhood caused by respiratory failure after pneumonia in one case. UNC13A variants in these patients were homozygous or compound heterozygous missense, insertion–deletion or splice-site variants with gene-disrupting splicing effects proven by minigene assays.

A second group of 13 patients (21 months to 32 years old) harboured pathogenic, heterozygous de novo missense variants with multiple substitutions at amino acids 808, 811 and 814. They presented with variable degrees of GDD, hypotonia, seizures of different types (mainly refractory to treatment) and typically exhibited ataxia, tremor or dyskinetic movements rarely observed in other patients.

The third group of patients consisted of a family with at least four affected members across two generations (4 years to 35 years old) harbouring a pathogenic heterozygous missense variant (p.Cys587Phe) that caused learning difficulties to mild–moderate intellectual disability as well as controlled seizures.

Both monoallelic and biallelic UNC13A variants have been associated with relevant phenotypes in Gene2Phenotype (both with 'moderate' rating on the DD panel), but not yet in OMIM (last accessed 02 January 2026).; Changed publications to: 28192369, 39634123, 41125872; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v9.213 TM2D3 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are four unrelated patients reported with severe global developmental delay. Hence, this gene can be promoted to green rating in the next GMS update.
Intellectual disability v9.212 TM2D3 Achchuthan Shanmugasundram changed review comment from: PMID:40449487 (2025) reported four unrelated individuals with overlapping clinical presentations, including microcephaly, severe global developmental delay with absent speech, autistic features, heart malformation, and dysmorphic facial features. Severe GDD was reported in all four patients. They were all identified with homozygous or compound heterozygous variants in TM2D3 gene via exome sequencing.

There is also functional evidence available from SNB75 TM2D3-knockout cells as well as skin fibroblasts from affected individuals harboring the recurrent c.503G>A (p.Gly168Asp) allele.

This gene has been associated with relevant phenotype in OMIM (MIM #621379, last accessed 02 January 2026) and Gene2Phenotype (with 'moderate' rating on DD panel), but not yet in ClinGen.
Sources: Literature; to: PMID:40449487 (2025) reported four unrelated individuals with overlapping clinical presentations, including microcephaly, severe global developmental delay with absent speech, autistic features, heart malformation, and dysmorphic facial features. Severe GDD was reported in all four patients. They were all identified with homozygous or compound heterozygous variants in TM2D3 gene via exome sequencing.

There is also functional evidence available from SNB75 TM2D3-knockout cells as well as skin fibroblasts from affected individuals harbouring the recurrent c.503G>A (p.Gly168Asp) allele.

This gene has been associated with relevant phenotype in OMIM (MIM #621379, last accessed 02 January 2026) and Gene2Phenotype (with 'moderate' rating on DD panel), but not yet in ClinGen.
Sources: Literature
Intellectual disability v9.212 TM2D3 Achchuthan Shanmugasundram gene: TM2D3 was added
gene: TM2D3 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: TM2D3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TM2D3 were set to 40449487
Phenotypes for gene: TM2D3 were set to Neurocardiorenal malformation syndrome, OMIM:621379
Review for gene: TM2D3 was set to GREEN
Added comment: PMID:40449487 (2025) reported four unrelated individuals with overlapping clinical presentations, including microcephaly, severe global developmental delay with absent speech, autistic features, heart malformation, and dysmorphic facial features. Severe GDD was reported in all four patients. They were all identified with homozygous or compound heterozygous variants in TM2D3 gene via exome sequencing.

There is also functional evidence available from SNB75 TM2D3-knockout cells as well as skin fibroblasts from affected individuals harboring the recurrent c.503G>A (p.Gly168Asp) allele.

This gene has been associated with relevant phenotype in OMIM (MIM #621379, last accessed 02 January 2026) and Gene2Phenotype (with 'moderate' rating on DD panel), but not yet in ClinGen.
Sources: Literature
Intellectual disability v9.211 WSB2 Achchuthan Shanmugasundram changed review comment from: PMID:40374945 reported five patients from four unrelated families with developmental delays, brain anomalies, and dysmorphic features with or without intrauterine growth restriction (IUGR) and hypotonia. All five patients had global developmental delay. They were all identified with homozygous predicted loss-of-function (pLoF) or missense variants in WSB2 gene (c.128G>A/ p.Trp43Ter, p.Gln134ArgfsTer14, c.1121G>A/ p.Arg374Gln & c.1187_1188delAA/ p.Lys396ArgfsTer19) inherited from asymptomatic consanguineous parents.

There is also functional evidence available from Wsb2-mutant mice, which exhibited several neurological findings that included hyperactivity, altered exploration, and hyper alertness. They also weighed less, had a lower heart rate, and presented an abnormal retinal blood vessel morphology and vasculature pattern along with decreased total thickness of the retina.

This gene has not been associated with relevant phenotypes either in OMIM, Gene2Phenotype or ClinGen
Sources: Literature; to: PMID:40374945 reported five patients from four unrelated families with developmental delays, brain anomalies, and dysmorphic features with or without intrauterine growth restriction (IUGR) and hypotonia. All five patients had global developmental delay. They were all identified with homozygous predicted loss-of-function (pLoF) or missense variants in WSB2 gene (c.128G>A/ p.Trp43Ter, p.Gln134ArgfsTer14, c.1121G>A/ p.Arg374Gln & c.1187_1188delAA/ p.Lys396ArgfsTer19) inherited from asymptomatic consanguineous parents.

There is also functional evidence available from Wsb2-mutant mice, which exhibited several neurological findings that included hyperactivity, altered exploration, and hyper alertness. They also weighed less, had a lower heart rate, and presented an abnormal retinal blood vessel morphology and vasculature pattern along with decreased total thickness of the retina.

This gene has not been associated with relevant phenotypes either in OMIM, Gene2Phenotype or ClinGen.
Sources: Literature
Intellectual disability v9.210 WSB2 Achchuthan Shanmugasundram gene: WSB2 was added
gene: WSB2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: WSB2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: WSB2 were set to 40374945
Phenotypes for gene: WSB2 were set to neurodevelopmental disorder, MONDO:0700092
Review for gene: WSB2 was set to GREEN
Added comment: PMID:40374945 reported five patients from four unrelated families with developmental delays, brain anomalies, and dysmorphic features with or without intrauterine growth restriction (IUGR) and hypotonia. All five patients had global developmental delay. They were all identified with homozygous predicted loss-of-function (pLoF) or missense variants in WSB2 gene (c.128G>A/ p.Trp43Ter, p.Gln134ArgfsTer14, c.1121G>A/ p.Arg374Gln & c.1187_1188delAA/ p.Lys396ArgfsTer19) inherited from asymptomatic consanguineous parents.

There is also functional evidence available from Wsb2-mutant mice, which exhibited several neurological findings that included hyperactivity, altered exploration, and hyper alertness. They also weighed less, had a lower heart rate, and presented an abnormal retinal blood vessel morphology and vasculature pattern along with decreased total thickness of the retina.

This gene has not been associated with relevant phenotypes either in OMIM, Gene2Phenotype or ClinGen
Sources: Literature
Intellectual disability v9.208 ZNF865 Ida Ertmanska gene: ZNF865 was added
gene: ZNF865 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: ZNF865 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ZNF865 were set to 40936200
Phenotypes for gene: ZNF865 were set to neurodevelopmental disorder, MONDO:0700092
Review for gene: ZNF865 was set to GREEN
Added comment: PMID: 40936200 Bradbrook et al., 2025
Report of 18 unrelated individuals (Caucasian / Latino ethnicity) with developmental delay and shared dysmorphic features, harbouring heterozygous variants in ZNF865. Method: WGS / WES. Majority described as severely delayed, with speech delay and moderate to severe learning difficulties; avg age of walking = 24 months, 9/18 patients presented with hypotonia, 1 patient diagnosed with epilepsy, 9/15 had digit anomalies.
On MRI, 8/14 patients had brain abnormalities, including hypoplasia of corpus callosum and ventriculomegaly. Shared dysmorphic features: broad nasal bridge, hypertelorism, low-set ears.
14 unique variants (nonsense of frameshift) were detected, mostly towards the C-terminus. Variants were confirmed as de novo in 15 individuals.

This gene is not yet linked to any phenotype in OMIM (accessed 30th Dec 2025).
Sources: Literature
Intellectual disability v9.206 TSEN34 Ida Ertmanska changed review comment from: Comment on list classification: There is one patient reported in literature with a biallelic variant in TSEN34 and Pontocerebellar hypoplasia type 2. While TSEN34 shares a biochemical function with other genes known to cause Pontocerebellar hypoplasia type 2, the clinical evidence for this gene-disease association is lacking in literature. Hence, TSEN34 should be demoted to Amber for Intellectual disability until more evidence emerges.; to: Comment on list classification: There is one patient reported in literature with a biallelic variant in TSEN34 and Pontocerebellar hypoplasia type 2. While TSEN34 shares a biochemical function with other genes known to cause Pontocerebellar hypoplasia type 2, the clinical evidence for this gene-disease association is lacking in literature. Hence, TSEN34 should be demoted to Amber for Intellectual disability until more evidence emerges.
Intellectual disability v9.206 TSEN34 Ida Ertmanska changed review comment from: Comment on list classification: There is one patient reported in literature with a biallelic variant in TSEN34 and Pontocerebellar hypoplasia type 2. While TSEN34 shares a biochemical function with other genes known to cause Pontocerebellar hypoplasia type 2, the clinical evidence for this gene-disease association is lacking in literature. In addition, there is no mention Hence, TSEN34 should be demoted to Amber for Intellectual disability until more evidence emerges.; to: Comment on list classification: There is one patient reported in literature with a biallelic variant in TSEN34 and Pontocerebellar hypoplasia type 2. While TSEN34 shares a biochemical function with other genes known to cause Pontocerebellar hypoplasia type 2, the clinical evidence for this gene-disease association is lacking in literature. Hence, TSEN34 should be demoted to Amber for Intellectual disability until more evidence emerges.
Intellectual disability v9.206 SOX3 Ida Ertmanska changed review comment from: PMID: 35295983 Li et al., 2022
Chinese boy found to have growth hormone deficiency, hypogonadotropic hypogonadism, and borderline intellectual disability (full-scale IQ = 72). WES revealed a hemizygous variant in SOX3 (c.287 delG, p.G96Afs*44), as well as a SEMA3A c.2198G>R (p.R733H) variant.

PMID: 35114986 Du et al., 2022
8yo Chinese boy with a 6 Mb duplication on Xq26.3q27.1 encompassing SOX (and 9 other genes). Presented with congenital hypopituitarism, short stature. Normal intelligence, total IQ = 92.

PMID: 29175558 Jelsig et al., 2018
Family with 3 affected male siblings, harbouring a hemizygous SOX3 variant NM_005634.2:c.449C > A; p.(Ser150Tyr). Phenotype included mild intellectual disability, microphthalmia, coloboma, hypopituitarism, facial dysmorphology, microcephaly and dental anomalies.

SOX3 is associated with Intellectual developmental disorder, X-linked, with isolated growth hormone deficiency, MIM:300123 in OMIM (accessed 19th Dec 2025).; to: PMID: 35295983 Li et al., 2022
Chinese boy found to have growth hormone deficiency, hypogonadotropic hypogonadism, and borderline intellectual disability (full-scale IQ = 72). WES revealed a hemizygous variant in SOX3 (c.287 delG, p.G96Afs*44), as well as a SEMA3A c.2198G>R (p.R733H) variant.

PMID: 35114986 Du et al., 2022
8yo Chinese boy with a 6 Mb duplication on Xq26.3q27.1 encompassing SOX (and 9 other genes). Presented with congenital hypopituitarism, short stature. Normal intelligence, total IQ = 92.

PMID: 29175558 Jelsig et al., 2018
Family with 3 affected male siblings, harbouring a hemizygous SOX3 variant NM_005634.2:c.449C > A; p.(Ser150Tyr). Phenotype included mild intellectual disability, microphthalmia, coloboma, hypopituitarism, facial dysmorphology, microcephaly and dental anomalies.

SOX3 is associated with Intellectual developmental disorder, X-linked, with isolated growth hormone deficiency, MIM:300123 and Panhypopituitarism, X-linked, MIM:312000 in OMIM (accessed 19th Dec 2025).
Intellectual disability v9.206 SOX3 Ida Ertmanska Phenotypes for gene: SOX3 were changed from Mental retardation, X-linked, with isolated growth hormone deficiency, OMIM:300123; Intellectual disability, X-linked, with panhypopituitarism, MONDO:0010252 to Intellectual developmental disorder, X-linked, with isolated growth hormone deficiency, OMIM:300123; X-linked intellectual disability with isolated growth hormone deficiency, MONDO:0019032
Intellectual disability v9.203 SOX3 Ida Ertmanska edited their review of gene: SOX3: Added comment: Comment on list classification: While variants in SOX3 have been reported to cause a cognitive impairment, its severity does not meet the panel eligibility criteria of moderate/severe/profound global developmental delay/intellectual disability. Based on available evidence, this gene should be rated Amber for Intellectual disability, until more evidence emerges.; Changed rating: AMBER; Changed phenotypes to: Intellectual developmental disorder, X-linked, with isolated growth hormone deficiency, OMIM:300123, X-linked intellectual disability with isolated growth hormone deficiency, MONDO:0019032; Changed mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability v9.202 PAN2 Achchuthan Shanmugasundram Phenotypes for gene: PAN2 were changed from Developmental delay with variable cardiac and renal congenital anomalies and dysmorphic facies, OMIM:62138 to Developmental delay with variable cardiac and renal congenital anomalies and dysmorphic facies, OMIM:621384
Intellectual disability v9.201 PAN2 Achchuthan Shanmugasundram Phenotypes for gene: PAN2 were changed from Global developmental delay; Intellectual disability; Sensorineural hearing impairment; Abnormality of the genitourinary system; Abnormality of the cardiovascular system; Abnormality of blood and blood-forming tissues; EEG abnormality; Seizures; Anorectal anomaly; Abnormality of the skeletal system; Abnormality of the eye; Abnormality of head or neck to Developmental delay with variable cardiac and renal congenital anomalies and dysmorphic facies, OMIM:62138
Intellectual disability v9.198 TSEN34 Ida Ertmanska changed review comment from: Comment on list classification: There is one patient reported in literature with a biallelic variant in TSEN34 and Pontocerebellar hypoplasia type 2. While TSEN34 shares a biochemical function with other genes known to cause Pontocerebellar hypoplasia type 2, the clinical evidence for this gene-disease association is lacking in literature. In addition, there is no mention Hence, TSEN34 should be demoted to Amber for Intellectual disability at the next GMS update.; to: Comment on list classification: There is one patient reported in literature with a biallelic variant in TSEN34 and Pontocerebellar hypoplasia type 2. While TSEN34 shares a biochemical function with other genes known to cause Pontocerebellar hypoplasia type 2, the clinical evidence for this gene-disease association is lacking in literature. In addition, there is no mention Hence, TSEN34 should be demoted to Amber for Intellectual disability until more evidence emerges.
Intellectual disability v9.198 TSEN34 Ida Ertmanska changed review comment from: PMID: 20952379 Namavar et al., 2011
Reported one Pontocerebellar hypoplasia type 2C patient with a homozygous p.R58W variant in TSEN34 and epileptic seizures. PCH2 patient with seizures and TSEN34 variant reported in (most likely the same patient as in PMID:18711368 Budde et al., 2008). Sequenced exon-intron boundaries of TSEN54, TSEN34, TSEN2, TSEN15, RARS2 and VRK1 only.
Patient details from PMID:18711368: Patient hg1, male, phenotype: progressive microcephaly, chorea/dystonia, visual impairment, spontaneous breath; MRI typical.

PMID: 27370523 Balbi, Taicher & Litman, 2016
Brief mention of a 2-year-old female child diagnosed with TSEN34-related pontocerebellar hypoplasia Type 2 - no variant/clinical details.

Functional evidence:
PMID: 32476018 Hayne et al., 2020 / PMID: 37544645 Hayne et al., 2023
Human tRNA splicing endonuclease (TSEN) is comprised of four core subunits (TSEN54, TSEN2, TSEN34 and TSEN15), and it co-purifies with CLP1. Other TSEN subunits and CLP1 are all known to cause PCH. The TSEN34 R58W mutation eliminates a salt bridge between R58 and E218, affecting protein stability.

Additional info:
Variant NM_001077446.4(TSEN34):c.862_865dup (p.Leu289fs) was reported as Likely Pathogenic for Pontocerebellar hypoplasia type 2C in ClinVar by Mendelics (source: clinical testing).

This gene is putatively linked to AR Pontocerebellar hypoplasia type 2C, MIM:612390 (OMIM accessed 15th Dec 2025).; to: PMID: 20952379 Namavar et al., 2011
Reported one Pontocerebellar hypoplasia type 2C patient with a homozygous p.R58W variant in TSEN34 and epileptic seizures. PCH2 patient with seizures and TSEN34 variant reported in (most likely the same patient as in PMID:18711368 Budde et al., 2008). Sequenced exon-intron boundaries of TSEN54, TSEN34, TSEN2, TSEN15, RARS2 and VRK1 only.
Patient details from PMID:18711368: Patient hg1, male, phenotype: progressive microcephaly, chorea/dystonia, visual impairment, spontaneous breath; MRI typical.

PMID: 27370523 Balbi, Taicher & Litman, 2016
Brief mention of a 2-year-old female child diagnosed with TSEN34-related pontocerebellar hypoplasia Type 2 - no variant/clinical details.

Functional evidence:
PMID: 32476018 Hayne et al., 2020 / PMID: 37544645 Hayne et al., 2023
Human tRNA splicing endonuclease (TSEN) is comprised of four core subunits (TSEN54, TSEN2, TSEN34 and TSEN15), and it co-purifies with CLP1. Other TSEN subunits and CLP1 are all known to cause PCH. The TSEN34 R58W mutation eliminates a salt bridge between R58 and E218, affecting protein stability.

Additional info:
Variant NM_001077446.4(TSEN34):c.862_865dup (p.Leu289fs) was reported as Likely Pathogenic for Pontocerebellar hypoplasia type 2C in ClinVar by Mendelics (source: clinical testing).

This gene is putatively linked to AR Pontocerebellar hypoplasia type 2C, MIM:612390 (OMIM accessed 16th Dec 2025).
Intellectual disability v9.198 TSEN34 Ida Ertmanska Phenotypes for gene: TSEN34 were changed from PONTOCEREBELLAR HYPOPLASIA TYPE 2 AND TYPE 4 to Pontocerebellar hypoplasia type 2C, OMIM:612390; pontocerebellar hypoplasia type 2C, MONDO:0012891
Intellectual disability v9.196 TSEN34 Ida Ertmanska changed review comment from: PMID: 20952379 Namavar et al., 2011
Reported one Pontocerebellar hypoplasia type 2C patient with a homozygous p.R58W variant in TSEN34 and epileptic seizures. PCH2 patient with seizures and TSEN34 variant reported in (most likely the same patient as in PMID:18711368 Budde et al., 2008). Sequenced exon-intron boundaries of TSEN54, TSEN34, TSEN2, TSEN15, RARS2 and VRK1 only.
Patient details from PMID:18711368: Patient hg1, male, phenotype: progressive microcephaly, chorea/dystonia, visual impairment, spontaneous breath; MRI typical.


PMID: 27370523 Balbi, Taicher & Litman, 2016
Brief mention of a 2-year-old female child diagnosed with TSEN34-related pontocerebellar hypoplasia Type 2 - no variant/clinical details.

Functional evidence:
PMID: 32476018 Hayne et al., 2020 / PMID: 37544645 Hayne et al., 2023
Human tRNA splicing endonuclease (TSEN) is comprised of four core subunits (TSEN54, TSEN2, TSEN34 and TSEN15), and it co-purifies with CLP1. Other TSEN subunits and CLP1 are all known to cause PCH. The TSEN34 R58W mutation eliminates a salt bridge between R58 and E218, affecting protein stability.

Additional info:
Variant NM_001077446.4(TSEN34):c.862_865dup (p.Leu289fs) was reported as Likely Pathogenic for Pontocerebellar hypoplasia type 2C in ClinVar by Mendelics (source: clinical testing).

This gene is putatively linked to AR Pontocerebellar hypoplasia type 2C, MIM:612390 (OMIM accessed 15th Dec 2025).; to: PMID: 20952379 Namavar et al., 2011
Reported one Pontocerebellar hypoplasia type 2C patient with a homozygous p.R58W variant in TSEN34 and epileptic seizures. PCH2 patient with seizures and TSEN34 variant reported in (most likely the same patient as in PMID:18711368 Budde et al., 2008). Sequenced exon-intron boundaries of TSEN54, TSEN34, TSEN2, TSEN15, RARS2 and VRK1 only.
Patient details from PMID:18711368: Patient hg1, male, phenotype: progressive microcephaly, chorea/dystonia, visual impairment, spontaneous breath; MRI typical.

PMID: 27370523 Balbi, Taicher & Litman, 2016
Brief mention of a 2-year-old female child diagnosed with TSEN34-related pontocerebellar hypoplasia Type 2 - no variant/clinical details.

Functional evidence:
PMID: 32476018 Hayne et al., 2020 / PMID: 37544645 Hayne et al., 2023
Human tRNA splicing endonuclease (TSEN) is comprised of four core subunits (TSEN54, TSEN2, TSEN34 and TSEN15), and it co-purifies with CLP1. Other TSEN subunits and CLP1 are all known to cause PCH. The TSEN34 R58W mutation eliminates a salt bridge between R58 and E218, affecting protein stability.

Additional info:
Variant NM_001077446.4(TSEN34):c.862_865dup (p.Leu289fs) was reported as Likely Pathogenic for Pontocerebellar hypoplasia type 2C in ClinVar by Mendelics (source: clinical testing).

This gene is putatively linked to AR Pontocerebellar hypoplasia type 2C, MIM:612390 (OMIM accessed 15th Dec 2025).
Intellectual disability v9.196 TSEN34 Ida Ertmanska changed review comment from: PMID: 20952379 Namavar et al., 2011
Reported one Pontocerebellar hypoplasia type 2C patient with a homozygous p.R58W variant in TSEN34 and epileptic seizures. PCH2 patient with seizures and TSEN34 variant reported in (most likely the same patient as in PMID:18711368 Budde et al., 2008). Sequenced exon-intron boundaries of TSEN54, TSEN34, TSEN2, TSEN15, RARS2 and VRK1 only.
Patient details from PMID:18711368: Patient hg1, male, phenotype: progressive microcephaly, chorea/dystonia, visual impairment, spontaneous breath; MRI typical. No mention of cognitive ability.


PMID: 27370523 Balbi, Taicher & Litman, 2016
Brief mention of a 2-year-old female child diagnosed with TSEN34-related pontocerebellar hypoplasia Type 2 - no variant/clinical details.

Functional evidence:
PMID: 32476018 Hayne et al., 2020 / PMID: 37544645 Hayne et al., 2023
Human tRNA splicing endonuclease (TSEN) is comprised of four core subunits (TSEN54, TSEN2, TSEN34 and TSEN15), and it co-purifies with CLP1. Other TSEN subunits and CLP1 are all known to cause PCH. The TSEN34 R58W mutation eliminates a salt bridge between R58 and E218, affecting protein stability.

Additional info:
Variant NM_001077446.4(TSEN34):c.862_865dup (p.Leu289fs) was reported as Likely Pathogenic for Pontocerebellar hypoplasia type 2C in ClinVar by Mendelics (source: clinical testing).

This gene is putatively linked to AR Pontocerebellar hypoplasia type 2C, MIM:612390 (OMIM accessed 15th Dec 2025).; to: PMID: 20952379 Namavar et al., 2011
Reported one Pontocerebellar hypoplasia type 2C patient with a homozygous p.R58W variant in TSEN34 and epileptic seizures. PCH2 patient with seizures and TSEN34 variant reported in (most likely the same patient as in PMID:18711368 Budde et al., 2008). Sequenced exon-intron boundaries of TSEN54, TSEN34, TSEN2, TSEN15, RARS2 and VRK1 only.
Patient details from PMID:18711368: Patient hg1, male, phenotype: progressive microcephaly, chorea/dystonia, visual impairment, spontaneous breath; MRI typical.


PMID: 27370523 Balbi, Taicher & Litman, 2016
Brief mention of a 2-year-old female child diagnosed with TSEN34-related pontocerebellar hypoplasia Type 2 - no variant/clinical details.

Functional evidence:
PMID: 32476018 Hayne et al., 2020 / PMID: 37544645 Hayne et al., 2023
Human tRNA splicing endonuclease (TSEN) is comprised of four core subunits (TSEN54, TSEN2, TSEN34 and TSEN15), and it co-purifies with CLP1. Other TSEN subunits and CLP1 are all known to cause PCH. The TSEN34 R58W mutation eliminates a salt bridge between R58 and E218, affecting protein stability.

Additional info:
Variant NM_001077446.4(TSEN34):c.862_865dup (p.Leu289fs) was reported as Likely Pathogenic for Pontocerebellar hypoplasia type 2C in ClinVar by Mendelics (source: clinical testing).

This gene is putatively linked to AR Pontocerebellar hypoplasia type 2C, MIM:612390 (OMIM accessed 15th Dec 2025).
Intellectual disability v9.196 TSEN34 Ida Ertmanska commented on gene: TSEN34: Comment on list classification: There is one patient reported in literature with a biallelic variant in TSEN34 and Pontocerebellar hypoplasia type 2. While TSEN34 shares a biochemical function with other genes known to cause Pontocerebellar hypoplasia type 2, the clinical evidence for this gene-disease association is lacking in literature. In addition, there is no mention Hence, TSEN34 should be demoted to Amber for Intellectual disability at the next GMS update.
Intellectual disability v9.196 TSEN34 Ida Ertmanska reviewed gene: TSEN34: Rating: RED; Mode of pathogenicity: None; Publications: 20952379, 27370523, 32476018, 37544645; Phenotypes: Pontocerebellar hypoplasia type 2C, OMIM:612390, pontocerebellar hypoplasia type 2C, MONDO:0012891; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v9.194 ANKS1B Ida Ertmanska changed review comment from: PMID: 31388001 Carbonell et al., 2019
Report of 2 unrelated families (EIN-1 and EIN-2), with 6 affected members. The individuals presented with a pattern of developmental delays, oculomotor and oromotor irregularities, dysmetria, impaired fine-motor dexterity, and problems with balance and gait. The individuals had normal ntelligence (FSIQ = 85-105), except patient EIN-2-1 (FSIQ = 81, slightly below average).
Also reported 10 individuals from other sources (Decipher, University of Toronto, GeneMatcher), with microdeletions in ANKS1B.
9 individuals from 7 families with monogenic deletions in ANKS1B are described in Table 1. 1 family was South Asian and 6 had Caucasian ancestry. Craniofacial dysmorphism was reported in 5/7 families. 3/9 patients were diagnosed with ID, however the severity is not specified, and two of the individuals were under 5 years of age - diagnosis is difficult before age 5. 6/9 individuals had developmental delay, 5/9 had ASD, and 4/9 had ADHD. 4/9 patients had some abnormalities reported on MRI (thin corpus callosum, enlarged ventricles).

Functional evidence: PMID: 38129387 Cho et al., 2023
'Anks1b-deficient mouse models display deficits in oligodendrocyte maturation, myelination, and Rac1 function'

This gene is not yet associated with a phenotype in OMIM (accessed 12th Dec 2025).; to: PMID: 31388001 Carbonell et al., 2019
Report of 2 unrelated families (EIN-1 and EIN-2), with 6 affected members. The individuals presented with a complex neurodevelopmental disorder, with normal ntelligence (FSIQ = 85-105), except patient EIN-2-1 (FSIQ = 81, slightly below average).

Also reported 10 individuals from other sources (Decipher, University of Toronto, GeneMatcher), with microdeletions in ANKS1B.

9 individuals from 7 families with monogenic deletions in ANKS1B are described in Table 1. 1 family was South Asian and 6 had Caucasian ancestry. Craniofacial dysmorphism was reported in 5/7 families. 3/9 patients were diagnosed with ID, however the severity is not specified, and two of the individuals were under 5 years of age - diagnosis is difficult before age 5. 6/9 individuals had developmental delay, 5/9 had ASD, and 4/9 had ADHD. 4/9 patients had some abnormalities reported on MRI (thin corpus callosum, enlarged ventricles).

Functional evidence: PMID: 38129387 Cho et al., 2023
'Anks1b-deficient mouse models display deficits in oligodendrocyte maturation, myelination, and Rac1 function'

This gene is not yet associated with a phenotype in OMIM (accessed 12th Dec 2025).
Intellectual disability v9.194 ANKS1B Ida Ertmanska changed review comment from: PMID: 31388001 Carbonell et al., 2019
Report of 2 unrelated families (EIN-1 and EIN-2), with 6 affected members. The individuals presented with a pattern of developmental delays, oculomotor and oromotor irregularities, dysmetria, impaired fine-motor dexterity, and problems with balance and gait. The individuals had normal ntelligence (FSIQ = 85-105), except patient EIN-2-1 (FSIQ = 81, slightly below average).
Also reported 10 individuals from other sources (Decipher, University of Toronto, GeneMatcher), with microdeletions in ANKS1B.
9 individuals from 7 families with monogenic deletions in ANKS1B are described in Table 1. 1 family was South Asian and 6 had Caucasian ancestry. Craniofacial dysmorphism was reported in 5/7 families. 3/9 patients were diagnosed with ID, however the severity is not specified, and two of the individuals were under 5 years of age - diagnosis is difficult before age 5. 6/9 individuals had developmental delay, 5/9 had ASD, and 4/9 had ADHD.

This gene is not yet associated with a phenotype in OMIM (accessed 12th Dec 2025).; to: PMID: 31388001 Carbonell et al., 2019
Report of 2 unrelated families (EIN-1 and EIN-2), with 6 affected members. The individuals presented with a pattern of developmental delays, oculomotor and oromotor irregularities, dysmetria, impaired fine-motor dexterity, and problems with balance and gait. The individuals had normal ntelligence (FSIQ = 85-105), except patient EIN-2-1 (FSIQ = 81, slightly below average).
Also reported 10 individuals from other sources (Decipher, University of Toronto, GeneMatcher), with microdeletions in ANKS1B.
9 individuals from 7 families with monogenic deletions in ANKS1B are described in Table 1. 1 family was South Asian and 6 had Caucasian ancestry. Craniofacial dysmorphism was reported in 5/7 families. 3/9 patients were diagnosed with ID, however the severity is not specified, and two of the individuals were under 5 years of age - diagnosis is difficult before age 5. 6/9 individuals had developmental delay, 5/9 had ASD, and 4/9 had ADHD. 4/9 patients had some abnormalities reported on MRI (thin corpus callosum, enlarged ventricles).

Functional evidence: PMID: 38129387 Cho et al., 2023
'Anks1b-deficient mouse models display deficits in oligodendrocyte maturation, myelination, and Rac1 function'

This gene is not yet associated with a phenotype in OMIM (accessed 12th Dec 2025).
Intellectual disability v9.194 ANKS1B Ida Ertmanska changed review comment from: PMID: 31388001 Carbonell et al., 2019
Report of 2 unrelated families (EIN-1 and EIN-2), with 6 affected members. The individuals presented with a pattern of developmental delays, oculomotor and oromotor irregularities, dysmetria, impaired fine-motor dexterity, and problems with balance and gait. The individuals had normal ntelligence (FSIQ = 85-105), except patient EIN-2-1 (FSIQ = 81, slightly below average).
Also reported 10 individuals from other sources (Decipher, University of Toronto, GeneMatcher), with microdeletions in ANKS1B.
9 individuals from 7 families with monogenic deletions in ANKS1B are described in Table 1. 1 family was South Asian and 6 had Caucasian ancestry. Craniofacial dysmorphism was reported in 5/7 families. 3/9 patients were diagnosed with ID, however the severity is not specified, and two of the individuals were under 5 years of age - diagnosis is difficult before age 5. 6/9 individuals had developmental delay, 5/9 had ASD, and 4/9 had ADHD.

This gene is not yet associated with a phenotype in OMIM (accessed 12th Dec 2025).; to: PMID: 31388001 Carbonell et al., 2019
Report of 2 unrelated families (EIN-1 and EIN-2), with 6 affected members. The individuals presented with a pattern of developmental delays, oculomotor and oromotor irregularities, dysmetria, impaired fine-motor dexterity, and problems with balance and gait. The individuals had normal ntelligence (FSIQ = 85-105), except patient EIN-2-1 (FSIQ = 81, slightly below average).
Also reported 10 individuals from other sources (Decipher, University of Toronto, GeneMatcher), with microdeletions in ANKS1B.
9 individuals from 7 families with monogenic deletions in ANKS1B are described in Table 1. 1 family was South Asian and 6 had Caucasian ancestry. Craniofacial dysmorphism was reported in 5/7 families. 3/9 patients were diagnosed with ID, however the severity is not specified, and two of the individuals were under 5 years of age - diagnosis is difficult before age 5. 6/9 individuals had developmental delay, 5/9 had ASD, and 4/9 had ADHD.

This gene is not yet associated with a phenotype in OMIM (accessed 12th Dec 2025).
Intellectual disability v9.194 LDB1 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update.

Although ventriculomegaly and/or hydrocephalus are the primary feature of the disorder, at least seven unrelated individuals have been reported with GDD and several also exhibited hypotonia. Taking this into account and the broader syndromic presentation, it would be appropriate to include this gene on the R27 Paediatric disorders and R69 Hypotonic infant super panels, both of which incorporate Intellectual disability as a component panel.
Intellectual disability v9.193 LDB1 Arina Puzriakova gene: LDB1 was added
gene: LDB1 was added to Intellectual disability. Sources: Literature
Q4_25_promote_green tags were added to gene: LDB1.
Mode of inheritance for gene: LDB1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: LDB1 were set to 39680505; 38091987; 33077954
Phenotypes for gene: LDB1 were set to Congenital hydrocephalus, MONDO:0016349
Review for gene: LDB1 was set to GREEN
Added comment: - Allington et al. 2024 (PMID: 39680505) investigate a cohort of 2697 trios with congenital primary cerebral ventriculomegaly using WES. Eight unrelated individuals identified with de novo variants in LDB1 (7 LOF, 1 predicted damaging missense) - exhibiting perinatally diagnosed cerebral ventriculomegaly, including neurosurgically treated congenital hydrocephalus. Additionally, 5/8 GDD, 3/8 autism, 2/8 delayed gross motor development, 2/8 had congenital heart defects (inc. coarctation, PDA), 2/8 camptodactyly.

Additional case was identified from GeneMatcher with a de novo frameshift variants in LDB1. Phenotypes include severe ventriculomegaly, absence of well formed gyri, severe limb contractures and camptodactyly. Search of Decipher/DDD also revealed 4 pathogenic de novo variants in LDB1 and associated binding partners in individuals congenital ventriculomegaly.

- Torene et al. 2023 (PMID: 38091987) identified three individuals with protein truncating variants. Two individuals with de novo variants both had ventriculomegaly, hypotonia, GDD, craniofacial abnormalities. The third individual inherited the variants from an asymptomatic mother, and displayed developmental delay, hypotonia, congenital heart defects and a small hypoplastic hippocampi but did not have ventriculomegaly or craniofacial anomalies.

- Jin et al. 2020 (PMID: 33077954) also report an individual with a de novo LOF variant in this gene who had congenital hydrocephalus but details on this case are otherwise limited.
Sources: Literature
Intellectual disability v9.192 CIAO1 Arina Puzriakova Phenotypes for gene: CIAO1 were changed from CIAO1 associated neuromuscular disorder to Multiple mitochondrial dysfunctions syndrome 10, OMIM:620960
Intellectual disability v9.190 CCNK Ida Ertmanska changed review comment from: PMID: 30122539 Fan et al., 2018
Report of 3 unrelated Chinese individuals with de novo heterozygous copy number loss of CCNK in an overlapping 14q32.3 region (with several other genes being deleted) and 1 African American individual harbouring a de novo CCNK variant c.331A>G (p.Lys111Glu) - variant not present in gnomAD v4; Revel score = 0.52. Common phenotype: developmental delay and moderate (1/4) to severe (3/4) intellectual disability (DD/ID), language defects, distinctive facial dysmorphism. 4/4 cases confirmed as de novo.
Functional evidence: Ccnk knockdown in zebrafish resulted in defective brain development, small eyes, and curly spinal cord; defects were partially rescued by WT CCNK mRNA but not by the c.331A>G mRNA variant.

PMID: 35063350 Rouxel et al., 2022
ID B5 - 1.5 yr old female, het for a missense variant in CCNK (variant not specified); phenotype: distinctive facial features matching CDK13-deficient patients, neuropsychological assessment not conducted; high methylation variant pathogenicity (MVP) score - methylation score matched individuals with pathogenic CDK13 variants; CDK13 forms a complex with cyclin K (encoded by CCNK).

PMID: 37597256 Dai et al., 2023
Report of 2 new (P1 & P3) and 3 previously reported cases. Seq method: exome seq + Sanger.
Patient 1 - Chinese Female 1 y 4 mo; het for c.556T>C, p.(Trp186Arg) - de novo; Moderate DD/ID, distinctive facial features, congenital cardiac defects.
Patient 3 - Chinese Female 5 y 4 mo; het for c.772T>C, p.(Tyr258His) - de novo; Mild DD/ID (IQ 59 - WPPSI scale), facial dysmorphisms
Functional evidence: Ccnk +/- knockdown mouse model showed deficient neural progenitor cell proliferation and enhanced apoptotic cell death.

PMID: 41101726 Xiol et al., Oct 2025 - online ahead of print
Report of an 11yr old girl with a de novo CCNK missense variant c.549A>C, p.(Gln183His) - not in gnomAD v4.1.0, Revel score = 0.43; phenotype: mild intellectual disability (WISC-V at 10yrs showed IQ of 69), subtle dysmorphism (hypertelorism, depressed/broad nasal bridge), ventriculomegaly, delayed motor milestones & hypotonia.

CCNK pLI score = 1.00 - predicted to be extremely intolerant to LoF. CCNK is putatively associated with AD Intellectual developmental disorder with hypertelorism and distinctive facies, MIM:618147 (OMIM accessed 24th Nov 2025).
Sources: Literature; to: PMID: 30122539 Fan et al., 2018
Report of 3 unrelated Chinese individuals with de novo heterozygous copy number loss of CCNK in an overlapping 14q32.3 region (with several other genes being deleted) and 1 African American individual harbouring a de novo CCNK variant c.331A>G (p.Lys111Glu) - variant not present in gnomAD v4; Revel score = 0.52. Common phenotype: developmental delay and moderate (1/4) to severe (3/4) intellectual disability (DD/ID), language defects, distinctive facial dysmorphism. 4/4 cases confirmed as de novo.
Functional evidence: Ccnk knockdown in zebrafish resulted in defective brain development, small eyes, and curly spinal cord; defects were partially rescued by WT CCNK mRNA but not by the c.331A>G mRNA variant.

PMID: 35063350 Rouxel et al., 2022
ID B5 - 1.5 yr old female, het for a missense variant in CCNK (variant not specified); phenotype: distinctive facial features matching CDK13-deficient patients, neuropsychological assessment not conducted; high methylation variant pathogenicity (MVP) score - methylation score matched individuals with pathogenic CDK13 variants; CDK13 forms a complex with cyclin K (encoded by CCNK).

PMID: 37597256 Dai et al., 2023
Report of 2 new (P1 & P3) and 3 previously reported cases. Seq method: exome seq + Sanger.
Patient 1 - Chinese Female 1 y 4 mo; het for c.556T>C, p.(Trp186Arg) - de novo; Moderate DD/ID, distinctive facial features, congenital cardiac defects. Variant not reported in gnomAD v4.
Patient 3 - Chinese Female 5 y 4 mo; het for c.772T>C, p.(Tyr258His) - de novo; Mild DD/ID (IQ 59 - WPPSI scale), facial dysmorphisms. Variant not reported in gnomAD v4.
Functional evidence: Ccnk +/- knockdown mouse model showed deficient neural progenitor cell proliferation and enhanced apoptotic cell death.

PMID: 41101726 Xiol et al., Oct 2025 - online ahead of print
Report of an 11yr old girl with a de novo CCNK missense variant c.549A>C, p.(Gln183His) - not in gnomAD v4.1.0, Revel score = 0.43; phenotype: mild intellectual disability (WISC-V at 10yrs showed IQ of 69), subtle dysmorphism (hypertelorism, depressed/broad nasal bridge), ventriculomegaly, delayed motor milestones & hypotonia.

CCNK pLI score = 1.00 - predicted to be extremely intolerant to LoF. CCNK is putatively associated with AD Intellectual developmental disorder with hypertelorism and distinctive facies, MIM:618147 (OMIM accessed 24th Nov 2025).
Sources: Literature
Intellectual disability v9.190 CCNK Ida Ertmanska changed review comment from: Comment on list classification: There are at least 3 unrelated individuals reported in literature with de novo missense variants in CCNK, diagnosed with Intellectual developmental disorder with hypertelorism and distinctive facies. There are several individuals reported with deletions affecting CCNK among other genes - these deletions are generally associated with a more severe phenotype. Functional evidence for this gene-disease association includes zebrafish and mouse knockdowns, which recapitulate features of human disease. Based on the available evidence, this gene should be promoted to Green for Intellectual disability.; to: Comment on list classification: There are at least 3 unrelated individuals reported in literature with de novo missense variants in CCNK, diagnosed with Intellectual developmental disorder with hypertelorism and distinctive facies. There are also several individuals reported with deletions affecting CCNK among other genes - these deletions are generally associated with a more severe phenotype. Functional evidence for this gene-disease association includes zebrafish and mouse knockdowns, which recapitulate features of human disease. Based on the available evidence, this gene should be promoted to Green for Intellectual disability.
Intellectual disability v9.190 CCNK Ida Ertmanska commented on gene: CCNK: Comment on list classification: There are at least 3 unrelated individuals reported in literature with de novo missense variants in CCNK, diagnosed with Intellectual developmental disorder with hypertelorism and distinctive facies. There are several individuals reported with deletions affecting CCNK among other genes - these deletions are generally associated with a more severe phenotype. Functional evidence for this gene-disease association includes zebrafish and mouse knockdowns, which recapitulate features of human disease. Based on the available evidence, this gene should be promoted to Green for Intellectual disability.
Intellectual disability v9.190 CCNK Ida Ertmanska changed review comment from: PMID: 30122539 Fan et al., 2018
Report of 3 unrelated Chinese individuals with de novo heterozygous copy number loss of CCNK in an overlapping 14q32.3 region (with several other genes being deleted) and 1 African American individual harbouring a de novo CCNK variant c.331A>G (p.Lys111Glu) - variant not present in gnomAD v4; Revel score = 0.52. Common phenotype: developmental delay and moderate (1/4) to severe (3/4) intellectual disability (DD/ID), language defects, distinctive facial dysmorphism. 4/4 cases confirmed as de novo.
Functional evidence: Ccnk knockdown in zebrafish resulted in defective brain development, small eyes, and curly spinal cord; defects were partially rescued by WT CCNK mRNA but not by the c.331A>G mRNA variant.

PMID: 35063350 Rouxel et al., 2022
ID B5 - 1.5 yr old female, het for a missense variant in CCNK (variant not specified); phenotype: distinctive facial features matching CDK13-deficient patients, neuropsychological assessment not conducted; high methylation variant pathogenicity (MVP) score - methylation score matched individuals with pathogenic CDK13 variants; CDK13 forms a complex with cyclin K (encoded by CCNK).

PMID: 37597256 Dai et al., 2023
Report of 2 new (P1 & P3) and 3 previously reported cases. Seq method: exome seq + Sanger.
Patient 1 - Chinese Female 1 y 4 mo; het for c.556T>C, p.(Trp186Arg) - de novo; Moderate DD/ID, distinctive facial features, congenital cardiac defects.
Patient 3 - Chinese Female 5 y 4 mo; het for c.772T>C, p.(Tyr258His) - de novo; Mild DD/ID (IQ 59 - WPPSI scale), facial dysmorphisms
Functional evidence: Ccnk +/- mouse model

PMID: 41101726 Xiol et al., Oct 2025 - online ahead of print
Report of an 11yr old girl with a de novo CCNK missense variant c.549A>C, p.(Gln183His) - not in gnomAD v4.1.0, Revel score = 0.43; phenotype: mild intellectual disability (WISC-V at 10yrs showed IQ of 69), subtle dysmorphism (hypertelorism, depressed/broad nasal bridge), ventriculomegaly, delayed motor milestones & hypotonia.

CCNK pLI score = 1.00 - predicted to be extremely intolerant to LoF. CCNK is putatively associated with AD Intellectual developmental disorder with hypertelorism and distinctive facies, MIM:618147 (OMIM accessed 24th Nov 2025).
Sources: Literature; to: PMID: 30122539 Fan et al., 2018
Report of 3 unrelated Chinese individuals with de novo heterozygous copy number loss of CCNK in an overlapping 14q32.3 region (with several other genes being deleted) and 1 African American individual harbouring a de novo CCNK variant c.331A>G (p.Lys111Glu) - variant not present in gnomAD v4; Revel score = 0.52. Common phenotype: developmental delay and moderate (1/4) to severe (3/4) intellectual disability (DD/ID), language defects, distinctive facial dysmorphism. 4/4 cases confirmed as de novo.
Functional evidence: Ccnk knockdown in zebrafish resulted in defective brain development, small eyes, and curly spinal cord; defects were partially rescued by WT CCNK mRNA but not by the c.331A>G mRNA variant.

PMID: 35063350 Rouxel et al., 2022
ID B5 - 1.5 yr old female, het for a missense variant in CCNK (variant not specified); phenotype: distinctive facial features matching CDK13-deficient patients, neuropsychological assessment not conducted; high methylation variant pathogenicity (MVP) score - methylation score matched individuals with pathogenic CDK13 variants; CDK13 forms a complex with cyclin K (encoded by CCNK).

PMID: 37597256 Dai et al., 2023
Report of 2 new (P1 & P3) and 3 previously reported cases. Seq method: exome seq + Sanger.
Patient 1 - Chinese Female 1 y 4 mo; het for c.556T>C, p.(Trp186Arg) - de novo; Moderate DD/ID, distinctive facial features, congenital cardiac defects.
Patient 3 - Chinese Female 5 y 4 mo; het for c.772T>C, p.(Tyr258His) - de novo; Mild DD/ID (IQ 59 - WPPSI scale), facial dysmorphisms
Functional evidence: Ccnk +/- knockdown mouse model showed deficient neural progenitor cell proliferation and enhanced apoptotic cell death.

PMID: 41101726 Xiol et al., Oct 2025 - online ahead of print
Report of an 11yr old girl with a de novo CCNK missense variant c.549A>C, p.(Gln183His) - not in gnomAD v4.1.0, Revel score = 0.43; phenotype: mild intellectual disability (WISC-V at 10yrs showed IQ of 69), subtle dysmorphism (hypertelorism, depressed/broad nasal bridge), ventriculomegaly, delayed motor milestones & hypotonia.

CCNK pLI score = 1.00 - predicted to be extremely intolerant to LoF. CCNK is putatively associated with AD Intellectual developmental disorder with hypertelorism and distinctive facies, MIM:618147 (OMIM accessed 24th Nov 2025).
Sources: Literature
Intellectual disability v9.190 CCNK Ida Ertmanska commented on gene: CCNK: Comment on list classification: There are at least 3 unrelated individuals reported in literature with de novo missense variants in CCNK, diagnosed with Intellectual developmental disorder with hypertelorism and distinctive facies. There are several individuals reported with deletions affecting CCNK among other genes - these deletions are generally associated with a more severe phenotype. Functional evidence for this gene-disease association includes zebrafish and mouse knockdowns, which recapitulate the human disease phenotype. Based on the available evidence, this gene should be promoted to Green for Intellectual disability.
Intellectual disability v9.190 CCNK Ida Ertmanska changed review comment from: PMID: 30122539 Fan et al., 2018
Report of 3 unrelated Chinese individuals with de novo heterozygous copy number loss of CCNK in an overlapping 14q32.3 region (with several other genes being deleted) and 1 African American individual harbouring a de novo CCNK variant c.331A>G (p.Lys111Glu) - variant not present in gnomAD v4; Revel score = 0.52. Common phenotype: developmental delay and moderate (1/4) to severe (3/4) intellectual disability (DD/ID), language defects, distinctive facial dysmorphism. 4/4 cases confirmed as de novo.
Functional evidence: Ccnk knockdown in zebrafish resulted in defective brain development, small eyes, and curly spinal cord; defects were partially rescued by WT CCNK mRNA but not by the c.331A>G mRNA variant.

PMID: 35063350 Rouxel et al., 2022
ID B5 - 1.5 yr old female, het for a missense variant in CCNK (variant not specified); phenotype: distinctive facial features matching CDK13-deficient patients, neuropsychological assessment not conducted; high methylation variant pathogenicity (MVP) score - methylation score matched individuals with pathogenic CDK13 variants; CDK13 forms a complex with cyclin K (encoded by CCNK).

PMID: 37597256 Dai et al., 2023
Report of 2 new and 3 previously reported cases

PMID: 41101726 Xiol et al., Oct 2025 - online ahead of print
Report of an 11yr old girl with a de novo CCNK missense variant c.549A>C, p.(Gln183His) - not in gnomAD v4.1.0, Revel score = 0.43; phenotype: mild intellectual disability (WISC-V at 10yrs showed IQ of 69), subtle dysmorphism (hypertelorism, depressed/broad nasal bridge), ventriculomegaly, delayed motor milestones & hypotonia.

CCNK pLI score = 1.00 - predicted to be extremely intolerant to LoF. CCNK is putatively associated with AD Intellectual developmental disorder with hypertelorism and distinctive facies, MIM:618147 (OMIM accessed 24th Nov 2025).
Sources: Literature; to: PMID: 30122539 Fan et al., 2018
Report of 3 unrelated Chinese individuals with de novo heterozygous copy number loss of CCNK in an overlapping 14q32.3 region (with several other genes being deleted) and 1 African American individual harbouring a de novo CCNK variant c.331A>G (p.Lys111Glu) - variant not present in gnomAD v4; Revel score = 0.52. Common phenotype: developmental delay and moderate (1/4) to severe (3/4) intellectual disability (DD/ID), language defects, distinctive facial dysmorphism. 4/4 cases confirmed as de novo.
Functional evidence: Ccnk knockdown in zebrafish resulted in defective brain development, small eyes, and curly spinal cord; defects were partially rescued by WT CCNK mRNA but not by the c.331A>G mRNA variant.

PMID: 35063350 Rouxel et al., 2022
ID B5 - 1.5 yr old female, het for a missense variant in CCNK (variant not specified); phenotype: distinctive facial features matching CDK13-deficient patients, neuropsychological assessment not conducted; high methylation variant pathogenicity (MVP) score - methylation score matched individuals with pathogenic CDK13 variants; CDK13 forms a complex with cyclin K (encoded by CCNK).

PMID: 37597256 Dai et al., 2023
Report of 2 new (P1 & P3) and 3 previously reported cases. Seq method: exome seq + Sanger.
Patient 1 - Chinese Female 1 y 4 mo; het for c.556T>C, p.(Trp186Arg) - de novo; Moderate DD/ID, distinctive facial features, congenital cardiac defects.
Patient 3 - Chinese Female 5 y 4 mo; het for c.772T>C, p.(Tyr258His) - de novo; Mild DD/ID (IQ 59 - WPPSI scale), facial dysmorphisms
Functional evidence: Ccnk +/- mouse model

PMID: 41101726 Xiol et al., Oct 2025 - online ahead of print
Report of an 11yr old girl with a de novo CCNK missense variant c.549A>C, p.(Gln183His) - not in gnomAD v4.1.0, Revel score = 0.43; phenotype: mild intellectual disability (WISC-V at 10yrs showed IQ of 69), subtle dysmorphism (hypertelorism, depressed/broad nasal bridge), ventriculomegaly, delayed motor milestones & hypotonia.

CCNK pLI score = 1.00 - predicted to be extremely intolerant to LoF. CCNK is putatively associated with AD Intellectual developmental disorder with hypertelorism and distinctive facies, MIM:618147 (OMIM accessed 24th Nov 2025).
Sources: Literature
Intellectual disability v9.190 CCNK Ida Ertmanska changed review comment from: PMID: 30122539 Fan et al., 2018
Report of 3 unrelated Chinese individuals with de novo heterozygous copy number loss of CCNK in an overlapping 14q32.3 region (with several other genes being deleted) and 1 African American individual harbouring a de novo CCNK variant c.331A>G (p.Lys111Glu) - variant not present in gnomAD v4; Revel score = 0.52. Common phenotype: developmental delay and moderate (1/4) to severe (3/4) intellectual disability (DD/ID), language defects, distinctive facial dysmorphism. 4/4 cases confirmed as de novo.
Functional evidence: Ccnk knockdown in zebrafish resulted in defective brain development, small eyes, and curly spinal cord; defects were partially rescued by WT CCNK mRNA but not by the c.331A>G mRNA variant.

PMID: 35063350 Rouxel et al., 2022
ID B5 - 1.5 yr old female, het for a missense variant in CCNK (variant not specified); phenotype: distinctive facial features matching CDK13-deficient patients, neuropsychological assessment not conducted; high methylation variant pathogenicity (MVP) score - methylation score matched individuals with pathogenic CDK13 variants; CDK13 forms a complex with cyclin K (encoded by CCNK).

PMID: 37597256 Dai et al., 2023
Report of 2 new and 3 previously reported cases

PMID: 41101726 Xiol et al., Oct 2025 - online ahead of print
Report of an 11yr old girl with a de novo CCNK missense variant c.549A>C, p.(Gln183His) - not in gnomAD v4.1.0, Revel score = 0.43; phenotype: mild intellectual disability (WISC-V at 10yrs showed IQ of 69), subtle dysmorphism (hypertelorism, depressed/broad nasal bridge), ventriculomegaly, delayed motor milestones & hypotonia.
Sources: Literature; to: PMID: 30122539 Fan et al., 2018
Report of 3 unrelated Chinese individuals with de novo heterozygous copy number loss of CCNK in an overlapping 14q32.3 region (with several other genes being deleted) and 1 African American individual harbouring a de novo CCNK variant c.331A>G (p.Lys111Glu) - variant not present in gnomAD v4; Revel score = 0.52. Common phenotype: developmental delay and moderate (1/4) to severe (3/4) intellectual disability (DD/ID), language defects, distinctive facial dysmorphism. 4/4 cases confirmed as de novo.
Functional evidence: Ccnk knockdown in zebrafish resulted in defective brain development, small eyes, and curly spinal cord; defects were partially rescued by WT CCNK mRNA but not by the c.331A>G mRNA variant.

PMID: 35063350 Rouxel et al., 2022
ID B5 - 1.5 yr old female, het for a missense variant in CCNK (variant not specified); phenotype: distinctive facial features matching CDK13-deficient patients, neuropsychological assessment not conducted; high methylation variant pathogenicity (MVP) score - methylation score matched individuals with pathogenic CDK13 variants; CDK13 forms a complex with cyclin K (encoded by CCNK).

PMID: 37597256 Dai et al., 2023
Report of 2 new and 3 previously reported cases

PMID: 41101726 Xiol et al., Oct 2025 - online ahead of print
Report of an 11yr old girl with a de novo CCNK missense variant c.549A>C, p.(Gln183His) - not in gnomAD v4.1.0, Revel score = 0.43; phenotype: mild intellectual disability (WISC-V at 10yrs showed IQ of 69), subtle dysmorphism (hypertelorism, depressed/broad nasal bridge), ventriculomegaly, delayed motor milestones & hypotonia.

CCNK pLI score = 1.00 - predicted to be extremely intolerant to LoF. CCNK is putatively associated with AD Intellectual developmental disorder with hypertelorism and distinctive facies, MIM:618147 (OMIM accessed 24th Nov 2025).
Sources: Literature
Intellectual disability v9.188 CCNK Ida Ertmanska gene: CCNK was added
gene: CCNK was added to Intellectual disability. Sources: Literature
Q4_25_promote_green tags were added to gene: CCNK.
Mode of inheritance for gene: CCNK was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CCNK were set to 30122539; 35063350; 37597256; 41101726
Phenotypes for gene: CCNK were set to ?Intellectual developmental disorder with hypertelorism and distinctive facies, OMIM:618147
Review for gene: CCNK was set to GREEN
Added comment: PMID: 30122539 Fan et al., 2018
Report of 3 unrelated Chinese individuals with de novo heterozygous copy number loss of CCNK in an overlapping 14q32.3 region (with several other genes being deleted) and 1 African American individual harbouring a de novo CCNK variant c.331A>G (p.Lys111Glu) - variant not present in gnomAD v4; Revel score = 0.52. Common phenotype: developmental delay and moderate (1/4) to severe (3/4) intellectual disability (DD/ID), language defects, distinctive facial dysmorphism. 4/4 cases confirmed as de novo.
Functional evidence: Ccnk knockdown in zebrafish resulted in defective brain development, small eyes, and curly spinal cord; defects were partially rescued by WT CCNK mRNA but not by the c.331A>G mRNA variant.

PMID: 35063350 Rouxel et al., 2022
ID B5 - 1.5 yr old female, het for a missense variant in CCNK (variant not specified); phenotype: distinctive facial features matching CDK13-deficient patients, neuropsychological assessment not conducted; high methylation variant pathogenicity (MVP) score - methylation score matched individuals with pathogenic CDK13 variants; CDK13 forms a complex with cyclin K (encoded by CCNK).

PMID: 37597256 Dai et al., 2023
Report of 2 new and 3 previously reported cases

PMID: 41101726 Xiol et al., Oct 2025 - online ahead of print
Report of an 11yr old girl with a de novo CCNK missense variant c.549A>C, p.(Gln183His) - not in gnomAD v4.1.0, Revel score = 0.43; phenotype: mild intellectual disability (WISC-V at 10yrs showed IQ of 69), subtle dysmorphism (hypertelorism, depressed/broad nasal bridge), ventriculomegaly, delayed motor milestones & hypotonia.
Sources: Literature
Intellectual disability v9.186 ANKS1B Nour Elkhateeb gene: ANKS1B was added
gene: ANKS1B was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: ANKS1B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ANKS1B were set to 31388001; 38129387
Phenotypes for gene: ANKS1B were set to Developmental delay; Intellectual disability; Autism; Speech and language delay
Review for gene: ANKS1B was set to GREEN
Added comment: Monoallelic ANKS1B microdeletion resulting in Haploinsufficiency have been reported to be associated with variable developmental delays, intellectual disability, behavioural difficulties, as well as other features such as Craniofacial dysmorphism, and MRI brain abnormalities in 4 families (PMID 31388001, 38129387).
Sources: Literature
Intellectual disability v9.186 AFF3_GGC Eleanor Williams commented on STR: AFF3_GGC: To align with other STRs within PanelApp, the STR name AFF3_GCC was changed to AFF3_GGC and the repeat sequence has been changed from GCC to GGC in March 2025.
Intellectual disability v9.185 BSN Ida Ertmanska changed review comment from: Literature review by Helen Lord (Oxford Medical Genetics Laboratories) copied from the Epilepsy panel:

There are a lot of cases to support an AD phenotype but unsure as to whether there is also an AR pheontype associated with disease...

PMID:36600631 - Ye et al, 2023:
BSN gene encodes the Bsssoon protein which is highly expressed in the mammalian brain especially the cerebral cortex and the hippocampus.
WES in 313 trios with epilepsies of unknown causes novel BSN variants identifed in 5 cases and 3 additional variants identified in 3 cases from different centres:
Cases 1-4 compound het - variants shown to be inherited in trans
Cases 5-8 - het variants idenitied in case 5 & 6 inherited from affected parent (febrile seizure in these parents) and in cases 7 & 8 - arise de novo.
The 9 variants present in low or no allele freq in all populations or East Asian populations - no hom in gnomAD. No other pathogenic/likely pathogenic variants in other epilepsy genes identiifed.
Fig 3:
B:The 2 nonsense variants in exon 5 thought to result in the truncation of the basson protein and trigger NMD. Both de novo. They state LOF and haploinsuffucency of BSN are potentially pathogenic.
C: 6/9 missense variants led to hydrogen bond alterations - mostly creation of hydrogen bonds which were not predicted orignally. 5/9 missense variants clustered in the C-terminus. Among the 4 pairs of compound het variants at least 1 variant in each pair had hydrogen bond alterations.
In the discussion they state LOF of Bassoon is potentially the underlying mechanism of pathogenicity of BSN variants, which is consistent with the pathogenisi of other genes encoding CAZ proteins such as UNC13A and UNC13B; however, the functional effects of BSN variants warrants further investigation.
In het BSN knockout mice - no phenotype; however, hom knockout mice null led to spontaneous seizures and partial preamture lethality. Clinically the patients with monoallelic BSN missense variants achieved seizure free status without treatment or under monotherapy; whereas, the majority of patients with biallelic missense variants required combination therapy, possible correlation between genotype and phenotype severity.

PMID 39616287: Yacoub et al, 2025: WES in 10 JME (juvenille myoclonic epilepsy) patients - P4 found to have a het BSN missense variant - c.2534G>A p.(Arg845Gln), also identified in her affected brother who has GTCs, but also detected in an unaffected brother. Presumably also inherited from an unaffected pedogree (pedigree included - no mention of parental testing).

PMID: 40393460 Guzman et al, 2025: cohort of 29 individuals with BSN variants including 14 with de novo vairants, 13 individuals with PTVs (protein truncating variants) of unknown inheritance and 2 individuals with PTVs with paternal inheritance. Affected individuals had diverse neurodevelopmental phenotypes including behavioural abnormalities; delayed speech, learning difficulties and variable seizure types.
Recruitment: 2/29 - enrolled in the Epilepsy genetics research project at Childrens Hospital Philadelphia (CHOP) confirmed de novo; 14/29 identified via gene matcher - 9/14 confirmed de novo by respective institutions; 7/29 identified through Penn medicine biobank; 1/29 missense de novo BSN variant identified from birth defects biorepositary at CHOP; 3/29 BSN PTVs idenitifed through the center for applied genomics at CHOP and a lit review identified 2/29 previously reported individuals with de novo PTVs in BSN.
Table 1 details the 14 individuals with de novo BSN variants - 8/14 had seizures (different types); 12/14 had developmental features.
They suggest haploinsuffucency as as a likely mechanism.
Sources: Other
Sources: Other; to: Literature review by Helen Lord (Oxford Medical Genetics Laboratories) copied from the Epilepsy panel:

There are a lot of cases to support an AD phenotype but unsure as to whether there is also an AR pheontype associated with disease...

PMID:36600631 - Ye et al, 2023:
BSN gene encodes the Bsssoon protein which is highly expressed in the mammalian brain especially the cerebral cortex and the hippocampus.
WES in 313 trios with epilepsies of unknown causes novel BSN variants identifed in 5 cases and 3 additional variants identified in 3 cases from different centres:
Cases 1-4 compound het - variants shown to be inherited in trans
Cases 5-8 - het variants idenitied in case 5 & 6 inherited from affected parent (febrile seizure in these parents) and in cases 7 & 8 - arise de novo.
The 9 variants present in low or no allele freq in all populations or East Asian populations - no hom in gnomAD. No other pathogenic/likely pathogenic variants in other epilepsy genes identiifed.
Fig 3:
B:The 2 nonsense variants in exon 5 thought to result in the truncation of the basson protein and trigger NMD. Both de novo. They state LOF and haploinsuffucency of BSN are potentially pathogenic.
C: 6/9 missense variants led to hydrogen bond alterations - mostly creation of hydrogen bonds which were not predicted orignally. 5/9 missense variants clustered in the C-terminus. Among the 4 pairs of compound het variants at least 1 variant in each pair had hydrogen bond alterations.
In the discussion they state LOF of Bassoon is potentially the underlying mechanism of pathogenicity of BSN variants, which is consistent with the pathogenisi of other genes encoding CAZ proteins such as UNC13A and UNC13B; however, the functional effects of BSN variants warrants further investigation.
In het BSN knockout mice - no phenotype; however, hom knockout mice null led to spontaneous seizures and partial preamture lethality. Clinically the patients with monoallelic BSN missense variants achieved seizure free status without treatment or under monotherapy; whereas, the majority of patients with biallelic missense variants required combination therapy, possible correlation between genotype and phenotype severity.

PMID 39616287: Yacoub et al, 2025: WES in 10 JME (juvenille myoclonic epilepsy) patients - P4 found to have a het BSN missense variant - c.2534G>A p.(Arg845Gln), also identified in her affected brother who has GTCs, but also detected in an unaffected brother. Presumably also inherited from an unaffected pedogree (pedigree included - no mention of parental testing).

PMID: 40393460 Guzman et al, 2025: cohort of 29 individuals with BSN variants including 14 with de novo vairants, 13 individuals with PTVs (protein truncating variants) of unknown inheritance and 2 individuals with PTVs with paternal inheritance. Affected individuals had diverse neurodevelopmental phenotypes including behavioural abnormalities; delayed speech, learning difficulties and variable seizure types.
Recruitment: 2/29 - enrolled in the Epilepsy genetics research project at Childrens Hospital Philadelphia (CHOP) confirmed de novo; 14/29 identified via gene matcher - 9/14 confirmed de novo by respective institutions; 7/29 identified through Penn medicine biobank; 1/29 missense de novo BSN variant identified from birth defects biorepositary at CHOP; 3/29 BSN PTVs idenitifed through the center for applied genomics at CHOP and a lit review identified 2/29 previously reported individuals with de novo PTVs in BSN.
Table 1 details the 14 individuals with de novo BSN variants - 8/14 had seizures (different types); 12/14 had developmental features.
They suggest haploinsuffucency as as a likely mechanism.
Intellectual disability v9.185 BSN Ida Ertmanska commented on gene: BSN: Comment on list classification: As reviewed by Helen Lord, there are numerous individuals reported in literature with a neurodevelopmental disorder with monoallelic variants in BSN. The disorder includes a range of variably penetrant features, with DD/ID and epilepsy being the most common (PMID: 40393460 Guzman et al., 2025). There are 4 individuals reported with compound heterozygous variants in BSN with early onset epilepsy. However, only 1/4 of the biallelic cases presented with developmental delay (PMID: 36600631, Ye et al., 2023). Based on the available evidence this gene should be rated Green for Intellectual disability, with MOI set to BIALLELIC, autosomal or pseudoautosomal.

BSN is not yet associated with a phenotype in OMIM (accessed 17th Nov 2025).
Intellectual disability v9.185 BSN Ida Ertmanska gene: BSN was added
gene: BSN was added to Intellectual disability. Sources: Other
Mode of inheritance for gene: BSN was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BSN were set to 36600631; 39616287; 40393460
Phenotypes for gene: BSN were set to neurodevelopmental disorder, MONDO:0700092
Review for gene: BSN was set to GREEN
Added comment: Literature review by Helen Lord (Oxford Medical Genetics Laboratories) copied from the Epilepsy panel:

There are a lot of cases to support an AD phenotype but unsure as to whether there is also an AR pheontype associated with disease...

PMID:36600631 - Ye et al, 2023:
BSN gene encodes the Bsssoon protein which is highly expressed in the mammalian brain especially the cerebral cortex and the hippocampus.
WES in 313 trios with epilepsies of unknown causes novel BSN variants identifed in 5 cases and 3 additional variants identified in 3 cases from different centres:
Cases 1-4 compound het - variants shown to be inherited in trans
Cases 5-8 - het variants idenitied in case 5 & 6 inherited from affected parent (febrile seizure in these parents) and in cases 7 & 8 - arise de novo.
The 9 variants present in low or no allele freq in all populations or East Asian populations - no hom in gnomAD. No other pathogenic/likely pathogenic variants in other epilepsy genes identiifed.
Fig 3:
B:The 2 nonsense variants in exon 5 thought to result in the truncation of the basson protein and trigger NMD. Both de novo. They state LOF and haploinsuffucency of BSN are potentially pathogenic.
C: 6/9 missense variants led to hydrogen bond alterations - mostly creation of hydrogen bonds which were not predicted orignally. 5/9 missense variants clustered in the C-terminus. Among the 4 pairs of compound het variants at least 1 variant in each pair had hydrogen bond alterations.
In the discussion they state LOF of Bassoon is potentially the underlying mechanism of pathogenicity of BSN variants, which is consistent with the pathogenisi of other genes encoding CAZ proteins such as UNC13A and UNC13B; however, the functional effects of BSN variants warrants further investigation.
In het BSN knockout mice - no phenotype; however, hom knockout mice null led to spontaneous seizures and partial preamture lethality. Clinically the patients with monoallelic BSN missense variants achieved seizure free status without treatment or under monotherapy; whereas, the majority of patients with biallelic missense variants required combination therapy, possible correlation between genotype and phenotype severity.

PMID 39616287: Yacoub et al, 2025: WES in 10 JME (juvenille myoclonic epilepsy) patients - P4 found to have a het BSN missense variant - c.2534G>A p.(Arg845Gln), also identified in her affected brother who has GTCs, but also detected in an unaffected brother. Presumably also inherited from an unaffected pedogree (pedigree included - no mention of parental testing).

PMID: 40393460 Guzman et al, 2025: cohort of 29 individuals with BSN variants including 14 with de novo vairants, 13 individuals with PTVs (protein truncating variants) of unknown inheritance and 2 individuals with PTVs with paternal inheritance. Affected individuals had diverse neurodevelopmental phenotypes including behavioural abnormalities; delayed speech, learning difficulties and variable seizure types.
Recruitment: 2/29 - enrolled in the Epilepsy genetics research project at Childrens Hospital Philadelphia (CHOP) confirmed de novo; 14/29 identified via gene matcher - 9/14 confirmed de novo by respective institutions; 7/29 identified through Penn medicine biobank; 1/29 missense de novo BSN variant identified from birth defects biorepositary at CHOP; 3/29 BSN PTVs idenitifed through the center for applied genomics at CHOP and a lit review identified 2/29 previously reported individuals with de novo PTVs in BSN.
Table 1 details the 14 individuals with de novo BSN variants - 8/14 had seizures (different types); 12/14 had developmental features.
They suggest haploinsuffucency as as a likely mechanism.
Sources: Other
Sources: Other
Intellectual disability v9.184 BAIAP2 Ida Ertmanska Added comment: Comment on list classification: Comment on list classification: There are 7 unrelated individuals reported in literature with de novo heterozygous missense variants in BAIAP2. 6 individuals presented with developmental and epileptic encephalopathy (PMID: 41133935), while 1 individual was diagnosed with classic lissencephaly (PMID: 38149472). All 7 individuals presented with global developmental delay, intellectual disability, poor motor milestone achievement, and poor / lack of speech development.
Baiap2 knockdown in mouse cause abnormalities in neuronal migration, morphogenesis, and differentiation (PMID: 38149472). Additional functional evidence from coimmunoprecipitation studies shows that missense variants around aa 340-366 in BAIAP2 are likely to disrupt binding of 14-3-3, necessary for BAIAP2 inhibition (PMID: 30696821). Based on the available evidence, BAIAP2 should be promoted to Green for Intellectual disability.
Intellectual disability v9.183 BAIAP2 Ida Ertmanska gene: BAIAP2 was added
gene: BAIAP2 was added to Intellectual disability. Sources: Other
Q4_25_promote_green tags were added to gene: BAIAP2.
Mode of inheritance for gene: BAIAP2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: BAIAP2 were set to 30696821; 38149472; 41133935
Phenotypes for gene: BAIAP2 were set to developmental and epileptic encephalopathy, MONDO:0100620; classic lissencephaly, MONDO:0015146
Review for gene: BAIAP2 was set to GREEN
Added comment: PMID: 38149472 Tsai et al., 2024
6yo individual from Taiwan with a de novo c.85C>T, p.Arg29Trp variant in BAIAP2 with lissencephaly. Method: WES +Sanger.
Phenotype: severe global developmental delay since infancy, lack of speech development, poor motor milestone achievement; refractory epilepsy with multiple seizure patterns, including focal, myoclonic, tonic, absence and tonic-clonic seizures, and epileptic spasms since infancy. Classical lissencephaly features noted on brain MRI at 5yrs.
Functional evidence: Baiap2 knockdown in mouse cause abnormalities in neuronal migration, morphogenesis, and differentiation. Expression of p.Arg29Trp failed to rescue the defect - suggests LoF effect for this variant.

PMID: 41133935 Zhang et al., 2025
6 patients reported with de novo missense variants in BAIAP2. All six patients exhibited severe infantile or early childhood onset epilepsy - refractory seizures in four individuals. Age of onset of epilepsy: 5 mo - 1 yr 7 mo. Additionally, 6/6 individuals presented with global developmental delay; 4/6 are nonverbal and 2/6 only know a few words; ID severity was variable: mild (1/6), moderate-severe (3/6), and severe-profound (2/6). Diverse ancestry: Chinese, British, Turkish, White Kosovar, Austrian. Patients were heterozygous for the following missense variants: c.1088G>A, p.Arg363His; c.1019C>A, p.Thr340Lys; c.1018A>G, p.Thr340Ala; c.566A>T, p.Glu189Val; c.1019C>T, p.Thr340Ile; c.1024C>G, p.Pro342Ala. The variants are not present in gnomAD v4.1.0.
Authors pose that 5/6 variants reported are likely to destabilise binding of 14-3-3 to BAIAP2.

Functional evidence: PMID: 30696821 Kast & Dominguez, 2019
Protein 14-3-3 binds to two pairs of sites in the linker between the CRIB-PR and SH3 domains of BAIAP2 (pT340/pT360 or pT340/pS366) - consistent with the hotspot region seen in patients (5/6 variants reported in PMID: 41133935 are in the 340-366 region). The binding of 14-3-3 is crucial for inhibition of BAIAP2 action - particularly regulating actin and filopodia formation.

This gene is not yet associated with a phenotype in OMIM (accessed 17th Nov 2025).
Sources: Other
Intellectual disability v9.180 UROC1 Ida Ertmanska changed review comment from: Comment on list classification: There are 5 individuals from 4 families reported in literature with biallelic variants in UROC1 and urocanic aciduria. 2/5 individuals with Urocanase deficiency were asymptomatic, 2/5 presented with intellectual disability (1 mild, 1 not specified), and 1 individual was noted to have a non-specific 'neurologic' phenotype. In addition, PMID: 30619714 and PMID: 32439973 state that the biochemical phenotype of Urocanase deficiency is benign. In 2/4 studies, only UROC1 targeted sequencing was performed. As there is conflicting evidence for this gene-disease association, UROC1 should be downgraded to Red for Intellectual disability.; to: Comment on list classification: There are 5 individuals from 4 families reported in literature with biallelic variants in UROC1 and urocanic aciduria. 2/5 individuals with Urocanase deficiency were asymptomatic, 2/5 presented with intellectual disability (1 mild, 1 not specified), and 1 individual was noted to have a non-specific 'neurologic' phenotype. In addition, PMID: 30619714 and PMID: 32439973 state that the biochemical phenotype of Urocanase deficiency is benign. In 2/4 studies, only UROC1 targeted sequencing was performed. As there is conflicting evidence for this gene-disease association, UROC1 should be downgraded to Red for Intellectual disability.
Intellectual disability v9.180 UROC1 Ida Ertmanska changed review comment from: Comment on list classification: There are 5 individuals from 4 families reported in literature with biallelic variants in UROC1 and urocanic aciduria. 2/5 individuals with Urocanase deficiency were asymptomatic, 2/5 presented with intellectual disability, and 1 individual was noted to have a non-specific 'neurologic' phenotype. In addition, PMID: 30619714 and PMID: 32439973 state that the biochemical phenotype of Urocanase deficiency is benign. In 2/4 studies, only UROC1 targeted sequencing was performed. As there is conflicting evidence for this gene-disease association, UROC1 should be downgraded to Red for Intellectual disability.; to: Comment on list classification: There are 5 individuals from 4 families reported in literature with biallelic variants in UROC1 and urocanic aciduria. 2/5 individuals with Urocanase deficiency were asymptomatic, 2/5 presented with intellectual disability (1 mild, 1 not specified), and 1 individual was noted to have a non-specific 'neurologic' phenotype. In addition, PMID: 30619714 and PMID: 32439973 state that the biochemical phenotype of Urocanase deficiency is benign. In 2/4 studies, only UROC1 targeted sequencing was performed. As there is conflicting evidence for this gene-disease association, UROC1 should be downgraded to Red for Intellectual disability.
Intellectual disability v9.180 UROC1 Ida Ertmanska changed review comment from: PMID: 19304569 Espinos et al., 2009
Female proband, compound het for NM_144639.3(UROC1):c.1348C>T (p.Arg450Cys) & NM_144639.3(UROC1):c.209T>C (p.Leu70Pro). Sequenced UROC1 gene only. Phenotype: ataxia, ataxic gait, action tremor, dysarthric speech, slight nystagmus. Cognitive evaluation rated her IQ at 54 - mild (Wechsler Intelligence Scale for ChildrenRevised: verbal 57 and manipulation 60).
Disease association disputed in PMID: 30619714.

PMID: 27391121 Al-Shamsi et al., 2016
Proband homozygous for NM_144639.3(UROC1):c.855G>A (p.Trp285Ter) - rare in gnomAD v4.1.0, 10 alleles, no homozygotes. Patient phenotype: Intellectual disabilities, attention deficit and hyperactivity disorder, hyperextensible joints, elevated imidazole propionate. Seq method: WES.

PMID: 30619714 Glinton et al., 2018
Case 1 - 27yo female - urocanic aciduria detected at 8 weeks of age; developed normally, psychological assessment at 3yo using the McCarthy Scales of Children's Abilities gave a general cognitive score of 115 (83rd percentile for age).
Case 2 - 21yo male, asymptomatic brother of Case1 with urocanic aciduria (detected on biochemical testing).
Both siblings compound het for NM_144639.3(UROC1):c.356C>G (p.Pro119Arg) and NM_144639.3(UROC1):c.907G>C (p.Ala303Pro) - parents confirmed as carriers. Seq method: UROC1 only.

PMID: 32439973 Alaimo et al., 2020
Patient 75 - phenotype: "Neurologic (with or without other organ systems)"; 5yo male homozygous for NM_144639.3(UROC1):c.855G>A (p.Trp285Ter) with urocanic aciduria. Seq method: exome seq. Authors note that 'the biochemical phenotype is benign and not causative of the patient phenotype'.
Patient 65 - Phenotype: "Neurologic (with or without other organ systems)" - 7months old female - normal metabolomic findings; homozygous for c.1054G>A, p.Ala352Thr in UROC1 - MAF 0.001684 in gnomAD v4.1.0 - Likely Benign.

This gene is putatively associated with Urocanase deficiency , OMIM:276880 (OMIM accessed 13th Nov 2025). Gene is currently rated Red for Intellectual disability in PanelApp Australia. ; to: PMID: 19304569 Espinos et al., 2009
Female proband, compound het for NM_144639.3(UROC1):c.1348C>T (p.Arg450Cys) & NM_144639.3(UROC1):c.209T>C (p.Leu70Pro). Sequenced UROC1 gene only. Phenotype: ataxia, ataxic gait, action tremor, dysarthric speech, slight nystagmus. Cognitive evaluation rated her IQ at 54 - mild ID (Wechsler Intelligence Scale for ChildrenRevised: verbal 57 and manipulation 60).
Disease association disputed in PMID: 30619714.

PMID: 27391121 Al-Shamsi et al., 2016
Proband homozygous for NM_144639.3(UROC1):c.855G>A (p.Trp285Ter) - rare in gnomAD v4.1.0, 10 alleles, no homozygotes. Patient phenotype: Intellectual disabilities, attention deficit and hyperactivity disorder, hyperextensible joints, elevated imidazole propionate. Seq method: WES.

PMID: 30619714 Glinton et al., 2018
Case 1 - 27yo female - urocanic aciduria detected at 8 weeks of age; developed normally, psychological assessment at 3yo using the McCarthy Scales of Children's Abilities gave a general cognitive score of 115 (83rd percentile for age).
Case 2 - 21yo male, asymptomatic brother of Case1 with urocanic aciduria (detected on biochemical testing).
Both siblings compound het for NM_144639.3(UROC1):c.356C>G (p.Pro119Arg) and NM_144639.3(UROC1):c.907G>C (p.Ala303Pro) - parents confirmed as carriers. Seq method: UROC1 only.

PMID: 32439973 Alaimo et al., 2020
Patient 75 - phenotype: "Neurologic (with or without other organ systems)"; 5yo male homozygous for NM_144639.3(UROC1):c.855G>A (p.Trp285Ter) with urocanic aciduria. Seq method: exome seq. Authors note that 'the biochemical phenotype is benign and not causative of the patient phenotype'.
Patient 65 - Phenotype: "Neurologic (with or without other organ systems)" - 7months old female - normal metabolomic findings; homozygous for c.1054G>A, p.Ala352Thr in UROC1 - MAF 0.001684 in gnomAD v4.1.0 - Likely Benign.

This gene is putatively associated with Urocanase deficiency , OMIM:276880 (OMIM accessed 13th Nov 2025). Gene is currently rated Red for Intellectual disability in PanelApp Australia.
Intellectual disability v9.180 UROC1 Ida Ertmanska changed review comment from: PMID: 19304569 Espinos et al., 2009
Female proband, compound het for NM_144639.3(UROC1):c.1348C>T (p.Arg450Cys) & NM_144639.3(UROC1):c.209T>C (p.Leu70Pro). Sequenced UROC1 gene only. Phenotype: ataxia, ataxic gait, action tremor, dysarthric speech, slight nystagmus. Cognitive evaluation rated her IQ at 54 (Wechsler Intelligence Scale for ChildrenRevised: verbal 57 and manipulation 60).
Disease association disputed in PMID: 30619714.

PMID: 27391121 Al-Shamsi et al., 2016
Proband homozygous for NM_144639.3(UROC1):c.855G>A (p.Trp285Ter) - rare in gnomAD v4.1.0, 10 alleles, no homozygotes. Patient phenotype: Intellectual disabilities, attention deficit and hyperactivity disorder, hyperextensible joints, elevated imidazole propionate. Seq method: WES.

PMID: 30619714 Glinton et al., 2018
Case 1 - 27yo female - urocanic aciduria detected at 8 weeks of age; developed normally, psychological assessment at 3yo using the McCarthy Scales of Children's Abilities gave a general cognitive score of 115 (83rd percentile for age).
Case 2 - 21yo male, asymptomatic brother of Case1 with urocanic aciduria (detected on biochemical testing).
Both siblings compound het for NM_144639.3(UROC1):c.356C>G (p.Pro119Arg) and NM_144639.3(UROC1):c.907G>C (p.Ala303Pro) - parents confirmed as carriers. Seq method: UROC1 only.

PMID: 32439973 Alaimo et al., 2020
Patient 75 - phenotype: "Neurologic (with or without other organ systems)"; 5yo male homozygous for NM_144639.3(UROC1):c.855G>A (p.Trp285Ter) with urocanic aciduria. Seq method: exome seq. Authors note that 'the biochemical phenotype is benign and not causative of the patient phenotype'.
Patient 65 - Phenotype: "Neurologic (with or without other organ systems)" - 7months old female - normal metabolomic findings; homozygous for c.1054G>A, p.Ala352Thr in UROC1 - MAF 0.001684 in gnomAD v4.1.0 - Likely Benign.

This gene is putatively associated with Urocanase deficiency , OMIM:276880 (OMIM accessed 13th Nov 2025). Gene is currently rated Red for Intellectual disability in PanelApp Australia. ; to: PMID: 19304569 Espinos et al., 2009
Female proband, compound het for NM_144639.3(UROC1):c.1348C>T (p.Arg450Cys) & NM_144639.3(UROC1):c.209T>C (p.Leu70Pro). Sequenced UROC1 gene only. Phenotype: ataxia, ataxic gait, action tremor, dysarthric speech, slight nystagmus. Cognitive evaluation rated her IQ at 54 - mild (Wechsler Intelligence Scale for ChildrenRevised: verbal 57 and manipulation 60).
Disease association disputed in PMID: 30619714.

PMID: 27391121 Al-Shamsi et al., 2016
Proband homozygous for NM_144639.3(UROC1):c.855G>A (p.Trp285Ter) - rare in gnomAD v4.1.0, 10 alleles, no homozygotes. Patient phenotype: Intellectual disabilities, attention deficit and hyperactivity disorder, hyperextensible joints, elevated imidazole propionate. Seq method: WES.

PMID: 30619714 Glinton et al., 2018
Case 1 - 27yo female - urocanic aciduria detected at 8 weeks of age; developed normally, psychological assessment at 3yo using the McCarthy Scales of Children's Abilities gave a general cognitive score of 115 (83rd percentile for age).
Case 2 - 21yo male, asymptomatic brother of Case1 with urocanic aciduria (detected on biochemical testing).
Both siblings compound het for NM_144639.3(UROC1):c.356C>G (p.Pro119Arg) and NM_144639.3(UROC1):c.907G>C (p.Ala303Pro) - parents confirmed as carriers. Seq method: UROC1 only.

PMID: 32439973 Alaimo et al., 2020
Patient 75 - phenotype: "Neurologic (with or without other organ systems)"; 5yo male homozygous for NM_144639.3(UROC1):c.855G>A (p.Trp285Ter) with urocanic aciduria. Seq method: exome seq. Authors note that 'the biochemical phenotype is benign and not causative of the patient phenotype'.
Patient 65 - Phenotype: "Neurologic (with or without other organ systems)" - 7months old female - normal metabolomic findings; homozygous for c.1054G>A, p.Ala352Thr in UROC1 - MAF 0.001684 in gnomAD v4.1.0 - Likely Benign.

This gene is putatively associated with Urocanase deficiency , OMIM:276880 (OMIM accessed 13th Nov 2025). Gene is currently rated Red for Intellectual disability in PanelApp Australia.
Intellectual disability v9.180 UROC1 Ida Ertmanska changed review comment from: Comment on list classification: There are 5 individuals from 4 families reported in literature with biallelic variants in UROC1 and urocanic aciduria. 2/5 individuals with Urocanase deficiency were asymptomatic, 2/5 presented with intellectual disability, and 1 individual was noted to have a non-specific 'neurologic' phenotype. In addition, PMID: 30619714 and PMID: 32439973 state that the biochemical phenotype of Urocanase deficiency is benign. In 2/4 studies, only UROC1 targeted sequencing was performed. As there is conflicting evidence for this gene-disease association, UROC1 should be downgraded to Red for Intellectual disability.; to: Comment on list classification: There are 5 individuals from 4 families reported in literature with biallelic variants in UROC1 and urocanic aciduria. 2/5 individuals with Urocanase deficiency were asymptomatic, 2/5 presented with intellectual disability, and 1 individual was noted to have a non-specific 'neurologic' phenotype. In addition, PMID: 30619714 and PMID: 32439973 state that the biochemical phenotype of Urocanase deficiency is benign. In 2/4 studies, only UROC1 targeted sequencing was performed. As there is conflicting evidence for this gene-disease association, UROC1 should be downgraded to Red for Intellectual disability.
Intellectual disability v9.180 UROC1 Ida Ertmanska changed review comment from: PMID: 19304569 Espinos et al., 2009
Female proband, compound het for NM_144639.3(UROC1):c.1348C>T (p.Arg450Cys) & NM_144639.3(UROC1):c.209T>C (p.Leu70Pro). Sequenced UROC1 gene only. Cognitive evaluation rated her IQ at 54.
Disease association disputed in PMID: 30619714.

PMID: 27391121 Al-Shamsi et al., 2016
Proband homozygous for NM_144639.3(UROC1):c.855G>A (p.Trp285Ter) - rare in gnomAD v4.1.0, 10 alleles, no homozygotes. Patient phenotype: Intellectual disabilities, attention deficit and hyperactivity disorder, hyperextensible joints, elevated imidazole propionate. Seq method: WES.

PMID: 30619714 Glinton et al., 2018
Case 1 - 27yo female - urocanic aciduria detected at 8 weeks of age; developed normally, psychological assessment at 3yo using the McCarthy Scales of Children's Abilities gave a general cognitive score of 115 (83rd percentile for age).
Case 2 - 21yo male, asymptomatic brother of Case1 with urocanic aciduria (detected on biochemical testing).
Both siblings compound het for NM_144639.3(UROC1):c.356C>G (p.Pro119Arg) and NM_144639.3(UROC1):c.907G>C (p.Ala303Pro) - parents confirmed as carriers. Seq method: UROC1 only.

PMID: 32439973 Alaimo et al., 2020
Patient 75 - phenotype: "Neurologic (with or without other organ systems)"; 5yo male homozygous for NM_144639.3(UROC1):c.855G>A (p.Trp285Ter) with urocanic aciduria. Seq method: exome seq. Authors note that 'the biochemical phenotype is benign and not causative of the patient phenotype'.
Patient 65 - Phenotype: "Neurologic (with or without other organ systems)" - 7months old female - normal metabolomic findings; homozygous for c.1054G>A, p.Ala352Thr in UROC1 - MAF 0.001684 in gnomAD v4.1.0 - Likely Benign.

This gene is putatively associated with Urocanase deficiency , OMIM:276880 (OMIM accessed 13th Nov 2025). Gene is currently rated Red for Intellectual disability in PanelApp Australia. ; to: PMID: 19304569 Espinos et al., 2009
Female proband, compound het for NM_144639.3(UROC1):c.1348C>T (p.Arg450Cys) & NM_144639.3(UROC1):c.209T>C (p.Leu70Pro). Sequenced UROC1 gene only. Phenotype: ataxia, ataxic gait, action tremor, dysarthric speech, slight nystagmus. Cognitive evaluation rated her IQ at 54 (Wechsler Intelligence Scale for ChildrenRevised: verbal 57 and manipulation 60).
Disease association disputed in PMID: 30619714.

PMID: 27391121 Al-Shamsi et al., 2016
Proband homozygous for NM_144639.3(UROC1):c.855G>A (p.Trp285Ter) - rare in gnomAD v4.1.0, 10 alleles, no homozygotes. Patient phenotype: Intellectual disabilities, attention deficit and hyperactivity disorder, hyperextensible joints, elevated imidazole propionate. Seq method: WES.

PMID: 30619714 Glinton et al., 2018
Case 1 - 27yo female - urocanic aciduria detected at 8 weeks of age; developed normally, psychological assessment at 3yo using the McCarthy Scales of Children's Abilities gave a general cognitive score of 115 (83rd percentile for age).
Case 2 - 21yo male, asymptomatic brother of Case1 with urocanic aciduria (detected on biochemical testing).
Both siblings compound het for NM_144639.3(UROC1):c.356C>G (p.Pro119Arg) and NM_144639.3(UROC1):c.907G>C (p.Ala303Pro) - parents confirmed as carriers. Seq method: UROC1 only.

PMID: 32439973 Alaimo et al., 2020
Patient 75 - phenotype: "Neurologic (with or without other organ systems)"; 5yo male homozygous for NM_144639.3(UROC1):c.855G>A (p.Trp285Ter) with urocanic aciduria. Seq method: exome seq. Authors note that 'the biochemical phenotype is benign and not causative of the patient phenotype'.
Patient 65 - Phenotype: "Neurologic (with or without other organ systems)" - 7months old female - normal metabolomic findings; homozygous for c.1054G>A, p.Ala352Thr in UROC1 - MAF 0.001684 in gnomAD v4.1.0 - Likely Benign.

This gene is putatively associated with Urocanase deficiency , OMIM:276880 (OMIM accessed 13th Nov 2025). Gene is currently rated Red for Intellectual disability in PanelApp Australia.
Intellectual disability v9.180 UROC1 Ida Ertmanska commented on gene: UROC1: Comment on list classification: There are 5 individuals from 4 families reported in literature with biallelic variants in UROC1 and urocanic aciduria. 2/5 individuals with Urocanase deficiency were asymptomatic, 2/5 presented with intellectual disability, and 1 individual was noted to have a non-specific 'neurologic' phenotype. In addition, PMID: 30619714 and PMID: 32439973 state that the biochemical phenotype of Urocanase deficiency is benign. In 2/4 studies, only UROC1 targeted sequencing was performed. As there is conflicting evidence for this gene-disease association, UROC1 should be downgraded to Red for Intellectual disability.
Intellectual disability v9.180 UROC1 Ida Ertmanska changed review comment from: PMID: 19304569 Espinos et al., 2009
Female proband, compound het for NM_144639.3(UROC1):c.1348C>T (p.Arg450Cys) & NM_144639.3(UROC1):c.209T>C (p.Leu70Pro). Sequenced UROC1 gene only. Cognitive evaluation rated her IQ at 54.
Disease association disputed in PMID: 30619714.

PMID: 27391121 Al-Shamsi et al., 2016
Proband homozygous for NM_144639.3(UROC1):c.855G>A (p.Trp285Ter) - rare in gnomAD v4.1.0, 10 alleles, no homozygotes. Patient phenotype: Intellectual disabilities, attention deficit and hyperactivity disorder, hyperextensible joints, elevated imidazole propionate. Seq method: WES.

PMID: 30619714 Glinton et al., 2018
Case 1 - 27yo female - urocanic aciduria detected at 8 weeks of age; developed normally, psychological assessment at 3yo using the McCarthy Scales of Children's Abilities gave a general cognitive score of 115 (83rd percentile for age).
Case 2 - 21yo male, asymptomatic brother of Case1 with urocanic aciduria (detected on biochemical testing).
Both siblings compound het for NM_144639.3(UROC1):c.356C>G (p.Pro119Arg) and NM_144639.3(UROC1):c.907G>C (p.Ala303Pro) - parents confirmed as carriers. Seq method: UROC1 only.

PMID: 32439973 Alaimo et al., 2020
Patient 75 - 5yo male homozygous for NM_144639.3(UROC1):c.855G>A (p.Trp285Ter) with urocanic aciduria. Seq method: exome seq. Authors note that 'the biochemical phenotype is benign and not causative of the patient phenotype'.

This gene is putatively associated with Urocanase deficiency , OMIM:276880 (OMIM accessed 13th Nov 2025). Gene is currently rated Red for Intellectual disability in PanelApp Australia. ; to: PMID: 19304569 Espinos et al., 2009
Female proband, compound het for NM_144639.3(UROC1):c.1348C>T (p.Arg450Cys) & NM_144639.3(UROC1):c.209T>C (p.Leu70Pro). Sequenced UROC1 gene only. Cognitive evaluation rated her IQ at 54.
Disease association disputed in PMID: 30619714.

PMID: 27391121 Al-Shamsi et al., 2016
Proband homozygous for NM_144639.3(UROC1):c.855G>A (p.Trp285Ter) - rare in gnomAD v4.1.0, 10 alleles, no homozygotes. Patient phenotype: Intellectual disabilities, attention deficit and hyperactivity disorder, hyperextensible joints, elevated imidazole propionate. Seq method: WES.

PMID: 30619714 Glinton et al., 2018
Case 1 - 27yo female - urocanic aciduria detected at 8 weeks of age; developed normally, psychological assessment at 3yo using the McCarthy Scales of Children's Abilities gave a general cognitive score of 115 (83rd percentile for age).
Case 2 - 21yo male, asymptomatic brother of Case1 with urocanic aciduria (detected on biochemical testing).
Both siblings compound het for NM_144639.3(UROC1):c.356C>G (p.Pro119Arg) and NM_144639.3(UROC1):c.907G>C (p.Ala303Pro) - parents confirmed as carriers. Seq method: UROC1 only.

PMID: 32439973 Alaimo et al., 2020
Patient 75 - phenotype: "Neurologic (with or without other organ systems)"; 5yo male homozygous for NM_144639.3(UROC1):c.855G>A (p.Trp285Ter) with urocanic aciduria. Seq method: exome seq. Authors note that 'the biochemical phenotype is benign and not causative of the patient phenotype'.
Patient 65 - Phenotype: "Neurologic (with or without other organ systems)" - 7months old female - normal metabolomic findings; homozygous for c.1054G>A, p.Ala352Thr in UROC1 - MAF 0.001684 in gnomAD v4.1.0 - Likely Benign.

This gene is putatively associated with Urocanase deficiency , OMIM:276880 (OMIM accessed 13th Nov 2025). Gene is currently rated Red for Intellectual disability in PanelApp Australia.
Intellectual disability v9.180 UROC1 Ida Ertmanska changed review comment from: PMID: 19304569 Espinos et al., 2009
Female proband, compound het for NM_144639.3(UROC1):c.1348C>T (p.Arg450Cys) & NM_144639.3(UROC1):c.209T>C (p.Leu70Pro). Sequenced UROC1 gene only. Cognitive evaluation rated her IQ at 54.
Disease association disputed in PMID: 30619714.

PMID: 27391121 Al-Shamsi et al., 2016
Proband homozygous for NM_144639.3(UROC1):c.855G>A (p.Trp285Ter) - rare in gnomAD v4.1.0, 10 alleles, no homozygotes. Patient phenotype: Intellectual disabilities, attention deficit and hyperactivity disorder, hyperextensible joints, elevated imidazole propionate. Seq method: WES.

PMID: 30619714 Glinton et al., 2018
Case 1 - 27yo female - urocanic aciduria detected at 8 weeks of age; developed normally, psychological assessment at 3yo using the McCarthy Scales of Children's Abilities gave a general cognitive score of 115 (83rd percentile for age).
Case 2 - 21yo male, asymptomatic brother of Case1 with urocanic aciduria (detected on biochemical testing).
Both siblings compound het for NM_144639.3(UROC1):c.356C>G (p.Pro119Arg) and NM_144639.3(UROC1):c.907G>C (p.Ala303Pro) - parents confirmed as carriers. Seq method: UROC1 only.

PMID: 32439973 Alaimo et al., 2020
Patient 75 - 5yo male homozygous for NM_144639.3(UROC1):c.855G>A (p.Trp285Ter) with urocanic aciduria. Seq method: exome seq. Authors note that 'the biochemical phenotype is benign and not causative of the patient phenotype'.

This gene is putatively associated with Urocanase deficiency , OMIM:276880 (OMIM accessed 13th Nov 2025).; to: PMID: 19304569 Espinos et al., 2009
Female proband, compound het for NM_144639.3(UROC1):c.1348C>T (p.Arg450Cys) & NM_144639.3(UROC1):c.209T>C (p.Leu70Pro). Sequenced UROC1 gene only. Cognitive evaluation rated her IQ at 54.
Disease association disputed in PMID: 30619714.

PMID: 27391121 Al-Shamsi et al., 2016
Proband homozygous for NM_144639.3(UROC1):c.855G>A (p.Trp285Ter) - rare in gnomAD v4.1.0, 10 alleles, no homozygotes. Patient phenotype: Intellectual disabilities, attention deficit and hyperactivity disorder, hyperextensible joints, elevated imidazole propionate. Seq method: WES.

PMID: 30619714 Glinton et al., 2018
Case 1 - 27yo female - urocanic aciduria detected at 8 weeks of age; developed normally, psychological assessment at 3yo using the McCarthy Scales of Children's Abilities gave a general cognitive score of 115 (83rd percentile for age).
Case 2 - 21yo male, asymptomatic brother of Case1 with urocanic aciduria (detected on biochemical testing).
Both siblings compound het for NM_144639.3(UROC1):c.356C>G (p.Pro119Arg) and NM_144639.3(UROC1):c.907G>C (p.Ala303Pro) - parents confirmed as carriers. Seq method: UROC1 only.

PMID: 32439973 Alaimo et al., 2020
Patient 75 - 5yo male homozygous for NM_144639.3(UROC1):c.855G>A (p.Trp285Ter) with urocanic aciduria. Seq method: exome seq. Authors note that 'the biochemical phenotype is benign and not causative of the patient phenotype'.

This gene is putatively associated with Urocanase deficiency , OMIM:276880 (OMIM accessed 13th Nov 2025). Gene is currently rated Red for Intellectual disability in PanelApp Australia.
Intellectual disability v9.180 UROC1 Ida Ertmanska changed review comment from: PMID: 19304569 Espinos et al., 2009
Female proband, compound het for NM_144639.3(UROC1):c.1348C>T (p.Arg450Cys) & NM_144639.3(UROC1):c.209T>C (p.Leu70Pro). Sequenced UROC1 gene only. Cognitive evaluation rated her IQ at 54.
Association disputed in PMID: 30619714.

PMID: 27391121 Al-Shamsi et al., 2016
Proband homozygous for NM_144639.3(UROC1):c.855G>A (p.Trp285Ter) - rare in gnomAD v4.1.0, 10 alleles, no homozygotes. Patient phenotype: Intellectual disabilities, attention deficit and hyperactivity disorder, hyperextensible joints, elevated imidazole propionate. Seq method: WES.

PMID: 30619714 Glinton et al., 2018
Case 1 - 27yo female - urocanic aciduria detected at 8 weeks of age; developed normally, psychological assessment at 3yo using the McCarthy Scales of Children's Abilities gave a general cognitive score of 115 (83rd percentile for age).
Case 2 - 21yo male, asymptomatic brother of Case1 with urocanic aciduria (detected on biochemical testing).
Both siblings compound het for NM_144639.3(UROC1):c.356C>G (p.Pro119Arg) and NM_144639.3(UROC1):c.907G>C (p.Ala303Pro) - parents confirmed as carriers. Seq method: UROC1 only.

PMID: 32439973 Alaimo et al., 2020
Patient 75 - 5yo male homozygous for NM_144639.3(UROC1):c.855G>A (p.Trp285Ter) with urocanic aciduria. Seq method: exome seq. Authors note that 'the biochemical phenotype is benign and not causative of the patient phenotype'.

This gene is putatively associated with Urocanase deficiency , OMIM:276880 (OMIM accessed 13th Nov 2025).; to: PMID: 19304569 Espinos et al., 2009
Female proband, compound het for NM_144639.3(UROC1):c.1348C>T (p.Arg450Cys) & NM_144639.3(UROC1):c.209T>C (p.Leu70Pro). Sequenced UROC1 gene only. Cognitive evaluation rated her IQ at 54.
Disease association disputed in PMID: 30619714.

PMID: 27391121 Al-Shamsi et al., 2016
Proband homozygous for NM_144639.3(UROC1):c.855G>A (p.Trp285Ter) - rare in gnomAD v4.1.0, 10 alleles, no homozygotes. Patient phenotype: Intellectual disabilities, attention deficit and hyperactivity disorder, hyperextensible joints, elevated imidazole propionate. Seq method: WES.

PMID: 30619714 Glinton et al., 2018
Case 1 - 27yo female - urocanic aciduria detected at 8 weeks of age; developed normally, psychological assessment at 3yo using the McCarthy Scales of Children's Abilities gave a general cognitive score of 115 (83rd percentile for age).
Case 2 - 21yo male, asymptomatic brother of Case1 with urocanic aciduria (detected on biochemical testing).
Both siblings compound het for NM_144639.3(UROC1):c.356C>G (p.Pro119Arg) and NM_144639.3(UROC1):c.907G>C (p.Ala303Pro) - parents confirmed as carriers. Seq method: UROC1 only.

PMID: 32439973 Alaimo et al., 2020
Patient 75 - 5yo male homozygous for NM_144639.3(UROC1):c.855G>A (p.Trp285Ter) with urocanic aciduria. Seq method: exome seq. Authors note that 'the biochemical phenotype is benign and not causative of the patient phenotype'.

This gene is putatively associated with Urocanase deficiency , OMIM:276880 (OMIM accessed 13th Nov 2025).
Intellectual disability v9.174 ISCA-37498-Loss Arina Puzriakova changed review comment from: https://search.clinicalgenome.org/kb/gene-dosage/region/ISCA-37498

ClinGen review: Reported in at least 2 individuals with developmental delay/intellectual disability, dysmorphic features, dental anomalies, long slender fingers with 5th finger clinodactyly, and additional clinical features. Another patient (PMID: 28018436) was reported to have an overlapping 11q13 deletion that involves most of the recurrent region with a similar clinical phenotype. All reported deletions of the recurrent 11q13.2q13.4 region with informative parental testing have been shown to be de novo. Case-control data are currently uninformative due to the rarity of this deletion. Additionally, this deletion encompasses two curated dosage sensitive genes, KMT5B and SHANK2.

Sources: ClinGen; to: https://search.clinicalgenome.org/kb/gene-dosage/region/ISCA-37498

ClinGen review (Last Evaluated:06/25/2025): Reported in at least 2 individuals with developmental delay/intellectual disability, dysmorphic features, dental anomalies, long slender fingers with 5th finger clinodactyly, and additional clinical features. Another patient (PMID: 28018436) was reported to have an overlapping 11q13 deletion that involves most of the recurrent region with a similar clinical phenotype. All reported deletions of the recurrent 11q13.2q13.4 region with informative parental testing have been shown to be de novo. Case-control data are currently uninformative due to the rarity of this deletion. Additionally, this deletion encompasses two curated dosage sensitive genes, KMT5B and SHANK2.

Sources: ClinGen
Intellectual disability v9.174 ISCA-37448-Loss Arina Puzriakova Phenotypes for Region: ISCA-37448-Loss were changed from to Developmental delay/intellectual disability, epilepsy, autism spectrum disorder, schizophrenia, congenital heart disease, and variable dysmorphic features
Intellectual disability v9.172 ISCA-37448-Loss Arina Puzriakova changed review comment from: https://search.clinicalgenome.org/kb/gene-dosage/region/ISCA-37448

ClinGen review: Deletion of the 15q11.2 (BP1-BP2) region has historically been reported in association with highly variable clinical phenotypes. Features observed in carrier patients referred for clinical genome wide copy number testing have been relatively nonspecific, including developmental delay/intellectual disability (DD/ID), epilepsy, autism spectrum disorder (ASD), schizophrenia, congenital heart disease (CHD), and variable dysmorphic features, which are also generally common in this patient population. This deletion has been shown to be enriched in the clinical population across multiple case-control studies. However, in the clinical setting, it is often inherited from unaffected carriers, and the deletion is also observed in the general population at a relatively high frequency (0.14 - 0.39%; PMID: 25217958, 30767844). The expression of any phenotype associated with this deletion has been estimated to be between 8-10%. This has led to a high level of variability in how this region is reported clinically.

Large cohort studies involving 15q11.2 (BP1-BP2) deletion carriers from the general population have consistently demonstrated that individuals who carry this deletion perform worse on cognitive function tests than non-carrier individuals. This difference has been reported to be significant, but with a mild effect size, consistent with the deletion being a susceptibility locus for neurodevelopmental phenotypes. Additionally, these studies suggest ascertainment bias may be responsible for the association of this deletion with the more severe clinical phenotypes (ID, epilepsy, ASD and CHD) observed in cases identified through clinical testing.

Collectively, the current literature is consistent with the 15q11.2 (BP1-BP2) deletion having a subclinical, but measurable, effect on neurocognitive function. Other reported clinical associations are not conclusively established, and likely reflect a bias of ascertainment. Therefore, there is sufficient evidence for haploinsufficiency of this region.


Additional comments from Genomics England Clinical team: There are significant issues with penetrance for these but I understand the NHS would still report them in the context of disease (https://www.acgs.uk.com/media/12443/uk-practice-guidelines-for-variant-classification-v1-2023.pdf). Therefore, agree with the recommendations.
Sources: ClinGen; to: https://search.clinicalgenome.org/kb/gene-dosage/region/ISCA-37448

ClinGen review (Last Evaluated:04/12/2021): Deletion of the 15q11.2 (BP1-BP2) region has historically been reported in association with highly variable clinical phenotypes. Features observed in carrier patients referred for clinical genome wide copy number testing have been relatively nonspecific, including developmental delay/intellectual disability (DD/ID), epilepsy, autism spectrum disorder (ASD), schizophrenia, congenital heart disease (CHD), and variable dysmorphic features, which are also generally common in this patient population. This deletion has been shown to be enriched in the clinical population across multiple case-control studies. However, in the clinical setting, it is often inherited from unaffected carriers, and the deletion is also observed in the general population at a relatively high frequency (0.14 - 0.39%; PMID: 25217958, 30767844). The expression of any phenotype associated with this deletion has been estimated to be between 8-10%. This has led to a high level of variability in how this region is reported clinically.

Large cohort studies involving 15q11.2 (BP1-BP2) deletion carriers from the general population have consistently demonstrated that individuals who carry this deletion perform worse on cognitive function tests than non-carrier individuals. This difference has been reported to be significant, but with a mild effect size, consistent with the deletion being a susceptibility locus for neurodevelopmental phenotypes. Additionally, these studies suggest ascertainment bias may be responsible for the association of this deletion with the more severe clinical phenotypes (ID, epilepsy, ASD and CHD) observed in cases identified through clinical testing.

Collectively, the current literature is consistent with the 15q11.2 (BP1-BP2) deletion having a subclinical, but measurable, effect on neurocognitive function. Other reported clinical associations are not conclusively established, and likely reflect a bias of ascertainment. Therefore, there is sufficient evidence for haploinsufficiency of this region.


Additional comments from Genomics England Clinical team: There are significant issues with penetrance for these but I understand the NHS would still report them in the context of disease (https://www.acgs.uk.com/media/12443/uk-practice-guidelines-for-variant-classification-v1-2023.pdf). Therefore, agree with the recommendations.
Sources: ClinGen
Intellectual disability v9.172 ISCA-37448-Loss Arina Puzriakova Region: ISCA-37448-Loss was added
Region: ISCA-37448-Loss was added to Intellectual disability. Sources: ClinGen
Q3_25_promote_green tags were added to Region: ISCA-37448-Loss.
Mode of inheritance for Region: ISCA-37448-Loss was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for Region: ISCA-37448-Loss were set to 31451536; 24352232; 30767844; 31665216
Review for Region: ISCA-37448-Loss was set to GREEN
Added comment: https://search.clinicalgenome.org/kb/gene-dosage/region/ISCA-37448

ClinGen review: Deletion of the 15q11.2 (BP1-BP2) region has historically been reported in association with highly variable clinical phenotypes. Features observed in carrier patients referred for clinical genome wide copy number testing have been relatively nonspecific, including developmental delay/intellectual disability (DD/ID), epilepsy, autism spectrum disorder (ASD), schizophrenia, congenital heart disease (CHD), and variable dysmorphic features, which are also generally common in this patient population. This deletion has been shown to be enriched in the clinical population across multiple case-control studies. However, in the clinical setting, it is often inherited from unaffected carriers, and the deletion is also observed in the general population at a relatively high frequency (0.14 - 0.39%; PMID: 25217958, 30767844). The expression of any phenotype associated with this deletion has been estimated to be between 8-10%. This has led to a high level of variability in how this region is reported clinically.

Large cohort studies involving 15q11.2 (BP1-BP2) deletion carriers from the general population have consistently demonstrated that individuals who carry this deletion perform worse on cognitive function tests than non-carrier individuals. This difference has been reported to be significant, but with a mild effect size, consistent with the deletion being a susceptibility locus for neurodevelopmental phenotypes. Additionally, these studies suggest ascertainment bias may be responsible for the association of this deletion with the more severe clinical phenotypes (ID, epilepsy, ASD and CHD) observed in cases identified through clinical testing.

Collectively, the current literature is consistent with the 15q11.2 (BP1-BP2) deletion having a subclinical, but measurable, effect on neurocognitive function. Other reported clinical associations are not conclusively established, and likely reflect a bias of ascertainment. Therefore, there is sufficient evidence for haploinsufficiency of this region.


Additional comments from Genomics England Clinical team: There are significant issues with penetrance for these but I understand the NHS would still report them in the context of disease (https://www.acgs.uk.com/media/12443/uk-practice-guidelines-for-variant-classification-v1-2023.pdf). Therefore, agree with the recommendations.
Sources: ClinGen
Intellectual disability v9.170 ISCA-46296-Loss Arina Puzriakova Region: ISCA-46296-Loss was added
Region: ISCA-46296-Loss was added to Intellectual disability. Sources: ClinGen
Q3_25_promote_green tags were added to Region: ISCA-46296-Loss.
Mode of inheritance for Region: ISCA-46296-Loss was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for Region: ISCA-46296-Loss were set to 22180641; 19921647
Phenotypes for Region: ISCA-46296-Loss were set to Developmental delays, intellectual disability, brain anomalies, non-specific craniofacial abnormalities, hypotonia, ocular abnormalities, hearing loss, and other variable clinical features
Review for Region: ISCA-46296-Loss was set to GREEN
Added comment: https://search.clinicalgenome.org/kb/gene-dosage/region/ISCA-46296

ClinGen review (Last Evaluated:10/24/2025): Deletion of the 15q24 LCR A-C recurrent region has been reported in at least 5 patients. The reported clinical findings include developmental delays (speech and motor), intellectual disability, brain anomalies, non-specific craniofacial abnormalities, hypotonia, ocular abnormalities, hearing loss, and other variable clinical features. In all cases where parental studies have been performed, deletions were found to be de novo. Case-control comparison studies have provided evidence for enrichment of this deletion in the clinical population, although overall numbers are somewhat limited.
Sources: ClinGen
Intellectual disability v9.168 ISCA-46300-Loss Arina Puzriakova changed review comment from: https://search.clinicalgenome.org/kb/gene-dosage/region/ISCA-46300

ClinGen review: Deletion of the 15q24 recurrent region (C-D) has been reported in at least 4 patients with a syndromic clinical phenotype characterized by developmental delays (speech and motor), intellectual disability, brain anomalies, craniofacial abnormalities, hypermobile joints, digital findings, and other variable clinical features. Two additional patients have also been reported with atypical deletions encompassed by the 15q24 LCR C-D region, but with breakpoints proximal to LCR D. Both of these patients had a similar clinical presentation to patients with the typical 15q24 LCR C-D deletion. Parental studies have demonstrated that each of the deletions in this region (6 total) represent de novo events. Case-control data are currently uninformative due to the rarity of this deletion. The known haploinsufficient gene SIN3A is thought to represent the critical gene within this region, as SIN3A sequence level have a similar clinical presentation to recurrent deletion.
Sources: ClinGen; to: https://search.clinicalgenome.org/kb/gene-dosage/region/ISCA-46300

ClinGen review (Last Evaluated:10/24/2025): Deletion of the 15q24 recurrent region (C-D) has been reported in at least 4 patients with a syndromic clinical phenotype characterized by developmental delays (speech and motor), intellectual disability, brain anomalies, craniofacial abnormalities, hypermobile joints, digital findings, and other variable clinical features. Two additional patients have also been reported with atypical deletions encompassed by the 15q24 LCR C-D region, but with breakpoints proximal to LCR D. Both of these patients had a similar clinical presentation to patients with the typical 15q24 LCR C-D deletion. Parental studies have demonstrated that each of the deletions in this region (6 total) represent de novo events. Case-control data are currently uninformative due to the rarity of this deletion. The known haploinsufficient gene SIN3A is thought to represent the critical gene within this region, as SIN3A sequence level have a similar clinical presentation to recurrent deletion.
Sources: ClinGen
Intellectual disability v9.168 ISCA-46300-Loss Arina Puzriakova Region: ISCA-46300-Loss was added
Region: ISCA-46300-Loss was added to Intellectual disability. Sources: ClinGen
Q3_25_promote_green tags were added to Region: ISCA-46300-Loss.
Mode of inheritance for Region: ISCA-46300-Loss was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for Region: ISCA-46300-Loss were set to 27399968; 22180641
Phenotypes for Region: ISCA-46300-Loss were set to Developmental delays/intellectual disability, brain anomalies, craniofacial abnormalities, hypermobile joints, digital findings, and other variable clinical features
Review for Region: ISCA-46300-Loss was set to GREEN
Added comment: https://search.clinicalgenome.org/kb/gene-dosage/region/ISCA-46300

ClinGen review: Deletion of the 15q24 recurrent region (C-D) has been reported in at least 4 patients with a syndromic clinical phenotype characterized by developmental delays (speech and motor), intellectual disability, brain anomalies, craniofacial abnormalities, hypermobile joints, digital findings, and other variable clinical features. Two additional patients have also been reported with atypical deletions encompassed by the 15q24 LCR C-D region, but with breakpoints proximal to LCR D. Both of these patients had a similar clinical presentation to patients with the typical 15q24 LCR C-D deletion. Parental studies have demonstrated that each of the deletions in this region (6 total) represent de novo events. Case-control data are currently uninformative due to the rarity of this deletion. The known haploinsufficient gene SIN3A is thought to represent the critical gene within this region, as SIN3A sequence level have a similar clinical presentation to recurrent deletion.
Sources: ClinGen
Intellectual disability v9.167 ISCA-37498-Loss Arina Puzriakova changed review comment from: https://search.clinicalgenome.org/kb/gene-dosage/region/ISCA-37498

ClinGen review: Reported in at least 2 individuals with developmental delay/intellectual disability, dysmorphic features, dental anomalies, long slender fingers with 5th finger clinodactyly, and additional clinical features. Another patient (PMID: 28018436) was reported to have an overlapping 11q13 deletion that involves most of the recurrent region with a similar clinical phenotype. All reported deletions of the recurrent 11q13.2q13.4 region with informative parental testing have been shown to be de novo. Case-control data are currently uninformative due to the rarity of this deletion. Additionally, this deletion encompasses two curated dosage sensitive genes, KMT5B and SHANK2.

Panel inclusion has been reviewed and approved by the Genomics England Clinical team.
Sources: ClinGen; to: https://search.clinicalgenome.org/kb/gene-dosage/region/ISCA-37498

ClinGen review: Reported in at least 2 individuals with developmental delay/intellectual disability, dysmorphic features, dental anomalies, long slender fingers with 5th finger clinodactyly, and additional clinical features. Another patient (PMID: 28018436) was reported to have an overlapping 11q13 deletion that involves most of the recurrent region with a similar clinical phenotype. All reported deletions of the recurrent 11q13.2q13.4 region with informative parental testing have been shown to be de novo. Case-control data are currently uninformative due to the rarity of this deletion. Additionally, this deletion encompasses two curated dosage sensitive genes, KMT5B and SHANK2.

Sources: ClinGen
Intellectual disability v9.166 ISCA-37498-Loss Arina Puzriakova Region: ISCA-37498-Loss was added
Region: ISCA-37498-Loss was added to Intellectual disability. Sources: ClinGen
Q3_25_promote_green tags were added to Region: ISCA-37498-Loss.
Mode of inheritance for Region: ISCA-37498-Loss was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for Region: ISCA-37498-Loss were set to 28211979; 21373257; 37152320
Phenotypes for Region: ISCA-37498-Loss were set to Developmental delay/intellectual disability, dysmorphic features, dental anomalies, long slender fingers with 5th finger clinodactyly, and additional clinical features
Review for Region: ISCA-37498-Loss was set to GREEN
Added comment: https://search.clinicalgenome.org/kb/gene-dosage/region/ISCA-37498

ClinGen review: Reported in at least 2 individuals with developmental delay/intellectual disability, dysmorphic features, dental anomalies, long slender fingers with 5th finger clinodactyly, and additional clinical features. Another patient (PMID: 28018436) was reported to have an overlapping 11q13 deletion that involves most of the recurrent region with a similar clinical phenotype. All reported deletions of the recurrent 11q13.2q13.4 region with informative parental testing have been shown to be de novo. Case-control data are currently uninformative due to the rarity of this deletion. Additionally, this deletion encompasses two curated dosage sensitive genes, KMT5B and SHANK2.

Panel inclusion has been reviewed and approved by the Genomics England Clinical team.
Sources: ClinGen
Intellectual disability v9.165 LRRC45 Ida Ertmanska edited their review of gene: LRRC45: Added comment: Comment on list classification: There are 5 individuals form 4 unrelated families reported in literature with biallelic variants in LRRC45. 2/5 patients did not live beyond 3 months of age. In remaining 3 cases, 3/3 presented with severe developmental delay, delayed milestone attainment, and intellectual disability (severity not stated). Based on available evidence, this gene should be promoted to Green for Intellectual disability at the next GMS update.; Changed rating: GREEN
Intellectual disability v9.164 LRRC45 Ida Ertmanska gene: LRRC45 was added
gene: LRRC45 was added to Intellectual disability. Sources: Other
Mode of inheritance for gene: LRRC45 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LRRC45 were set to 30131441; 34716235; 39638757
Phenotypes for gene: LRRC45 were set to ciliopathy, MONDO:0005308; Abnormal brain morphology, HP:0012443; neurodevelopmental disorder, MONDO:0700092
Review for gene: LRRC45 was set to AMBER
Added comment: PMID: 34716235 Best et al., 2022
2 unrelated individuals with LP biallelic variants in LRRC45.
Proband 1 (CMC Patient 48): Bardet-Biedl syndrome-like multi-systemic ciliopathy - homozygous for NM_144999.4: c.1074_1075insTG, p.(Leu359CysfsTer19), also homozygous for CFAP45 (CCDC19) NM_012337.3: c.433C>T, p.(Arg145Ter).
Sibling with developmental delay and ID was homozygous for the LRRC45 variant, did not harbour the CFAP45 mutation (proposed to account for the ciliopathy phenotype); parents confirmed as het for each.
Proband 2: presented with cone-rod dystrophy (possible ciliopathy basis) - compound het: NM_144999.4: c.1A>T, p.Met1? & NM_144999.4: c.1126–1G>A. Singleton case.

PMID: 39638757 Radhakrishnan et al., 2025
Report of 3 individuals from 2 unrelated families with severe central nervous system anomalies, harbouring biallelic variants in LRRC45: P1: c.1402-2A>G; P2 and P3: c.1262G>C (p.Arg421Thr). Method: Exome seq.
P1 - female, onset at 1yr 8months, Indian origin, presented with febrile seizures and developmental delay, severe brain anomalies. At 3yr 7 mo: titubation, nystagmus, axial and peripheral hypotonia, normal deep tendon reflexes and pes planus.
P2 & 3 - born to Turkish consanguineous parents; P2 - female, presented with severe muscular hypotonia, respiratory insufficiency, and apnea bradycardia syndrome; ophthalmological exam was normal; patient died at 3 months old. P3 - male fetus, pregnancy terminated.
Functional evidence - P1 fibroblasts - variant c.1402-2A>G shown to result in a transcript lacking exon 14 (total 17 exons); LRRC45 mRNA and protein levels significantly reduced; significant reduction of primary cilia frequency and length.
c.1402-2A>G - splice acceptor - MAF 0.0001647 (South Asian population, 14 heterozygotes - gnomAD v4.1).
c.1262G>C (p.Arg421Thr) - MAF 8.475e-7 (1 het in European pop - gnomAD v4.1); Revel score =
Uncertain (0.31).

Functional evidence:
PMID: 30131441 Kurtulmus et al., 2018 - LRRC45 shown to be associated with the basal body of primary and motile cilia in both differentiated and stem cells - broad function in ciliogenesis.

This gene is not yet associated with a disease in OMIM (accessed 11th Nov 2025).
Sources: Other
Intellectual disability v9.161 KIF26A Ida Ertmanska Added comment: Comment on list classification: At least 13 patients from 10 families have been described in literature with biallelic variants in KIF26A and KIF26A‐related disorder (PMIDs: 36228617; 36564622; 39305096). 6/8 individuals assessed presented with developmental delay and/or intellectual disability: 3 cases with mild cognitive impairment, 2 with moderate ID, 1 with 'growth retardation and developmental delay' - severity not specified. As only 2 cases meet the panel criteria of moderate/severe impairment, this gene should be rated Amber for Intellectual disability until more evidence emerges.
Intellectual disability v9.160 KIF26A Ida Ertmanska gene: KIF26A was added
gene: KIF26A was added to Intellectual disability. Sources: Other
Mode of inheritance for gene: KIF26A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KIF26A were set to 36228617; 36564622; 39305096
Phenotypes for gene: KIF26A were set to Cortical dysplasia, complex, with other brain malformations 11, OMIM:620156; cortical dysplasia, complex, with other brain malformations 11 MONDO:0859332
Review for gene: KIF26A was set to AMBER
Added comment: At least 13 patients from 10 families have been described in literature with biallelic variants in KIF26A and KIF26A‐related disorder (PMIDs: 36228617; 36564622; 39305096).

The heterogenous syndromic presentation may include developmental delay / intellectual disability (6/8, mild to moderate), cardiac defects (6/7), neurological features e.g. hypotonia (2), spasticity (2), paediatric intestinal pseudo‐obstruction (PIPO) (3/13). While only 3/13 patients were diagnosed with PIPO, 8/13 patients had gastrointestinal issues, including megacolon, ischemic small bowels, severe ascites, abdominal distension, vomiting, and intestinal obstruction. Note: several individuals died before certain clinical features could be assessed.

Brain MRI showed Ventriculomegaly/Hydrocephalus in 12/12 patients and corpus callosum agenesis / hypoplasia in 7/12 cases; unavailable in 1 case. Other malformations noted on MRI: Hypogenesis of septum pellucidum, Brainstem patterning disorder, Long midbrain, Small pons, Brain atrophy, Reduced white matter, Bilateral schizencephaly, Absent hippocampal commissure.

PMID: 39305096 Nosrati et al., 2025
Seq method: Trio exome.
Case #1 - 8yo Italian male; at birth: axial hypotonia, poor suction, failed to pass meconium, leading to surgery for Hirschsprung's disease. Compound het c.4378C > T, p.(Arg1460Trp); c.5238C > G, p.(Phe1746Leu).
Case #2 - 6mo Syrian female; presented with abdominal distension and intestinal obstruction symptoms; imaging revealed dilated bowels without mechanical obstruction; biopsies of small and large intestine showed hypoganglionosis. Homozygous for c.4085dup, p.(Ala1363Glyfs*47).
Case #3 - female born to consanguineous parents (Palestinian / Jordanian) - very different presentation: severe spastic quadriplegic cerebral palsy (CP) with epilepsy, hearing problems and cognitive impairments. Homozygous for c.3996C > A, p.(Cys1332*).

PMID: 36564622 Almannai et al., 2023
Seq method: clinical WES.
Report of 2 families with KIF26A‐related disorder.
Family 1: 4 affected individuals, homozygous for c.792dupC, p.(Val265Argfs*5), all presented with persistent abdominal distension and vomiting after birth. 3 individuals died between 2-11 months, 1 patient alive at 3.5 years.
Family 2: proband presented at 3 months with symptoms indicating intestinal obstruction and marked abdominal distension. Symptoms persist at 7yo. Homozygous for c.3330delC, p.(Ser1111Alafs*137).

36228617 Qian et al., 2022
Seq method: WES.
5 unrelated subjects with congenital brain malformations who had inherited biallelic mutations in KIF26A
A01 - consanguineous Turkish family, microcephaly (−3.45SD) and an MRI suggesting a component of cerebral atrophy, as well as dysmorphic features and ileus with megacolon. Homozygous for c.3440dupC, p.Ala1148Cysfs*20.
B01 - diagnosed prenatally with bilateral schizencephaly at 21 weeks; pregnancy terminated; compound heterozygous c.2161C>T, p.Arg721Cys, and c.4676C>T, p.Ala1559Val
C01 - male, non-consanguineous parents, presented with mild developmental delay and learning disability. Brain MRI at 18 years demonstrated agenesis of the corpus callosum; compound het KIF26A: c.4676C>T, p.Arg1624Cys, and c.4870C>T, p.Ala1559Val
D01 - was diagnosed with polymicrogyria and hydrocephalus, with inherited compound heterozygous variants in KIF26A: c.2845C>T, p.Pro949Ser, and c.4676C>T, p.Ala1559Val
E01 - male born to consanguineous parents with growth retardation and developmental delay. Brain MRI performed at 18 months revealed a thin CC, ventriculomegaly and polymicrogyria; homozygous for c.4804C>T; p.Arg1602Trp.

KIF26A is associated with Cortical dysplasia, complex, with other brain malformations 11, 620156 in OMIM (accessed 31st Oct 2025).
The association of KIF26A and 'complex cortical dysplasia with other brain malformations' is classified as Strong in ClinGen (March 2024).
Sources: Other
Intellectual disability v9.155 KIAA0556 Arina Puzriakova Added comment: Comment on list classification: This gene was added to this panel following consultation with the Genomics England Clinical Team. Although the ID phenotype is less clear than some other features, there are two families with severe ID and another two where extent of ID is unclear or milder. There are also sufficient cases of hypotonia which is tested via the Hypotonic infant super panel, as well as short stature/hypopituitarism/growth hormone deficiency which are more likely to be picked up via the Paediatric disorders super panel. Inclusion on the ID panel would also ensure inclusion on these two super panels, where ID is a component panel.

Overall the evidence supports promotion of this gene to Green at the next GMS panel update.
Intellectual disability v9.154 KIAA0556 Arina Puzriakova gene: KIAA0556 was added
gene: KIAA0556 was added to Intellectual disability. Sources: ClinGen,Literature
new-gene-name, Q3_25_promote_green tags were added to gene: KIAA0556.
Mode of inheritance for gene: KIAA0556 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: KIAA0556 were set to Joubert syndrome 26, OMIM:616784; Joubert syndrome 26, MONDO:0014771
Review for gene: KIAA0556 was set to GREEN
Added comment: KIAA0556 (also known as KATNIP) is now associated with Joubert syndrome 26, OMIM:616784 (AR) in OMIM (accessed 21st Oct 2025), and has a DEFINITIVE gene disease association with autosomal recessive ciliopathy-KATNIP (MONDO:0005308) in ClinGen (curation entry from 07/10/2023).

The ClinGen summary states that there are eight variants (nonsense, frameshift, splice-site) reported in 6 probands in 6 publications (PMIDs: 26714646, 27245168, 31197031, 36580738, 32164589, 30982090). There have been 2 additional reports since their review (PMIDs: 40725402, 40428346)

In total there are now 13 individuals from 8 families. In 2 of the families additional variants were found in other genes. These families are listed last in this review. Main phenotypes observed in the cases with only KIAA0556 variants:

- Brain abnormalities (including molar tooth sign) were seen in 9 individuals (5 families, 1 of these mild).
- Hypotonia was observed in 6 individuals (4 families).
- Short stature/Growth hormone deficiency/pituitary abnormalities were seen in 4 individuals (3 families)
- Developmental delay/intellectual disability was reported as severe in 4 individuals( 2 families), mild/unknown severity in an additional 3 individuals (2 families).
- An eye phenotype was observed in 4 individuals (3 families)
- A renal phenotype was only observed in 1 family (PMID: 40725402).

Evidence:

PMID:26714646 (Sanders et al 2015) - 3 children in a consanguineous Saudi Arabian family with global developmental delay and suspected Jouberts syndrome based on neuroimaging studies. Variable features between the children included recurrent infections (2), hypotonia( 2), cleft palate (1), small penis (1), short stature (1), hypopituitarism (2). No renal involvement. In patient fibroblasts there were a significant reduction in cilia compared to controls, and cilia that were present were abnormally long. Kiaa0556 knockout mice showed brain-specific defects resulting in hydrocephalus. In human cells KIAA0556 was found to locate a the ciliary base, axoneme and tip.

PMID:27245168 (Roosing et al 2016) - WES in consanguineous family from India identified a KIAA0556 homozygous single base pair deletion mutation in 2 siblings. Both showed nystagmus and oculomotor apraxia, bilaterial ptosis, hypotonia, characteristic ‘molar tooth’ sign on brain imaging and developmental delay (severity not noted). Cone dystrophy was identified, but gross visual function was not impaired. No renal or liver phenotype. A zebrafish model with kiaa0556 knocked down showed curly tails, smaller head size and perithoracic and abdominal edema which is like other ciliopathy morphants.

PMID:31197031 (Fujita et al 2019) - blood and/or hypothalamic hamartoma (HH, congenital brain malformation associated with drug-resistant epilepsy) tissue samples from 38 undiagnosed patients were analysed using WES. Germline, compound heterozygous variants in KIAA0556 were found in one 5 yo female patient (individual 12698), c.2373del (p.Asp791Glufs*206),c.4551+1G>A. Brain anomalies in this patient included agenesis of the corpus callosum, pituitary hypoplasia, the molar tooth sign, and HH. Other clinical features reported include hypotonia, oculomotor apraxia and developmental delay.

PMID:36580738 (Aksu Uzunhan et al 2023) - 2-year-old male with compound heterozygous variants KATNIP gene. He had growth hormone deficiency and central hypothyroidism, with some minor dysmorphic features. His neurodevelopment seemed normal, but cranial MRI abnormalities without a classical molar tooth sign, ectopic neurohypophysis and combined pituitary hormone deficiency. No renal, liver or eye phenotype.

PMID: 40725402 (Kulyamzin et al 2025) - 24 yo female from a non-consanguineous family of mixed Jewish origin who presented with type 2 glomerulonephritis at age 7 and underwent 2 kidney transplantations. She later developed SNHL, which was attributed to antibiotic toxicity, high intracranial pressure, and a differential diagnosis of cone rod dystrophy vs macular dystrophy with peripheral involvement. WES revealed two rare heterozygous variants in the KATNIP (KIAA0556) gene (NM_015202.4): c.49C>T; p.(Arg17*) and c.4711A>G; p.(Ser1571Gly). The proband was also heterozygous for a likely-pathogenic variant in POLG. Heterozygous variants in POLG have been linked to progressive external ophthalmoplegia (weakness of eye muscles), but the proband did not present with this.

PMID: 40428346 (Tedesco et al 2025) 5-year-old male from a consanguineous family of Roma ethnic background. Clinical features include severe developmental delay, hypotonia, and post-axial polydactyly. He had a normal cerebral MRI without the molar tooth sign, but showed severe anemia and esophageal atresia. WES identified a homozygous novel frameshift variant c.808del, p.Ser270ValfsTer28 in KATNIP. A good summary of all cases to date is provided.

Patients with variants in KIAA0556/KATNIP and another gene:

PMID:32164589 (Niceta et al 2020) - 7 year old with homozygosity for mutations in KIF7 and KIAA0556 identified by WES. The patient displayed Joubert syndrome complicated by iris and retinochoroidal coloboma, hypogonadism pituitary malformation, and growth hormone deficiency. Severe intellectual disability was reported.

PMID:30982090 (Cauley et al 2019) - Sudanese family in 3 siblings with homozygous truncating variants in both KIAA0556 and ADGRG1/GPR56 and a severe brain malformation (bilateral frontal polymicrogyra, mild molar tooth sign), severe psychomotor delay, intellectual disability and seizures.
Sources: ClinGen, Literature
Intellectual disability v9.151 SETBP1 Ida Ertmanska changed review comment from: SETBP1 is associated with two distinct autosomal dominant disorders: Intellectual developmental disorder, known as SETBP1 disorder, and Schinzel-Giedion syndrome.

SETBP1 disorder (Filges et al., PMID: 21037274) is characterised by intellectual disability, autism, speech difficulty, motor and developmental delays, seizures, hypotonia, and facial dysmorphisms. The mechanism of disease is haploinsufficiency - PMID: 21037274.
There are at least 7 unrelated individuals reported in literature, diagnosed with SETBP1 disorder and harbouring LOF variants in SETBP1 (nonsense, frameshift, large deletions) - PMIDs: 23020937, 25217958, 29463886, 25356899.

Schinzel-Giedion syndrome is caused by missense variants in SETBP1, particularly variants affecting amino acids 868-871 - a specific ‘hotspot’ region of the SETBP1 gene that codes for a degron. Clinical features of Schinzel-Giedion syndrome include developmental delay, epilepsy, facial dysmorphisms, and genitourinary and skeletal anomalies. The proposed mechanism of Schinzel-Giedion syndrome is gain-of-function (GOF), causing SETBP1 protein to accumulate (PMID: 28346496). There are at least 15 unrelated individuals with Schinzel-Giedion syndrome and heterozygous missense variants in SETBP1 reported in literature (PMIDs: 20436468, 26188272, 32460883, 22473152, 25028416, 25082129, 25663181, 26096993, 32445275, 28346496).

SETBP1 is associated with Intellectual developmental disorder, autosomal dominant 29, OMIM: 616078 and Schinzel-Giedion midface retraction syndrome, OMIM: 269150 (OMIM, accessed 28th Oct 2025).; to: SETBP1 is associated with two distinct autosomal dominant disorders: Intellectual developmental disorder, known as SETBP1 disorder, and Schinzel-Giedion syndrome.

SETBP1 disorder is characterised by intellectual disability, autism, speech difficulty, motor and developmental delays, seizures, hypotonia, and facial dysmorphisms (PMID: 21037274). The mechanism of disease is haploinsufficiency (PMID: 21037274).
There are at least 7 unrelated individuals reported in literature, diagnosed with SETBP1 disorder and harbouring LOF variants in SETBP1 (nonsense, frameshift, large deletions) - PMIDs: 23020937, 25217958, 29463886, 25356899.

Schinzel-Giedion syndrome is caused by missense variants in SETBP1, particularly variants affecting amino acids 868-871 - a specific ‘hotspot’ region of the SETBP1 gene that codes for a degron. Clinical features of Schinzel-Giedion syndrome include developmental delay, epilepsy, facial dysmorphisms, and genitourinary and skeletal anomalies. The proposed mechanism of Schinzel-Giedion syndrome is gain-of-function (GOF), causing SETBP1 protein to accumulate (PMID: 28346496). There are at least 15 unrelated individuals with Schinzel-Giedion syndrome and heterozygous missense variants in SETBP1 reported in literature (PMIDs: 20436468, 26188272, 32460883, 22473152, 25028416, 25082129, 25663181, 26096993, 32445275, 28346496).

SETBP1 is associated with Intellectual developmental disorder, autosomal dominant 29, OMIM: 616078 and Schinzel-Giedion midface retraction syndrome, OMIM: 269150 (OMIM, accessed 28th Oct 2025).
Intellectual disability v9.149 BRSK1 Arina Puzriakova changed review comment from: Comment on list classification: Rating Amber on the ID panel, as based on 7 unrelated cases reported in PMID:41035394, developmental and cognitive impairment appears to be secondary to early onset seizures which represent the most prominent feature of the disorder associated with this gene. This is further supported by the case with later onset of epilepsy compared to other cases (6 yrs), where no developmental deficits were observed before or after seizures.; to: Comment on list classification: Rating Amber on the ID panel, as evidence from 7 unrelated cases reported in PMID:41035394 indicates that developmental and cognitive impairment is not a universal feature and these deficits are likely secondary to early-onset seizures, which represent the most prominent manifestation associated with this gene. This is further supported by a case with later onset epilepsy (6 yrs), where no developmental deficits were observed before (or after) seizures.
Intellectual disability v9.149 BRSK1 Arina Puzriakova changed review comment from: Comment on list classification: Rating Amber on the ID panel, as based on 7 unrelated cases reported in PMID:41035394, developmental and cognitive impairment appears to be secondary to early onset seizures which represent the most prominent feature of the disorder associated with this gene. This is further supported by the case with later onset (6 yrs) who did not exhibit any developmental deficits before or after onset of seizures.; to: Comment on list classification: Rating Amber on the ID panel, as based on 7 unrelated cases reported in PMID:41035394, developmental and cognitive impairment appears to be secondary to early onset seizures which represent the most prominent feature of the disorder associated with this gene. This is further supported by the case with later onset of epilepsy compared to other cases (6 yrs), where no developmental deficits were observed before or after seizures.
Intellectual disability v9.149 BRSK1 Arina Puzriakova changed review comment from: Comment on list classification: Rating Amber on the ID panel, as based on 7 unrelated cases reported in PMID:41035394, developmental and cognitive impairment appear to be secondary to early onset seizures which represent the most prominent feature of the disorder associated with this gene. This is further supported by the case with later onset (6 yrs) who did not exhibit any developmental deficits before or after onset of seizures.; to: Comment on list classification: Rating Amber on the ID panel, as based on 7 unrelated cases reported in PMID:41035394, developmental and cognitive impairment appears to be secondary to early onset seizures which represent the most prominent feature of the disorder associated with this gene. This is further supported by the case with later onset (6 yrs) who did not exhibit any developmental deficits before or after onset of seizures.
Intellectual disability v9.149 BRSK1 Arina Puzriakova changed review comment from: Comment on list classification: Rating Amber on the ID panel as based on 7 unrelated cases reported in PMID:41035394, developmental and cognitive impairment appears to be secondary to early onset seizures which represent the most prominent feature of the disorder associated with this gene. This is further supported by the case with later onset (6 yrs) who did not exhibit any developmental deficits before or after onset of seizures.; to: Comment on list classification: Rating Amber on the ID panel, as based on 7 unrelated cases reported in PMID:41035394, developmental and cognitive impairment appear to be secondary to early onset seizures which represent the most prominent feature of the disorder associated with this gene. This is further supported by the case with later onset (6 yrs) who did not exhibit any developmental deficits before or after onset of seizures.
Intellectual disability v9.149 BRSK1 Arina Puzriakova Added comment: Comment on list classification: Rating Amber on the ID panel as based on 7 unrelated cases reported in PMID:41035394, developmental and cognitive impairment appears to be secondary to early onset seizures which represent the most prominent feature of the disorder associated with this gene. This is further supported by the case with later onset (6 yrs) who did not exhibit any developmental deficits before or after onset of seizures.
Intellectual disability v9.148 BRSK1 Arina Puzriakova gene: BRSK1 was added
gene: BRSK1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: BRSK1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: BRSK1 were set to 41035394
Phenotypes for gene: BRSK1 were set to Neurodevelopmental disorder, MONDO:0700092
Review for gene: BRSK1 was set to AMBER
Added comment: Zhang et al. 2025 (PMID: 41035394) describe 7 unrelated individuals, born to non-consanguineous Chinese parents, with unexplained epilepsy and heterozygous variants in the BRSK1 gene identified by trio WES. Variants include four SNVs and two indels (2 frameshift, 1 nonsense, 3 missense) - five were de novo, one inherited from an affected parent and one recurrent. No other pathogenic variants in epilepsy genes were identified. BRSK1 is intolerant to LoF variants (pLI = 1 in gnomAD v4.1.0).

Clinical features in affected individuals include epilepsy (7/7) with age of onset before age 1 (with exception of 1 case with age of onset at 6 yrs), variable brain MRI abnormalities (3/7), developmental delay (2 GDD, 1 mental delay, 1 motor delay, 2 without DD). One individual also had ASD and ADHD.

Frameshift and nonsense variants led to complete loss of BRSK1 protein, while one missense variant reduced protein levels. Proteomic analyses demonstrated axonal and synaptic dysfunction. Brsk1 exon 4-7 knockout mice (heterozygous and homozygous) exhibited seizures, neuronal hyperexcitability and neurobehavioral impairments which recapitulated clinical features observed in humans.
Sources: Literature
Intellectual disability v9.146 LAMC3 Achchuthan Shanmugasundram Added comment: Comment on list classification: The association of monoallelic variants with intellectual disability is disputed by the expert panel in ClinGen. There is no evidence of ID of moderate severity or worse in patients with biallelic variants. The patients only displayed developmental delay or mild ID. Hence, this gene should be demoted from green rating in the next GMS update.
Intellectual disability v9.144 MED12L Eleanor Williams changed review comment from: Since the last review additional cases have been reported.
In OMIM this gene is associated with Nizon-Isidor syndrome, OMIM:618872 (AD) - accessed 21st October 2025
In ClinGen the gene has a definitive rating with Nizon-Isidor syndrome, MONDO:0030030

There are now 3 more reports of plausable pathogenic variants in this gene in patients with an intellectual disability phenotype. 2 cases with de novo variants and 1 with a maternally inherited variant.

PMID: 36212160 - Park et al 2022 - WES to analyse 1,180 Korean patients with neurological symptoms. 1 individual with a de novo variant c.1895C>T; p.Ser632Leu in MED12L and a phenotype of global developmental delay and facial dysmorphism.

PMID: 35920825 - Ferraz et al 2022 - a male proband with a confirmed de novo germline frameshift variant in MED12L (NM_053002.6 (MED12L_v001):c.971del;p.(pro324Glnfs∗18)) identified by WES. The clinical phenotype included mild motor and speech delay, oligodontia, and dysmorphic signs. Of note the patient also carried 2 de novo chromosomal balanced reciprocal translocations: 46,XY,t(1;2)(p33;p22),t(5;9)(p15;q21) and the authors note that Nizon et al. 2019 report a patient with a balanced reciprocal translocation suggesting that the MED12L loss-of-function variant may contribute to chromosomal instability.

PMID: 40957966 - Dutta et al 2025 - report a proband with likely pathogenic MED12L nonsense variant (p.Arg1210Ter) which is maternally inherited (father also sequenced). At 2.5 yo the proband was diagnosed with global developmental delay, absent speech, ASD, hyperactivity, exophoria and myopia. Developmental regression began between 18 - 24 months. She has frequent respiratory infections. The 19 yo mother has a clinical history which includes speech delay and learning disability, but features are much milder than the proband. The proband also has inherited a pathogenic GAMT variant from her mother and a pathogenic TNFRSF13B variant from her father but these are not thought to contribute to the ID phenotype.; to: Since the last review additional cases have been reported.
In OMIM this gene is associated with Nizon-Isidor syndrome, OMIM:618872 (AD) - accessed 21st October 2025
In ClinGen the gene has a definitive rating with Nizon-Isidor syndrome, MONDO:0030030 (last curated November 19th, 2024)

There are now 3 more reports of plausable pathogenic variants in this gene in patients with an intellectual disability phenotype. 2 cases with de novo variants and 1 with a maternally inherited variant.

PMID: 36212160 - Park et al 2022 - WES to analyse 1,180 Korean patients with neurological symptoms. 1 individual with a de novo variant c.1895C>T; p.Ser632Leu in MED12L and a phenotype of global developmental delay and facial dysmorphism.

PMID: 35920825 - Ferraz et al 2022 - a male proband with a confirmed de novo germline frameshift variant in MED12L (NM_053002.6 (MED12L_v001):c.971del;p.(pro324Glnfs∗18)) identified by WES. The clinical phenotype included mild motor and speech delay, oligodontia, and dysmorphic signs. Of note the patient also carried 2 de novo chromosomal balanced reciprocal translocations: 46,XY,t(1;2)(p33;p22),t(5;9)(p15;q21) and the authors note that Nizon et al. 2019 report a patient with a balanced reciprocal translocation suggesting that the MED12L loss-of-function variant may contribute to chromosomal instability.

PMID: 40957966 - Dutta et al 2025 - report a proband with likely pathogenic MED12L nonsense variant (p.Arg1210Ter) which is maternally inherited (father also sequenced). At 2.5 yo the proband was diagnosed with global developmental delay, absent speech, ASD, hyperactivity, exophoria and myopia. Developmental regression began between 18 - 24 months. She has frequent respiratory infections. The 19 yo mother has a clinical history which includes speech delay and learning disability, but features are much milder than the proband. The proband also has inherited a pathogenic GAMT variant from her mother and a pathogenic TNFRSF13B variant from her father but these are not thought to contribute to the ID phenotype.
Intellectual disability v9.141 MED12L Eleanor Williams edited their review of gene: MED12L: Added comment: Since the last review additional cases have been reported.
In OMIM this gene is associated with Nizon-Isidor syndrome, OMIM:618872 (AD) - accessed 21st October 2025
In ClinGen the gene has a definitive rating with Nizon-Isidor syndrome, MONDO:0030030

There are now 3 more reports of plausable pathogenic variants in this gene in patients with an intellectual disability phenotype. 2 cases with de novo variants and 1 with a maternally inherited variant.

PMID: 36212160 - Park et al 2022 - WES to analyse 1,180 Korean patients with neurological symptoms. 1 individual with a de novo variant c.1895C>T; p.Ser632Leu in MED12L and a phenotype of global developmental delay and facial dysmorphism.

PMID: 35920825 - Ferraz et al 2022 - a male proband with a confirmed de novo germline frameshift variant in MED12L (NM_053002.6 (MED12L_v001):c.971del;p.(pro324Glnfs∗18)) identified by WES. The clinical phenotype included mild motor and speech delay, oligodontia, and dysmorphic signs. Of note the patient also carried 2 de novo chromosomal balanced reciprocal translocations: 46,XY,t(1;2)(p33;p22),t(5;9)(p15;q21) and the authors note that Nizon et al. 2019 report a patient with a balanced reciprocal translocation suggesting that the MED12L loss-of-function variant may contribute to chromosomal instability.

PMID: 40957966 - Dutta et al 2025 - report a proband with likely pathogenic MED12L nonsense variant (p.Arg1210Ter) which is maternally inherited (father also sequenced). At 2.5 yo the proband was diagnosed with global developmental delay, absent speech, ASD, hyperactivity, exophoria and myopia. Developmental regression began between 18 - 24 months. She has frequent respiratory infections. The 19 yo mother has a clinical history which includes speech delay and learning disability, but features are much milder than the proband. The proband also has inherited a pathogenic GAMT variant from her mother and a pathogenic TNFRSF13B variant from her father but these are not thought to contribute to the ID phenotype.; Changed rating: GREEN; Changed publications to: 31155615, 36212160, 35920825, 40957966; Changed phenotypes to: Nizon-Isidor syndrome, OMIM:618872, Nizon-Isidor syndrome, MONDO:0030030; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v9.139 PTBP1 Arina Puzriakova changed review comment from: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update based on 27 individuals from 25 families identified in PMID: 40965981 with start-loss (89%) or missense (11%) variants, confirmed de novo in 23/27 (plus 2 sibs with variant inherited from symptomatic mother, and segregation data unavailable in 2 others).

Skeletal anomalies were seen in 24 (89%), with the most prominent abnormalities comprising shortening and dysplasia of long bones and phalanges. Radiographic features included brachymetacarpia, brachymetatarsia, brachydactyly, brachytelephalangy, brachymesophalangy, and rhizomelia. Advanced bone maturation, cone-shaped epiphyses, and other features such as vertebral dysplasia were also observed.; to: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update based on 27 individuals from 25 families identified in PMID: 40965981 with start-loss (89%) or missense (11%) variants, confirmed de novo in 23/27 (plus 2 sibs with variant inherited from symptomatic mother, and segregation data unavailable in 2 others).

DD was noted in 78%, behavioural problems in 30%, and ID in 26%, generally mild to moderate. Although ID is only seen in a subset of cases, inclusion on this panel would be beneficial in cases where other features such as skeletal abnormalities are less prominent or non existent. Inclusion on this panel would also ensure inclusion on the Hypotonic infant super panel which is plausibly relevant to younger patients with this condition.
Intellectual disability v9.137 AP1B1 Achchuthan Shanmugasundram Phenotypes for gene: AP1B1 were changed from Failure to thrive; Abnormality of the skin; Hearing abnormality; Abnormality of copper homeostasis; Global developmental delay; Intellectual disability to Keratitis-ichthyosis-deafness syndrome, autosomal recessive, OMIM:242150; KID syndrome, MONDO:0018781
Intellectual disability v9.136 RELN Achchuthan Shanmugasundram changed review comment from: Biallelic variants in RELN are associated with 'lissencephaly with cerebellar hypoplasia' (MONDO:0019450) with 'Definitive' rating by the Brain Malformations GCEP expert panel in ClinGen. Intellectual disability is one of the presenting phenotypes of this disease as recorded in OMIM (MIM # 257320, record accessed on 17 October 2025). Biallelic RELN variants are also associated with the same phenotype with 'definitive' rating on the DD panel in Gene2Phenotype.

Monoallelic variants in RELN are associated with 'complex neurodevelopmental disorder' (MONDO:0100038) with 'Disputed' rating by the Intellectual Disability and Autism GCEP expert panel in ClinGen. However, the recent cases reported in PMID:35769015 were not included in ClinGen curation.

PMID:35769015 reported 13 individuals from seven families with six different heterozygous variants (four missense and two splice site variants). Of these 13 individuals, 11 had intellectual disability of variable severity (two severe, four moderate, four mild and one borderline). The missense variants were either absent or present at a very low allele frequency in gnomAD v4.1.0.

This gene is rated green with the MOI of 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' on the 'Intellectual disability syndromic and non-syndromic' panel of PanelApp Australia.; to: Biallelic variants in RELN are associated with 'lissencephaly with cerebellar hypoplasia' (MONDO:0019450) with 'Definitive' rating by the Brain Malformations GCEP expert panel in ClinGen. Intellectual disability is one of the presenting phenotypes of this disease as recorded in OMIM (MIM # 257320, record accessed on 17 October 2025). Biallelic RELN variants are also associated with the same phenotype with 'definitive' rating on the DD panel in Gene2Phenotype.

Monoallelic variants in RELN are associated with 'complex neurodevelopmental disorder' (MONDO:0100038) with 'Disputed' rating by the Intellectual Disability and Autism GCEP expert panel in ClinGen. However, the recent cases reported in PMID:35769015 were not included in ClinGen curation.

PMID:35769015 reported 13 individuals from seven families with six different heterozygous variants (four missense and two splice site variants). Of these 13 individuals, 11 had intellectual disability of variable severity (two severe, four moderate, four mild and one borderline). The missense variants were either absent or present at a very low allele frequency in gnomAD v4.1.0.

This gene is rated green with the MOI of 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' on the 'Intellectual disability syndromic and non-syndromic' panel of PanelApp Australia.

This gene can therefore remain green with the MOI of 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' on this panel.
Intellectual disability v9.136 RELN Achchuthan Shanmugasundram changed review comment from: Biallelic variants in RELN are associated with 'lissencephaly with cerebellar hypoplasia' (MONDO:0019450) with 'Definitive' rating by the Brain Malformations GCEP expert panel in ClinGen. Intellectual disability is one of the presenting phenotypes of this disease as recorded in OMIM (MIM # 257320, record accessed on 17 October 2025). Biallelic RELN variants are also associated with the same phenotype with 'definitive' rating on the DD panel in Gene2Phenotype.

Monoallelic variants in RELN are associated with 'complex neurodevelopmental disorder' (MONDO:0100038) with 'Disputed' rating by the Intellectual Disability and Autism GCEP expert panel in ClinGen. However, the recent cases reported in PMID:35769015 were not included in ClinGen curation.

PMID:35769015 reported 13 individuals from seven families with six different heterozygous variants (four missense, one frameshift and one exon. Of these 13 individuals, 11 had intellectual disability of variable severity (two severe, four moderate, four mild and one borderline). The missense variants were either absent present at a very low allele frequency in gnomAD v4.1.0; to: Biallelic variants in RELN are associated with 'lissencephaly with cerebellar hypoplasia' (MONDO:0019450) with 'Definitive' rating by the Brain Malformations GCEP expert panel in ClinGen. Intellectual disability is one of the presenting phenotypes of this disease as recorded in OMIM (MIM # 257320, record accessed on 17 October 2025). Biallelic RELN variants are also associated with the same phenotype with 'definitive' rating on the DD panel in Gene2Phenotype.

Monoallelic variants in RELN are associated with 'complex neurodevelopmental disorder' (MONDO:0100038) with 'Disputed' rating by the Intellectual Disability and Autism GCEP expert panel in ClinGen. However, the recent cases reported in PMID:35769015 were not included in ClinGen curation.

PMID:35769015 reported 13 individuals from seven families with six different heterozygous variants (four missense and two splice site variants). Of these 13 individuals, 11 had intellectual disability of variable severity (two severe, four moderate, four mild and one borderline). The missense variants were either absent or present at a very low allele frequency in gnomAD v4.1.0.

This gene is rated green with the MOI of 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' on the 'Intellectual disability syndromic and non-syndromic' panel of PanelApp Australia.
Intellectual disability v9.136 RELN Achchuthan Shanmugasundram changed review comment from: Biallelic variants in RELN are associated with 'lissencephaly with cerebellar hypoplasia' (MONDO:0019450) with 'Definitive' rating by the Brain Malformations GCEP expert panel in ClinGen. Intellectual disability is one of the presenting phenotypes of this disease as recorded in OMIM (MIM # 257320, record accessed on 17 October 2025). Biallelic RELN variants are also associated with the same phenotype with 'definitive' rating on the DD panel in Gene2Phenotype.

Monoallelic variants in RELN are associated with 'complex neurodevelopmental disorder' (MONDO:0100038) with 'Disputed' rating by the Intellectual Disability and Autism GCEP expert panel in ClinGen. However, the recent cases reported in PMID:35769015 were not included in ClinGen curation.

PMID:35769015 reported 13 individuals from seven families with six different heterozygous variants (four missense, one frameshift and one exon. Of these 13 individuals, 11 had intellectual disability of variable severity (two severe, four moderate, four mild and one borderline). The missense variants were either absent present at a very low allele frequency in gnomAD v4.1.0); to: Biallelic variants in RELN are associated with 'lissencephaly with cerebellar hypoplasia' (MONDO:0019450) with 'Definitive' rating by the Brain Malformations GCEP expert panel in ClinGen. Intellectual disability is one of the presenting phenotypes of this disease as recorded in OMIM (MIM # 257320, record accessed on 17 October 2025). Biallelic RELN variants are also associated with the same phenotype with 'definitive' rating on the DD panel in Gene2Phenotype.

Monoallelic variants in RELN are associated with 'complex neurodevelopmental disorder' (MONDO:0100038) with 'Disputed' rating by the Intellectual Disability and Autism GCEP expert panel in ClinGen. However, the recent cases reported in PMID:35769015 were not included in ClinGen curation.

PMID:35769015 reported 13 individuals from seven families with six different heterozygous variants (four missense, one frameshift and one exon. Of these 13 individuals, 11 had intellectual disability of variable severity (two severe, four moderate, four mild and one borderline). The missense variants were either absent present at a very low allele frequency in gnomAD v4.1.0
Intellectual disability v9.136 RELN Achchuthan Shanmugasundram changed review comment from: Biallelic variants in RELN are associated with 'lissencephaly with cerebellar hypoplasia' (MONDO:0019450) with 'Definitive' rating by the Brain Malformations GCEP expert panel in ClinGen. Intellectual disability is one of the presenting phenotypes of this disease as recorded in OMIM (MIM # 257320, record accessed on 17 October 2025). Biallelic RELN variants are also associated with the same phenotype with 'definitive' rating on the DD panel in Gene2Phenotype.

Monoallelic variants in RELN are associated with 'complex neurodevelopmental disorder' (MONDO:0100038) with 'Disputed' rating by the Intellectual Disability and Autism GCEP expert panel in ClinGen. However, the recent cases reported in PMID:35769015 were not included in ClinGen curation.

PMID:35769015 reported 13 individuals from seven families with seven different heterozygous variants. Of these 13 individuals, 6 patients from four families had moderate/ severe intellectual disability, while 4 patients had mild ID and one had ID of unspecified severity.; to: Biallelic variants in RELN are associated with 'lissencephaly with cerebellar hypoplasia' (MONDO:0019450) with 'Definitive' rating by the Brain Malformations GCEP expert panel in ClinGen. Intellectual disability is one of the presenting phenotypes of this disease as recorded in OMIM (MIM # 257320, record accessed on 17 October 2025). Biallelic RELN variants are also associated with the same phenotype with 'definitive' rating on the DD panel in Gene2Phenotype.

Monoallelic variants in RELN are associated with 'complex neurodevelopmental disorder' (MONDO:0100038) with 'Disputed' rating by the Intellectual Disability and Autism GCEP expert panel in ClinGen. However, the recent cases reported in PMID:35769015 were not included in ClinGen curation.

PMID:35769015 reported 13 individuals from seven families with six different heterozygous variants (four missense, one frameshift and one exon. Of these 13 individuals, 11 had intellectual disability of variable severity (two severe, four moderate, four mild and one borderline). The missense variants were either absent present at a very low allele frequency in gnomAD v4.1.0)
Intellectual disability v9.136 AP1B1 Ida Ertmanska changed review comment from: PMID: 31630791 Alsaif et al., 2019
Family 1: UK and Pakistani origin, consanguineous. Individual II:1, female, presented with congenital ichthyosis, enteropathy, and mild persisting hepatopathy, followed by failure to thrive, global developmental delay, and bilateral severe to profound sensorineural hearing loss.
Similarly affected brother II:2: ichthyosis with erythroderma and diarrhea in the neonatal period. Subsequent problems included enteropathy, severe failure to thrive, global developmental delay, hearing loss, narrow and incomplete cleft of the soft palate, anemia, and respiratory infections. Both homozygous for a gross deletion, (GRCh37/hg19) chr22: 29758984–29815476, which spans AP1B1 and RFPL1 (not yet associated with a disease). Persistently low plasma copper in both siblings.

Family 2: individual II:2 - 4yo boy born to consanguineous healthy Saudi parents. Phenotype: scaly skin, which evolved into generalized ichthyosis with associated palmoplantar hyperkeratosis. He later developed developmental delay, bilateral profound sensorineural deafness, and failure to thrive. Homozygous for AP1B1 NM_001127:c.38-1G>A, p.(Glu14Argfs∗5) - clinical exome.

PMID: 33452671 Vornweg et al., 2021
Female patient with compound het mutations in AP1B1: c.322C>T (p. Arg108Trp) and c.2254delC (p.Leu752Serfs*26). Method: WES + Sanger. Presented with ichthyosiform erythroderma and chronic, severe pruritus from birth; global developmental delay and failure to thrive, thickened plantar surface, bilateral ectropion and partial alopecia; developed bilateral deafness and moderate photophobia. Molecular examination demonstrated complete loss of AP1B1 protein in epidermis and isolated keratinocytes from patient’s skin.

PMID: 33349978 Ito et al., 2021
Report of 2yo Japanese boy. Compound het for AP1B1 c.1852C>T p.Gln618* and 2677C>T p.Gln893*. Method: WES. Presented with ichthyosis, moderate motor & mental retardation, failed the auditory brainstem response test bilatreally. Low calcium and serum copper levels.

PMID: 32969855 Meriç et al., 2021
11mo Turkish girl; consanguineous parents. Homozygous for (AP1B1:NM_001127) c.668T>C, p.Leu223Pro - WES. Presented with ichthyosis and developmental delay. Other symptoms: hearing loss, hepatomegaly, chronic diarrhea, partial alopecia, hyperkeratosis; eye examination showed photophobia and high myopia; diagnosed with mild ID at 7yo. Serum copper within normal limits.

PMID: 35144013 Faghihi et al., 2022
Proband: 6.5yr old boy, consanguineous parents. Homozygous for AP1B1 (NM_001127.4: c.1263C>A, p.Tyr421*) - WES. Presented with developmental delay, keratitis, ichthyosis, and hearing loss. Plasma copper (9 mmol/L) was decreased on several occasions.

AP1B1 is associated with Keratitis-ichthyosis-deafness syndrome, autosomal recessive, 242150 in OMIM (accessed 17th Oct 2025).; to: PMID: 31630791 Alsaif et al., 2019
Family 1: UK and Pakistani origin, consanguineous. Individual II:1, female, presented with congenital ichthyosis, enteropathy, and mild persisting hepatopathy, followed by failure to thrive, global developmental delay, and bilateral severe to profound sensorineural hearing loss.
Similarly affected brother II:2: ichthyosis with erythroderma and diarrhea in the neonatal period. Subsequent problems included enteropathy, severe failure to thrive, global developmental delay, hearing loss, narrow and incomplete cleft of the soft palate, anemia, and respiratory infections. Both homozygous for a gross deletion, (GRCh37/hg19) chr22: 29758984–29815476, which spans AP1B1 and RFPL1 (not yet associated with a disease). Persistently low plasma copper in both siblings.

Family 2: individual II:2 - 4yo boy born to consanguineous healthy Saudi parents. Phenotype: scaly skin, which evolved into generalized ichthyosis with associated palmoplantar hyperkeratosis. He later developed developmental delay, bilateral profound sensorineural deafness, and failure to thrive. Homozygous for AP1B1 NM_001127:c.38-1G>A, p.(Glu14Argfs∗5) - clinical exome.

PMID: 33452671 Vornweg et al., 2021
Female patient with compound het mutations in AP1B1: c.322C>T (p. Arg108Trp) and c.2254delC (p.Leu752Serfs*26). Method: WES + Sanger. Presented with ichthyosiform erythroderma and chronic, severe pruritus from birth; global developmental delay and failure to thrive, thickened plantar surface, bilateral ectropion and partial alopecia; developed bilateral deafness and moderate photophobia. Molecular examination demonstrated complete loss of AP1B1 protein in epidermis and isolated keratinocytes from patient’s skin.

PMID: 33349978 Ito et al., 2021
Report of 2yo Japanese boy. Compound het for AP1B1 c.1852C>T p.Gln618* and 2677C>T p.Gln893*. Method: WES. Presented with ichthyosis, moderate motor & mental retardation, failed the auditory brainstem response test bilatreally. Low calcium and serum copper levels.

PMID: 32969855 Meriç et al., 2021
11mo Turkish girl; consanguineous parents. Homozygous for (AP1B1:NM_001127) c.668T>C, p.Leu223Pro - WES. Presented with ichthyosis and developmental delay. Other symptoms: hearing loss, hepatomegaly, chronic diarrhea, partial alopecia, hyperkeratosis; eye examination showed photophobia and high myopia; diagnosed with mild ID at 7yo. Serum copper within normal limits.

PMID: 35144013 Faghihi et al., 2022
Proband: 6.5yr old boy, consanguineous parents. Homozygous for AP1B1 (NM_001127.4: c.1263C>A, p.Tyr421*) - WES. Presented with developmental delay, keratitis, ichthyosis, and hearing loss. Plasma copper (9 mmol/L) was decreased on several occasions.

AP1B1 is associated with Keratitis-ichthyosis-deafness syndrome, autosomal recessive, 242150 in OMIM (accessed 17th Oct 2025).
This gene was classified as Definitive for AR ichthyosiform erythroderma, corneal involvement, and hearing loss by ClinGen (General Inborn Errors of Metabolism Expert Panel, Aug 2024).
Intellectual disability v9.136 AP1B1 Ida Ertmanska changed review comment from: PMID: 31630791 Alsaif et al., 2019
Family 1: UK and Pakistani origin, consanguineous. Individual II:1, female, presented with congenital ichthyosis, enteropathy, and mild persisting hepatopathy, followed by failure to thrive, global developmental delay, and bilateral severe to profound sensorineural hearing loss.
Similarly affected brother II:2: ichthyosis with erythroderma and diarrhea in the neonatal period. Subsequent problems included enteropathy, severe failure to thrive, global developmental delay, hearing loss, narrow and incomplete cleft of the soft palate, anemia, and respiratory infections. Both homozygous for a gross deletion, (GRCh37/hg19) chr22: 29758984–29815476, which spans AP1B1 and RFPL1 (not yet associated with a disease). Persistently low plasma copper in both siblings.

Family 2: individual II:2 - 4yo boy born to consanguineous healthy Saudi parents. Phenotype: scaly skin, which evolved into generalized ichthyosis with associated palmoplantar hyperkeratosis. He later developed developmental delay, bilateral profound sensorineural deafness, and failure to thrive. Homozygous for AP1B1 NM_001127:c.38-1G>A, p.(Glu14Argfs∗5) - clinical exome.

PMID: 33452671 Vornweg et al., 2021
Female patient with compound het mutations in AP1B1: c.322C>T (p. Arg108Trp) and c.2254delC (p.Leu752Serfs*26). Method: WES + Sanger. Presented with ichthyosiform erythroderma and chronic, severe pruritus from birth; global developmental delay and failure to thrive, thickened plantar surface, bilateral ectropion and partial alopecia. Molecular examination demonstrated complete loss of AP1B1 protein in epidermis and isolated keratinocytes from patient’s skin.

PMID: 33349978 Ito et al., 2021
Report of 2yo Japanese boy. Compound het for AP1B1 c.1852C>T p.Gln618* and 2677C>T p.Gln893*. Method: WES. Presented with ichthyosis, moderate motor & mental retardation, failed the auditory brainstem response test bilatreally. Low calcium and serum copper levels.

PMID: 32969855 Meriç et al., 2021
11mo Turkish girl; consanguineous parents. Homozygous for (AP1B1:NM_001127) c.668T>C, p.Leu223Pro - WES. Presented with ichthyosis and developmental delay. Other symptoms: hearing loss, hepatomegaly, chronic diarrhea, partial alopecia, hyperkeratosis; eye examination showed photophobia and high myopia; diagnosed with mild ID at 7yo. Serum copper within normal limits.

PMID: 35144013 Faghihi et al., 2022
Proband: 6.5yr old boy, consanguineous parents. Homozygous for AP1B1 (NM_001127.4: c.1263C>A, p.Tyr421*) - WES. Presented with developmental delay, keratitis, ichthyosis, and hearing loss. Plasma copper (9 mmol/L) was decreased on several occasions.

AP1B1 is associated with Keratitis-ichthyosis-deafness syndrome, autosomal recessive, 242150 in OMIM (accessed 17th Oct 2025).; to: PMID: 31630791 Alsaif et al., 2019
Family 1: UK and Pakistani origin, consanguineous. Individual II:1, female, presented with congenital ichthyosis, enteropathy, and mild persisting hepatopathy, followed by failure to thrive, global developmental delay, and bilateral severe to profound sensorineural hearing loss.
Similarly affected brother II:2: ichthyosis with erythroderma and diarrhea in the neonatal period. Subsequent problems included enteropathy, severe failure to thrive, global developmental delay, hearing loss, narrow and incomplete cleft of the soft palate, anemia, and respiratory infections. Both homozygous for a gross deletion, (GRCh37/hg19) chr22: 29758984–29815476, which spans AP1B1 and RFPL1 (not yet associated with a disease). Persistently low plasma copper in both siblings.

Family 2: individual II:2 - 4yo boy born to consanguineous healthy Saudi parents. Phenotype: scaly skin, which evolved into generalized ichthyosis with associated palmoplantar hyperkeratosis. He later developed developmental delay, bilateral profound sensorineural deafness, and failure to thrive. Homozygous for AP1B1 NM_001127:c.38-1G>A, p.(Glu14Argfs∗5) - clinical exome.

PMID: 33452671 Vornweg et al., 2021
Female patient with compound het mutations in AP1B1: c.322C>T (p. Arg108Trp) and c.2254delC (p.Leu752Serfs*26). Method: WES + Sanger. Presented with ichthyosiform erythroderma and chronic, severe pruritus from birth; global developmental delay and failure to thrive, thickened plantar surface, bilateral ectropion and partial alopecia; developed bilateral deafness and moderate photophobia. Molecular examination demonstrated complete loss of AP1B1 protein in epidermis and isolated keratinocytes from patient’s skin.

PMID: 33349978 Ito et al., 2021
Report of 2yo Japanese boy. Compound het for AP1B1 c.1852C>T p.Gln618* and 2677C>T p.Gln893*. Method: WES. Presented with ichthyosis, moderate motor & mental retardation, failed the auditory brainstem response test bilatreally. Low calcium and serum copper levels.

PMID: 32969855 Meriç et al., 2021
11mo Turkish girl; consanguineous parents. Homozygous for (AP1B1:NM_001127) c.668T>C, p.Leu223Pro - WES. Presented with ichthyosis and developmental delay. Other symptoms: hearing loss, hepatomegaly, chronic diarrhea, partial alopecia, hyperkeratosis; eye examination showed photophobia and high myopia; diagnosed with mild ID at 7yo. Serum copper within normal limits.

PMID: 35144013 Faghihi et al., 2022
Proband: 6.5yr old boy, consanguineous parents. Homozygous for AP1B1 (NM_001127.4: c.1263C>A, p.Tyr421*) - WES. Presented with developmental delay, keratitis, ichthyosis, and hearing loss. Plasma copper (9 mmol/L) was decreased on several occasions.

AP1B1 is associated with Keratitis-ichthyosis-deafness syndrome, autosomal recessive, 242150 in OMIM (accessed 17th Oct 2025).
Intellectual disability v9.136 AP1B1 Ida Ertmanska edited their review of gene: AP1B1: Changed phenotypes to: Keratitis-ichthyosis-deafness syndrome, autosomal recessive, OMIM:242150, ichthyosiform erythroderma, corneal involvement, and hearing loss, MONDO:0009440
Intellectual disability v9.136 AP1B1 Ida Ertmanska changed review comment from: Comment on list classification: There are at least 6 unrelated individuals with Keratitis-ichthyosis-deafness syndrome, harbouring biallelic variants in AP1B1. 6/6 individuals presented with global developmental delay from birth - including delayed motor milestones and delay in speech development. While there is severe developmental delay within the first months of life, it seems to mostly resolve in later childhood, it may be the first presenting symptom, alongside ichthyosis. Hence, this gene fits into the scope of the Intellectual disability panel, and should be promoted to Green at the next GMS update.; to: Comment on list classification: There are at least 6 unrelated individuals with Keratitis-ichthyosis-deafness syndrome, harbouring biallelic variants in AP1B1. 6/6 individuals presented with global developmental delay from birth - including delayed motor milestones and delay in speech development. While the severe developmental delay in the neonatal period seems to mostly resolve in later childhood, it may be the first presenting symptom, alongside ichthyosis. Hence, this gene fits into the scope of the Intellectual disability panel, and should be promoted to Green at the next GMS update.
Intellectual disability v9.136 AP1B1 Ida Ertmanska changed review comment from: PMID: 31630791 Alsaif et al., 2019
Family 1: UK and Pakistani origin, consanguineous. Individual II:1, female, presented with congenital ichthyosis, enteropathy, and mild persisting hepatopathy, followed by failure to thrive, global developmental delay, and bilateral severe to profound sensorineural hearing loss.
Similarly affected brother II:2: ichthyosis with erythroderma and diarrhea in the neonatal period. Subsequent problems included enteropathy, severe failure to thrive, global developmental delay, hearing loss, narrow and incomplete cleft of the soft palate, anemia, and respiratory infections. Both homozygous for a gross deletion, (GRCh37/hg19) chr22: 29758984–29815476, which spans AP1B1 and RFPL1 (not yet associated with a disease). Persistently low plasma copper in both siblings.

Family 2: individual II:2 - 4yo boy born to consanguineous healthy Saudi parents. Phenotype: scaly skin, which evolved into generalized ichthyosis with associated palmoplantar hyperkeratosis. He later developed developmental delay, bilateral profound sensorineural deafness, and failure to thrive. Homozygous for AP1B1 NM_001127:c.38-1G>A, p.(Glu14Argfs∗5) - clinical exome.


PMID: 33452671 Vornweg et al., 2021
Female patient with compound het mutations in AP1B1: c.322C>T (p. Arg108Trp) and c.2254delC (p.Leu752Serfs*26). Method: WES + Sanger. Presented with ichthyosiform erythroderma and chronic, severe pruritus from birth; global developmental delay and failure to thrive, thickened plantar surface, bilateral ectropion and partial alopecia. Molecular examination demonstrated complete loss of AP1B1 protein in epidermis and isolated keratinocytes from patient’s skin.

PMID: 33349978 Ito et al., 2021
Report of 2yo Japanese boy. Compound het for AP1B1 c.1852C>T p.Gln618* and 2677C>T p.Gln893*. Method: WES. Presented with ichthyosis, moderate motor & mental retardation, failed the auditory brainstem response test bilatreally. Low calcium and serum copper levels.

PMID: 32969855 Meriç et al., 2021
11mo Turkish girl; consanguineous parents. Homozygous for (AP1B1:NM_001127) c.668T>C, p.Leu223Pro - WES. Presented with ichthyosis and developmental delay. Other symptoms: hearing loss, hepatomegaly, chronic diarrhea, partial alopecia, hyperkeratosis; eye examination showed photophobia and high myopia; diagnosed with mild ID at 7yo. Serum copper within normal limits.

PMID: 35144013 Faghihi et al., 2022
Proband: 6.5yr old boy, consanguineous parents. Homozygous for AP1B1 (NM_001127.4: c.1263C>A, p.Tyr421*) - WES. Presented with developmental delay, keratitis, ichthyosis, and hearing loss. Plasma copper (9 mmol/L) was decreased on several occasions.

Severe failure to thrive and developmental delay within the first months of life seem to be compensated in later childhood.

AP1B1 is associated with Keratitis-ichthyosis-deafness syndrome, autosomal recessive, 242150 in OMIM (accessed 17th Oct 2025).; to: PMID: 31630791 Alsaif et al., 2019
Family 1: UK and Pakistani origin, consanguineous. Individual II:1, female, presented with congenital ichthyosis, enteropathy, and mild persisting hepatopathy, followed by failure to thrive, global developmental delay, and bilateral severe to profound sensorineural hearing loss.
Similarly affected brother II:2: ichthyosis with erythroderma and diarrhea in the neonatal period. Subsequent problems included enteropathy, severe failure to thrive, global developmental delay, hearing loss, narrow and incomplete cleft of the soft palate, anemia, and respiratory infections. Both homozygous for a gross deletion, (GRCh37/hg19) chr22: 29758984–29815476, which spans AP1B1 and RFPL1 (not yet associated with a disease). Persistently low plasma copper in both siblings.

Family 2: individual II:2 - 4yo boy born to consanguineous healthy Saudi parents. Phenotype: scaly skin, which evolved into generalized ichthyosis with associated palmoplantar hyperkeratosis. He later developed developmental delay, bilateral profound sensorineural deafness, and failure to thrive. Homozygous for AP1B1 NM_001127:c.38-1G>A, p.(Glu14Argfs∗5) - clinical exome.

PMID: 33452671 Vornweg et al., 2021
Female patient with compound het mutations in AP1B1: c.322C>T (p. Arg108Trp) and c.2254delC (p.Leu752Serfs*26). Method: WES + Sanger. Presented with ichthyosiform erythroderma and chronic, severe pruritus from birth; global developmental delay and failure to thrive, thickened plantar surface, bilateral ectropion and partial alopecia. Molecular examination demonstrated complete loss of AP1B1 protein in epidermis and isolated keratinocytes from patient’s skin.

PMID: 33349978 Ito et al., 2021
Report of 2yo Japanese boy. Compound het for AP1B1 c.1852C>T p.Gln618* and 2677C>T p.Gln893*. Method: WES. Presented with ichthyosis, moderate motor & mental retardation, failed the auditory brainstem response test bilatreally. Low calcium and serum copper levels.

PMID: 32969855 Meriç et al., 2021
11mo Turkish girl; consanguineous parents. Homozygous for (AP1B1:NM_001127) c.668T>C, p.Leu223Pro - WES. Presented with ichthyosis and developmental delay. Other symptoms: hearing loss, hepatomegaly, chronic diarrhea, partial alopecia, hyperkeratosis; eye examination showed photophobia and high myopia; diagnosed with mild ID at 7yo. Serum copper within normal limits.

PMID: 35144013 Faghihi et al., 2022
Proband: 6.5yr old boy, consanguineous parents. Homozygous for AP1B1 (NM_001127.4: c.1263C>A, p.Tyr421*) - WES. Presented with developmental delay, keratitis, ichthyosis, and hearing loss. Plasma copper (9 mmol/L) was decreased on several occasions.

AP1B1 is associated with Keratitis-ichthyosis-deafness syndrome, autosomal recessive, 242150 in OMIM (accessed 17th Oct 2025).
Intellectual disability v9.136 AP1B1 Ida Ertmanska edited their review of gene: AP1B1: Added comment: Comment on list classification: There are at least 6 unrelated individuals with Keratitis-ichthyosis-deafness syndrome, harbouring biallelic variants in AP1B1. 6/6 individuals presented with global developmental delay from birth - including delayed motor milestones and delay in speech development. While there is severe developmental delay within the first months of life, it seems to mostly resolve in later childhood, it may be the first presenting symptom, alongside ichthyosis. Hence, this gene fits into the scope of the Intellectual disability panel, and should be promoted to Green at the next GMS update.; Changed rating: GREEN; Changed publications to: 31630791, 33452671, 33349978, 32969855, 35144013; Changed phenotypes to: Keratitis-ichthyosis-deafness syndrome, autosomal recessive, OMIM:242150; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v9.136 AP1B1 Ida Ertmanska changed review comment from: PMID: 31630791 Alsaif et al., 2019
Family 1: UK and Pakistani origin, consanguineous. Individual II:1, female, presented with congenital ichthyosis, enteropathy, and mild persisting hepatopathy, followed by failure to thrive, global developmental delay, and bilateral severe to profound sensorineural hearing loss.
Similarly affected brother II:2: ichthyosis with erythroderma and diarrhea in the neonatal period. Subsequent problems included enteropathy, severe failure to thrive, global developmental delay, hearing loss, narrow and incomplete cleft of the soft palate, anemia, and respiratory infections. Both homozygous for a gross deletion, (GRCh37/hg19) chr22: 29758984–29815476, which spans AP1B1 and RFPL1 (not yet associated with a disease). Persistently low plasma copper in both siblings.

Family 2: individual II:2 - 4yo boy born to consanguineous healthy Saudi parents. Phenotype: scaly skin, which evolved into generalized ichthyosis with associated palmoplantar hyperkeratosis. He later developed developmental delay, bilateral profound sensorineural deafness, and failure to thrive. Homozygous for AP1B1 NM_001127:c.38-1G>A, p.(Glu14Argfs∗5) - clinical exome.


PMID: 33452671 Vornweg et al., 2021
Female patient with compound het mutations in AP1B1: c.322C>T (p. Arg108Trp) and c.2254delC (p.Leu752Serfs*26). Method: WES + Sanger. Presented with ichthyosiform erythroderma and chronic, severe pruritus from birth; global developmental delay and failure to thrive, thickened plantar surface, bilateral ectropion and partial alopecia. Molecular examination demonstrated complete loss of AP1B1 protein in epidermis and isolated keratinocytes from patient’s skin.

PMID: 33349978 Ito et al., 2021
Report of 2yo Japanese boy. Compound het for AP1B1 c.1852C>T p.Gln618* and 2677C>T p.Gln893*. Method: WES. Presented with ichthyosis, moderate motor & mental retardation, failed the auditory brainstem response test bilatreally. Low calcium and serum copper levels.

PMID: 32969855 Meriç et al., 2021
11mo Turkish girl; consanguineous parents. Homozygous for (AP1B1:NM_001127) c.668T>C, p.Leu223Pro - WES. Presented with ichthyosis and developmental delay. Other symptoms: hearing loss, hepatomegaly, chronic diarrhea, partial alopecia, hyperkeratosis; eye examination showed photophobia and high myopia; diagnosed with mild ID at 7yo. Serum copper within normal limits.

Severe failure to thrive and developmental delay within the first months of life seem to be compensated in later childhood.


AP1B1 is associated with Keratitis-ichthyosis-deafness syndrome, autosomal recessive, 242150 in OMIM (accessed 17th Oct 2025).; to: PMID: 31630791 Alsaif et al., 2019
Family 1: UK and Pakistani origin, consanguineous. Individual II:1, female, presented with congenital ichthyosis, enteropathy, and mild persisting hepatopathy, followed by failure to thrive, global developmental delay, and bilateral severe to profound sensorineural hearing loss.
Similarly affected brother II:2: ichthyosis with erythroderma and diarrhea in the neonatal period. Subsequent problems included enteropathy, severe failure to thrive, global developmental delay, hearing loss, narrow and incomplete cleft of the soft palate, anemia, and respiratory infections. Both homozygous for a gross deletion, (GRCh37/hg19) chr22: 29758984–29815476, which spans AP1B1 and RFPL1 (not yet associated with a disease). Persistently low plasma copper in both siblings.

Family 2: individual II:2 - 4yo boy born to consanguineous healthy Saudi parents. Phenotype: scaly skin, which evolved into generalized ichthyosis with associated palmoplantar hyperkeratosis. He later developed developmental delay, bilateral profound sensorineural deafness, and failure to thrive. Homozygous for AP1B1 NM_001127:c.38-1G>A, p.(Glu14Argfs∗5) - clinical exome.


PMID: 33452671 Vornweg et al., 2021
Female patient with compound het mutations in AP1B1: c.322C>T (p. Arg108Trp) and c.2254delC (p.Leu752Serfs*26). Method: WES + Sanger. Presented with ichthyosiform erythroderma and chronic, severe pruritus from birth; global developmental delay and failure to thrive, thickened plantar surface, bilateral ectropion and partial alopecia. Molecular examination demonstrated complete loss of AP1B1 protein in epidermis and isolated keratinocytes from patient’s skin.

PMID: 33349978 Ito et al., 2021
Report of 2yo Japanese boy. Compound het for AP1B1 c.1852C>T p.Gln618* and 2677C>T p.Gln893*. Method: WES. Presented with ichthyosis, moderate motor & mental retardation, failed the auditory brainstem response test bilatreally. Low calcium and serum copper levels.

PMID: 32969855 Meriç et al., 2021
11mo Turkish girl; consanguineous parents. Homozygous for (AP1B1:NM_001127) c.668T>C, p.Leu223Pro - WES. Presented with ichthyosis and developmental delay. Other symptoms: hearing loss, hepatomegaly, chronic diarrhea, partial alopecia, hyperkeratosis; eye examination showed photophobia and high myopia; diagnosed with mild ID at 7yo. Serum copper within normal limits.

PMID: 35144013 Faghihi et al., 2022
Proband: 6.5yr old boy, consanguineous parents. Homozygous for AP1B1 (NM_001127.4: c.1263C>A, p.Tyr421*) - WES. Presented with developmental delay, keratitis, ichthyosis, and hearing loss. Plasma copper (9 mmol/L) was decreased on several occasions.

Severe failure to thrive and developmental delay within the first months of life seem to be compensated in later childhood.

AP1B1 is associated with Keratitis-ichthyosis-deafness syndrome, autosomal recessive, 242150 in OMIM (accessed 17th Oct 2025).
Intellectual disability v9.136 AP1B1 Ida Ertmanska changed review comment from: PMID: 31630791 Alsaif et al., 2019
Family 1: UK and Pakistani origin, consanguineous. Individual II:1, female, presented with congenital ichthyosis, enteropathy, and mild persisting hepatopathy, followed by failure to thrive, global developmental delay, and bilateral severe to profound sensorineural hearing loss.
Similarly affected brother II:2: ichthyosis with erythroderma and diarrhea in the neonatal period. Subsequent problems included enteropathy, severe failure to thrive, global developmental delay, hearing loss, narrow and incomplete cleft of the soft palate, anemia, and respiratory infections. Both homozygous for a gross deletion, (GRCh37/hg19) chr22: 29758984–29815476, which spans AP1B1 and RFPL1 (not yet associated with a disease). Persistently low plasma copper in both siblings.

Family 2: individual II:2 - 4yo boy born to consanguineous healthy Saudi parents. Phenotype: scaly skin, which evolved into generalized ichthyosis with associated palmoplantar hyperkeratosis. He later developed developmental delay, bilateral profound sensorineural deafness, and failure to thrive. Homozygous for AP1B1 NM_001127:c.38-1G>A, p.(Glu14Argfs∗5) - clinical exome.


PMID: 33452671 Vornweg et al., 2021
Female patient with compound het mutations in AP1B1: c.322C>T (p. Arg108Trp) and c.2254delC (p.Leu752Serfs*26). Method: WES + Sanger. Presented with ichthyosiform erythroderma and chronic, severe pruritus from birth; global developmental delay and failure to thrive, thickened plantar surface, bilateral ectropion and partial alopecia. Molecular examination demonstrated complete loss of AP1B1 protein in epidermis and isolated keratinocytes from patient’s skin.

PMID: 33349978 Ito et al., 2021
Report of 2yo Japanese boy. Compound het for AP1B1 c.1852C>T p.Gln618* and 2677C>T p.Gln893*. Method: WES. Presented with ichthyosis, moderate motor & mental retardation, failed the auditory brainstem response test bilatreally. Low calcium and serum copper levels.

Severe failure to thrive and developmental delay within the first months of life seem to be compensated in later childhood.


AP1B1 is associated with Keratitis-ichthyosis-deafness syndrome, autosomal recessive, 242150 in OMIM (accessed 17th Oct 2025).; to: PMID: 31630791 Alsaif et al., 2019
Family 1: UK and Pakistani origin, consanguineous. Individual II:1, female, presented with congenital ichthyosis, enteropathy, and mild persisting hepatopathy, followed by failure to thrive, global developmental delay, and bilateral severe to profound sensorineural hearing loss.
Similarly affected brother II:2: ichthyosis with erythroderma and diarrhea in the neonatal period. Subsequent problems included enteropathy, severe failure to thrive, global developmental delay, hearing loss, narrow and incomplete cleft of the soft palate, anemia, and respiratory infections. Both homozygous for a gross deletion, (GRCh37/hg19) chr22: 29758984–29815476, which spans AP1B1 and RFPL1 (not yet associated with a disease). Persistently low plasma copper in both siblings.

Family 2: individual II:2 - 4yo boy born to consanguineous healthy Saudi parents. Phenotype: scaly skin, which evolved into generalized ichthyosis with associated palmoplantar hyperkeratosis. He later developed developmental delay, bilateral profound sensorineural deafness, and failure to thrive. Homozygous for AP1B1 NM_001127:c.38-1G>A, p.(Glu14Argfs∗5) - clinical exome.


PMID: 33452671 Vornweg et al., 2021
Female patient with compound het mutations in AP1B1: c.322C>T (p. Arg108Trp) and c.2254delC (p.Leu752Serfs*26). Method: WES + Sanger. Presented with ichthyosiform erythroderma and chronic, severe pruritus from birth; global developmental delay and failure to thrive, thickened plantar surface, bilateral ectropion and partial alopecia. Molecular examination demonstrated complete loss of AP1B1 protein in epidermis and isolated keratinocytes from patient’s skin.

PMID: 33349978 Ito et al., 2021
Report of 2yo Japanese boy. Compound het for AP1B1 c.1852C>T p.Gln618* and 2677C>T p.Gln893*. Method: WES. Presented with ichthyosis, moderate motor & mental retardation, failed the auditory brainstem response test bilatreally. Low calcium and serum copper levels.

PMID: 32969855 Meriç et al., 2021
11mo Turkish girl; consanguineous parents. Homozygous for (AP1B1:NM_001127) c.668T>C, p.Leu223Pro - WES. Presented with ichthyosis and developmental delay. Other symptoms: hearing loss, hepatomegaly, chronic diarrhea, partial alopecia, hyperkeratosis; eye examination showed photophobia and high myopia; diagnosed with mild ID at 7yo. Serum copper within normal limits.

Severe failure to thrive and developmental delay within the first months of life seem to be compensated in later childhood.


AP1B1 is associated with Keratitis-ichthyosis-deafness syndrome, autosomal recessive, 242150 in OMIM (accessed 17th Oct 2025).
Intellectual disability v9.136 AP1B1 Ida Ertmanska changed review comment from: PMID: 31630791 Alsaif et al., 2019
Family 1: UK and Pakistani origin, consanguineous. Individual II:1, female, presented with congenital ichthyosis, enteropathy, and mild persisting hepatopathy, followed by failure to thrive, global developmental delay, and bilateral severe to profound sensorineural hearing loss. Similarly affected brother II:2: ichthyosis with erythroderma and diarrhea in the neonatal period. Subsequent problems included enteropathy, severe failure to thrive, global developmental delay, hearing loss, narrow and incomplete cleft of the soft palate, anemia, and respiratory infections. Both homozygous for a gross deletion, (GRCh37/hg19) chr22: 29758984–29815476, which spans AP1B1 and RFPL1 (not yet associated with a disease).
Family 2: individual II:2 - 4yo boy born to consanguineous healthy Saudi parents. Phenotype: scaly skin, which evolved into generalized ichthyosis with associated palmoplantar hyperkeratosis. He later developed developmental delay, bilateral profound sensorineural deafness, and failure to thrive. Homozygous for AP1B1 NM_001127:c.38-1G>A, p.(Glu14Argfs∗5) - clinical exome.
Persistently low plasma copper in both siblings.

PMID: 33452671 Vornweg et al., 2021
Female patient with compound het mutations in AP1B1: c.322C>T (p. Arg108Trp) and c.2254delC (p.Leu752Serfs*26). Method: WES + Sanger. Presented with ichthyosiform erythroderma and chronic, severe pruritus from birth; global developmental delay and failure to thrive, thickened plantar surface, bilateral ectropion and partial alopecia. Molecular examination demonstrated complete loss of AP1B1 protein in epidermis and isolated keratinocytes from patient’s skin.

PMID: 33349978 Ito et al., 2021
Report of 2yo Japanese boy. Compound het for AP1B1 c.1852C>T p.Gln618* and 2677C>T p.Gln893*. Method: WES. Presented with ichthyosis, moderate motor & mental retardation, failed the auditory brainstem response test bilatreally. Low calcium and serum copper levels.

Severe failure to thrive and developmental delay within the first months of life seem to be compensated in later childhood.


AP1B1 is associated with Keratitis-ichthyosis-deafness syndrome, autosomal recessive, 242150 in OMIM (accessed 17th Oct 2025).; to: PMID: 31630791 Alsaif et al., 2019
Family 1: UK and Pakistani origin, consanguineous. Individual II:1, female, presented with congenital ichthyosis, enteropathy, and mild persisting hepatopathy, followed by failure to thrive, global developmental delay, and bilateral severe to profound sensorineural hearing loss.
Similarly affected brother II:2: ichthyosis with erythroderma and diarrhea in the neonatal period. Subsequent problems included enteropathy, severe failure to thrive, global developmental delay, hearing loss, narrow and incomplete cleft of the soft palate, anemia, and respiratory infections. Both homozygous for a gross deletion, (GRCh37/hg19) chr22: 29758984–29815476, which spans AP1B1 and RFPL1 (not yet associated with a disease). Persistently low plasma copper in both siblings.

Family 2: individual II:2 - 4yo boy born to consanguineous healthy Saudi parents. Phenotype: scaly skin, which evolved into generalized ichthyosis with associated palmoplantar hyperkeratosis. He later developed developmental delay, bilateral profound sensorineural deafness, and failure to thrive. Homozygous for AP1B1 NM_001127:c.38-1G>A, p.(Glu14Argfs∗5) - clinical exome.


PMID: 33452671 Vornweg et al., 2021
Female patient with compound het mutations in AP1B1: c.322C>T (p. Arg108Trp) and c.2254delC (p.Leu752Serfs*26). Method: WES + Sanger. Presented with ichthyosiform erythroderma and chronic, severe pruritus from birth; global developmental delay and failure to thrive, thickened plantar surface, bilateral ectropion and partial alopecia. Molecular examination demonstrated complete loss of AP1B1 protein in epidermis and isolated keratinocytes from patient’s skin.

PMID: 33349978 Ito et al., 2021
Report of 2yo Japanese boy. Compound het for AP1B1 c.1852C>T p.Gln618* and 2677C>T p.Gln893*. Method: WES. Presented with ichthyosis, moderate motor & mental retardation, failed the auditory brainstem response test bilatreally. Low calcium and serum copper levels.

Severe failure to thrive and developmental delay within the first months of life seem to be compensated in later childhood.


AP1B1 is associated with Keratitis-ichthyosis-deafness syndrome, autosomal recessive, 242150 in OMIM (accessed 17th Oct 2025).
Intellectual disability v9.136 RELN Achchuthan Shanmugasundram commented on gene: RELN: Biallelic variants in RELN are associated with 'lissencephaly with cerebellar hypoplasia' (MONDO:0019450) with 'Definitive' rating by the Brain Malformations GCEP expert panel in ClinGen. Intellectual disability is one of the presenting phenotypes of this disease as recorded in OMIM (MIM # 257320, record accessed on 17 October 2025). Biallelic RELN variants are also associated with the same phenotype with 'definitive' rating on the DD panel in Gene2Phenotype.

Monoallelic variants in RELN are associated with 'complex neurodevelopmental disorder' (MONDO:0100038) with 'Disputed' rating by the Intellectual Disability and Autism GCEP expert panel in ClinGen. However, the recent cases reported in PMID:35769015 were not included in ClinGen curation.

PMID:35769015 reported 13 individuals from seven families with seven different heterozygous variants. Of these 13 individuals, 6 patients from four families had moderate/ severe intellectual disability, while 4 patients had mild ID and one had ID of unspecified severity.
Intellectual disability v9.135 SOD1 Arina Puzriakova changed review comment from: At least 10 individuals from 7 unrelated families have been identified with biallelic variants in the SOD1 gene and progressive spastic tetraplegia with age of onset before 2 years old. A recurrent variant (c.335dupG, p.Cys112Trpfs*11) was found in four apparently unrelated families of Afghan or Lebanese descent, while the other three families carried other homozygous LOF variants (c.357_357+2delGGT, c.52_56del5ins154, c.369_371del). Variants are predicted to lead to a completely non-functional enzyme product. The phenotype comprises early-onset progressive neuromuscular and developmental degeneration, leading to spastic tetraplegia and axial hypotonia. Most patients display global developmental delay (ranging from mild to profound cognitive impairment) and cerebellar atrophy.
Sources: Literature; to: At least 10 individuals from 7 unrelated families have been identified with biallelic variants in the SOD1 gene and progressive spastic tetraplegia with age of onset before 2 years old. A recurrent variant (c.335dupG, p.Cys112Trpfs*11) was found in four apparently unrelated families of Afghan or Lebanese descent, while the other three families carried other homozygous LOF variants (c.357_357+2delGGT, c.52_56del5ins154, c.369_371del). Variants are predicted to lead to a completely non-functional enzyme product. The phenotype comprises early-onset progressive neuromuscular and developmental degeneration, leading to spastic tetraplegia and axial hypotonia. Most patients display global developmental delay (ranging from mild to profound cognitive impairment) and cerebellar atrophy (PMIDs: 31314961; 31332433; 34380534; 34788402; 36935613; 39629626)

This gene is associated with a relevant phenotype in OMIM - Spastic tetraplegia and axial hypotonia, progressive, OMIM:618598 (accessed on 17-10-2025)
Sources: Literature
Intellectual disability v9.135 SOD1 Arina Puzriakova gene: SOD1 was added
gene: SOD1 was added to Intellectual disability. Sources: Literature
Q3_25_promote_green tags were added to gene: SOD1.
Mode of inheritance for gene: SOD1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SOD1 were set to 31314961; 31332433; 34380534; 34788402; 36935613; 39629626
Phenotypes for gene: SOD1 were set to Spastic tetraplegia and axial hypotonia, progressive, OMIM:618598
Review for gene: SOD1 was set to GREEN
Added comment: At least 10 individuals from 7 unrelated families have been identified with biallelic variants in the SOD1 gene and progressive spastic tetraplegia with age of onset before 2 years old. A recurrent variant (c.335dupG, p.Cys112Trpfs*11) was found in four apparently unrelated families of Afghan or Lebanese descent, while the other three families carried other homozygous LOF variants (c.357_357+2delGGT, c.52_56del5ins154, c.369_371del). Variants are predicted to lead to a completely non-functional enzyme product. The phenotype comprises early-onset progressive neuromuscular and developmental degeneration, leading to spastic tetraplegia and axial hypotonia. Most patients display global developmental delay (ranging from mild to profound cognitive impairment) and cerebellar atrophy.
Sources: Literature
Intellectual disability v9.134 RELN Achchuthan Shanmugasundram changed review comment from: In addition to previously reported cases, PMID:35769015 reported four families with biallelic RELN variants and neurodevelopmental disorder, of which one patient had global developmental delay and patients from another unrelated family had severe intellectual disability.

PMID:35769015 also reported seven unrelated families with monoallelic RELN variants and neurodevelopmental disorder, of which patients from three families had mild-severe intellectual disability.

Biallelic variants have been associated with Lissencephaly 2 in both OMIM (MIM #257320) and Gene2Phenotype (with 'definitive' rating in the DD panel), and impaired intellectual development has been associated as one of the clinical presentations in OMIM. Monoallelic variants have been associated with "{Epilepsy, familial temporal lobe, 7}" (MIM # 616436) in OMIM, which does not currently record ID as one of the clinical presentations.; to: In addition to previously reported cases, PMID:35769015 reported four families with biallelic RELN variants and neurodevelopmental disorder, of which one patient had global developmental delay and patients from another unrelated family had severe intellectual disability.

PMID:35769015 also reported seven unrelated families with monoallelic RELN variants and neurodevelopmental disorder, of which patients from all seven families had mild-severe intellectual disability.

Biallelic variants have been associated with Lissencephaly 2 in both OMIM (MIM #257320) and Gene2Phenotype (with 'definitive' rating in the DD panel), and impaired intellectual development has been associated as one of the clinical presentations in OMIM. Monoallelic variants have been associated with "{Epilepsy, familial temporal lobe, 7}" (MIM # 616436) in OMIM, which does not currently record ID as one of the clinical presentations.
Intellectual disability v9.130 KIRREL3 Achchuthan Shanmugasundram edited their review of gene: KIRREL3: Added comment: Monoallelic variants in KIRREL3 gene have been associated with complex neurodevelopmental disorder (MONDO:0100038) with 'Disputed' rating by the Intellectual Disability and Autism expert panel in ClinGen (https://search.clinicalgenome.org/CCID:005235).

ClinGen curation reported the reason for 'Disputed' rating as below:
To date, over 20 probands (PMIDs: 29271092, 32503885, 37007974) with KIRREL3 truncating or missense variants and complex neurodevelopmental disorder have been reported. However, none of the missense variants were scored due to their presence in gnomAD and/or inheritance from reportedly unaffected parents and a lack of evidence of pathogenicity. Although three truncating variants were reported, KIRREL3 is not constrained for truncating variants (pLI = 0, gnomAD v4.0.0) or missense variants (Z = 1.59). Hence, the truncating variants were also not scored. Although functional in vitro studies of five KIRREL3 missense variants observed in affected individuals showed decreased synapse formation in hippocampal neurons, and studies in homozygous null Kirrel3-/- mice and synapse deficits in cultured Kirrel3+/- mouse hippocampal neurons suggest that KIRREL3 plays a role in central nervous system development, none of the experimental evidence was scored due to the lack of compelling genetic evidence.

Small variants in this gene have not been associated with any phenotypes ion OMIM (record accessed on 17 October 2025). This gene is also associated with 'limited' rating on the DD panel of Gene2Phenotype and with red rating on the 'Intellectual disability syndromic and non-syndromic' panel of PanelApp Australia (https://panelapp-aus.org/panels/250/gene/KIRREL3/).; Changed rating: RED; Changed publications to: 19012874, 29271092, 32503885, 37007974
Intellectual disability v9.129 CDK9 Achchuthan Shanmugasundram Phenotypes for gene: CDK9 were changed from Global developmental delay; Intellectual disability; Abnormality of vision; Congenital cataract; Iris coloboma; Abnormal heart morphology; Choanal atresia; Abnormality of the ear; Preauricular skin tag; Hearing impairment; Abnormality of the genitourinary system; Abnormality of limbs; Abnormality of the vertebrae; Abnormality of nervous system morphology; Seizures to Global developmental delay HP:0001263; syndromic intellectual disability MONDO:0000508
Intellectual disability v9.128 CDK9 Ida Ertmanska changed review comment from: Comment on list classification: As reviewed by Konstantinos Varvagiannis and Sarah Leigh, there are at least 9 individuals from x unrelated families with biallelic CDK9 variants (PMID: 26633546; 29302074; 30237576; 33640901). These patients presented with a CHARGE-like syndromic phenotype that consistently includes global developmental delay (9/9) and/or intellectual disability (1 patient with 'severe ID'; 3 patients with moderate ID: WAIS-IV IQ of 40-43). Four different missense variants have been reported - all 4 are rare in gnomAD v4, with no homozygotes reported. Sequencing method: WES/WGS for all studies.
CDK9 is not yet associated with any phenotype in OMIM (accessed 14th Oct 2025). Based on the available evidence, CDK9 should be promoted to Green for Intellectual disability at the next GMS panel update.; to: Comment on list classification: As reviewed by Konstantinos Varvagiannis and Sarah Leigh, there are at least 9 unrelated individuals from consanguineous families with biallelic CDK9 variants (PMID: 26633546; 29302074; 30237576; 33640901). These patients presented with a CHARGE-like syndromic phenotype that consistently includes global developmental delay (9/9) and/or intellectual disability (1 patient with 'severe ID'; 3 patients with moderate ID: WAIS-IV IQ of 40-43). Four different missense variants have been reported - all 4 are rare in gnomAD v4, with no homozygotes reported. Sequencing method: WES/WGS for all studies.
CDK9 is not yet associated with any phenotype in OMIM (accessed 14th Oct 2025). Based on the available evidence, CDK9 should be promoted to Green for Intellectual disability at the next GMS panel update.
Intellectual disability v9.128 CDK9 Ida Ertmanska changed review comment from: Comment on list classification: As reviewed by Konstantinos Varvagiannis and Sarah Leigh, there are at least 9 individuals from x unrelated families with biallelic CDK9 variants (PMID: 26633546; 29302074; 30237576; 33640901). These patients presented with a CHARGE-like syndromic phenotype that consistently includes global developmental delay (9/9) and/or intellectual disability (1 patient with 'severe ID'; 3 patients with moderate ID: WAIS-IV IQ of 40-43). Four different missense variants have been reported - all 4 are rare in gnomAD v4, with no homozygotes reported. CDK9 is not yet associated with any phenotype in OMIM (accessed 14th Oct 2025). Based on the available evidence, CDK9 should be promoted to Green for Intellectual disability at the next GMS panel update.; to: Comment on list classification: As reviewed by Konstantinos Varvagiannis and Sarah Leigh, there are at least 9 individuals from x unrelated families with biallelic CDK9 variants (PMID: 26633546; 29302074; 30237576; 33640901). These patients presented with a CHARGE-like syndromic phenotype that consistently includes global developmental delay (9/9) and/or intellectual disability (1 patient with 'severe ID'; 3 patients with moderate ID: WAIS-IV IQ of 40-43). Four different missense variants have been reported - all 4 are rare in gnomAD v4, with no homozygotes reported. Sequencing method: WES/WGS for all studies.
CDK9 is not yet associated with any phenotype in OMIM (accessed 14th Oct 2025). Based on the available evidence, CDK9 should be promoted to Green for Intellectual disability at the next GMS panel update.
Intellectual disability v9.128 CDK9 Ida Ertmanska changed review comment from: Comment on list classification: As reviewed by Konstantinos Varvagiannis and Sarah Leigh, there are at least 9 individuals from x unrelated families with biallelic CDK9 variants (PMID: 26633546;29302074;30237576;33640901). These patients presented with a CHARGE-like syndromic phenotype that consistently includes global developmental delay (9/9) and/or intellectual disability (1 patient with 'severe ID'; 3 patients with moderate ID: WAIS-IV IQ of 40-43). Four different missense variants have been reported - all 4 are rare in gnomAD v4, with no homozygotes reported. CDK9 is not yet associated with any phenotype in OMIM (accessed 14th Oct 2025). Based on the available evidence, CDK9 should be promoted to Green for Intellectual disability at the next GMS panel update.; to: Comment on list classification: As reviewed by Konstantinos Varvagiannis and Sarah Leigh, there are at least 9 individuals from x unrelated families with biallelic CDK9 variants (PMID: 26633546; 29302074; 30237576; 33640901). These patients presented with a CHARGE-like syndromic phenotype that consistently includes global developmental delay (9/9) and/or intellectual disability (1 patient with 'severe ID'; 3 patients with moderate ID: WAIS-IV IQ of 40-43). Four different missense variants have been reported - all 4 are rare in gnomAD v4, with no homozygotes reported. CDK9 is not yet associated with any phenotype in OMIM (accessed 14th Oct 2025). Based on the available evidence, CDK9 should be promoted to Green for Intellectual disability at the next GMS panel update.
Intellectual disability v9.127 FICD Arina Puzriakova changed review comment from: Paper by Perera et al 2022 has now been published (PMID: 36704923).

An additional 6 unrelated families have been reported with biallelic variants in this gene presenting with motor neuron disease. Unlike the cases reported by Perera et al, these individuals did not display any significant cognitive deficits (PMID: 36136088; 40062579); to: Paper by Perera et al 2022 has now been published (PMID: 36704923).

An additional 6 unrelated families have been reported with biallelic variants in this gene presenting with motor neuron disease. Unlike the cases reported by Perera et al, these individuals did not display any significant cognitive deficits (PMID: 36136088; 40062579). Therefore maintaining the Amber rating on this panel.
Intellectual disability v9.125 PPOX Arina Puzriakova Phenotypes for gene: PPOX were changed from Porphyria variegata, 176200 to Variegate porphyria, childhood-onset, OMIM:620483; variegate porphyria, MONDO:0008297
Intellectual disability v9.122 OGDHL Ida Ertmanska changed review comment from: As reviewed by Arina Puzriakova, there are at least 10 individuals from 9 unrelated families with biallelic variants in OGDHL (PMIDs: 28017472; 34800363). The individuals present with a complex neurodevelopmental disorder, also known as Yoon-Bellen syndrome. The phenotype is highly variable between the cases and includes developmental delay / intellectual disability.

PMID: 38031187 Lin et al. 2023 - authors re-evaluate the evidence for the association between Yoon-Bellen neurodevelopmental syndrome and the OGDHL gene. The article reports further 14 individuals from 12 unrelated, diverse families, with biallelic OGDHL variants. Patients presented with a range of heterogeneous symptoms: neurodevelopmental disorder, neurodegeneration, infantile-onset epileptic encephalopathy, skeletal dysplasia, childhood-onset epilepsy, multiple congenital anomalies, dysmorphism, non-syndromic hearing loss, neuromuscular disorders, and congenital heart defects. 9/14 reported patients had developmental delay/intellectual disability. Due to the highly variable phenotype, authors propose 3 possible hypotheses: ‘biallelic OGDHL variants lead to a highly variable monogenic disorder, variants in OGDHL are following a complex pattern of inheritance, or they may not be causative at all’.

In total, 17/21 families reported in the above articles have history of consanguinity. In most cases, additional likely pathogenic mutations were discovered in other genes, which complicates the phenotypic understanding.

Functional evidence: A zebrafish knockout of Ogdhl (78% identical gene ortholog) resulted in a range of phenotypes: smaller head, eye, and body, and heart edema. No seizure manifestation, visual impairment, or hearing deficiencies were observed. Authors note elevated neuronal cell death in the eye, hindbrain, and spinal cord of knockout animals. The phenotype was rescued by injection of human OGDHL. Moreover, OGDHL, OGDH, and DHTKD1 are isoenzymes – through double and triple gene knockouts, authors provide evidence indicating a complex compensatory relationship (PMID: 38031187).

This gene should remain Green for Intellectual disability. There is strong evidence for the association between OGDHL and Yoon-Bellen neurodevelopmental syndrome. However, care should be taken not to attribute all clinical symptoms to OGDHL dysfunction.; to: As reviewed by Arina Puzriakova, there are at least 10 individuals from 9 unrelated families with biallelic variants in OGDHL (PMIDs: 28017472; 34800363). The individuals present with a complex neurodevelopmental disorder, also known as Yoon-Bellen syndrome. The phenotype is highly variable between the cases and includes developmental delay / intellectual disability.

PMID: 38031187 Lin et al. 2023 - authors re-evaluate the evidence for the association between Yoon-Bellen neurodevelopmental syndrome and the OGDHL gene. The article reports further 14 individuals from 12 unrelated, diverse families, with biallelic OGDHL variants. Patients presented with a range of heterogeneous symptoms: hypotonia (9/14), short stature and variable dysmorphic facial features (each 8/14), failure to thrive (7/14), developmental delay/intellectual disability (9/14), seizures (4/14), hearing loss (4/14), and microcephaly (3/14). Due to the highly variable phenotype, authors propose 3 possible hypotheses: ‘biallelic OGDHL variants lead to a highly variable monogenic disorder, variants in OGDHL are following a complex pattern of inheritance, or they may not be causative at all’.

In total, 17/21 families reported in the above articles have history of consanguinity. In most cases, additional likely pathogenic mutations were discovered in other genes, which complicates the phenotypic understanding.

Functional evidence: A zebrafish knockout of Ogdhl (78% identical gene ortholog) resulted in a range of phenotypes: smaller head, eye, and body, and heart edema. No seizure manifestation, visual impairment, or hearing deficiencies were observed. Authors note elevated neuronal cell death in the eye, hindbrain, and spinal cord of knockout animals. The phenotype was rescued by injection of human OGDHL. Moreover, OGDHL, OGDH, and DHTKD1 are isoenzymes – through double and triple gene knockouts, authors provide evidence indicating a complex compensatory relationship (PMID: 38031187).

This gene should remain Green for Intellectual disability. There is strong evidence for the association between OGDHL and Yoon-Bellen neurodevelopmental syndrome. However, care should be taken not to attribute all clinical symptoms to OGDHL dysfunction.
Intellectual disability v9.122 NAA60 Ida Ertmanska gene: NAA60 was added
gene: NAA60 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: NAA60 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NAA60 were set to 38480682
Phenotypes for gene: NAA60 were set to Basal ganglia calcification, idiopathic, 9, autosomal recessive, 620786; basal ganglia calcification, idiopathic, 9, autosomal recessive, MONDO:0968977
Review for gene: NAA60 was set to RED
Added comment: PMID: 38480682 Chelban et al., 2024
Report of 7 unrelated families with homozygous variants in NAA60 with primary familial brain calcifications. Families originated from UK, France/Algeria, France/Morocco, UK/India, Turkey, and Saudi Arabia. 5/7 families had reported consanguinity. Sequencing method: WGS, WES.
Variants reported: c.321_327del, (p.Arg108Thrfs*3); c.338-1G>C, p.(Gly113Valfs*32); c.391C>T, (p.His131Tyr); c.130C>T, (p.Arg44Cys); c.50T>G, (p.Leu17Arg); c.428A>C, (p.Asn143Thr). No homozygotes reported in gnomAD v4.
9/10 patients had some motor features: extrapyramidal, pyramidal, cerebellar syndrome, dystonia - onset mostly in 20s-30s, one individual had symptoms from age 10 years. 3/10 individuals had mild intellectual disability, 3/10 had developmental delay from birth. 5/10 patients had some dysmorphic features. All 10 patients had some cognitive features (mostly mild): cognitive impairment (adult-onset), mild frontal syndrome, learning difficulties.
CT and brain MRI confirmed the presence of brain calcifications in all reported adult cases (9).
Phenotype and age of onset was variable, even in individuals who harboured the same variant - e.g. siblings in Family 2, homozygous for the same variant: sib II-2 had no motor features, only presented with mild frontal syndrome in her early 30s; sib II-1 presented with global developmental delay from birth, with onset of motor symptoms at age 20 - extrapyramidal and cerebellar syndrome, dystonia.

NAA60 is associated with AR Basal ganglia calcification, idiopathic, 9, autosomal recessive, 620786 in OMIM (accessed 10th Oct 2025).
In summary, while some individuals presented with intellectual disability and cognitive impairment, their symptoms were mild. Thus, these cases do not meet the eligibility criteria of moderate/severe/profound global developmental delay/intellectual disability. Based on the available evidence, this gene should be rated Red for Intellectual disability.
Sources: Literature
Intellectual disability v9.122 SLC46A1 Arina Puzriakova Phenotypes for gene: SLC46A1 were changed from HEREDITARY FOLATE MALABSORPTION (HFM) to Folate malabsorption, hereditary, OMIM:229050
Intellectual disability v9.121 SF1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are fifteen unrelated patients reported with monoallelic SF1 variants and a neurodevelopmental disorder, of which four patients had intellectual disability of moderate severity. Hence, this gene can be promoted to green rating in the next update.
Intellectual disability v9.120 SF1 Achchuthan Shanmugasundram changed review comment from: As reviewed by Mike Spiller, PMID:40987292 reported a cohort of 15 unrelated individuals (eight males and seven females, aged from 2 to 22 years) with 15 different heterozygous variants in SF1 gene identified via exome or genome sequencing. All except two variants are absent in gnomAD v2.1.1, while two variants were identified with allele counts of 9 (intronic variant) and 1 in non-UK Biobank version of the database. 7 missense, 1 inframe delins, 4 NMD, 2 final exon truncations were reported in addition to the one intronic variant that should be disregarded.

All these 15 patients had developmental delay during the first years of life with seven of them having global developmental delay. Intellectual disability was reported in eight patients, of which four patients had ID of moderate severity and others had either ID of mild or unknown severity.

This gene has not yet been associated with relevant phenotypes in OMIM or in Gene2Phenotype.; to: As reviewed by Mike Spiller, PMID:40987292 reported a cohort of 15 unrelated individuals (eight males and seven females, aged from 2 to 22 years) with 15 different heterozygous variants in SF1 gene identified via exome or genome sequencing. All except two variants are absent in gnomAD v4.1.0 non-UK Biobank, while two variants were identified with allele counts of 9 (intronic variant) and 1 in non-UK Biobank version of the database. 7 missense, 1 inframe delins, 4 NMD, 2 final exon truncations were reported in addition to the one intronic variant that should be disregarded.

All these 15 patients had developmental delay during the first years of life with seven of them having global developmental delay. Intellectual disability was reported in eight patients, of which four patients had ID of moderate severity and others had either ID of mild or unknown severity.

This gene has not yet been associated with relevant phenotypes in OMIM or in Gene2Phenotype.
Intellectual disability v9.118 SF1 Achchuthan Shanmugasundram changed review comment from: As reviewed by Mike Spiller, PMID:40987292 reported a cohort of 15 unrelated individuals (eight males and seven females, aged from 2 to 22 years) with 15 different heterozygous variants in SF1 gene identified via exome or genome sequencing. All except two variants are absent in gnomAD v2.1.1, while two variants were identified with allele counts of 9 (intronic variant) and 1 in non-UK Biobank version of the database. 7 missense, 1 inframe delins, 4 NMD, 2 final exon truncations were reported in addition to the one intronic variant that should be disregarded.; to: As reviewed by Mike Spiller, PMID:40987292 reported a cohort of 15 unrelated individuals (eight males and seven females, aged from 2 to 22 years) with 15 different heterozygous variants in SF1 gene identified via exome or genome sequencing. All except two variants are absent in gnomAD v2.1.1, while two variants were identified with allele counts of 9 (intronic variant) and 1 in non-UK Biobank version of the database. 7 missense, 1 inframe delins, 4 NMD, 2 final exon truncations were reported in addition to the one intronic variant that should be disregarded.

All these 15 patients had developmental delay during the first years of life with seven of them having global developmental delay. Intellectual disability was reported in eight patients, of which four patients had ID of moderate severity and others had either ID of mild or unknown severity.

This gene has not yet been associated with relevant phenotypes in OMIM or in Gene2Phenotype.
Intellectual disability v9.117 PPOX Ida Ertmanska changed review comment from: Comment on mode of inheritance: Monoallelic PPOX variants usually result in Variegate Porphyria limited to cutaneous manifestations, with disease onset in adolescence or adulthood. Biallelic variants are known to cause Variegate Porphyria with a more severe, early-onset phenotype - skin lesions, along with neurologic and/ or neurodevelopmental symptoms. Hence, the mode of inheritance should be set to 'BIALLELIC, autosomal or pseudoautosomal'.; to: Comment on mode of inheritance: Monoallelic PPOX variants usually result in Variegate Porphyria limited to cutaneous manifestations, with disease onset in adolescence or adulthood. Biallelic variants are known to cause Variegate Porphyria with a more severe, early-onset phenotype - skin lesions, along with neurologic and/ or neurodevelopmental symptoms. Hence, the mode of inheritance should be set to 'BIALLELIC, autosomal or pseudoautosomal' for Intellectual disability.
Intellectual disability v9.117 PPOX Ida Ertmanska changed review comment from: Comment on mode of inheritance: Monoallelic PPOX variants usually result in Variegate Porphyria limited to cutaneous manifestations, with disease onset in adolescence or adulthood. Biallelic variants are known to cause Variegate Porphyria with a more severe, early-onset phenotype - skin lesions, along with neurologic and/ or neurodevelopmental symptoms. Hence, the mode of inheritance should be set to 'BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal'.; to: Comment on mode of inheritance: Monoallelic PPOX variants usually result in Variegate Porphyria limited to cutaneous manifestations, with disease onset in adolescence or adulthood. Biallelic variants are known to cause Variegate Porphyria with a more severe, early-onset phenotype - skin lesions, along with neurologic and/ or neurodevelopmental symptoms. Hence, the mode of inheritance should be set to 'BIALLELIC, autosomal or pseudoautosomal'.
Intellectual disability v9.117 LGI1 Ida Ertmanska changed review comment from: Comment on mode of inheritance: Monoallelic variants in LGI1 are associated with Autosomal Dominant Epilepsy with Auditory Features (ADEAF), which presents with later-onset and incomplete penetrance (e.g. PMID: 26773249 - cohort of 26 patients, average onset of epilepsy at 16.83 years).
Recent evidence identifies cases with biallelic LGI1 variants, presenting with a more severe phenotype, including seizures from birth, infantile lethality and severe developmental delay. There are at least 5 unrelated individuals reported with biallelic variants in LGI1, with infantile onset developmental and epileptic encephalopathy (PMID:40455867 Hirano et al., 2025; PMID:41000458 Mouhi et al., 2025).
Hence, the MOI should be updated from 'MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted' to 'BIALLELIC, autosomal or pseudoautosomal'.; to: Comment on mode of inheritance: Monoallelic variants in LGI1 are associated with Autosomal Dominant Epilepsy with Auditory Features (ADEAF), which presents with later-onset and incomplete penetrance (e.g. PMID: 26773249 - cohort of 26 patients, average onset of epilepsy at 16.83 years; not associated with intellectual disability).
Recent evidence identifies cases with biallelic LGI1 variants, presenting with a more severe phenotype, including seizures from birth, infantile lethality and severe developmental delay. There are at least 5 unrelated individuals reported with biallelic variants in LGI1, with infantile onset developmental and epileptic encephalopathy (PMID:40455867 Hirano et al., 2025; PMID:41000458 Mouhi et al., 2025).
Hence, the MOI should be updated from 'MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted' to 'BIALLELIC, autosomal or pseudoautosomal'.
Intellectual disability v9.117 LGI1 Ida Ertmanska changed review comment from: Comment on mode of inheritance: Monoallelic variants in LGI1 are associated with Autosomal Dominant Epilepsy with Auditory Features (ADEAF), which presents with later-onset and incomplete penetrance (e.g. PMID: 26773249 - cohort of 26 patients, average onset of epilepsy at 16.83 years).
Recent evidence identifies cases with biallelic LGI1 variants, presenting with a more severe phenotype, including seizures from birth, infantile lethality and severe developmental delay. There are at least 5 unrelated individuals reported with biallelic variants in LGI1, with infantile onset developmental and epileptic encephalopathy (PMID:40455867 Hirano et al., 2025; PMID:41000458 Mouhi et al., 2025).
Hence, the MOI should be updated 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: Monoallelic variants in LGI1 are associated with Autosomal Dominant Epilepsy with Auditory Features (ADEAF), which presents with later-onset and incomplete penetrance (e.g. PMID: 26773249 - cohort of 26 patients, average onset of epilepsy at 16.83 years).
Recent evidence identifies cases with biallelic LGI1 variants, presenting with a more severe phenotype, including seizures from birth, infantile lethality and severe developmental delay. There are at least 5 unrelated individuals reported with biallelic variants in LGI1, with infantile onset developmental and epileptic encephalopathy (PMID:40455867 Hirano et al., 2025; PMID:41000458 Mouhi et al., 2025).
Hence, the MOI should be updated from 'MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted' to 'BIALLELIC, autosomal or pseudoautosomal'.
Intellectual disability v9.116 PPOX Ida Ertmanska changed review comment from: Comment on list classification: Monoallelic PPOX variants usually result in Variegate Porphyria limited to cutaneous manifestations, with onset in adolescence or adulthood. Biallelic variants are known to cause Variegate Porphyria with a more severe, early-onset phenotype - skin lesions, along with neurologic and/ or neurodevelopmental symptoms: nystagmus, epileptic seizures, developmental delay, intellectual disability, and sensory neuropathy. As reviewed by Sharon Whatley, there are more than 3 unrelated individuals with Variegate Porphyria with biallelic variants in PPOX, who presented with developmental delay / childhood-onset intellectual disability: delayed motor skill acquisition, lack of speech acquisition, aggressivity, and other learning disabilities (PMIDs: 8290408; 9811936; 2004012; 35164799; 37879139; 40114189).
PPOX is associated with AD Variegate porphyria (176200) and AR Variegate porphyria, childhood onset (620483) in OMIM - accessed 7th October 2025.
Based on the available evidence, this gene should be rated Green for Intellectual disability.; to: Comment on list classification: Monoallelic PPOX variants usually result in Variegate Porphyria limited to cutaneous manifestations, with onset in adolescence or adulthood. Biallelic variants are known to cause Variegate Porphyria with a more severe, early-onset phenotype - skin lesions, along with neurologic and/ or neurodevelopmental symptoms: nystagmus, epileptic seizures, developmental delay, intellectual disability, and sensory neuropathy. As reviewed by Sharon Whatley, there are more than 3 unrelated individuals with Variegate Porphyria with biallelic variants in PPOX, who presented with severe developmental delay / childhood-onset intellectual disability: delayed motor skill acquisition, lack of speech acquisition, aggressivity, and other learning disabilities (PMIDs: 8290408; 9811936; 2004012; 35164799; 37879139; 40114189).
PPOX is associated with AD Variegate porphyria (176200) and AR Variegate porphyria, childhood onset (620483) in OMIM - accessed 7th October 2025.
Based on the available evidence, this gene should be rated Green for Intellectual disability.
Intellectual disability v9.116 PPOX Ida Ertmanska commented on gene: PPOX: Comment on mode of inheritance: Monoallelic PPOX variants usually result in Variegate Porphyria limited to cutaneous manifestations, with disease onset in adolescence or adulthood. Biallelic variants are known to cause Variegate Porphyria with a more severe, early-onset phenotype - skin lesions, along with neurologic and/ or neurodevelopmental symptoms. Hence, the mode of inheritance should be set to 'BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal'.
Intellectual disability v9.116 PPOX Ida Ertmanska changed review comment from: Comment on list classification: Variegate Porphyria symptoms include skin lesions, epileptic seizures, developmental delay, intellectual disability. As reviewed by Sharon Whatley, there are more than 3 unrelated individuals with Variegate Porphyria with biallelic variants in PPOX, who presented with developmental delay / childhood-onset intellectual disability, including: delayed motor skill acquisition, lack of speech acquisition, aggressivity, and other learning disabilities (PMIDs: 6143163; 8290408; 9811936; 2004012; 35164799; 37879139; 40114189).
Both monoallelic and biallelic variants are known to cause Variegate Porphyria; biallelic cases present with a more severe, earlier-onset phenotype than monoallelic. PPOX is associated with AD Variegate porphyria (176200) and AR Variegate porphyria, childhood onset (620483) in OMIM - accessed 7th October 2025.
Based on the available evidence, this gene should be rated Green for Intellectual disability.; to: Comment on list classification: Monoallelic PPOX variants usually result in Variegate Porphyria limited to cutaneous manifestations, with onset in adolescence or adulthood. Biallelic variants are known to cause Variegate Porphyria with a more severe, early-onset phenotype - skin lesions, along with neurologic and/ or neurodevelopmental symptoms: nystagmus, epileptic seizures, developmental delay, intellectual disability, and sensory neuropathy. As reviewed by Sharon Whatley, there are more than 3 unrelated individuals with Variegate Porphyria with biallelic variants in PPOX, who presented with developmental delay / childhood-onset intellectual disability: delayed motor skill acquisition, lack of speech acquisition, aggressivity, and other learning disabilities (PMIDs: 8290408; 9811936; 2004012; 35164799; 37879139; 40114189).
PPOX is associated with AD Variegate porphyria (176200) and AR Variegate porphyria, childhood onset (620483) in OMIM - accessed 7th October 2025.
Based on the available evidence, this gene should be rated Green for Intellectual disability.
Intellectual disability v9.116 PPOX Ida Ertmanska changed review comment from: Comment on list classification: Variegate Porphyria symptoms include skin lesions, epileptic seizures, developmental delay, intellectual disability. As reviewed by Sharon Whatley, there are more than 3 unrelated individuals with Variegate Porphyria with biallelic variants in PPOX, who presented with developmental delay / childhood-onset intellectual disability, including: delayed motor skill acquisition, lack of speech acquisition, aggressivity, and other learning disabilities (PMIDs: 6143163;8290408;9811936;2004012;35164799;37879139;40114189).
Both monoallelic and biallelic variants are known to cause Variegate Porphyria; biallelic cases present with a more severe, earlier-onset phenotype than monoallelic. PPOX is associated with AD Variegate porphyria (176200) and AR Variegate porphyria, childhood onset (620483) in OMIM - accessed 7th October 2025.
Based on the available evidence, this gene should be rated Green for Intellectual disability.; to: Comment on list classification: Variegate Porphyria symptoms include skin lesions, epileptic seizures, developmental delay, intellectual disability. As reviewed by Sharon Whatley, there are more than 3 unrelated individuals with Variegate Porphyria with biallelic variants in PPOX, who presented with developmental delay / childhood-onset intellectual disability, including: delayed motor skill acquisition, lack of speech acquisition, aggressivity, and other learning disabilities (PMIDs: 6143163; 8290408; 9811936; 2004012; 35164799; 37879139; 40114189).
Both monoallelic and biallelic variants are known to cause Variegate Porphyria; biallelic cases present with a more severe, earlier-onset phenotype than monoallelic. PPOX is associated with AD Variegate porphyria (176200) and AR Variegate porphyria, childhood onset (620483) in OMIM - accessed 7th October 2025.
Based on the available evidence, this gene should be rated Green for Intellectual disability.
Intellectual disability v9.116 LGI1 Arina Puzriakova Phenotypes for gene: LGI1 were changed from Epilepsy, familial temporal lobe, 1 600512; AUTOSOMAL DOMINANT PARTIAL EPILEPSY WITH AUDITORY FEATURES to Epilepsy, familial temporal lobe, 1, OMIM:600512; developmental and epileptic encephalopathy, MONDO:0100620
Intellectual disability v9.115 PPOX Ida Ertmanska changed review comment from: Variegate Porphyria symptoms include skin lesions, epileptic seizures, developmental delay, intellectual disability. As reviewed by Sharon Whatley, there are more than 3 unrelated individuals with Variegate Porphyria with biallelic variants in PPOX, who presented with developmental delay / childhood-onset intellectual disability, including: delayed motor skill acquisition, lack of speech acquisition, aggressivity, and other learning disabilities (PMIDs: 6143163;8290408;9811936;2004012;35164799;37879139;40114189).
Both monoallelic and biallelic variants are known to cause Variegate Porphyria; biallelic cases present with a more severe, earlier-onset phenotype than monoallelic. PPOX is associated with AD Variegate porphyria (176200) and AR Variegate porphyria, childhood onset (620483) in OMIM - accessed 7th October 2025.
Based on the available evidence, this gene should be rated Green for Intellectual disability.; to: Comment on list classification: Variegate Porphyria symptoms include skin lesions, epileptic seizures, developmental delay, intellectual disability. As reviewed by Sharon Whatley, there are more than 3 unrelated individuals with Variegate Porphyria with biallelic variants in PPOX, who presented with developmental delay / childhood-onset intellectual disability, including: delayed motor skill acquisition, lack of speech acquisition, aggressivity, and other learning disabilities (PMIDs: 6143163;8290408;9811936;2004012;35164799;37879139;40114189).
Both monoallelic and biallelic variants are known to cause Variegate Porphyria; biallelic cases present with a more severe, earlier-onset phenotype than monoallelic. PPOX is associated with AD Variegate porphyria (176200) and AR Variegate porphyria, childhood onset (620483) in OMIM - accessed 7th October 2025.
Based on the available evidence, this gene should be rated Green for Intellectual disability.
Intellectual disability v9.115 PPOX Ida Ertmanska reviewed gene: PPOX: Rating: GREEN; Mode of pathogenicity: None; Publications: 6143163, 8290408, 9811936, 2004012, 35164799, 37879139, 40114189; Phenotypes: Variegate porphyria, childhood-onset, 620483, variegate porphyria, MONDO:0008297; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Intellectual disability v9.113 LGI1 Ida Ertmanska changed review comment from: Comment on mode of inheritance: Monoallelic variants in LGI1 are associated with Autosomal Dominant Epilepsy with Auditory Features (ADEAF), which presents with later-onset and incomplete penetrance (e.g. PMID: 26773249 - cohort of 26 patients, average onset of epilepsy at 16.83 years).
Recent evidence identifies cases with biallelic LGI1 variants, presenting with a more severe phenotype, including seizures from birth, infantile lethality and severe developmental delay. There are at least 5 unrelated individuals reported with biallelic variants in LGI1, with infantile onset developmental and epileptic encephalopathy (PMID:40455867 Hirano et al., 2025; PMID:41000458 Mouhi et al., 2025).
Hence, the MOI should be updated 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: Monoallelic variants in LGI1 are associated with Autosomal Dominant Epilepsy with Auditory Features (ADEAF), which presents with later-onset and incomplete penetrance (e.g. PMID: 26773249 - cohort of 26 patients, average onset of epilepsy at 16.83 years).
Recent evidence identifies cases with biallelic LGI1 variants, presenting with a more severe phenotype, including seizures from birth, infantile lethality and severe developmental delay. There are at least 5 unrelated individuals reported with biallelic variants in LGI1, with infantile onset developmental and epileptic encephalopathy (PMID:40455867 Hirano et al., 2025; PMID:41000458 Mouhi et al., 2025).
Hence, the MOI should be updated from 'MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted' to 'BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal'.
Intellectual disability v9.113 LGI1 Ida Ertmanska commented on gene: LGI1: Comment on mode of inheritance: Monoallelic variants in LGI1 are associated with Autosomal Dominant Epilepsy with Auditory Features (ADEAF), which presents with later-onset and incomplete penetrance (e.g. PMID: 26773249 - cohort of 26 patients, average onset of epilepsy at 16.83 years).
Recent evidence identifies cases with biallelic LGI1 variants, presenting with a more severe phenotype, including seizures from birth, infantile lethality and severe developmental delay. There are at least 5 unrelated individuals reported with biallelic variants in LGI1, with infantile onset developmental and epileptic encephalopathy (PMID:40455867 Hirano et al., 2025; PMID:41000458 Mouhi et al., 2025).
Hence, the MOI should be updated from 'MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted' to 'BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal'.
Intellectual disability v9.113 LGI1 Ida Ertmanska changed review comment from: Monoallelic variants in LGI1 are associated with Autosomal Dominant Epilepsy with Auditory Features (ADEAF) - not associated with intellectual disability / developmental delay. Recent evidence identifies cases with biallelic LGI1 variants, presenting with a more severe phenotype, including infantile lethality and severe intellectual disability:

PMID: 40455867 Hirano et al., 2025
Report of 6 cases from 4 consanguineous unrelated families (Saudi Arabian, Pakistani, Jordanian, Turkish). All affected individuals presented with drug-resistant neonatal/infantile-onset seizures, as well as intellectual disability (mild in P4, severe ID in 5 other patients) and delayed motor milestones. P2 died at age 9 months due to status epilepticus; P3 died of unknown cause at 4yo; patients 1A-C died of respiratory failure aged 11-24yo. Seq method: Trio WES (all), Sanger confirmation (with exception of P3).
Variants:
P1A-C: c.143G>T p.(Cys48Phe) – Revel 0.93, not in gnomAD v4
P2: c.931C>T p.(Arg311*) - not in gnomAD v4
P3: c.1570T>C p.(Ser524Pro) – Revel 0.67, 1 allele in gnomAD v4 (exome only)
P4: c.1672T>G p.(Ter558GlyextTer23) – not in gnomAD v4

PMID: 41000458 Mouhi et al., 2025
Consanguineous Moroccan family, siblings with epileptic encephalopathy due to a homozygous variant within the LGI1 gene: c.245T>C (p.Ile82Thr) - Method: WES +Sanger; Revel = 0.97, not in gnomAD v4
Proband VI.1: seizures from birth, generalised clonic seizures, focal and generalised tonicoclonic seizures. Severe developmental delay at 4yo. Repeated EEG showed abnormal background activity.
Younger brother (IV.2): seizures from the 1st week of life, died at the age of 11 months after repeated pulmonary infections.

LGI1 is associated with AD Epilepsy, familial temporal lobe, 1 (600512) in OMIM - accessed 7th Oct 2025. LGI1 association with autosomal dominant epilepsy with auditory features is Definitive in ClinGen (July 2020).

Since epilepsy is the first presenting symptom, and possibly the leading cause of intellectual disability and developmental delay in the above patients, LGI1 should be rated RED for Intellectual disability.; to: Monoallelic variants in LGI1 are associated with Autosomal Dominant Epilepsy with Auditory Features (ADEAF) - later-onset epilepsy, not associated with intellectual disability / developmental delay (PMID: 26773249). Recent evidence identifies cases with biallelic LGI1 variants, presenting with a more severe phenotype, including infantile lethality and severe intellectual disability:

PMID: 40455867 Hirano et al., 2025
Report of 6 cases from 4 consanguineous unrelated families (Saudi Arabian, Pakistani, Jordanian, Turkish). All affected individuals presented with drug-resistant neonatal/infantile-onset seizures, as well as intellectual disability (mild in P4, severe ID in 5 other patients) and delayed motor milestones. P2 died at age 9 months due to status epilepticus; P3 died of unknown cause at 4yo; patients 1A-C died of respiratory failure aged 11-24yo. Seq method: Trio WES (all), Sanger confirmation (with exception of P3).
Variants:
P1A-C: c.143G>T p.(Cys48Phe) – Revel 0.93, not in gnomAD v4
P2: c.931C>T p.(Arg311*) - not in gnomAD v4
P3: c.1570T>C p.(Ser524Pro) – Revel 0.67, 1 allele in gnomAD v4 (exome only)
P4: c.1672T>G p.(Ter558GlyextTer23) – not in gnomAD v4

PMID: 41000458 Mouhi et al., 2025
Consanguineous Moroccan family, siblings with epileptic encephalopathy due to a homozygous variant within the LGI1 gene: c.245T>C (p.Ile82Thr) - Method: WES +Sanger; Revel = 0.97, not in gnomAD v4
Proband VI.1: seizures from birth, generalised clonic seizures, focal and generalised tonicoclonic seizures. Severe developmental delay at 4yo. Repeated EEG showed abnormal background activity.
Younger brother (IV.2): seizures from the 1st week of life, died at the age of 11 months after repeated pulmonary infections.

LGI1 is associated with AD Epilepsy, familial temporal lobe, 1 (600512) in OMIM - accessed 7th Oct 2025. LGI1 association with autosomal dominant epilepsy with auditory features is Definitive in ClinGen (July 2020).

Since epilepsy is the first presenting symptom, and possibly the leading cause of intellectual disability and developmental delay in the above patients, LGI1 should be rated RED for Intellectual disability.
Intellectual disability v9.113 LGI1 Ida Ertmanska changed review comment from: Monoallelic variants in LGI1 are associated with Autosomal Dominant Epilepsy with Auditory Features (ADEAF) - not associated with intellectual disability / developmental delay. Recent evidence identifies cases with biallelic LGI1 variants, presenting with a more severe phenotype, including infantile lethality and severe intellectual disability:

PMID: 40455867 Hirano et al., 2025
Report of 6 cases from 4 consanguineous unrelated families (Saudi Arabian, Pakistani, Jordanian, Turkish). All affected individuals presented with drug-resistant neonatal/infantile-onset seizures, as well as intellectual disability (mild in P4, severe ID in 5 other patients) and delayed motor milestones. P2 died at age 9 months due to status epilepticus; P3 died of unknown cause at 4yo; patients 1A-C died of respiratory failure aged 11-24yo. Seq method: Trio WES (all), Sanger confirmation (with exception of P3).
Variants:
P1A-C: c.143G>T p.(Cys48Phe) – Revel 0.93, not in gnomAD v4
P2: c.931C>T p.(Arg311*) - not in gnomAD v4
P3: c.1570T>C p.(Ser524Pro) – Revel 0.67, 1 allele in gnomAD v4 (exome only)
P4: c.1672T>G p.(Ter558GlyextTer23) – not in gnomAD v4

PMID: 41000458 Mouhi et al., 2025
Consanguineous Moroccan family, siblings with epileptic encephalopathy due to a homozygous variant within the LGI1 gene: c.245T>C (p.Ile82Thr) - Method: WES +Sanger; Revel = 0.97, not in gnomAD v4
Proband VI.1: seizures from birth, generalised clonic seizures, focal and generalised tonicoclonic seizures. Severe developmental delay at 4yo. Repeated EEG showed abnormal background activity.
Younger brother (IV.2): seizures from the 1st week of life, died at the age of 11 months after repeated pulmonary infections.

LGI1 is associated with AD Epilepsy, familial temporal lobe, 1 (600512) in OMIM - accessed 7th Oct 2025. LGI1 association with autosomal dominant epilepsy with auditory features is Definitive in ClinGen (July 2020).

Since epilepsy is the first presenting symptom, and possibly the leading cause of intellectual disability and developmental delay in those patients, LGI1 should be rated RED for Intellectual disability.; to: Monoallelic variants in LGI1 are associated with Autosomal Dominant Epilepsy with Auditory Features (ADEAF) - not associated with intellectual disability / developmental delay. Recent evidence identifies cases with biallelic LGI1 variants, presenting with a more severe phenotype, including infantile lethality and severe intellectual disability:

PMID: 40455867 Hirano et al., 2025
Report of 6 cases from 4 consanguineous unrelated families (Saudi Arabian, Pakistani, Jordanian, Turkish). All affected individuals presented with drug-resistant neonatal/infantile-onset seizures, as well as intellectual disability (mild in P4, severe ID in 5 other patients) and delayed motor milestones. P2 died at age 9 months due to status epilepticus; P3 died of unknown cause at 4yo; patients 1A-C died of respiratory failure aged 11-24yo. Seq method: Trio WES (all), Sanger confirmation (with exception of P3).
Variants:
P1A-C: c.143G>T p.(Cys48Phe) – Revel 0.93, not in gnomAD v4
P2: c.931C>T p.(Arg311*) - not in gnomAD v4
P3: c.1570T>C p.(Ser524Pro) – Revel 0.67, 1 allele in gnomAD v4 (exome only)
P4: c.1672T>G p.(Ter558GlyextTer23) – not in gnomAD v4

PMID: 41000458 Mouhi et al., 2025
Consanguineous Moroccan family, siblings with epileptic encephalopathy due to a homozygous variant within the LGI1 gene: c.245T>C (p.Ile82Thr) - Method: WES +Sanger; Revel = 0.97, not in gnomAD v4
Proband VI.1: seizures from birth, generalised clonic seizures, focal and generalised tonicoclonic seizures. Severe developmental delay at 4yo. Repeated EEG showed abnormal background activity.
Younger brother (IV.2): seizures from the 1st week of life, died at the age of 11 months after repeated pulmonary infections.

LGI1 is associated with AD Epilepsy, familial temporal lobe, 1 (600512) in OMIM - accessed 7th Oct 2025. LGI1 association with autosomal dominant epilepsy with auditory features is Definitive in ClinGen (July 2020).

Since epilepsy is the first presenting symptom, and possibly the leading cause of intellectual disability and developmental delay in the above patients, LGI1 should be rated RED for Intellectual disability.
Intellectual disability v9.113 ADCY5 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There are patients from two different families reported with biallelic ADCY5 variants and severe intellectual disability. Hence, the MOPI has been updated to 'BIALLELIC, autosomal or pseudoautosomal' and the rating has been changes to amber with the current evidence.; to: Comment on list classification: There are patients from two different families reported with biallelic ADCY5 variants and severe intellectual disability. Hence, the MOI and rating have been updated to 'BIALLELIC, autosomal or pseudoautosomal' and amber respectively.
Intellectual disability v9.113 ADCY5 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are patients from two different families reported with biallelic ADCY5 variants and severe intellectual disability. Hence, the MOPI has been updated to 'BIALLELIC, autosomal or pseudoautosomal' and the rating has been changes to amber with the current evidence.
Intellectual disability v9.109 ADCY5 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: Biallelic variants in ADCY5 gene has been associated with 'Neurodevelopmental disorder with hyperkinetic movements and dyskinesia' phenotype in OMIM (MIM #619651, OMIM accessed on 06 October 2025).
Intellectual disability v9.108 KCND3 Eleanor Williams Phenotypes for gene: KCND3 were changed from Spinocerebellar ataxia 19, 607346 to Spinocerebellar ataxia 19, OMIM: 607346; spinocerebellar ataxia type 19/22, MONDO:0011819
Intellectual disability v9.106 KCND3 Eleanor Williams Added comment: Comment on list classification: Promoting to amber as there are some cases with intellectual disability/cognitive impairment however this appears to be at the milder end of the phenotypic spectrum.
Intellectual disability v9.105 KCND3 Ida Ertmanska changed review comment from: Comment on list classification: KCND3 is associated with autosomal dominant Spinocerebellar ataxia 19, with a range of variably penetrant phenotypes. While there are published articles with at least 6 individuals with early-onset intellectual disability/ developmental delay, only 2 cases meet the eligibility criteria of moderate/ severe/ profound ID. Additionally, the cognitive impairment may have developed as a result of seizures and cerebellar atrophy. Many patients with KCND3 mutations do not have any cognitive impariment.
Thus, based on the available evidence, this gene should be rated Amber for Intellectual disability.; to: Comment on list classification: KCND3 is associated with autosomal dominant Spinocerebellar ataxia 19, with a range of variably penetrant phenotypes. While there are published articles with at least 6 individuals with early-onset intellectual disability/ developmental delay, only 2 cases meet the eligibility criteria of moderate/ severe/ profound ID. Additionally, the cognitive impairment may have developed as a result of seizures and cerebellar atrophy. Many patients with KCND3 mutations do not have any cognitive impariment.
Knock-in mice (p.Phe227del equivalent) displayed defects in motor coordination and balance, and neuroinflammation. Knock-out Kcnd3 -/- mice showed no observable phenotype. Molecular evidence suggests that the misfolded protein induces a trafficking defect in the Golgi apparatus - a dominant negative effect (PMID: 39562497).
Based on the available evidence, this gene should be rated Amber for Intellectual disability.
Intellectual disability v9.105 KCND3 Ida Ertmanska changed review comment from: Comment on list classification: KCND3 is associated with autosomal dominant Spinocerebellar ataxia 19, with a range of variably penetrant phenotypes. While there published articles with at least 6 individuals with early-onset intellectual disability/ developmental delay, only 2 cases meet the eligibility criteria of moderate/ severe/ profound ID. Additionally, the cognitive impairment may have developed as a result of seizures and cerebellar atrophy. Many patients with KCND3 mutations do not have any cognitive impariment.
Thus, based on the available evidence, this gene should be rated Amber for Intellectual disability.; to: Comment on list classification: KCND3 is associated with autosomal dominant Spinocerebellar ataxia 19, with a range of variably penetrant phenotypes. While there are published articles with at least 6 individuals with early-onset intellectual disability/ developmental delay, only 2 cases meet the eligibility criteria of moderate/ severe/ profound ID. Additionally, the cognitive impairment may have developed as a result of seizures and cerebellar atrophy. Many patients with KCND3 mutations do not have any cognitive impariment.
Thus, based on the available evidence, this gene should be rated Amber for Intellectual disability.
Intellectual disability v9.105 KCND3 Ida Ertmanska changed review comment from: KCND3 is associated with autosomal dominant Spinocerebellar ataxia 19 (SCA 19) - progressive cerebellar ataxia with a variable age of onset (age 2 years to late adulthood). A range of additional phenotypes has also been reported, with variable penetrance: developmental delay and cognitive impairment; myoclonus, dystonia, rigidity, seizures. As reviewed by Nour Elkhateeb, there are reports of individuals with early onset intellectual disability / developmental delay:

PMID: 26189493 Smets et al., 2015
Male patient, Belgian, non-consanguineous parents. Het for a de novo KCND3 mutation c.877_885dup; p.(Arg293_Phe295dup) not in gnomAD v4.
Phenotype: early onset cerebellar ataxia complicated by intellectual disability, epilepsy, attention deficit hyperactivity disorder, strabismus, oral apraxia and joint hyperlaxity. Intellectual Disability diagnosed at 3yo. IQ = 54 at 6yo – mild. Sequencing method: WES.
Demonstrated pathogenic effect of variant in a patch clamp assay - severe Kv4.3 channel dysfunction.

PMID: 28895081 Kurihara et al., 2018
30-year-old Japanese man with intellectual disability (IQ = 59, mild), infantile onset developmental delay, early onset cerebellar ataxia, myoclonus, and dystonia without a family history. MRI showed cerebellar atrophy.
Carried a de novo novel missense mutation c.1150G>A, p.(Gly384Ser) in KCND3 – Revel score = 0.88 Deleterious, variant not in gnomAD v4; seq method: trio WES.

PMID: 31293010 Hsiao et al., 2019
Patient A.III-1 - Male, 24 yo - developmental delay, ataxia (since 15yo), MMSE score 12/30, brain atrophy reported. Het for c.950G>A, p.(Cys317Tyr) - Revel = 0.97, not in gnomAD v4.
Patient B.II-2 - Male, 39yo, cognitive impairment (first symptom), ataxia since age 10-15, dystonia, bradykinesia, MMSE score 14/30, brain atrophy reported. Het for c.1123C>T, p.(Pro375Ser) - Revel = 0.95, not in gnomAD v4.

PMID: 32823520 Pollini et al. 2020
Case report, 37yo male, mild ID (onset at 5 yo), IQ=67, speech difficulties; suffered from focal and generalised motor seizures; At age 7yo, IQ = 41 - secondary effect of seizures/brain atrophy?
Brain MRI at age 23 revealed isolated vermis atrophy.
Variant: de novo c.901T>C p.(Ser301Pro) in KCND3. Discrepant frequencies in gnomAD between exome and genome (not reliable). Seq method: WES.

PMID: 32823520 also summarises previously reported cases of SCA19. Patients can be split into early-onset and late-onset cohorts. In the early-onset group, neurodevelopmental disorder/cognitive impairment was the main finding (15/15), followed by ataxia 14/15, and epilepsy (7/15). Conversely, later-onset patients tend to first present with ataxia (50/53).

PMID: 32921676 Nakajima et al., 2020
Two teenage siblings exhibiting both cardiac (early repolarization syndrome and paroxysmal atrial fibrillation) and cerebral phenotypes (epilepsy and intellectual disability), heterozygous for a KCND3 c.1174G>A p.(Val392Ile) mutation - not in gnomAD v4, Revel score = 0.84 Deleterious.
Proband, 19yo female III-1: (WISC-III, FIQ: 64 at 13 years of age - mild ID), episodes of focal impaired awareness seizures.
Younger sister III-2: ID (WISC-III, FIQ: 41 at 12 years of age – moderate ID); episodes of focal impaired awareness seizures; suddenly lost consciousness at home and died at 16 years of age, posed to be due to Early Repolarisation Syndrome.

Supporting evidence:
https://research.rug.nl/en/publications/molecular-genetics-of-monogenic-movement-disorders-making-meaning (internal PhD thesis)
International cohort (mostly European descent) of 21 patients with de novo missense variants in KCND3, aged 2-55 years. All 21 patients had developmental delay and developed a mild to profound intellectual disability. Cerebellar ataxia was present in 11/21 patients. 10/21 patients experienced seizures, 8 diagnosed with epilepsy.
Patient 14 (United States): IQ = 44 at 13yo - c.1111G>A p.(Gly371Arg) / de novo; variant not in gnomAD v4, Revel = 0.99.
Patient 16 (Netherlands): IQ = 45 at 9yo, 25 at 12yo - c.1123C>T p.(Pro375Ser)/de novo; variant not in gnomAD v4, Revel = 0.95.
Patient 4 (Netherlands): Developmental age of 10-11 m at age 44 m; ‘Severe ID’, regression; c.917G>T p.(Gly306Val)/de novo; variant not in gnomAD v4, Revel = 0.97.

KCND3 is associated with Spinocerebellar ataxia 19 (OMIM:607346, accessed 3rd Oct 2025). Based on the available evidence, this gene should be rated Amber for Intellectual Disability.; to: KCND3 is associated with autosomal dominant Spinocerebellar ataxia 19 (SCA 19) - progressive cerebellar ataxia with a variable age of onset (age 2 years to late adulthood). A range of additional phenotypes has also been reported, with variable penetrance: developmental delay and cognitive impairment; myoclonus, dystonia, rigidity, seizures. As reviewed by Nour Elkhateeb, there are reports of individuals with childhood onset intellectual disability / developmental delay:

PMID: 26189493 Smets et al., 2015
Male patient, Belgian, non-consanguineous parents. Het for a de novo KCND3 mutation c.877_885dup; p.(Arg293_Phe295dup) not in gnomAD v4.
Phenotype: early onset cerebellar ataxia complicated by intellectual disability, epilepsy, attention deficit hyperactivity disorder, strabismus, oral apraxia and joint hyperlaxity. Intellectual Disability diagnosed at 3yo. IQ = 54 at 6yo – mild. Sequencing method: WES.
Demonstrated pathogenic effect of variant in a patch clamp assay - severe Kv4.3 channel dysfunction.

PMID: 28895081 Kurihara et al., 2018
30-year-old Japanese man with intellectual disability (IQ = 59, mild), infantile onset developmental delay, early onset cerebellar ataxia, myoclonus, and dystonia without a family history. MRI showed cerebellar atrophy.
Carried a de novo novel missense mutation c.1150G>A, p.(Gly384Ser) in KCND3 – Revel score = 0.88 Deleterious, variant not in gnomAD v4; seq method: trio WES.

PMID: 31293010 Hsiao et al., 2019
Patient A.III-1 - Male, 24 yo - developmental delay, ataxia (since 15yo), MMSE score 12/30, brain atrophy reported. Het for c.950G>A, p.(Cys317Tyr) - Revel = 0.97, not in gnomAD v4.
Patient B.II-2 - Male, 39yo, cognitive impairment (first symptom), ataxia since age 10-15, dystonia, bradykinesia, MMSE score 14/30, brain atrophy reported. Het for c.1123C>T, p.(Pro375Ser) - Revel = 0.95, not in gnomAD v4.

PMID: 32823520 Pollini et al. 2020
Case report, 37yo male, mild ID (onset at 5 yo), IQ=67, speech difficulties; suffered from focal and generalised motor seizures; At age 7yo, IQ = 41 - secondary effect of seizures/brain atrophy?
Brain MRI at age 23 revealed isolated vermis atrophy.
Variant: de novo c.901T>C p.(Ser301Pro) in KCND3. Discrepant frequencies in gnomAD between exome and genome (not reliable). Seq method: WES.

PMID: 32823520 also summarises previously reported cases of SCA19. Patients can be split into early-onset and late-onset cohorts. In the early-onset group, neurodevelopmental disorder/cognitive impairment was the main finding (15/15), followed by ataxia 14/15, and epilepsy (7/15). Conversely, later-onset patients tend to first present with ataxia (50/53).

PMID: 32921676 Nakajima et al., 2020
Two teenage siblings exhibiting both cardiac (early repolarization syndrome and paroxysmal atrial fibrillation) and cerebral phenotypes (epilepsy and intellectual disability), heterozygous for a KCND3 c.1174G>A p.(Val392Ile) mutation - not in gnomAD v4, Revel score = 0.84 Deleterious.
Proband, 19yo female III-1: (WISC-III, FIQ: 64 at 13 years of age - mild ID), episodes of focal impaired awareness seizures.
Younger sister III-2: ID (WISC-III, FIQ: 41 at 12 years of age – moderate ID); episodes of focal impaired awareness seizures; suddenly lost consciousness at home and died at 16 years of age, posed to be due to Early Repolarisation Syndrome.

Supporting evidence:
https://research.rug.nl/en/publications/molecular-genetics-of-monogenic-movement-disorders-making-meaning (internal PhD thesis)
International cohort (mostly European descent) of 21 patients with de novo missense variants in KCND3, aged 2-55 years. All 21 patients had developmental delay and developed a mild to profound intellectual disability. Cerebellar ataxia was present in 11/21 patients. 10/21 patients experienced seizures, 8 diagnosed with epilepsy.
Patient 14 (United States): IQ = 44 at 13yo - c.1111G>A p.(Gly371Arg) / de novo; variant not in gnomAD v4, Revel = 0.99.
Patient 16 (Netherlands): IQ = 45 at 9yo, 25 at 12yo - c.1123C>T p.(Pro375Ser)/de novo; variant not in gnomAD v4, Revel = 0.95.
Patient 4 (Netherlands): Developmental age of 10-11 m at age 44 m; ‘Severe ID’, regression; c.917G>T p.(Gly306Val)/de novo; variant not in gnomAD v4, Revel = 0.97.

KCND3 is associated with Spinocerebellar ataxia 19 (OMIM:607346, accessed 3rd Oct 2025). Based on the available evidence, this gene should be rated Amber for Intellectual Disability.
Intellectual disability v9.105 KCND3 Ida Ertmanska edited their review of gene: KCND3: Changed phenotypes to: Spinocerebellar ataxia 19 (OMIM: 607346), spinocerebellar ataxia type 19/22, MONDO:0011819
Intellectual disability v9.105 KCND3 Ida Ertmanska changed review comment from: Comment on list classification: KCND3 is associated with autosomal dominant Spinocerebellar ataxia 19, with a range of variably penetrant phenotypes. While there published articles with at least 6 individuals with early-onset intellectual disability/ developmental delay, only 2 cases meet the eligibility criteria of moderate/ severe/ profound ID. Additionally, the cognitive impairment may have developed as a result of seizures and cerebellar atrophy.
Based on the available evidence, this gene should be rated Amber for Intellectual disability.; to: Comment on list classification: KCND3 is associated with autosomal dominant Spinocerebellar ataxia 19, with a range of variably penetrant phenotypes. While there published articles with at least 6 individuals with early-onset intellectual disability/ developmental delay, only 2 cases meet the eligibility criteria of moderate/ severe/ profound ID. Additionally, the cognitive impairment may have developed as a result of seizures and cerebellar atrophy. Many patients with KCND3 mutations do not have any cognitive impariment.
Thus, based on the available evidence, this gene should be rated Amber for Intellectual disability.
Intellectual disability v9.105 KCND3 Ida Ertmanska changed review comment from: Comment on list classification: KCND3 is associated with autosomal dominant Spinocerebellar ataxia 19, with a range of variably penetrant phenotypes. While there published articles with at least 6 individuals with early-onset intellectual disability/ developmental delay, only 2 cases meet the eligibility criteria of moderate/ severe/ profound ID. Additionally, the cognitive impairment may have developed as a result of seizures and cerebellar atrophy. Based on the available evidence, this gene should be rated Amber for Intellectual disability.; to: Comment on list classification: KCND3 is associated with autosomal dominant Spinocerebellar ataxia 19, with a range of variably penetrant phenotypes. While there published articles with at least 6 individuals with early-onset intellectual disability/ developmental delay, only 2 cases meet the eligibility criteria of moderate/ severe/ profound ID. Additionally, the cognitive impairment may have developed as a result of seizures and cerebellar atrophy.
Based on the available evidence, this gene should be rated Amber for Intellectual disability.
Intellectual disability v9.105 KCND3 Ida Ertmanska changed review comment from: Comment on list classification: KCND3 is associated with autosomal dominant Spinocerebellar ataxia 19, with a range of variably penetrant phenotypes. While there published articles with at least 6 individuals with early-onset intellectual disability/ developmental delay, only 2 cases meet the eligibility criteria of moderate/severe/profound ID. Additionally, the cognitive impairment may have developed as a result of seizures and cerebellar atrophy. Based on the available evidence, this gene should be rated Amber for Intellectual disability.; to: Comment on list classification: KCND3 is associated with autosomal dominant Spinocerebellar ataxia 19, with a range of variably penetrant phenotypes. While there published articles with at least 6 individuals with early-onset intellectual disability/ developmental delay, only 2 cases meet the eligibility criteria of moderate/ severe/ profound ID. Additionally, the cognitive impairment may have developed as a result of seizures and cerebellar atrophy. Based on the available evidence, this gene should be rated Amber for Intellectual disability.
Intellectual disability v9.105 KCND3 Ida Ertmanska changed review comment from: Comment on list classification: KCND3 is associated with autosomal dominant Spinocerebellar ataxia 19, with a range of variably penetrant phenotypes. While there are at least 4 published reports of individuals with early onset intellectual disability/ developmental delay, only 2 cases meet the eligibility criteria of moderate/severe/profound ID. Additionally, their cognitive impairment may have developed as a result of seizures and cerebellar atrophy. Based on the available evidence, this gene should be rated Amber for Intellectual disability.; to: Comment on list classification: KCND3 is associated with autosomal dominant Spinocerebellar ataxia 19, with a range of variably penetrant phenotypes. While there published articles with at least 6 individuals with early-onset intellectual disability/ developmental delay, only 2 cases meet the eligibility criteria of moderate/severe/profound ID. Additionally, the cognitive impairment may have developed as a result of seizures and cerebellar atrophy. Based on the available evidence, this gene should be rated Amber for Intellectual disability.
Intellectual disability v9.105 KCND3 Ida Ertmanska changed review comment from: KCND3 is associated with autosomal dominant Spinocerebellar ataxia 19 (SCA 19) - progressive cerebellar ataxia with a variable age of onset (age 2 years to late adulthood). A range of additional phenotypes has also been reported, with variable penetrance: developmental delay and cognitive impairment; myoclonus, dystonia, rigidity, seizures. As reviewed by Nour Elkhateeb, there are reports of individuals with early onset intellectual disability / developmental delay:

PMID: 26189493 Smets et al., 2015
Male patient, Belgian, non-consanguineous parents. Het for a de novo KCND3 mutation c.877_885dup; p.(Arg293_Phe295dup) not in gnomAD v4.
Phenotype: early onset cerebellar ataxia complicated by intellectual disability, epilepsy, attention deficit hyperactivity disorder, strabismus, oral apraxia and joint hyperlaxity. Intellectual Disability diagnosed at 3yo. IQ = 54 at 6yo – mild. Sequencing method: WES.
Demonstrated pathogenic effect of variant in a patch clamp assay - severe Kv4.3 channel dysfunction.

PMID: 28895081 Kurihara et al., 2018
30-year-old Japanese man with intellectual disability (IQ = 59, mild), infantile onset developmental delay, early onset cerebellar ataxia, myoclonus, and dystonia without a family history. MRI showed cerebellar atrophy.
Carried a de novo novel missense mutation c.1150G>A, p.(Gly384Ser) in KCND3 – Revel score = 0.88 Deleterious, variant not in gnomAD v4; seq method: trio WES.

PMID: 32823520 – Pollini et al. 2020
Case report, 37yo male, mild ID (onset at 5 yo), IQ=67, speech difficulties; suffered from focal and generalised motor seizures; At age 7yo, IQ = 41 - secondary effect of seizures/brain atrophy?
Brain MRI at age 23 revealed isolated vermis atrophy.
Variant: de novo c.901T>C p.(Ser301Pro) in KCND3. Discrepant frequencies in gnomAD between exome and genome (not reliable). Seq method: WES.

PMID: 32823520 also summarises previously reported cases of SCA19. Patients can be split into early-onset and late-onset cohorts. In the early-onset group, neurodevelopmental disorder/cognitive impairment was the main finding (15/15), followed by ataxia 14/15, and epilepsy (7/15). Conversely, later-onset patients tend to first present with ataxia (50/53).

PMID: 32921676 Nakajima et al., 2020
Two teenage siblings exhibiting both cardiac (early repolarization syndrome and paroxysmal atrial fibrillation) and cerebral phenotypes (epilepsy and intellectual disability), heterozygous for a KCND3 c.1174G>A p.(Val392Ile) mutation - not in gnomAD v4, Revel score = 0.84 Deleterious.
Proband, 19yo female III-1: (WISC-III, FIQ: 64 at 13 years of age - mild ID), episodes of focal impaired awareness seizures.
Younger sister III-2: ID (WISC-III, FIQ: 41 at 12 years of age – moderate ID); episodes of focal impaired awareness seizures; suddenly lost consciousness at home and died at 16 years of age, posed to be due to Early Repolarisation Syndrome.

Supporting evidence:
https://research.rug.nl/en/publications/molecular-genetics-of-monogenic-movement-disorders-making-meaning (internal PhD thesis)
International cohort (mostly European descent) of 21 patients with de novo missense variants in KCND3, aged 2-55 years. All 21 patients had developmental delay and developed a mild to profound intellectual disability. Cerebellar ataxia was present in 11/21 patients. 10/21 patients experienced seizures, 8 diagnosed with epilepsy.
Patient 14 (United States): IQ = 44 at 13yo - c.1111G>A p.(Gly371Arg) / de novo; variant not in gnomAD v4, Revel = 0.99.
Patient 16 (Netherlands): IQ = 45 at 9yo, 25 at 12yo - c.1123C>T p.(Pro375Ser)/de novo; variant not in gnomAD v4, Revel = 0.95.
Patient 4 (Netherlands): Developmental age of 10-11 m at age 44 m; ‘Severe ID’, regression; c.917G>T p.(Gly306Val)/de novo; variant not in gnomAD v4, Revel = 0.97.

KCND3 is associated with Spinocerebellar ataxia 19 (OMIM:607346, accessed 3rd Oct 2025). Based on the available evidence, this gene should be rated Amber for Intellectual Disability.; to: KCND3 is associated with autosomal dominant Spinocerebellar ataxia 19 (SCA 19) - progressive cerebellar ataxia with a variable age of onset (age 2 years to late adulthood). A range of additional phenotypes has also been reported, with variable penetrance: developmental delay and cognitive impairment; myoclonus, dystonia, rigidity, seizures. As reviewed by Nour Elkhateeb, there are reports of individuals with early onset intellectual disability / developmental delay:

PMID: 26189493 Smets et al., 2015
Male patient, Belgian, non-consanguineous parents. Het for a de novo KCND3 mutation c.877_885dup; p.(Arg293_Phe295dup) not in gnomAD v4.
Phenotype: early onset cerebellar ataxia complicated by intellectual disability, epilepsy, attention deficit hyperactivity disorder, strabismus, oral apraxia and joint hyperlaxity. Intellectual Disability diagnosed at 3yo. IQ = 54 at 6yo – mild. Sequencing method: WES.
Demonstrated pathogenic effect of variant in a patch clamp assay - severe Kv4.3 channel dysfunction.

PMID: 28895081 Kurihara et al., 2018
30-year-old Japanese man with intellectual disability (IQ = 59, mild), infantile onset developmental delay, early onset cerebellar ataxia, myoclonus, and dystonia without a family history. MRI showed cerebellar atrophy.
Carried a de novo novel missense mutation c.1150G>A, p.(Gly384Ser) in KCND3 – Revel score = 0.88 Deleterious, variant not in gnomAD v4; seq method: trio WES.

PMID: 31293010 Hsiao et al., 2019
Patient A.III-1 - Male, 24 yo - developmental delay, ataxia (since 15yo), MMSE score 12/30, brain atrophy reported. Het for c.950G>A, p.(Cys317Tyr) - Revel = 0.97, not in gnomAD v4.
Patient B.II-2 - Male, 39yo, cognitive impairment (first symptom), ataxia since age 10-15, dystonia, bradykinesia, MMSE score 14/30, brain atrophy reported. Het for c.1123C>T, p.(Pro375Ser) - Revel = 0.95, not in gnomAD v4.

PMID: 32823520 Pollini et al. 2020
Case report, 37yo male, mild ID (onset at 5 yo), IQ=67, speech difficulties; suffered from focal and generalised motor seizures; At age 7yo, IQ = 41 - secondary effect of seizures/brain atrophy?
Brain MRI at age 23 revealed isolated vermis atrophy.
Variant: de novo c.901T>C p.(Ser301Pro) in KCND3. Discrepant frequencies in gnomAD between exome and genome (not reliable). Seq method: WES.

PMID: 32823520 also summarises previously reported cases of SCA19. Patients can be split into early-onset and late-onset cohorts. In the early-onset group, neurodevelopmental disorder/cognitive impairment was the main finding (15/15), followed by ataxia 14/15, and epilepsy (7/15). Conversely, later-onset patients tend to first present with ataxia (50/53).

PMID: 32921676 Nakajima et al., 2020
Two teenage siblings exhibiting both cardiac (early repolarization syndrome and paroxysmal atrial fibrillation) and cerebral phenotypes (epilepsy and intellectual disability), heterozygous for a KCND3 c.1174G>A p.(Val392Ile) mutation - not in gnomAD v4, Revel score = 0.84 Deleterious.
Proband, 19yo female III-1: (WISC-III, FIQ: 64 at 13 years of age - mild ID), episodes of focal impaired awareness seizures.
Younger sister III-2: ID (WISC-III, FIQ: 41 at 12 years of age – moderate ID); episodes of focal impaired awareness seizures; suddenly lost consciousness at home and died at 16 years of age, posed to be due to Early Repolarisation Syndrome.

Supporting evidence:
https://research.rug.nl/en/publications/molecular-genetics-of-monogenic-movement-disorders-making-meaning (internal PhD thesis)
International cohort (mostly European descent) of 21 patients with de novo missense variants in KCND3, aged 2-55 years. All 21 patients had developmental delay and developed a mild to profound intellectual disability. Cerebellar ataxia was present in 11/21 patients. 10/21 patients experienced seizures, 8 diagnosed with epilepsy.
Patient 14 (United States): IQ = 44 at 13yo - c.1111G>A p.(Gly371Arg) / de novo; variant not in gnomAD v4, Revel = 0.99.
Patient 16 (Netherlands): IQ = 45 at 9yo, 25 at 12yo - c.1123C>T p.(Pro375Ser)/de novo; variant not in gnomAD v4, Revel = 0.95.
Patient 4 (Netherlands): Developmental age of 10-11 m at age 44 m; ‘Severe ID’, regression; c.917G>T p.(Gly306Val)/de novo; variant not in gnomAD v4, Revel = 0.97.

KCND3 is associated with Spinocerebellar ataxia 19 (OMIM:607346, accessed 3rd Oct 2025). Based on the available evidence, this gene should be rated Amber for Intellectual Disability.
Intellectual disability v9.105 KCND3 Ida Ertmanska edited their review of gene: KCND3: Added comment: Comment on list classification: KCND3 is associated with autosomal dominant Spinocerebellar ataxia 19, with a range of variably penetrant phenotypes. While there are at least 4 published reports of individuals with early onset intellectual disability/ developmental delay, only 2 cases meet the eligibility criteria of moderate/severe/profound ID. Additionally, their cognitive impairment may have developed as a result of seizures and cerebellar atrophy. Based on the available evidence, this gene should be rated Amber for Intellectual disability.; Changed publications to: 26189493, 28895081, 32823520, 32921676
Intellectual disability v9.105 KCND3 Ida Ertmanska reviewed gene: KCND3: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Spinocerebellar ataxia 19 (OMIM: 607346); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v9.105 SF1 Mike Spiller gene: SF1 was added
gene: SF1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: SF1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SF1 were set to PMID: 40987292
Review for gene: SF1 was set to GREEN
Added comment: Gene-disease associated reported in PMID: 40987292.
15 patients with varying levels of global developmental delay and ASD. One of these is intronic with gnomad AC = 9 so can be disregarded.
Of the remaining 14 almost all are de novo. 13 absent from gnomad, 1 with AC = 1.
7 missense, 1 inframe delins, 4 NMD, 2 final exon truncations. 6/7 missenses at conserved residues within missense-constrained regions, but no hotspot cluster..

NMD variants show the most consistent phenotype of mild-moderate ID/GDD.
Of the total 14 cases ID/GDD mild in 5, moderate in 4, level not stated in 5. Language delays most consistent characteristic..

Functional studies using SF1 knockdown in neural progenitor cells show substantial effects on gene regulation and alternative splicing, consistent with SF1 loss of function. However paper does not record if this led to any effects on NPC function.

Gene constrained for LOF (gnomad v4 o/e 0.12, LOEUF 0.22).
Sources: Literature
Intellectual disability v9.102 UGGT1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the association of biallelic UGGT1 variants with intellectual disability (six families with severe ID). Hence, this gene can be promoted to green rating in the next GMS update.
Intellectual disability v9.101 UGGT1 Achchuthan Shanmugasundram Phenotypes for gene: UGGT1 were changed from intellectual disability; seizures; characteristic facial features; microcephaly; congenital heart malformations, variable skeletal abnormalities; hepatic and renal involvement; polycystic kidneys to congenital disorder of glycosylation, MONDO:0015286
Intellectual disability v9.99 EMX2 Ida Ertmanska changed review comment from: Comment on list classification: There are at least 4 unrelated families where individuals harbouring de novo variants in EMX2 have schizencephaly - a rare severe brain malformation, leading to neurologic deficits and developmental delay (PMIDs: 8528262, 9153481, 9359037). However, the 1996-1997 studies are limited by their sequencing method (targeted gene sequencing). Subsequent studies of 3 different schizencephaly patient cohorts showed that none of the 175 affected individuals carried pathogenic EMX2 mutations (PMIDs: 17506092, 18409201, 20157829).
No other cases with EMX2 variants were published in literature since 1997. Other genes, such as SIX3 and SHH, have been putatively linked to schizencephaly (PMID: 20157829). Furthermore, schizencephaly may stem from non-genetic causes, such as in utero viral infections, teratogen exposure, maternal trauma, and more (PMID: 18409201). Due to outdated / conflicting evidence, this gene should be downgraded to Amber for Intellectual disability.; to: Comment on list classification: There are at least 4 unrelated families where individuals harbouring de novo variants in EMX2 have schizencephaly - a rare severe brain malformation, leading to neurologic deficits and developmental delay (PMIDs: 8528262, 9153481, 9359037). However, the 1996-1997 studies are limited by their sequencing method (targeted gene sequencing). Subsequent studies of 3 different schizencephaly patient cohorts showed that none of the 175 affected individuals carried pathogenic EMX2 mutations (PMIDs: 17506092, 18409201, 20157829).
No other schizencephaly cases with EMX2 variants were published in literature since 1997. Other genes, such as SIX3 and SHH, have been putatively linked to schizencephaly (PMID: 20157829). Furthermore, schizencephaly may stem from non-genetic causes, such as in utero viral infections, teratogen exposure, maternal trauma, and more (PMID: 18409201). Due to outdated / conflicting evidence, this gene should be downgraded to Amber for Intellectual disability.
Intellectual disability v9.99 EMX2 Ida Ertmanska changed review comment from: Comment on list classification: There are at least 4 unrelated families where individuals harbouring de novo variants in EMX2 have schizencephaly - a rare severe brain malformation, leading to neurologic deficits and developmental delay (PMIDs: 8528262, 9153481, 9359037). However, the 1996-1997 studies are limited by their sequencing method (targeted gene sequencing). Subsequent studies of 3 different schizencephaly patient cohorts showed that none of the 175 affected individuals carried pathogenic EMX2 mutations (PMIDs: 17506092, 18409201, 20157829).
No other cases with EMX2 variants were published in literature since 1997. Other genes, such as SIX3 and SHH, have been putatively linked to schizencephaly. Furthermore, schizencephaly may stem from non-genetic causes, such as in utero viral infections, teratogen exposure, maternal trauma, and more (PMID: 18409201 Merello et al., 2008). Due to outdated / conflicting evidence, this gene should be downgraded to Amber for Intellectual disability.; to: Comment on list classification: There are at least 4 unrelated families where individuals harbouring de novo variants in EMX2 have schizencephaly - a rare severe brain malformation, leading to neurologic deficits and developmental delay (PMIDs: 8528262, 9153481, 9359037). However, the 1996-1997 studies are limited by their sequencing method (targeted gene sequencing). Subsequent studies of 3 different schizencephaly patient cohorts showed that none of the 175 affected individuals carried pathogenic EMX2 mutations (PMIDs: 17506092, 18409201, 20157829).
No other cases with EMX2 variants were published in literature since 1997. Other genes, such as SIX3 and SHH, have been putatively linked to schizencephaly (PMID: 20157829). Furthermore, schizencephaly may stem from non-genetic causes, such as in utero viral infections, teratogen exposure, maternal trauma, and more (PMID: 18409201). Due to outdated / conflicting evidence, this gene should be downgraded to Amber for Intellectual disability.
Intellectual disability v9.99 EMX2 Ida Ertmanska changed review comment from: Comment on list classification: There are at least 4 unrelated families where individuals harbouring de novo variants in EMX2 have schizencephaly - a rare severe brain malformation, leading to neurologic deficits and developmental delay (PMIDs: 8528262, 9153481, 9359037). However, the 1996-1997 studies are limited by their sequencing method (targeted gene sequencing). Subsequent studies of 3 different schizencephaly patient cohorts showed that none of the 175 affected individuals carried pathogenic EMX2 mutations (PMIDs: 17506092, 18409201, 20157829).
No other cases with EMX2 variants were published in literature since 1997. Other genes, such as SIX3 and SHH, have been implicated in schizencephaly. Furthermore, schizencephaly may stem from non-genetic causes, such as in utero viral infections, teratogen exposure, maternal trauma, and more (PMID: 18409201 Merello et al., 2008). Due to outdated / conflicting evidence, this gene should be downgraded to Amber for Intellectual disability.; to: Comment on list classification: There are at least 4 unrelated families where individuals harbouring de novo variants in EMX2 have schizencephaly - a rare severe brain malformation, leading to neurologic deficits and developmental delay (PMIDs: 8528262, 9153481, 9359037). However, the 1996-1997 studies are limited by their sequencing method (targeted gene sequencing). Subsequent studies of 3 different schizencephaly patient cohorts showed that none of the 175 affected individuals carried pathogenic EMX2 mutations (PMIDs: 17506092, 18409201, 20157829).
No other cases with EMX2 variants were published in literature since 1997. Other genes, such as SIX3 and SHH, have been putatively linked to schizencephaly. Furthermore, schizencephaly may stem from non-genetic causes, such as in utero viral infections, teratogen exposure, maternal trauma, and more (PMID: 18409201 Merello et al., 2008). Due to outdated / conflicting evidence, this gene should be downgraded to Amber for Intellectual disability.
Intellectual disability v9.99 EMX2 Ida Ertmanska changed review comment from: Comment on list classification: There are at least 4 unrelated families where individuals harbouring de novo variants in EMX2 have schizencephaly - a rare severe brain malformation, leading to neurologic deficits and developmental delay (PMIDs: 8528262, 9153481, 9359037). However, the 1996-1997 studies are limited by their sequencing method (targeted gene sequencing). Subsequent studies of 3 different schizencephaly patient cohorts showed that none of the 175 affected individuals carried pathogenic EMX2 mutations (PMIDs: 17506092, 18409201, 20157829).
No other cases with EMX2 variants were published in literature since 1997. Other genes, such as SIX3 and SHH, have also been implicated in schizencephaly. Furthermore, schizencephaly may stem from non-genetic causes, such as in utero viral infections, teratogen exposure, maternal trauma, and more (PMID: 18409201 Merello et al., 2008). Due to outdated / conflicting evidence, this gene should be downgraded to Amber for Intellectual disability.; to: Comment on list classification: There are at least 4 unrelated families where individuals harbouring de novo variants in EMX2 have schizencephaly - a rare severe brain malformation, leading to neurologic deficits and developmental delay (PMIDs: 8528262, 9153481, 9359037). However, the 1996-1997 studies are limited by their sequencing method (targeted gene sequencing). Subsequent studies of 3 different schizencephaly patient cohorts showed that none of the 175 affected individuals carried pathogenic EMX2 mutations (PMIDs: 17506092, 18409201, 20157829).
No other cases with EMX2 variants were published in literature since 1997. Other genes, such as SIX3 and SHH, have been implicated in schizencephaly. Furthermore, schizencephaly may stem from non-genetic causes, such as in utero viral infections, teratogen exposure, maternal trauma, and more (PMID: 18409201 Merello et al., 2008). Due to outdated / conflicting evidence, this gene should be downgraded to Amber for Intellectual disability.
Intellectual disability v9.99 EMX2 Ida Ertmanska changed review comment from: Comment on list classification: There are at least 4 unrelated families where individuals harbouring de novo variants in EMX2 have schizencephaly - a rare severe brain malformation, leading to neurologic deficits and developmental delay (PMIDs: 8528262, 9153481, 9359037). However, the 1996-1997 studies are limited by their sequencing method (targeted gene sequencing). Subsequent studies of 3 different schizencephaly patient cohorts showed that none of the 175 affected individuals carried pathogenic EMX2 mutations (PMIDs: 17506092, 18409201, 20157829). No other cases with EMX2 variants were published in literature since 1997. Schizencephaly may also stem from non-genetic causes, such as in utero viral infections, teratogen exposure, maternal trauma, and more (PMID: 18409201 Merello et al., 2008). Due to outdated and conflicting evidence, this gene should be downgraded to Amber for Intellectual disability.; to: Comment on list classification: There are at least 4 unrelated families where individuals harbouring de novo variants in EMX2 have schizencephaly - a rare severe brain malformation, leading to neurologic deficits and developmental delay (PMIDs: 8528262, 9153481, 9359037). However, the 1996-1997 studies are limited by their sequencing method (targeted gene sequencing). Subsequent studies of 3 different schizencephaly patient cohorts showed that none of the 175 affected individuals carried pathogenic EMX2 mutations (PMIDs: 17506092, 18409201, 20157829).
No other cases with EMX2 variants were published in literature since 1997. Other genes, such as SIX3 and SHH, have also been implicated in schizencephaly. Furthermore, schizencephaly may stem from non-genetic causes, such as in utero viral infections, teratogen exposure, maternal trauma, and more (PMID: 18409201 Merello et al., 2008). Due to outdated / conflicting evidence, this gene should be downgraded to Amber for Intellectual disability.
Intellectual disability v9.99 EMX2 Ida Ertmanska changed review comment from: There are at least 4 unrelated families where individuals harbouring de novo variants in EMX2 have schizencephaly (SCH) - a rare severe brain malformation, leading to neurologic deficits and developmental delay (PMIDs: 8528262, 9153481, 9359037). However, the articles, published in 1996-1997, are limited by their sequencing method (EMX2 targeted gene sequencing):

PMID: 8528262 Brunelli et al., 1996
Method: SSCP analysis on PCR amplification products of 4 genes: EMX1, EMX2, OTX1, OTX2. No variants were detected in EMX1, OTX1, or OTX2. 7/8 schizencephaly patients harboured heterozygous EMX2 variants, of which 3 were de novo and predicted to be pathogenic:
c.407-4G>T – spliceAI benign, 1 allele reported in European population in gnomAD v4.1
c.407-1G>A – spliceAI splice-altering Strong, not in gnomAD v4.1
c.575_576insA p.(Ser192Argfs*41) – not in gnomAD v4.1

PMID: 9153481 Granata et al., 1997 - two brothers aged 8 and 10 with severe bilateral schizencephaly, carrying an identical point mutation in EMX2. Phenotype: severe neurologic deficits and mental retardation. No access to full article
PMID: 9359037 Faiella et al., 1997 – same two brothers? Variant c.407G>T (p.Gly136Val) – Revel score 0.46 (Uncertain); not in gnomAD v4.1

Supporting evidence: https://iamg.in/genetic_clinics/full_textdfc6.html?id=212 – Clinical Vignette, Indian Academy of Medical Genetics – NO PMID.
Case report: 7 year old boy, bilateral schizencephaly, non-consanguineous parents; heterozygous for a de novo EMX2 variant: c.473G>A, (p.Arg158Gln) – Revel score 0.63, not found in gnomAD v4.1; method: trio sequencing of EMX2 exons only.
Phenotype: Severe developmental delay noticed at age 3-4 months. At 5 years old, the developmental age was 4 months. No meaningful speech was present. History of seizures since 4 years of age. Microcornea, widely spaced teeth, severe spasticity in all limbs.

CONTRADICTING EVIDENCE:
Subsequent studies of 3 different schizencephaly patient cohorts showed that none of the 175 affected individuals carried pathogenic EMX2 mutations:

PMID: 17506092 Tietjen et al., 2007
EMX2 genotyping of 84 affected probands with Schizencephaly – no EMX2 mutations detected.

PMID: 18409201 Merello et al., 2008
EMX2 sequencing in 39 SCH patients detected no pathogenic mutations. Only sequenced EMX2. Authors claimed that diagnostic testing of EMX2 is not justified, as any results would be uninterpretable.

PMID: 20157829 – Hehr et al., 2010
52 patients with SCH, no EMX2 mutations detected. Sequenced EMX2 (all 52 cases) as well SHH, SIX3 and ZIC2 in some of the individuals. SIX3 and SHH variants are reported as causative instead.

EMX2 is associated with Schizencephaly in OMIM (269160, accessed 29th Sep 2025) & classified as Limited for Schizencephaly in ClinGen (Epilepsy GCEP, 2024).

No other cases with EMX2 variants were published in literature since 1997. Due to outdated / conflicting evidence, this gene should be downgraded to Amber for Intellectual disability.; to: There are at least 4 unrelated families where individuals harbouring de novo variants in EMX2 have schizencephaly (SCH) - a rare severe brain malformation, leading to neurologic deficits and developmental delay (PMIDs: 8528262, 9153481, 9359037). However, the articles, published in 1996-1997, are limited by their sequencing method (EMX2 targeted gene sequencing):

PMID: 8528262 Brunelli et al., 1996
Method: SSCP analysis on PCR amplification products of 4 genes: EMX1, EMX2, OTX1, OTX2. No variants were detected in EMX1, OTX1, or OTX2. 7/8 schizencephaly patients harboured heterozygous EMX2 variants, of which 3 were de novo and predicted to be pathogenic:
c.407-4G>T – spliceAI benign, 1 allele reported in European population in gnomAD v4.1
c.407-1G>A – spliceAI splice-altering Strong, not in gnomAD v4.1
c.575_576insA p.(Ser192Argfs*41) – not in gnomAD v4.1

PMID: 9153481 Granata et al., 1997 - two brothers aged 8 and 10 with severe bilateral schizencephaly, carrying an identical point mutation in EMX2. Phenotype: severe neurologic deficits and mental retardation. No access to full article
PMID: 9359037 Faiella et al., 1997 – same two brothers? Variant c.407G>T (p.Gly136Val) – Revel score 0.46 (Uncertain); not in gnomAD v4.1

Supporting evidence: https://iamg.in/genetic_clinics/full_textdfc6.html?id=212 – Clinical Vignette, Indian Academy of Medical Genetics – NO PMID.
Case report: 7 year old boy, bilateral schizencephaly, non-consanguineous parents; heterozygous for a de novo EMX2 variant: c.473G>A, (p.Arg158Gln) – Revel score 0.63, not found in gnomAD v4.1; method: trio sequencing of EMX2 exons only.
Phenotype: Severe developmental delay noticed at age 3-4 months. At 5 years old, the developmental age was 4 months. No meaningful speech was present. History of seizures since 4 years of age. Microcornea, widely spaced teeth, severe spasticity in all limbs.

CONTRADICTING EVIDENCE:
Subsequent studies of 3 different schizencephaly patient cohorts showed that none of the 175 affected individuals carried pathogenic EMX2 mutations:

PMID: 17506092 Tietjen et al., 2007
EMX2 genotyping of 84 affected probands with Schizencephaly – no EMX2 mutations detected.

PMID: 18409201 Merello et al., 2008
EMX2 sequencing in 39 SCH patients detected no pathogenic mutations. Schizencephaly may also stem from non-genetic causes, such as in utero viral infections, teratogen exposure, maternal trauma, and more. Thus, authors claimed that diagnostic testing of EMX2 is not justified, as any results would be uninterpretable.

PMID: 20157829 – Hehr et al., 2010
52 patients with SCH, no EMX2 mutations detected. Sequenced EMX2 (all 52 cases) as well SHH, SIX3 and ZIC2 in some of the individuals. SIX3 and SHH variants are reported as causative instead.

EMX2 is associated with Schizencephaly in OMIM (269160, accessed 29th Sep 2025) & classified as Limited for Schizencephaly in ClinGen (Epilepsy GCEP, 2024).

No other cases with EMX2 variants were published in literature since 1997. Due to outdated / conflicting evidence, this gene should be downgraded to Amber for Intellectual disability.
Intellectual disability v9.99 EMX2 Ida Ertmanska commented on gene: EMX2: Comment on list classification: There are at least 4 unrelated families where individuals harbouring de novo variants in EMX2 have schizencephaly - a rare severe brain malformation, leading to neurologic deficits and developmental delay (PMIDs: 8528262, 9153481, 9359037). However, the 1996-1997 studies are limited by their sequencing method (targeted gene sequencing). Subsequent studies of 3 different schizencephaly patient cohorts showed that none of the 175 affected individuals carried pathogenic EMX2 mutations (PMIDs: 17506092, 18409201, 20157829). No other cases with EMX2 variants were published in literature since 1997. Schizencephaly may also stem from non-genetic causes, such as in utero viral infections, teratogen exposure, maternal trauma, and more (PMID: 18409201 Merello et al., 2008). Due to outdated and conflicting evidence, this gene should be downgraded to Amber for Intellectual disability.
Intellectual disability v9.99 OGDHL Ida Ertmanska changed review comment from: Comment on list classification: This gene should remain Green for Intellectual disability. There is strong evidence for the association between OGDHL and Yoon-Bellen neurodevelopmental syndrome. However, the phenotype is highly hetergoeneous, and care should be taken not to attribute all clinical symptoms to OGDHL dysfunction.; to: Comment on list classification: This gene should remain Green for Intellectual disability. There is strong evidence for the association between OGDHL and Yoon-Bellen neurodevelopmental syndrome. However, the phenotype is highly heterogeneous, and care should be taken not to attribute all clinical symptoms to OGDHL dysfunction.
Intellectual disability v9.99 OGDHL Ida Ertmanska changed review comment from: Comment on list classifcation: This gene should remain Green for Intellectual disability. There is strong evidence for the association between OGDHL and Yoon-Bellen neurodevelopmental syndrome. However, the phenotype is highly hetergoeneous, and care should be taken not to attribute all clinical symptoms to OGDHL dysfunction.; to: Comment on list classification: This gene should remain Green for Intellectual disability. There is strong evidence for the association between OGDHL and Yoon-Bellen neurodevelopmental syndrome. However, the phenotype is highly hetergoeneous, and care should be taken not to attribute all clinical symptoms to OGDHL dysfunction.
Intellectual disability v9.99 OGDHL Ida Ertmanska commented on gene: OGDHL: Comment on list classifcation: This gene should remain Green for Intellectual disability. There is strong evidence for the association between OGDHL and Yoon-Bellen neurodevelopmental syndrome. However, the phenotype is highly hetergoeneous, and care should be taken not to attribute all clinical symptoms to OGDHL dysfunction.
Intellectual disability v9.99 CCT6A Arina Puzriakova Added comment: Comment on list classification: This gene can be promoted to Green at the next GMS panel update. Phenotype is quite variable and unspecific - DD/ID is the most common feature observed among affected individuals so worth adding to this panel to enable capture of variants in this gene.
Intellectual disability v9.98 CCT6A Arina Puzriakova gene: CCT6A was added
gene: CCT6A was added to Intellectual disability. Sources: Literature
Q3_25_promote_green tags were added to gene: CCT6A.
Mode of inheritance for gene: CCT6A was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CCT6A were set to 39480921
Phenotypes for gene: CCT6A were set to Neurodevelopmental disorder, MONDO:0700092
Review for gene: CCT6A was set to GREEN
Added comment: PMID: 39480921 (2024) - 5 unrelated individuals with variants in the CCT6A gene, including 4 de novo (4 LoF, 2 missense), presenting with neurodevelopmental disorders. Main clinical features include DD/ID (4/5), pyramidal/cerebellar signs (3/4), variable brain abnormalities (3/5), microcephaly (2/5 - severe only in one) seizures (2/4), visual impairment (2/5).
Sources: Literature
Intellectual disability v9.96 TSPAN7 Eleanor Williams Phenotypes for gene: TSPAN7 were changed from Mental retardation, X-linked 58, 300210; MENTAL RETARDATION X-LINKED TYPE 58 to ntellectual developmental disorder, X-linked 58, OMIM:300210; intellectual disability, MONDO:0010266 X-linked 58,
Intellectual disability v9.94 TSPAN7 Ida Ertmanska changed review comment from: There are at least 7 unrelated families reported with mild to moderate intellectual disability with either LoF variants in TSPAN7, TSPAN7 duplication, or balanced translocations with a breakpoint within the TSPAN7 sequence. However, phenotype in most of the affected individuals does not meet the eligibility criteria of moderate/severe/profound global developmental delay/intellectual disability.

PMID: 10655063 Zemni et al., 2000: Sequencing method: DDGE + sequencing of PCR products (TSPAN7 sequence only).
Female patient with mild MR, mild autistic features, no dysmorphic features; IQ = 64 at 10yo. Heterozygous for a [46,X,t(X;2)(p11.4;p21.3)] balanced translocation affecting within TSPAN7 in a patient with mental retardation. TSPAN7 transcripts were barely detectable by RT-PCR.

Family L28, c.652G>T, p.(Gly218Ter) – IQ 45-60 in affected individuals (no age provided); authors claim variant segregates with disease, but data is not shown; RT-PCR showed normal levels of the transcript in affected patients; variant lies in a region of predicted NMD escape. Not found in gnomAD v4.1.0.

Family T15: 4 males hemizygous for c.515C>A, p.(Pro172His). IQ = 40-45 in 3 affected individuals (age 36-40 at report), individual 16 had IQ = 70 at age 10. In addition, individual 13 had low IQ (64) but did not carry the same mutation.
Conflicting evidence:
p.(Pro172His) variant-disease association disputed in PMID: 12376945 Gomot 2002 – linkage analysis in the same family excluded the TSPAN7 variant, authors suggest it to be a rare polymorphism instead.
Subsequently in PMID: 14735593 (da Costa Maranduba et al,, 2004), authors sequenced TSPAN7 in 105 males with mental retardation and found the same variant, p.Pro172His, in another patient – 21yo at time of report, delayed developmental milestones, severe speech acquisition impairment (started talking at 3.5 years); presented with dysmorphic facial features, abnormally folded ears, hypoplastic nails and alopecia spots.
Variant’s REVEL score = 0.62 (uncertain). Highest frequency in gnomAD v4 = 0.002106 (European population) – includes 2 homozygotes and 613 hemizygotes - unlikely to be causal, frequency too high.

PMID: 12070254 Abidi et al., 2002:
2-bp deletion c.572_573del p.(Val191fs) detected in a family with intellectual disability. Method: Screening exons of TM4SF2 gene only. Variant not in gnomAD v4.1.0. Family 'MRX58': five affected males in two generations with mild to moderate mental retardation (no IQ scores or ages given); affected males live in sheltered homes, are capable of doing simple jobs, and have no dysmorphic features; carrier females in the family have normal intelligence. BsrI restriction enzyme analysis determined that the deletion segregated with the XLMR in MRX58.

PMID: 22511893 Utine et al., 2012
FAMILY 1: moderately retarded 9-year-old patient and his similarly affected 11-year-old brother had infantile hypotonia and delayed motor development; did not acquire language abilities; No dysmorphic characteristics. TSPAN7 gene was duplicated. Unaffected mother had 3 copies of the same region. Copy number variation effect not yet clear as cause of ID.

PMID: 26290131 Moyses-Oliveira et al., 2015
Patient 1 - balanced translocation X;21 disrupting the 3’ UTR of TSPAN7; no TSPAN7 expression in peripheral blood sample. Authors pose that in women with balanced X-autosome translocations, the normal X chromosome is preferentially inactivated, resulting in a lack of expression. Array CGH did not cover the area of the autosomal breakpoint – effect unknown, method limitation. Patient phenotype: ‘borderline’ ID, microsomia, microcephaly.

Other variants reported as pathogenic in databases:
c.271-1G>T, Variation ID: 3767244. Hemizygous in proband with XLID, inherited from unaffected mother. Variant not in gnomAD v4, SpliceIAI = 1 Splice-Altering Strong. ClinVar submission by Kasturba Medical College, Manipal, India.

c.289del (p.Leu97fs), Variation ID: 1164055 – rated Pathogenic in ClinVar for XLID58 by Pediatric Genetics Clinic, Sheba Medical Center. Reported in an individual in clinical testing; Allele origin: inherited; Affected status: yes; Clinical Features: Neurodevelopmental delay, Attention deficit hyperactivity disorder, Abnormal cerebral white matter morphology, Short stature, Microcephaly; Test name: Whole exome sequencing; Zygosity: Hemizygote. Variant not present in gnomAD v4.

c.127dup p.(Thr43AsnfsTer42) – male patient (Patient: 318070) with intellectual disability reported in Decipher https://www.deciphergenomics.org/patient/318070/genotype/192961- variant not in gnomAD v4.

The association between TSPAN7 and non-syndromic X-linked intellectual disability was classified as Moderate by ClinGen (Intellectual Disability and Autism Gene Curation Expert Panel, Dec 2020). TSPAN7 is associated with Intellectual developmental disorder, X-linked 58 in OMIM (OMIM:300210, accessed 22 Sep 2025). Due to conflicting evidence in literature, the gene can only be rated Amber for Intellectual disability.; to: There are at least 7 unrelated families reported with mild to moderate intellectual disability with either LoF variants in TSPAN7, TSPAN7 duplication, or balanced translocations with a breakpoint within the TSPAN7 sequence. However, phenotype in most of the affected individuals does not meet the eligibility criteria of moderate/severe/profound global developmental delay/intellectual disability.

PMID: 10655063 Zemni et al., 2000: Sequencing method: DDGE + sequencing of PCR products (TSPAN7 sequence only).
Female patient with mild MR, mild autistic features, no dysmorphic features; IQ = 64 at 10yo. Heterozygous for a [46,X,t(X;2)(p11.4;p21.3)] balanced translocation affecting within TSPAN7 in a patient with mental retardation. TSPAN7 transcripts were barely detectable by RT-PCR.

Family L28, c.652G>T, p.(Gly218Ter) – IQ 45-60 in affected individuals (no age provided); authors claim variant segregates with disease, but data is not shown; RT-PCR showed normal levels of the transcript in affected patients; variant lies in a region of predicted NMD escape. Not found in gnomAD v4.1.0.

Family T15: 4 males hemizygous for c.515C>A, p.(Pro172His). IQ = 40-45 in 3 affected individuals (age 36-40 at report), individual 16 had IQ = 70 at age 10. In addition, individual 13 had low IQ (64) but did not carry the same mutation.
Conflicting evidence:
p.(Pro172His) variant-disease association disputed in PMID: 12376945 Gomot 2002 – linkage analysis in the same family excluded the TSPAN7 variant, authors suggest it to be a rare polymorphism instead.
Subsequently in PMID: 14735593 (da Costa Maranduba et al,, 2004), authors sequenced TSPAN7 in 105 males with mental retardation and found the same variant, p.Pro172His, in another patient – 21yo at time of report, delayed developmental milestones, severe speech acquisition impairment (started talking at 3.5 years); presented with dysmorphic facial features, abnormally folded ears, hypoplastic nails and alopecia spots.
Variant’s REVEL score = 0.62 (uncertain). Highest frequency in gnomAD v4 = 0.002106 (European population) – includes 2 homozygotes and 613 hemizygotes - unlikely to be causal, frequency too high.

PMID: 12070254 Abidi et al., 2002:
2-bp deletion c.572_573del p.(Val191fs) detected in a family with intellectual disability. Method: Screening exons of TM4SF2 gene only. Variant not in gnomAD v4.1.0. Family 'MRX58': five affected males in two generations with mild to moderate mental retardation (no IQ scores or ages given); affected males live in sheltered homes, are capable of doing simple jobs, and have no dysmorphic features; carrier females in the family have normal intelligence. BsrI restriction enzyme analysis determined that the deletion segregated with the XLMR in MRX58.

PMID: 22511893 Utine et al., 2012
FAMILY 1: moderately retarded 9-year-old patient and his similarly affected 11-year-old brother had infantile hypotonia and delayed motor development; did not acquire language abilities; No dysmorphic characteristics. TSPAN7 gene was duplicated. Unaffected mother had 3 copies of the same region. Copy number variation effect not yet clear as cause of ID.

PMID: 26290131 Moyses-Oliveira et al., 2015
Patient 1 - balanced translocation X;21 disrupting the 3’ UTR of TSPAN7; no TSPAN7 expression in peripheral blood sample. Authors pose that in women with balanced X-autosome translocations, the normal X chromosome is preferentially inactivated, resulting in a lack of expression. Array CGH did not cover the area of the autosomal breakpoint – effect unknown, method limitation. Patient phenotype: ‘borderline’ ID, microsomia, microcephaly.

Supporting evidence - variants in databases:
c.271-1G>T, Variation ID: 3767244. Hemizygous in proband with XLID, inherited from unaffected mother. Variant not in gnomAD v4, SpliceIAI = 1 Splice-Altering Strong. ClinVar submission by Kasturba Medical College, Manipal, India.

c.289del (p.Leu97fs), Variation ID: 1164055 – rated Pathogenic in ClinVar for XLID58 by Pediatric Genetics Clinic, Sheba Medical Center. Reported in an individual in clinical testing; Allele origin: inherited; Affected status: yes; Clinical Features: Neurodevelopmental delay, Attention deficit hyperactivity disorder, Abnormal cerebral white matter morphology, Short stature, Microcephaly; Test name: Whole exome sequencing; Zygosity: Hemizygote. Variant not present in gnomAD v4.

c.127dup p.(Thr43AsnfsTer42) – male patient (Patient: 318070) with intellectual disability reported in Decipher https://www.deciphergenomics.org/patient/318070/genotype/192961- variant not in gnomAD v4.

The association between TSPAN7 and non-syndromic X-linked intellectual disability was classified as Moderate by ClinGen (Intellectual Disability and Autism Gene Curation Expert Panel, Dec 2020). TSPAN7 is associated with Intellectual developmental disorder, X-linked 58 in OMIM (OMIM:300210, accessed 22 Sep 2025). Due to conflicting evidence in literature, the gene can only be rated Amber for Intellectual disability.
Intellectual disability v9.94 TSPAN7 Ida Ertmanska changed review comment from: Comment on list classification: There are at least 7 unrelated families reported with mild to moderate intellectual disability with either LoF variants in TSPAN7, TSPAN7 duplication, or balanced translocations with a breakpoint within the TSPAN7 sequence. However, phenotype in most of the affected individuals does not meet our criteria for Intellectual Disability testing: IQ<50, global developmental delay, childhood onset. There is also conflicting evidence for pathogenicity of the reported variants, including high population allele frequencies, predicted NMD escape, and sequencing method limitations. Based on the available evidence, the gene can only be rated Amber for Intellectual disability.; to: Comment on list classification: There are at least 7 unrelated families reported with mild to moderate intellectual disability with either LoF variants in TSPAN7, TSPAN7 duplication, or balanced translocations with a breakpoint within the TSPAN7 sequence. However, phenotype in most of the affected individuals does not meet the eligibility criteria of moderate/severe/profound global developmental delay/intellectual disability. There is also conflicting evidence for pathogenicity of the reported variants, including high population allele frequencies, predicted NMD escape, and sequencing method limitations. Based on the available evidence, the gene can only be rated Amber for Intellectual disability.
Intellectual disability v9.94 TSPAN7 Ida Ertmanska changed review comment from: There are at least 7 unrelated families reported with mild to moderate intellectual disability with either LoF variants in TSPAN7, TSPAN7 duplication, or balanced translocations with a breakpoint within the TSPAN7 sequence. However, phenotype in most of the affected individuals does not meet our criteria for Intellectual Disability testing, i.e. IQ<50, global developmental delay, childhood onset:

PMID: 10655063 Zemni et al., 2000: Sequencing method: DDGE + sequencing of PCR products (TSPAN7 sequence only).
Female patient with mild MR, mild autistic features, no dysmorphic features; IQ = 64 at 10yo. Heterozygous for a [46,X,t(X;2)(p11.4;p21.3)] balanced translocation affecting within TSPAN7 in a patient with mental retardation. TSPAN7 transcripts were barely detectable by RT-PCR.

Family L28, c.652G>T, p.(Gly218Ter) – IQ 45-60 in affected individuals (no age provided); authors claim variant segregates with disease, but data is not shown; RT-PCR showed normal levels of the transcript in affected patients; variant lies in a region of predicted NMD escape. Not found in gnomAD v4.1.0.

Family T15: 4 males hemizygous for c.515C>A, p.(Pro172His). IQ = 40-45 in 3 affected individuals (age 36-40 at report), individual 16 had IQ = 70 at age 10. In addition, individual 13 had low IQ (64) but did not carry the same mutation.
Conflicting evidence:
p.(Pro172His) variant-disease association disputed in PMID: 12376945 Gomot 2002 – linkage analysis in the same family excluded the TSPAN7 variant, authors suggest it to be a rare polymorphism instead.
Subsequently in PMID: 14735593 (da Costa Maranduba et al,, 2004), authors sequenced TSPAN7 in 105 males with mental retardation and found the same variant, p.Pro172His, in another patient – 21yo at time of report, delayed developmental milestones, severe speech acquisition impairment (started talking at 3.5 years); presented with dysmorphic facial features, abnormally folded ears, hypoplastic nails and alopecia spots.
Variant’s REVEL score = 0.62 (uncertain). Highest frequency in gnomAD v4 = 0.002106 (European population) – includes 2 homozygotes and 613 hemizygotes - unlikely to be causal, frequency too high.

PMID: 12070254 Abidi et al., 2002:
2-bp deletion c.572_573del p.(Val191fs) detected in a family with intellectual disability. Method: Screening exons of TM4SF2 gene only. Variant not in gnomAD v4.1.0. Family 'MRX58': five affected males in two generations with mild to moderate mental retardation (no IQ scores or ages given); affected males live in sheltered homes, are capable of doing simple jobs, and have no dysmorphic features; carrier females in the family have normal intelligence. BsrI restriction enzyme analysis determined that the deletion segregated with the XLMR in MRX58.

PMID: 22511893 Utine et al., 2012
FAMILY 1: moderately retarded 9-year-old patient and his similarly affected 11-year-old brother had infantile hypotonia and delayed motor development; did not acquire language abilities; No dysmorphic characteristics. TSPAN7 gene was duplicated. Unaffected mother had 3 copies of the same region. Copy number variation effect not yet clear as cause of ID.

PMID: 26290131 Moyses-Oliveira et al., 2015
Patient 1 - balanced translocation X;21 disrupting the 3’ UTR of TSPAN7; no TSPAN7 expression in peripheral blood sample. Authors pose that in women with balanced X-autosome translocations, the normal X chromosome is preferentially inactivated, resulting in a lack of expression. Array CGH did not cover the area of the autosomal breakpoint – effect unknown, method limitation. Patient phenotype: ‘borderline’ ID, microsomia, microcephaly.

Other variants reported as pathogenic in databases:
c.271-1G>T, Variation ID: 3767244. Hemizygous in proband with XLID, inherited from unaffected mother. Variant not in gnomAD v4, SpliceIAI = 1 Splice-Altering Strong. ClinVar submission by Kasturba Medical College, Manipal, India.

c.289del (p.Leu97fs), Variation ID: 1164055 – rated Pathogenic in ClinVar for XLID58 by Pediatric Genetics Clinic, Sheba Medical Center. Reported in an individual in clinical testing; Allele origin: inherited; Affected status: yes; Clinical Features: Neurodevelopmental delay, Attention deficit hyperactivity disorder, Abnormal cerebral white matter morphology, Short stature, Microcephaly; Test name: Whole exome sequencing; Zygosity: Hemizygote. Variant not present in gnomAD v4.

c.127dup p.(Thr43AsnfsTer42) – male patient (Patient: 318070) with intellectual disability reported in Decipher https://www.deciphergenomics.org/patient/318070/genotype/192961- variant not in gnomAD v4.

The association between TSPAN7 and non-syndromic X-linked intellectual disability was classified as Moderate by ClinGen (Intellectual Disability and Autism Gene Curation Expert Panel, Dec 2020). TSPAN7 is associated with Intellectual developmental disorder, X-linked 58 in OMIM (OMIM:300210, accessed 22 Sep 2025). Due to conflicting evidence in literature, the gene can only be rated Amber for Intellectual disability.; to: There are at least 7 unrelated families reported with mild to moderate intellectual disability with either LoF variants in TSPAN7, TSPAN7 duplication, or balanced translocations with a breakpoint within the TSPAN7 sequence. However, phenotype in most of the affected individuals does not meet the eligibility criteria of moderate/severe/profound global developmental delay/intellectual disability.

PMID: 10655063 Zemni et al., 2000: Sequencing method: DDGE + sequencing of PCR products (TSPAN7 sequence only).
Female patient with mild MR, mild autistic features, no dysmorphic features; IQ = 64 at 10yo. Heterozygous for a [46,X,t(X;2)(p11.4;p21.3)] balanced translocation affecting within TSPAN7 in a patient with mental retardation. TSPAN7 transcripts were barely detectable by RT-PCR.

Family L28, c.652G>T, p.(Gly218Ter) – IQ 45-60 in affected individuals (no age provided); authors claim variant segregates with disease, but data is not shown; RT-PCR showed normal levels of the transcript in affected patients; variant lies in a region of predicted NMD escape. Not found in gnomAD v4.1.0.

Family T15: 4 males hemizygous for c.515C>A, p.(Pro172His). IQ = 40-45 in 3 affected individuals (age 36-40 at report), individual 16 had IQ = 70 at age 10. In addition, individual 13 had low IQ (64) but did not carry the same mutation.
Conflicting evidence:
p.(Pro172His) variant-disease association disputed in PMID: 12376945 Gomot 2002 – linkage analysis in the same family excluded the TSPAN7 variant, authors suggest it to be a rare polymorphism instead.
Subsequently in PMID: 14735593 (da Costa Maranduba et al,, 2004), authors sequenced TSPAN7 in 105 males with mental retardation and found the same variant, p.Pro172His, in another patient – 21yo at time of report, delayed developmental milestones, severe speech acquisition impairment (started talking at 3.5 years); presented with dysmorphic facial features, abnormally folded ears, hypoplastic nails and alopecia spots.
Variant’s REVEL score = 0.62 (uncertain). Highest frequency in gnomAD v4 = 0.002106 (European population) – includes 2 homozygotes and 613 hemizygotes - unlikely to be causal, frequency too high.

PMID: 12070254 Abidi et al., 2002:
2-bp deletion c.572_573del p.(Val191fs) detected in a family with intellectual disability. Method: Screening exons of TM4SF2 gene only. Variant not in gnomAD v4.1.0. Family 'MRX58': five affected males in two generations with mild to moderate mental retardation (no IQ scores or ages given); affected males live in sheltered homes, are capable of doing simple jobs, and have no dysmorphic features; carrier females in the family have normal intelligence. BsrI restriction enzyme analysis determined that the deletion segregated with the XLMR in MRX58.

PMID: 22511893 Utine et al., 2012
FAMILY 1: moderately retarded 9-year-old patient and his similarly affected 11-year-old brother had infantile hypotonia and delayed motor development; did not acquire language abilities; No dysmorphic characteristics. TSPAN7 gene was duplicated. Unaffected mother had 3 copies of the same region. Copy number variation effect not yet clear as cause of ID.

PMID: 26290131 Moyses-Oliveira et al., 2015
Patient 1 - balanced translocation X;21 disrupting the 3’ UTR of TSPAN7; no TSPAN7 expression in peripheral blood sample. Authors pose that in women with balanced X-autosome translocations, the normal X chromosome is preferentially inactivated, resulting in a lack of expression. Array CGH did not cover the area of the autosomal breakpoint – effect unknown, method limitation. Patient phenotype: ‘borderline’ ID, microsomia, microcephaly.

Other variants reported as pathogenic in databases:
c.271-1G>T, Variation ID: 3767244. Hemizygous in proband with XLID, inherited from unaffected mother. Variant not in gnomAD v4, SpliceIAI = 1 Splice-Altering Strong. ClinVar submission by Kasturba Medical College, Manipal, India.

c.289del (p.Leu97fs), Variation ID: 1164055 – rated Pathogenic in ClinVar for XLID58 by Pediatric Genetics Clinic, Sheba Medical Center. Reported in an individual in clinical testing; Allele origin: inherited; Affected status: yes; Clinical Features: Neurodevelopmental delay, Attention deficit hyperactivity disorder, Abnormal cerebral white matter morphology, Short stature, Microcephaly; Test name: Whole exome sequencing; Zygosity: Hemizygote. Variant not present in gnomAD v4.

c.127dup p.(Thr43AsnfsTer42) – male patient (Patient: 318070) with intellectual disability reported in Decipher https://www.deciphergenomics.org/patient/318070/genotype/192961- variant not in gnomAD v4.

The association between TSPAN7 and non-syndromic X-linked intellectual disability was classified as Moderate by ClinGen (Intellectual Disability and Autism Gene Curation Expert Panel, Dec 2020). TSPAN7 is associated with Intellectual developmental disorder, X-linked 58 in OMIM (OMIM:300210, accessed 22 Sep 2025). Due to conflicting evidence in literature, the gene can only be rated Amber for Intellectual disability.
Intellectual disability v9.94 TSPAN7 Ida Ertmanska changed review comment from: There are at least 7 unrelated families reported with mild to moderate intellectual disability with either LoF variants in TSPAN7, TSPAN7 duplication, or balanced translocations with a breakpoint within the TSPAN7 sequence. However, phenotype in most of the affected individuals does not meet our criteria for Intellectual Disability testing, i.e. IQ<50, global developmental delay, childhood onset:

PMID: 10655063 Zemni et al., 2000: Sequencing method: DDGE + sequencing of PCR products (TSPAN7 sequence only).
Female patient with mild MR, mild autistic features, no dysmorphic features; IQ = 64 at 10yo. Heterozygous for a [46,X,t(X;2)(p11.4;p21.3)] balanced translocation affecting within TSPAN7 in a patient with mental retardation. TSPAN7 transcripts were barely detectable by RT-PCR.

Family L28, c.652G>T, p.(Gly218Ter) – IQ 45-60 in affected individuals (no age provided); authors claim variant segregates with disease, but data is not shown; RT-PCR showed normal levels of the transcript in affected patients; variant lies in a region of predicted NMD escape. Not found in gnomAD v4.1.0.

Family T15: 4 males hemizygous for c.515C>A, p.(Pro172His). IQ = 40-45 in 3 affected individuals (age 36-40 at report), individual 16 had IQ = 70 at age 10. In addition, individual 13 had low IQ (64) but did not carry the same mutation.
Conflicting evidence:
p.(Pro172His) variant-disease association disputed in PMID: 12376945 Gomot 2002 – linkage analysis in the same family excluded the TSPAN7 variant, authors suggest it to be a rare polymorphism instead.
Subsequently in PMID: 14735593 (da Costa Maranduba et al,, 2004), authors sequenced TSPAN7 in 105 males with mental retardation and found the same variant, p.Pro172His, in another patient – 21yo at time of report, delayed developmental milestones, severe speech acquisition impairment (started talking at 3.5 years); presented with dysmorphic facial features, abnormally folded ears, hypoplastic nails and alopecia spots.
Variant’s REVEL score = 0.62 (uncertain). Highest frequency in gnomAD v4 = 0.002106 (European population) – includes 2 homozygotes and 613 hemizygotes - unlikely to be causal, frequency too high.

PMID: 12070254 Abidi et al., 2002:
2-bp deletion c.572_573del p.(Val191fs) detected in a family with intellectual disability. Method: Screening exons of TM4SF2 gene only. Variant not in gnomAD v4.1.0. Family 'MRX58': five affected males in two generations with mild to moderate mental retardation (no IQ scores or ages given); affected males live in sheltered homes, are capable of doing simple jobs, and have no dysmorphic features; carrier females in the family have normal intelligence. BsrI restriction enzyme analysis determined that the deletion segregated with the XLMR in MRX58.

PMID: 22511893 Utine et al., 2012
FAMILY 1: moderately retarded 9-year-old patient and his similarly affected 11-year-old brother had infantile hypotonia and delayed motor development; did not acquire language abilities; No dysmorphic characteristics. TSPAN7 gene was duplicated. Unaffected mother had 3 copies of the same region. Copy number variation effect not yet clear as cause of ID.

PMID: 26290131 Moyses-Oliveira et al., 2015
Patient 1 - balanced translocation X;21 disrupting the 3’ UTR of TSPAN7; no TSPAN7 expression in peripheral blood sample. Authors pose that in women with balanced X-autosome translocations, the normal X chromosome is preferentially inactivated, resulting in a lack of expression. Array CGH did not cover the area of the autosomal breakpoint – effect unknown, method limitation. Patient phenotype: ‘borderline’ ID, microsomia, microcephaly.

Other variants reported as pathogenic in databases:
c.271-1G>T, Variation ID: 3767244. Hemizygous in proband with XLID, inherited from unaffected mother. Variant not in gnomAD v4, SpliceIAI = 1 Splice-Altering Strong. ClinVar submission by Kasturba Medical College, Manipal, India.

c.289del (p.Leu97fs), Variation ID: 1164055 – rated Pathogenic in ClinVar for XLID58 by Pediatric Genetics Clinic, Sheba Medical Center. Reported in an individual in clinical testing; Allele origin: inherited; Affected status: yes; Clinical Features: Neurodevelopmental delay, Attention deficit hyperactivity disorder, Abnormal cerebral white matter morphology, Short stature, Microcephaly; Test name: Whole exome sequencing; Zygosity: Hemizygote. Variant not present in gnomAD v4.

c.127dup p.(Thr43AsnfsTer42) – male patient (Patient: 318070) with intellectual disability reported in Decipher https://www.deciphergenomics.org/patient/318070/genotype/192961- variant not in gnomAD v4.

The association between TSPAN7 and non-syndromic X-linked intellectual disability was classified as Moderate by ClinGen (Intellectual Disability and Autism Gene Curation Expert Panel, Dec 2020). TSPAN7 is associated with Intellectual developmental disorder, X-linked 58 in OMIM (OMIM:300210, accessed 22 Sep 2025). Due to conflicting evidence in literature, the gene can only be rated Amber for Intellectual disability.; to: There are at least 7 unrelated families reported with mild to moderate intellectual disability with either LoF variants in TSPAN7, TSPAN7 duplication, or balanced translocations with a breakpoint within the TSPAN7 sequence. However, phenotype in most of the affected individuals does not meet our criteria for Intellectual Disability testing, i.e. IQ<50, global developmental delay, childhood onset:

PMID: 10655063 Zemni et al., 2000: Sequencing method: DDGE + sequencing of PCR products (TSPAN7 sequence only).
Female patient with mild MR, mild autistic features, no dysmorphic features; IQ = 64 at 10yo. Heterozygous for a [46,X,t(X;2)(p11.4;p21.3)] balanced translocation affecting within TSPAN7 in a patient with mental retardation. TSPAN7 transcripts were barely detectable by RT-PCR.

Family L28, c.652G>T, p.(Gly218Ter) – IQ 45-60 in affected individuals (no age provided); authors claim variant segregates with disease, but data is not shown; RT-PCR showed normal levels of the transcript in affected patients; variant lies in a region of predicted NMD escape. Not found in gnomAD v4.1.0.

Family T15: 4 males hemizygous for c.515C>A, p.(Pro172His). IQ = 40-45 in 3 affected individuals (age 36-40 at report), individual 16 had IQ = 70 at age 10. In addition, individual 13 had low IQ (64) but did not carry the same mutation.
Conflicting evidence:
p.(Pro172His) variant-disease association disputed in PMID: 12376945 Gomot 2002 – linkage analysis in the same family excluded the TSPAN7 variant, authors suggest it to be a rare polymorphism instead.
Subsequently in PMID: 14735593 (da Costa Maranduba et al,, 2004), authors sequenced TSPAN7 in 105 males with mental retardation and found the same variant, p.Pro172His, in another patient – 21yo at time of report, delayed developmental milestones, severe speech acquisition impairment (started talking at 3.5 years); presented with dysmorphic facial features, abnormally folded ears, hypoplastic nails and alopecia spots.
Variant’s REVEL score = 0.62 (uncertain). Highest frequency in gnomAD v4 = 0.002106 (European population) – includes 2 homozygotes and 613 hemizygotes - unlikely to be causal, frequency too high.

PMID: 12070254 Abidi et al., 2002:
2-bp deletion c.572_573del p.(Val191fs) detected in a family with intellectual disability. Method: Screening exons of TM4SF2 gene only. Variant not in gnomAD v4.1.0. Family 'MRX58': five affected males in two generations with mild to moderate mental retardation (no IQ scores or ages given); affected males live in sheltered homes, are capable of doing simple jobs, and have no dysmorphic features; carrier females in the family have normal intelligence. BsrI restriction enzyme analysis determined that the deletion segregated with the XLMR in MRX58.

PMID: 22511893 Utine et al., 2012
FAMILY 1: moderately retarded 9-year-old patient and his similarly affected 11-year-old brother had infantile hypotonia and delayed motor development; did not acquire language abilities; No dysmorphic characteristics. TSPAN7 gene was duplicated. Unaffected mother had 3 copies of the same region. Copy number variation effect not yet clear as cause of ID.

PMID: 26290131 Moyses-Oliveira et al., 2015
Patient 1 - balanced translocation X;21 disrupting the 3’ UTR of TSPAN7; no TSPAN7 expression in peripheral blood sample. Authors pose that in women with balanced X-autosome translocations, the normal X chromosome is preferentially inactivated, resulting in a lack of expression. Array CGH did not cover the area of the autosomal breakpoint – effect unknown, method limitation. Patient phenotype: ‘borderline’ ID, microsomia, microcephaly.

Other variants reported as pathogenic in databases:
c.271-1G>T, Variation ID: 3767244. Hemizygous in proband with XLID, inherited from unaffected mother. Variant not in gnomAD v4, SpliceIAI = 1 Splice-Altering Strong. ClinVar submission by Kasturba Medical College, Manipal, India.

c.289del (p.Leu97fs), Variation ID: 1164055 – rated Pathogenic in ClinVar for XLID58 by Pediatric Genetics Clinic, Sheba Medical Center. Reported in an individual in clinical testing; Allele origin: inherited; Affected status: yes; Clinical Features: Neurodevelopmental delay, Attention deficit hyperactivity disorder, Abnormal cerebral white matter morphology, Short stature, Microcephaly; Test name: Whole exome sequencing; Zygosity: Hemizygote. Variant not present in gnomAD v4.

c.127dup p.(Thr43AsnfsTer42) – male patient (Patient: 318070) with intellectual disability reported in Decipher https://www.deciphergenomics.org/patient/318070/genotype/192961- variant not in gnomAD v4.

The association between TSPAN7 and non-syndromic X-linked intellectual disability was classified as Moderate by ClinGen (Intellectual Disability and Autism Gene Curation Expert Panel, Dec 2020). TSPAN7 is associated with Intellectual developmental disorder, X-linked 58 in OMIM (OMIM:300210, accessed 22 Sep 2025). Due to conflicting evidence in literature, the gene can only be rated Amber for Intellectual disability.
Intellectual disability v9.94 TSPAN7 Ida Ertmanska commented on gene: TSPAN7: Comment on list classification: There are at least 7 unrelated families reported with mild to moderate intellectual disability with either LoF variants in TSPAN7, TSPAN7 duplication, or balanced translocations with a breakpoint within the TSPAN7 sequence. However, phenotype in most of the affected individuals does not meet our criteria for Intellectual Disability testing: IQ<50, global developmental delay, childhood onset. There is also conflicting evidence for pathogenicity of the reported variants, including high population allele frequencies, predicted NMD escape, and sequencing method limitations. Based on the available evidence, the gene can only be rated Amber for Intellectual disability.
Intellectual disability v9.94 TSPAN7 Ida Ertmanska changed review comment from: There are at least 7 unrelated families reported with mild to moderate intellectual disability with either LoF variants in TSPAN7, TSPAN7 duplication, or balanced translocations with a breakpoint within the TSPAN7 sequence. However, phenotype in most of the affected individuals does not meet our criteria for Intellectual Disability testing, i.e. IQ<50, global developmental delay, childhood onset:

PMID: 10655063 Zemni et al., 2000: Sequencing method: DDGE + sequencing of PCR products (TSPAN7 sequence only).
Female patient with mild MR, mild autistic features, no dysmorphic features; IQ = 64 at 10yo. Heterozygous for a [46,X,t(X;2)(p11.4;p21.3)] balanced translocation affecting within TSPAN7 in a patient with mental retardation. TSPAN7 transcripts were barely detectable by RT-PCR.

Family L28, c.652G>T, p.(Gly218Ter) – IQ 45-60 in affected individuals (no age provided); authors claim variant segregates with disease, but data is not shown; RT-PCR showed normal levels of the transcript in affected patients; variant lies in a region of predicted NMD escape. Not found in gnomAD v4.1.0.

Family T15: 4 males hemizygous for c.515C>A, p.(Pro172His). IQ = 40-45 in 3 affected individuals (age 36-40 at report), individual 16 had IQ = 70 at age 10. In addition, individual 13 had low IQ (64) but did not carry the same mutation.
Conflicting evidence:
p.(Pro172His) variant-disease association disputed in PMID: 12376945 Gomot 2002 – linkage analysis in the same family excluded the TSPAN7 variant, authors suggest it to be a rare polymorphism instead.
Subsequently in PMID: 14735593 (da Costa Maranduba et al,, 2004), authors sequenced TSPAN7 in 105 males with mental retardation and found the same variant, p.Pro172His, in another patient – 21yo at time of report, delayed developmental milestones, severe speech acquisition impairment (started talking at 3.5 years); presented with dysmorphic facial features, abnormally folded ears, hypoplastic nails and alopecia spots.
Variant’s REVEL score = 0.62 (uncertain). Highest frequency in gnomAD v4 = 0.002106 (European population) – includes 2 homozygotes and 613 hemizygotes - unlikely to be causal, frequency too high.

PMID: 12070254 Abidi et al., 2002:
2-bp deletion c.572_573del p.(Val191fs) detected in a family with intellectual disability. Method: Screening exons of TM4SF2 gene only. Variant not in gnomAD v4.1.0. Family 'MRX58': five affected males in two generations with mild to moderate mental retardation (no IQ scores or ages given); affected males live in sheltered homes, are capable of doing simple jobs, and have no dysmorphic features; carrier females in the family have normal intelligence. BsrI restriction enzyme analysis determined that the deletion segregated with the XLMR in MRX58.

PMID: 22511893 Utine et al., 2012
FAMILY 1: moderately retarded 9-year-old patient and his similarly affected 11-year-old brother had infantile hypotonia and delayed motor development; did not acquire language abilities; No dysmorphic characteristics. TSPAN7 gene was duplicated. Unaffected mother had 3 copies of the same region. Copy number variation effect not yet clear as cause of ID.

PMID: 26290131 Moyses-Oliveira et al., 2015
Patient 1 - balanced translocation X;21 disrupting the 3’ UTR of TSPAN7; no TSPAN7 expression in peripheral blood sample. Authors pose that in women with balanced X-autosome translocations, the normal X chromosome is preferentially inactivated, resulting in a lack of expression. Array CGH did not cover the area of the autosomal breakpoint – effect unknown, method limitation. Patient phenotype: ‘borderline’ ID, microsomia, microcephaly.

Other variants reported as pathogenic in databases:
c.271-1G>T in intron 2 of TSPAN7 hemizygous in proband with XLID, inherited from unaffected mother. Variant not in gnomAD v4, SpliceIAI = 1 Splice-Altering Strong. ClinVar submission by Kasturba Medical College, Manipal, India.

c.289del (p.Leu97fs) – rated Pathogenic in ClinVar for XLID58 by Pediatric Genetics Clinic, Sheba Medical Center. Collection method: clinical testing; Allele origin: inherited; Affected status: yes; Clinical Features: Neurodevelopmental delay, Attention deficit hyperactivity disorder, Abnormal cerebral white matter morphology, Short stature, Microcephaly; Test name: Whole exome sequencing; Zygosity: Hemizygote. Variant not present in gnomAD v4.

c.127dup p.(Thr43AsnfsTer42) – male patient (Patient: 318070) with intellectual disability reported in Decipher https://www.deciphergenomics.org/patient/318070/genotype/192961/browser - variant not in gnomAD v4.

The association between TSPAN7 and non-syndromic X-linked intellectual disability was classified as Moderate by ClinGen (Intellectual Disability and Autism Gene Curation Expert Panel, Dec 2020). TSPAN7 is associated with Intellectual developmental disorder, X-linked 58 in OMIM (OMIM:300210, accessed 22 Sep 2025). Due to conflicting evidence in literature, the gene can only be rated Amber for Intellectual disability.; to: There are at least 7 unrelated families reported with mild to moderate intellectual disability with either LoF variants in TSPAN7, TSPAN7 duplication, or balanced translocations with a breakpoint within the TSPAN7 sequence. However, phenotype in most of the affected individuals does not meet our criteria for Intellectual Disability testing, i.e. IQ<50, global developmental delay, childhood onset:

PMID: 10655063 Zemni et al., 2000: Sequencing method: DDGE + sequencing of PCR products (TSPAN7 sequence only).
Female patient with mild MR, mild autistic features, no dysmorphic features; IQ = 64 at 10yo. Heterozygous for a [46,X,t(X;2)(p11.4;p21.3)] balanced translocation affecting within TSPAN7 in a patient with mental retardation. TSPAN7 transcripts were barely detectable by RT-PCR.

Family L28, c.652G>T, p.(Gly218Ter) – IQ 45-60 in affected individuals (no age provided); authors claim variant segregates with disease, but data is not shown; RT-PCR showed normal levels of the transcript in affected patients; variant lies in a region of predicted NMD escape. Not found in gnomAD v4.1.0.

Family T15: 4 males hemizygous for c.515C>A, p.(Pro172His). IQ = 40-45 in 3 affected individuals (age 36-40 at report), individual 16 had IQ = 70 at age 10. In addition, individual 13 had low IQ (64) but did not carry the same mutation.
Conflicting evidence:
p.(Pro172His) variant-disease association disputed in PMID: 12376945 Gomot 2002 – linkage analysis in the same family excluded the TSPAN7 variant, authors suggest it to be a rare polymorphism instead.
Subsequently in PMID: 14735593 (da Costa Maranduba et al,, 2004), authors sequenced TSPAN7 in 105 males with mental retardation and found the same variant, p.Pro172His, in another patient – 21yo at time of report, delayed developmental milestones, severe speech acquisition impairment (started talking at 3.5 years); presented with dysmorphic facial features, abnormally folded ears, hypoplastic nails and alopecia spots.
Variant’s REVEL score = 0.62 (uncertain). Highest frequency in gnomAD v4 = 0.002106 (European population) – includes 2 homozygotes and 613 hemizygotes - unlikely to be causal, frequency too high.

PMID: 12070254 Abidi et al., 2002:
2-bp deletion c.572_573del p.(Val191fs) detected in a family with intellectual disability. Method: Screening exons of TM4SF2 gene only. Variant not in gnomAD v4.1.0. Family 'MRX58': five affected males in two generations with mild to moderate mental retardation (no IQ scores or ages given); affected males live in sheltered homes, are capable of doing simple jobs, and have no dysmorphic features; carrier females in the family have normal intelligence. BsrI restriction enzyme analysis determined that the deletion segregated with the XLMR in MRX58.

PMID: 22511893 Utine et al., 2012
FAMILY 1: moderately retarded 9-year-old patient and his similarly affected 11-year-old brother had infantile hypotonia and delayed motor development; did not acquire language abilities; No dysmorphic characteristics. TSPAN7 gene was duplicated. Unaffected mother had 3 copies of the same region. Copy number variation effect not yet clear as cause of ID.

PMID: 26290131 Moyses-Oliveira et al., 2015
Patient 1 - balanced translocation X;21 disrupting the 3’ UTR of TSPAN7; no TSPAN7 expression in peripheral blood sample. Authors pose that in women with balanced X-autosome translocations, the normal X chromosome is preferentially inactivated, resulting in a lack of expression. Array CGH did not cover the area of the autosomal breakpoint – effect unknown, method limitation. Patient phenotype: ‘borderline’ ID, microsomia, microcephaly.

Other variants reported as pathogenic in databases:
c.271-1G>T, Variation ID: 3767244. Hemizygous in proband with XLID, inherited from unaffected mother. Variant not in gnomAD v4, SpliceIAI = 1 Splice-Altering Strong. ClinVar submission by Kasturba Medical College, Manipal, India.

c.289del (p.Leu97fs), Variation ID: 1164055 – rated Pathogenic in ClinVar for XLID58 by Pediatric Genetics Clinic, Sheba Medical Center. Reported in an individual in clinical testing; Allele origin: inherited; Affected status: yes; Clinical Features: Neurodevelopmental delay, Attention deficit hyperactivity disorder, Abnormal cerebral white matter morphology, Short stature, Microcephaly; Test name: Whole exome sequencing; Zygosity: Hemizygote. Variant not present in gnomAD v4.

c.127dup p.(Thr43AsnfsTer42) – male patient (Patient: 318070) with intellectual disability reported in Decipher https://www.deciphergenomics.org/patient/318070/genotype/192961- variant not in gnomAD v4.

The association between TSPAN7 and non-syndromic X-linked intellectual disability was classified as Moderate by ClinGen (Intellectual Disability and Autism Gene Curation Expert Panel, Dec 2020). TSPAN7 is associated with Intellectual developmental disorder, X-linked 58 in OMIM (OMIM:300210, accessed 22 Sep 2025). Due to conflicting evidence in literature, the gene can only be rated Amber for Intellectual disability.
Intellectual disability v9.94 TSPAN7 Ida Ertmanska changed review comment from: There are at least 7 unrelated families reported with mild to moderate intellectual disability with either LoF variants in TSPAN7, TSPAN7 duplication, or balanced translocations with a breakpoint within the TSPAN7 sequence. However, phenotype in most of the affected individuals does not meet our criteria for Intellectual Disability testing, i.e. IQ<50, global developmental delay, childhood onset:

PMID: 10655063 Zemni et al., 2000: Sequencing method: DDGE + sequencing of PCR products (TSPAN7 sequence only).
Female patient with mild MR, mild autistic features, no dysmorphic features; IQ = 64 at 10yo. Heterozygous for a [46,X,t(X;2)(p11.4;p21.3)] balanced translocation affecting within TSPAN7 in a patient with mental retardation. TSPAN7 transcripts were barely detectable by RT-PCR.

Family L28, c.652G>T, p.(Gly218Ter) – IQ 45-60 in affected individuals (no age provided); authors claim variant segregates with disease, but data is not shown; RT-PCR showed normal levels of the transcript in affected patients; variant lies in a region of predicted NMD escape. Not found in gnomAD v4.1.0.

Family T15: 4 males hemizygous for c.515C>A, p.(Pro172His). IQ = 40-45 in 3 affected individuals (age 36-40 at report), individual 16 had IQ = 70 at age 10. In addition, individual 13 had low IQ (64) but did not carry the same mutation.
Conflicting evidence:
p.(Pro172His) variant-disease association disputed in PMID: 12376945 Gomot 2002 – linkage analysis in the same family excluded the TSPAN7 variant, authors suggest it to be a rare polymorphism instead.
Subsequently in PMID: 14735593 (da Costa Maranduba et al,, 2004), authors sequenced TSPAN7 in 105 males with mental retardation and found the same variant, p.Pro172His, in another patient – 21yo at time of report, delayed developmental milestones, severe speech acquisition impairment (started talking at 3.5 years); presented with dysmorphic facial features, abnormally folded ears, hypoplastic nails and alopecia spots.
Variant’s REVEL score = 0.62 (uncertain). Highest frequency in gnomAD v4 = 0.002106 (European population) – includes 2 homozygotes and 613 hemizygotes - unlikely to be causal, frequency too high.

PMID: 12070254 Abidi et al., 2002:
2-bp deletion c.572_573del p.(Val191fs) detected in a family with intellectual disability. Method: Screening exons of TM4SF2 gene only. Variant not in gnomAD v4.1.0. Family 'MRX58': five affected males in two generations with mild to moderate mental retardation (no IQ scores or ages given); affected males live in sheltered homes, are capable of doing simple jobs, and have no dysmorphic features; carrier females in the family have normal intelligence. BsrI restriction enzyme analysis determined that the deletion segregated with the XLMR in MRX58.

PMID: 22511893 Utine et al., 2012
FAMILY 1: moderately retarded 9-year-old patient and his similarly affected 11-year-old brother had infantile hypotonia and delayed motor development; did not acquire language abilities; No dysmorphic characteristics. TSPAN7 gene was duplicated. Unaffected mother had 3 copies of the same region. Copy number variation effect not yet clear as cause of ID.

PMID: 26290131 Moyses-Oliveira et al., 2015
Patient 1 - balanced translocation X;21 disrupting the 3’ UTR of TSPAN7; no TSPAN7 expression in peripheral blood sample. Authors pose that in women with balanced X-autosome translocations, the normal X chromosome is preferentially inactivated, resulting in a lack of expression. Array CGH did not cover the area of the autosomal breakpoint – effect unknown, method limitation. Patient phenotype: ‘borderline’ ID, microsomia, microcephaly.

Other variants reported as pathogenic in databases:
c.271-1G>T in intron 2 of TSPAN7 hemizygous in proband with XLID, inherited from unaffected mother. Variant not in gnomAD v4, SpliceIAI = 1 Splice-Altering Strong. ClinVar submission by Kasturba Medical College, Manipal, India.

c.289del (p.Leu97fs) – rated Pathogenic in ClinVar for XLID58 by Pediatric Genetics Clinic, Sheba Medical Center. Collection method: clinical testing; Allele origin: inherited; Affected status: yes; Clinical Features: Neurodevelopmental delay, Attention deficit hyperactivity disorder, Abnormal cerebral white matter morphology, Short stature, Microcephaly; Test name: Whole exome sequencing; Zygosity: Hemizygote. Variant not present in gnomAD v4.

c.127dup p.(Thr43AsnfsTer42) – male patient (Patient: 318070) with intellectual disability reported in Decipher https://www.deciphergenomics.org/patient/318070/genotype/192961/browser - variant not in gnomAD v4.

The association between TSPAN7 and non-syndromic X-linked intellectual disability was classified as Moderate by ClinGen (Intellectual Disability and Autism Gene Curation Expert Panel, Dec 2020). TSPAN7 is associated with Intellectual developmental disorder, X-linked 58 in OMIM (OMIM:300210, accessed 22 Sep 2025). Due to conflicting evidence in literature, the gene can only be rated Amber for Intellectual disability.; to: There are at least 7 unrelated families reported with mild to moderate intellectual disability with either LoF variants in TSPAN7, TSPAN7 duplication, or balanced translocations with a breakpoint within the TSPAN7 sequence. However, phenotype in most of the affected individuals does not meet our criteria for Intellectual Disability testing, i.e. IQ<50, global developmental delay, childhood onset:

PMID: 10655063 Zemni et al., 2000: Sequencing method: DDGE + sequencing of PCR products (TSPAN7 sequence only).
Female patient with mild MR, mild autistic features, no dysmorphic features; IQ = 64 at 10yo. Heterozygous for a [46,X,t(X;2)(p11.4;p21.3)] balanced translocation affecting within TSPAN7 in a patient with mental retardation. TSPAN7 transcripts were barely detectable by RT-PCR.

Family L28, c.652G>T, p.(Gly218Ter) – IQ 45-60 in affected individuals (no age provided); authors claim variant segregates with disease, but data is not shown; RT-PCR showed normal levels of the transcript in affected patients; variant lies in a region of predicted NMD escape. Not found in gnomAD v4.1.0.

Family T15: 4 males hemizygous for c.515C>A, p.(Pro172His). IQ = 40-45 in 3 affected individuals (age 36-40 at report), individual 16 had IQ = 70 at age 10. In addition, individual 13 had low IQ (64) but did not carry the same mutation.
Conflicting evidence:
p.(Pro172His) variant-disease association disputed in PMID: 12376945 Gomot 2002 – linkage analysis in the same family excluded the TSPAN7 variant, authors suggest it to be a rare polymorphism instead.
Subsequently in PMID: 14735593 (da Costa Maranduba et al,, 2004), authors sequenced TSPAN7 in 105 males with mental retardation and found the same variant, p.Pro172His, in another patient – 21yo at time of report, delayed developmental milestones, severe speech acquisition impairment (started talking at 3.5 years); presented with dysmorphic facial features, abnormally folded ears, hypoplastic nails and alopecia spots.
Variant’s REVEL score = 0.62 (uncertain). Highest frequency in gnomAD v4 = 0.002106 (European population) – includes 2 homozygotes and 613 hemizygotes - unlikely to be causal, frequency too high.

PMID: 12070254 Abidi et al., 2002:
2-bp deletion c.572_573del p.(Val191fs) detected in a family with intellectual disability. Method: Screening exons of TM4SF2 gene only. Variant not in gnomAD v4.1.0. Family 'MRX58': five affected males in two generations with mild to moderate mental retardation (no IQ scores or ages given); affected males live in sheltered homes, are capable of doing simple jobs, and have no dysmorphic features; carrier females in the family have normal intelligence. BsrI restriction enzyme analysis determined that the deletion segregated with the XLMR in MRX58.

PMID: 22511893 Utine et al., 2012
FAMILY 1: moderately retarded 9-year-old patient and his similarly affected 11-year-old brother had infantile hypotonia and delayed motor development; did not acquire language abilities; No dysmorphic characteristics. TSPAN7 gene was duplicated. Unaffected mother had 3 copies of the same region. Copy number variation effect not yet clear as cause of ID.

PMID: 26290131 Moyses-Oliveira et al., 2015
Patient 1 - balanced translocation X;21 disrupting the 3’ UTR of TSPAN7; no TSPAN7 expression in peripheral blood sample. Authors pose that in women with balanced X-autosome translocations, the normal X chromosome is preferentially inactivated, resulting in a lack of expression. Array CGH did not cover the area of the autosomal breakpoint – effect unknown, method limitation. Patient phenotype: ‘borderline’ ID, microsomia, microcephaly.

Other variants reported as pathogenic in databases:
c.271-1G>T in intron 2 of TSPAN7 hemizygous in proband with XLID, inherited from unaffected mother. Variant not in gnomAD v4, SpliceIAI = 1 Splice-Altering Strong. ClinVar submission by Kasturba Medical College, Manipal, India.

c.289del (p.Leu97fs) – rated Pathogenic in ClinVar for XLID58 by Pediatric Genetics Clinic, Sheba Medical Center. Collection method: clinical testing; Allele origin: inherited; Affected status: yes; Clinical Features: Neurodevelopmental delay, Attention deficit hyperactivity disorder, Abnormal cerebral white matter morphology, Short stature, Microcephaly; Test name: Whole exome sequencing; Zygosity: Hemizygote. Variant not present in gnomAD v4.

c.127dup p.(Thr43AsnfsTer42) – male patient (Patient: 318070) with intellectual disability reported in Decipher https://www.deciphergenomics.org/patient/318070/genotype/192961/browser - variant not in gnomAD v4.

The association between TSPAN7 and non-syndromic X-linked intellectual disability was classified as Moderate by ClinGen (Intellectual Disability and Autism Gene Curation Expert Panel, Dec 2020). TSPAN7 is associated with Intellectual developmental disorder, X-linked 58 in OMIM (OMIM:300210, accessed 22 Sep 2025). Due to conflicting evidence in literature, the gene can only be rated Amber for Intellectual disability.
Intellectual disability v9.94 BHLHE22 Arina Puzriakova changed review comment from: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - tone abnormalities were present in all individuals, presenting as lower limb or appendicular spasticity in 6 patients.; to: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - 6/7 individuals available for examination exhibited significant GDD and ID.
Intellectual disability v9.94 BHLHE22 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - tone abnormalities were present in all individuals, presenting as lower limb or appendicular spasticity in 6 patients.
Intellectual disability v9.93 BHLHE22 Arina Puzriakova gene: BHLHE22 was added
gene: BHLHE22 was added to Intellectual disability. Sources: Literature
Q3_25_promote_green tags were added to gene: BHLHE22.
Mode of inheritance for gene: BHLHE22 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: BHLHE22 were set to 39502664
Phenotypes for gene: BHLHE22 were set to Neurodevelopmental disorder, MONDO:0700092
Review for gene: BHLHE22 was set to GREEN
Added comment: PMID: 39502664 - 11 individuals from 9 unrelated families with BHLHE22 variants, presenting with a neurodevelopmental disorder including absent or limited speech, impaired motor function, intellectual disability, involuntary movements, autistic traits, abnormal muscle tone. Most had partial or complete agenesis of the corpus callosum, and some also showed epilepsy, dysmorphic features, and eye anomalies.

Four individuals had de novo missense variants within the helix-loop-helix domain, and seven carried a recurrent homozygous frameshift variant, p.(Gly74Alafs*18).

Mice lacking bhlhe22 show nearly complete loss of three brain comminsure, including the corpus callosum, recapitulating the structural anomalies seen in affected humans.
Sources: Literature
Intellectual disability v9.92 UGGT1 Karen Stals gene: UGGT1 was added
gene: UGGT1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: UGGT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: UGGT1 were set to PMID: 40267907
Phenotypes for gene: UGGT1 were set to intellectual disability; seizures; characteristic facial features; microcephaly; congenital heart malformations, variable skeletal abnormalities; hepatic and renal involvement; polycystic kidneys
Review for gene: UGGT1 was set to GREEN
gene: UGGT1 was marked as current diagnostic
Added comment: Dardas et al report biallelic UGGT1 variants in 10 families (15 individuals), with more severe phenotypes seen with biallelic loss of function variants. UGGT1 variants were shown to impair UGGT1 glycosylation and catalytic activity.
Sources: Literature
Intellectual disability v9.92 TNR Arina Puzriakova changed review comment from: Comment on list classification: There is sufficient evidence to rate this gene GREEN at the next major review - at least 7 unrelated cases with cognitive impairment associated with variants in this gene.; to: Comment on list classification: There is sufficient evidence to rate this gene Green at the next GMS panel update. Impaired intellectual development noted in multiple individuals with biallelic variants in this gene, although the severity was highly variable and no formal neuropsychological testing was done. Nonetheless, cognitive developmental delay was recorded as moderate in at least 5 unrelated cases which supports inclusion on the panel.
Intellectual disability v9.90 TNR Arina Puzriakova Phenotypes for gene: TNR were changed from Spastic para- or tetraparesis; Axial muscular hypotonia; Intellectual disability; Transient opisthotonus to Neurodevelopmental disorder, nonprogressive, with spasticity and transient opisthotonus, OMIM:619653
Intellectual disability v9.89 UPF1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the association of monoallelic UPF1 variants with intellectual disability and/or global developmental delay. Hence, this gene can be promoted to green rating in the next GMS update.
Intellectual disability v9.88 UPF1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the association of monoallelic UPF1 variants with intellectual disability and/or global developmental delay. Hence, this gene can be promoted to green rating in the next GMS update.
Intellectual disability v9.87 UPF1 Achchuthan Shanmugasundram changed review comment from: PMID:28135719 (2017) reported four unrelated patients with de novo heterozygous missense variants in UPF1 gene from the Deciphering Developmental Disorders Study cohort, for which no detailed phenotypic information was available in the publication. Three patients were reported with global developmental delay (mild in one) and the fourth patient was reported with neurodevelopmental delay as one of the presenting phenotypes in the Decipher database (https://www.deciphergenomics.org/gene/UPF1/patient-overlap/snvs).

PMID:28539120 (2017) reported a patient with significant intellectual disability (ID) and gross motor delay and with a heterozygous likely pathogenic variant in UPF1 gene (c.1576_1577delinsAA/ p.Ala526Asn). However, this patient also harboured a heterozygous likely pathogenic variant in SQSTM1 gene. As reviewed below by Ivone Leong, the authors suggested that it is plausible that the haploinsufficiency of SQSTM1 may have caused neurofunctional defects, which the haploinsufficiency of UPF1 may have exacerbated.

PMID:39571789 (2024) reported two unrelated paediatric patients with intellectual disabilities, frontal bossing, hypertelorism, high frontal hairline, and thin upper lip. They both had language and motor delays and were identified with de novo heterozygous variants in UPF1 gene (c.949_951del/ p.Asp317del & c.1984G>A/ p.Asp662Asn). The p.Asp662Asn variant has also been previously reported in a patient from PMID:28135719.

PMID:39993774 (2025) reported a 17‐year‐old male patient with moderate intellectual disability, atypical autism, ADHD, and aggressivity. He was identified with a de novo missense variant in UPF1 gene - c.1576G>A/ p.Ala526Thr.

This gene has been associated with relevant phenotype in Gene2Phenotype (with 'moderate' rating on the DD panel), but not yet in OMIM.; to: PMID:28135719 (2017) reported four unrelated patients with de novo heterozygous missense variants in UPF1 gene from the Deciphering Developmental Disorders Study cohort, for which no detailed phenotypic information was available in the publication. Three patients were reported with global developmental delay (mild in one) and the fourth patient was reported with neurodevelopmental delay as one of the presenting phenotypes in the Decipher database (https://www.deciphergenomics.org/gene/UPF1/patient-overlap/snvs).

PMID:28539120 (2017) reported a patient with significant intellectual disability (ID) and gross motor delay and with a heterozygous likely pathogenic variant in UPF1 gene (c.1576_1577delinsAA/ p.Ala526Asn). However, this patient also harboured a heterozygous likely pathogenic variant in SQSTM1 gene. As reviewed below by Ivone Leong, the authors suggested that it is plausible that the haploinsufficiency of SQSTM1 may have caused neurofunctional defects, which the haploinsufficiency of UPF1 may have exacerbated.

PMID:39571789 (2024) reported two unrelated paediatric patients with intellectual disabilities, frontal bossing, hypertelorism, high frontal hairline, and thin upper lip. They both had language and motor delays and were identified with de novo heterozygous variants in UPF1 gene (c.949_951del/ p.Asp317del & c.1984G>A/ p.Asp662Asn). The p.Asp662Asn variant has also been previously reported in a patient from PMID:28135719.

PMID:39993774 (2025) reported a 17‐year‐old male patient with moderate intellectual disability, atypical autism, ADHD, and aggressivity. He was identified with a de novo missense variant in UPF1 gene - c.1576G>A/ p.Ala526Thr.

As reviewed by Karen Stals, there is an additional patient identified with UPF1 variant in Exeter Genomics Laboratory.

This gene has been associated with relevant phenotype in Gene2Phenotype (with 'moderate' rating on the DD panel), but not yet in OMIM.
Intellectual disability v9.84 SLC35A3 Arina Puzriakova Phenotypes for gene: SLC35A3 were changed from Arthrogryposis, impaired intellectual development, and seizures, OMIM:615553 to Arthrogryposis, impaired intellectual development, and seizures, OMIM:615553
Intellectual disability v9.84 SLC35A3 Arina Puzriakova Phenotypes for gene: SLC35A3 were changed from ?Arthrogryposis, mental retardation, and seizures (MIM 615553) to Arthrogryposis, impaired intellectual development, and seizures, OMIM:615553
Intellectual disability v9.83 PUS3 Arina Puzriakova Phenotypes for gene: PUS3 were changed from Global developmental delay; Microcephaly; Mental retardation, autosomal recessive 55, 617051; Intellectual disability to Neurodevelopmental disorder with microcephaly and gray sclerae, OMIM:617051
Intellectual disability v9.82 PIGG Arina Puzriakova Phenotypes for gene: PIGG were changed from MRT53; Mental retardation, autosomal recessive 53, 616917; # 616917 MENTAL RETARDATION, AUTOSOMAL RECESSIVE 53 to Neurodevelopmental disorder with or without hypotonia, seizures, and cerebellar atrophy, OMIM:616917
Intellectual disability v9.79 MAPK1 Arina Puzriakova Phenotypes for gene: MAPK1 were changed from Global developmental delay; Intellectual disability; Behavioral abnormality; Growth delay; Abnormality of the face; Abnormality of the neck; Abnormality of the cardiovascular system; Abnormality of the skin to Noonan syndrome 13, OMIM:619087
Intellectual disability v9.78 IFT27 Arina Puzriakova Phenotypes for gene: IFT27 were changed from Bardet-Biedl syndrome 19, MIM#615996 to Bardet-Biedl syndrome 19, OMIM:615996
Intellectual disability v9.77 HNRNPU Arina Puzriakova Phenotypes for gene: HNRNPU were changed from Epileptic encephalopathy, early infantile, 54, 617391; intellectual disability to Developmental and epileptic encephalopathy 54, OMIM:617391
Intellectual disability v9.73 EXOSC8 Arina Puzriakova Added comment: Comment on list classification: There is now sufficient evidence to promote this gene to Green at the next GMS panel update - 5 unrelated families with pontocerebellar hypoplasia due to biallelic variants in this gene. Almost all described patients exhibited psychomotor retardation (PMIDs: 24989451; 38017281; 34210538)
Intellectual disability v9.72 EXOSC8 Arina Puzriakova edited their review of gene: EXOSC8: Added comment: PMID: 34210538 (2021) - 16-year-old Spanish boy with cerebellar and spinal muscular atrophy, spasticity, psychomotor retardation, nystagmus, ophthalmoparesis, epilepsy, and mitochondrial respiratory chain (MRC) deficiency. The phenotype was described as milder compared to previous cases. WES revealed three variants in the EXOSC8 gene (c.[390+1delG];[628C>T;815G>C]) which lead to reduced mRNA expression and protein levels.

PMID: 38017281 (2024) - Homozygous missense variant c.238G>A;p.Val80Ile causing exon skipping in a patient with psychomotor retardation, spasticity, spinal muscle atrophy, respiratory problems, diaphragmatic hernia, dilated lateral ventricles, hypoplastic temporal lobes, thinning of the brain stem, dysmorphic facies, nystagmus, congenital esotropia and contractures.; Changed rating: GREEN; Changed publications to: 24989451, 38017281, 34210538
Intellectual disability v9.72 EXOSC8 Arina Puzriakova Phenotypes for gene: EXOSC8 were changed from Pontocerebellar hypoplasia, type 1C, OMIM:616081 to Pontocerebellar hypoplasia, type 1C, OMIM:616081
Intellectual disability v9.71 EXOSC8 Arina Puzriakova Phenotypes for gene: EXOSC8 were changed from Pontocerebellar hypoplasia, type 1C, OMIM:616081 to Pontocerebellar hypoplasia, type 1C, OMIM:616081
Intellectual disability v9.70 EXOSC8 Arina Puzriakova Phenotypes for gene: EXOSC8 were changed from Pontocerebellar hypoplasia, type 1C, MIM#616081 to Pontocerebellar hypoplasia, type 1C, OMIM:616081
Intellectual disability v9.67 ELFN1 Arina Puzriakova gene: ELFN1 was added
gene: ELFN1 was added to Intellectual disability. Sources: Literature
Q3_25_promote_green tags were added to gene: ELFN1.
Mode of inheritance for gene: ELFN1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ELFN1 were set to 40576023; 34509675; 34452636
Phenotypes for gene: ELFN1 were set to Neurodevelopmental disorder, MONDO:0700092
Review for gene: ELFN1 was set to GREEN
Added comment: Total of 14 individuals from 7 unrelated families with biallelic loss of function variants in ELFN1 and a neurodevelopmental disorder comprising DD/ID ranging from moderate to severe (13/13) and epilepsy (12/13). Other features included dysmorphic features, behavioural disturbances, ADHD, ASD, hypotonia, muscle weakness, ataxia. Knockout and haploinsufficiency studies in mice resulted in detectable phenotypes compatible with ELFN1 deficiency disorder.
Sources: Literature
Intellectual disability v9.66 GNS Arina Puzriakova Phenotypes for gene: GNS were changed from Mucopolysaccharidosis type IIID, OMIM:252940 to Mucopolysaccharidosis type IIID, OMIM:252940
Intellectual disability v9.65 GNS Arina Puzriakova Phenotypes for gene: GNS were changed from Mucopolysaccharidosis type IIID, 252940; MUCOPOLYSACCHARIDOSIS TYPE 3D (MPS3D) to Mucopolysaccharidosis type IIID, OMIM:252940
Intellectual disability v9.64 UPF1 Karen Stals changed review comment from: At least 4 individuals reported in the literature with de novo variants in this gene and a neurodevelopmental disorder. Additional patient identified in Exeter. Moderate gene-disease association in Gene2Phenotype.; to: At least 4 individuals described in the literature with de novo variants in this gene and a neurodevelopmental disorder. Additional patient identified in Exeter. Moderate gene-disease association in Gene2Phenotype.
Intellectual disability v9.64 HNRNPC Achchuthan Shanmugasundram changed review comment from: PMID:37541189 reported a cohort of 13 individuals with heterozygous germline variants in HNRNPC gene, including a recurrent de novo in-frame deletion in five individuals (c.850_876del/ p.(Arg284_Asp292del) for HNRNPC-iso1 and c.889_915del/ p.(Arg297_Asp305del) for HNRNPC-iso2). They all presented with a neurodevelopmental disorder characterised by global developmental delay, intellectual disability, behavioural abnormalities, and subtle facial dysmorphic features in most individuals.

PMID:40004505 reported the identification of the missense variant, p.(Arg99Gln) in a patient showing a unique clinical presentation characterised by DD/ID, distinctive facial features, cochlear aplasia, and bilateral colobomatous microphthalmia. This variant was previously reported in an individual in PMID:37541189. The clinical phenotype of this individual fit that of the previously described individual with the same variant and only partially overlaps with the clinical spectrum of the disease.

This gene has already been associated with relevant phenotypes in OMIM (MIM #620688), but not yet in Gene2Phenotype.
Sources: Literature; to: PMID:37541189 reported a cohort of 13 individuals with heterozygous germline variants in HNRNPC gene, including a recurrent de novo in-frame deletion in five individuals (c.850_876del/ p.(Arg284_Asp292del) for HNRNPC-iso1 and c.889_915del/ p.(Arg297_Asp305del) for HNRNPC-iso2). They all presented with a neurodevelopmental disorder characterised by global developmental delay, intellectual disability, behavioural abnormalities, and subtle facial dysmorphic features in most individuals.

PMID:40004505 reported the identification of the missense variant, p.(Arg99Gln) in a patient showing a unique clinical presentation characterised by DD/ID, distinctive facial features, cochlear aplasia, and bilateral colobomatous microphthalmia. This variant was previously reported in an individual in PMID:37541189. The clinical phenotype of this individual fit that of the previously described individual with the same variant, and only partially overlaps with the clinical spectrum of the disease.

This gene has already been associated with relevant phenotypes in OMIM (MIM #620688), but not yet in Gene2Phenotype.
Sources: Literature
Intellectual disability v9.64 HNRNPC Achchuthan Shanmugasundram changed review comment from: PMID:37541189 reported a cohort of 13 individuals with heterozygous germline variants in HNRNPC gene, including a recurrent de novo in-frame deletion in five individuals (c.850_876del/ p.(Arg284_Asp292del) for HNRNPC-iso1 and c.889_915del/ p.(Arg297_Asp305del) for HNRNPC-iso2). They all presented with a neurodevelopmental disorder characterised by global developmental delay, intellectual disability, behavioural abnormalities, and subtle facial dysmorphic features in most individuals.

PMID:40004505 reported the identification of the missense variant, p.(Arg99Gln) in a patient showing a unique clinical presentation characterised by DD/ID, distinctive facial features, cochlear aplasia, and bilateral colobomatous microphthalmia. This variant was previously reported in an individual in PMID:37541189. The clinical phenotype of this individual fit that of the previously described individual and only partially overlaps with the clinical spectrum of the disease.

This gene has already been associated with relevant phenotypes in OMIM (MIM #620688), but not yet in Gene2Phenotype.
Sources: Literature; to: PMID:37541189 reported a cohort of 13 individuals with heterozygous germline variants in HNRNPC gene, including a recurrent de novo in-frame deletion in five individuals (c.850_876del/ p.(Arg284_Asp292del) for HNRNPC-iso1 and c.889_915del/ p.(Arg297_Asp305del) for HNRNPC-iso2). They all presented with a neurodevelopmental disorder characterised by global developmental delay, intellectual disability, behavioural abnormalities, and subtle facial dysmorphic features in most individuals.

PMID:40004505 reported the identification of the missense variant, p.(Arg99Gln) in a patient showing a unique clinical presentation characterised by DD/ID, distinctive facial features, cochlear aplasia, and bilateral colobomatous microphthalmia. This variant was previously reported in an individual in PMID:37541189. The clinical phenotype of this individual fit that of the previously described individual with the same variant and only partially overlaps with the clinical spectrum of the disease.

This gene has already been associated with relevant phenotypes in OMIM (MIM #620688), but not yet in Gene2Phenotype.
Sources: Literature
Intellectual disability v9.64 UNC13A Achchuthan Shanmugasundram Added comment: Comment on list classification: There are three unrelated patients reported with three different monoallelic UNC13A variants and with intellectual disability/ developmental delay. Hence, this gene can be promoted to green rating in the next GMS update.
Intellectual disability v9.61 INPP4A Achchuthan Shanmugasundram Added comment: Comment on list classification: There are a total of 33 patients from 19 unrelated families reported with biallelic INPP4A variants and a neurodevelopmental disorder. Of these, 29 patients presented with severe or profound intellectual disability/ global developmental delay. Hence, this gene should be promoted to green rating in the next GMS update.
Intellectual disability v9.55 RREB1 Achchuthan Shanmugasundram changed review comment from: PMID:38332451 (2024) reported the first patient with RREB1-associated Noonan-like RASopathy. A pathogenic de novo variant in RREB1 gene was identified by whole-genome sequencing and was confirmed by Sanger sequencing in the proband (c.2677del/ p.Ala893Argfs*20). The patient presented with severe intellectual disability, delayed motor skills, short stature, short neck, and distinctive facial dysmorphisms.

PMID:40418122 reported a cohort of six individuals with a RASopathy phenotype, which include mild dysmorphisms, congenital heart disease, genitourinary malformations, dental anomalies, and developmental delay. Global developmental delay was reported in two of these six patients. They were identified with six different truncating RREB1 variants via exome sequencing (five patients with de novo and one patient with paternally inherited variants).

This gene has not yet been associated with relevant phenotypes either in OMIM or in Gene2Phenotype.; to: PMID:38332451 (2024) reported the first patient with RREB1-associated Noonan-like RASopathy. A pathogenic de novo variant in RREB1 gene was identified by whole-genome sequencing and was confirmed by Sanger sequencing in the proband (c.2677del/ p.Ala893Argfs*20). The patient presented with severe intellectual disability, delayed motor skills, short stature, short neck, and distinctive facial dysmorphisms.

PMID:40418122 (2025) reported a cohort of six individuals with a RASopathy phenotype, which include mild dysmorphisms, congenital heart disease, genitourinary malformations, dental anomalies, and developmental delay. Global developmental delay was reported in two of these six patients. They were identified with six different truncating RREB1 variants via exome sequencing (five patients with de novo and one patient with paternally inherited variants).

This gene has not yet been associated with relevant phenotypes either in OMIM or in Gene2Phenotype.
Intellectual disability v9.55 RREB1 Achchuthan Shanmugasundram changed review comment from: PMID:38332451 (2024) reported the first patient with RREB1-associated Noonan-like RASopathy. A pathogenic de novo variant in RREB1 gene was identified by whole-genome sequencing and was confirmed by Sanger sequencing in the proband (c.2677del/ p.Ala893Argfs*20). The patient presented with severe intellectual disability and general muscular hypotonia among other features.

PMID:40418122 reported a cohort of six individuals with a RASopathy phenotype, which include mild dysmorphisms, congenital heart disease, genitourinary malformations, dental anomalies, and developmental delay. Global developmental delay was reported in two of these six patients. They were identified with six different truncating RREB1 variants via exome sequencing (five patients with de novo and one patient with paternally inherited variants).

This gene has not yet been associated with relevant phenotypes either in OMIM or in Gene2Phenotype.; to: PMID:38332451 (2024) reported the first patient with RREB1-associated Noonan-like RASopathy. A pathogenic de novo variant in RREB1 gene was identified by whole-genome sequencing and was confirmed by Sanger sequencing in the proband (c.2677del/ p.Ala893Argfs*20). The patient presented with severe intellectual disability, delayed motor skills, short stature, short neck, and distinctive facial dysmorphisms.

PMID:40418122 reported a cohort of six individuals with a RASopathy phenotype, which include mild dysmorphisms, congenital heart disease, genitourinary malformations, dental anomalies, and developmental delay. Global developmental delay was reported in two of these six patients. They were identified with six different truncating RREB1 variants via exome sequencing (five patients with de novo and one patient with paternally inherited variants).

This gene has not yet been associated with relevant phenotypes either in OMIM or in Gene2Phenotype.
Intellectual disability v9.55 RREB1 Achchuthan Shanmugasundram Added comment: Comment on list classification: Of the seven unrelated patients reported with monoallelic single nucleotide variants in RREB1 gene, three were reported with either intellectual disability or global developmental delay. Hence, this gene can be promoted to green rating in the next GMS update.
Intellectual disability v9.51 MED16 Karen Stals gene: MED16 was added
gene: MED16 was added to Intellectual disability. Sources: NHS GMS
Mode of inheritance for gene: MED16 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MED16 were set to PMID: 40081376
Phenotypes for gene: MED16 were set to developmental delay; multiple congenital abnormalities; Medopathy
Penetrance for gene: MED16 were set to unknown
Review for gene: MED16 was set to GREEN
gene: MED16 was marked as current diagnostic
Added comment: 25 individuals from 18 families reported with biallelic MED16 variants with multiple congenital anomalies (MCAs)-intellectual disability syndrome. Intellectual disability, speech delay, and/or motor delay of variable severity were constant and associated with variable combinations of craniofacial defects (micro/retrognathia, cleft palate, and preauricular tags), anomalies of the extremities, and heart defects (predominantly tetralogy of Fallot). Visual impairment, deafness, and magnetic resonance imaging (MRI) abnormalities were also frequent. 8 predicted protein-truncating and 18 missense or in-frame duplication variants identified.
Sources: NHS GMS
Intellectual disability v9.51 RREB1 Karen Stals gene: RREB1 was added
gene: RREB1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: RREB1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RREB1 were set to PMID: 40418122
Phenotypes for gene: RREB1 were set to Rasopathy; Noonan-like; developmental disorder
Penetrance for gene: RREB1 were set to Complete
Review for gene: RREB1 was set to GREEN
Added comment: 6 additional individuals with truncating variants in RREB1 gene and a Rasopathy phenotype, features including congenital heart disease, developmental delay, short stature, and dysmorphic facial features (PMID: 40418122). RREB1 encodes a transcriptional repressor of Ras-MAPK signalling. Supporting functional evidence and animal models.
Sources: Literature
Intellectual disability v9.51 RNU5A-1 Arina Puzriakova Added comment: Comment on list classification: Rating Red awaiting further evidence - limited number of cases currently reported with variable neurodevelopmental phenotype. Variants have been classified as VUS and additional evidence is required to ascertain pathogenicity.
Intellectual disability v9.50 RNU5A-1 Arina Puzriakova gene: RNU5A-1 was added
gene: RNU5A-1 was added to Intellectual disability. Sources: Literature
locus-type-rna-small-nuclear tags were added to gene: RNU5A-1.
Mode of inheritance for gene: RNU5A-1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: RNU5A-1 were set to 40379786
Phenotypes for gene: RNU5A-1 were set to Neurodevelopmental disorder, MONDO:0700092
Added comment: PMID: 40379786 (2025) - three unrelated individuals with de novo variants in the RNU5A-1 gene (classified as VUS) and a neurodevelopmental disorder. Six individuals with rare de novo variants were identified in total but clinical details were only available for 3/6. Of these three individuals, two harboured the same variant (n.40_41insA) on the maternal allele, while the third individual harboured a different variant (n.39del) but also on the 5′ loop I domain of RNU5A-1. Clinical data showed neurodevelopmental abnormalities (mild ID (2), severe ID (1), epilepsy (2), brain MRI abnormalities (1)) with variable congenital malformations.
Sources: Literature
Intellectual disability v9.48 RNU5B-1 Arina Puzriakova Tag locus-type-rna-small-nuclear tag was added to gene: RNU5B-1.
Tag dd_review tag was added to gene: RNU5B-1.
Intellectual disability v9.47 RNU5B-1 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 unrelated individuals reported with de novo (several recurrent) variants in the RNU5B-1 gene that lead to splicing disruption. All individuals present with a neurodevelopmental disorder, with variable degrees of intellectual disability reported in almost all cases. This disorder to relevant to the R27 Paediatric disorders superpanel, which will be added through inclusion on the Intellectual disability panel.
Intellectual disability v9.46 RNU5B-1 Arina Puzriakova gene: RNU5B-1 was added
gene: RNU5B-1 was added to Intellectual disability. Sources: Literature
Q3_25_promote_green tags were added to gene: RNU5B-1.
Mode of inheritance for gene: RNU5B-1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: RNU5B-1 were set to 40379786; 40442284
Phenotypes for gene: RNU5B-1 were set to Neurodevelopmental disorder, MONDO:0700092
Review for gene: RNU5B-1 was set to GREEN
Added comment: At least 19 individuals with de novo and/or recurrent variants in RNU5B-1 and a neurodevelopmental disorder characterised by ID/DD, brain MRI abnormalities, hypotonia, microcephaly or macrocephaly, failure to thrive, and in some cases seizures.

PMID: 40379786 (2025) - 15 unrelated probands with heterozygous variants in RNU5B-1. Clinical data was available for 9 individuals who presented with a neurodevelopmental disorder including severe ID/DD (although one patient had normal cognition but attention difficulties) and brain MRI abnormalities. Other features were variable and include hypotonia, epilepsy, ocular abnormalities, acquired microcephaly or macrocephaly and other variable congenital abnormalities. Variants typically arose de novo on the maternal allele and cluster in regions critical for splicing. Functional studies demonstrate variant-specific splicing abnormalities in patient-derived cells which may underline the clinical variability observed in patients.

PMID: 40442284 (2025) - 9 unrelated individuals with de novo variants in RNU5B-1 and a neurodevelopmental disorder characterised by GDD/ID, macrocephaly, eye abnormalities, seizures, hypotonia and failure to thrive, among other variable features - based on 6 cases where phenotype information was available. Variants were again found in regions critical for splicing.

Both studies investigated participants of the 100KGP and/or NHS GMS (6 in PMID: 40379786 and 5 in PMID: 40442284) so likely refer to the same individuals.
Sources: Literature
Intellectual disability v9.42 UBR5 Achchuthan Shanmugasundram gene: UBR5 was added
gene: UBR5 was added to Intellectual disability. Sources: Literature
dd_review tags were added to gene: UBR5.
Mode of inheritance for gene: UBR5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: UBR5 were set to 39721588
Phenotypes for gene: UBR5 were set to complex neurodevelopmental disorder, MONDO:0100038
Review for gene: UBR5 was set to GREEN
Added comment: PMID:39721588 reported 29 unrelated individuals with a complex neurodevelopmental syndrome, which includes developmental delay (26/28), autism (16/26), intellectual disability (14/25), epilepsy (11/27), movement disorders (6/26) and/ or genital anomalies (4/25) as presenting phenotypes. They were all identified with variants in UBR5 gene, of which 28 had monoallelic inheritance (24 with de novo, 1 with maternal, 1 with maternal mosaic and 2 with unknown inheritance), while one had recessive inheritance.

Of the 28 patients with monoallelic variants, 16 had global developmental delay, 13 had ID and 10 patients had epilepsy/ seizures. The single patient with biallelic variant had severe/ profound ID, developmental delay and epileptic encephalopathy.

Functional evidence is also available from C. elegans and in vitro ubiquitination assays.

This gene is associated with phenotype in Gene2Phenotype (with 'moderate' rating on the DD panel), but not yet in OMIM.
Sources: Literature
Intellectual disability v9.40 PDE1B Achchuthan Shanmugasundram changed review comment from: As reviewed by Sarah Dixon, PMID:40492975 reported seven individuals from five unrelated families identified with biallelic PDE1B variants. Three truncating (p.Gln45Ter, p.Gln86Ter, p.Ser298Alafs*6) and three splicing variants (c.594 + 2 T>G, c.735 + 5G>A, c.837-1G>C) were identified from these patients in total.

They presented with an early-onset movement disorder characterised by hypotonia in infancy, progressing to ataxia and dystonia in early childhood, with motor and speech delay, and intellectual disability (ID). ID was moderate in one patient, mild in three and severity not reported in one (ID noticed at the age of three years), while ID was not reported in two patients.

This gene has not yet been associated with relevant phenotypes in OMIM, Gene2Phenotype or ClinGen.; to: As reviewed by Sarah Dixon, PMID:40492975 reported seven individuals from five unrelated families identified with biallelic PDE1B variants. Three truncating (p.Gln45Ter, p.Gln86Ter, p.Ser298Alafs*6) and three splicing variants (c.594 + 2 T>G, c.735 + 5G>A, c.837-1G>C) were identified from these patients in total.

They presented with an early-onset movement disorder characterised by hypotonia in infancy, progressing to ataxia and dystonia in early childhood, with motor and speech delay, and intellectual disability (ID). ID was moderate in one patient, mild in three and severity not reported in one patient (ID noticed at the age of three years).

This gene has not yet been associated with relevant phenotypes in OMIM, Gene2Phenotype or ClinGen.
Intellectual disability v9.34 FLVCR1 Eleanor Williams edited their review of gene: FLVCR1: Added comment: Associated with Neurodevelopmental disorder with microcephaly, absent speech, and hypotonia, OMIM:621060.

Variants in this gene have been previously associated with a progressive Retinopathy-sensory neuropathy syndrome, OMIM:609033

PMID: 39306721 - Calame et al 2025 report 27 individuals from 20 families with homozygous/compound het variants in this gene (mainly missense, but also nonsense, frameshift and splice variants). 2 families from S Asia share the same variant and haplotype so could be a founder variant in the region.

13/27 individual had profound ID/DD. 3 were stillborn, and 10 others died before the age of 5, including one in the neonatal period. Severe microcephaly (Z score below -3.0) was observed in 12/27 individuals. Epilepsy was reported in 12 individuals, hypotonia in 17, spasticity in 9 (from 6 families), reduced brain volume in 19 , craniofacial malformations in 4 (those that were still born or died in neonatal period), and limb malformations in 7. An eye phenotype (Cortical visual impairment, Optic disk atrophy or Retinitis pigmentosa) was observed in 15 individuals.

All pathogenic FLVCR1 variants were rare and absent in the homozygous state in gnomAD v2.1.13. Functional studies show that pathogenic FLVCR1 missense variants primarily lie within transmembrane domains and reduce choline and ethanolamine transport activity compared with wild-type FLVCR1.

There are more than 3 cases reported with plausible disease causing variants in more than 3 cases for the intellectual disability, epilepsy, severe microcephaly, limb disorders, fetal anomalies and childhood onset hereditary spastic paraplegia panels. The gene will also be included in the Hypotonic infant superpanel through the inclusion on the Intellectual disability panel.; Changed publications to: 30656474, 22279524, 21267618, 21070897, 9409377, 30444160, 39306721; Changed phenotypes to: Neurodevelopmental disorder with microcephaly, absent speech, and hypotonia, OMIM:621060, neurodevelopmental disorder with microcephaly, absent speech, and hypotonia, MONDO:0976126
Intellectual disability v9.34 WARS Eleanor Williams Classified gene: WARS as Amber List (moderate evidence)
Intellectual disability v9.34 WARS Eleanor Williams Added comment: Comment on list classification: Promoting to amber with a recommendation for green rating following GMS review as there are 4 families with intellectual disability.
Intellectual disability v9.34 WARS Eleanor Williams Gene: wars has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.33 WARS Eleanor Williams Tag Q3_25_promote_green tag was added to gene: WARS.
Intellectual disability v9.33 WARS Eleanor Williams changed review comment from: Sources: Literature; to: Associated with Neurodevelopmental disorder with microcephaly and speech delay, with or without brain abnormalities OMIM:620317 (AR). Also associated with Neuronopathy, distal hereditary motor, autosomal dominant 9, OMIM:617721 (AD).

5 families reported with biallelic variants in WARS1 and phenotype of intellectual disability and progressive severe microcephaly in 4 families. Variable other phenotypes were also present such as hearing loss, skeletal and brain abnormalities and seizures.

PMID: 34585293 - Okamoto et al 2022 - 4 year old female Japanese proband with compound het variants in WARS1 (p.Arg448Trp and p.Ala333Thr). Parents were heterozygous. Variants are rare. She presented with hypotonia, developmental delay, delayed myelination in the cerebral white matter. She had a seizure age 2. Severe intellectual disability at age 4, did not walk independently. Head circumference was -0.4 SD at birth and -3.4 SD by age 4.

PMID: 35815345 - Lin et al 2022 - 3 probands from 2 consanguineous Pakistani families. In family 1, one proband at age 20 had developmental delay, mild ID, mild microcephaly, mild sensorineural hearing loss. The second proband at age 16 had severe delayed developmental milestones/intellectual disability, hypotonia, severe microcephaly (-7.8 SD), severe hearing impairment and skeletal abnormalities of the legs. In family 2, the 5 year male had global developmental delay, complex partial epilepsy, a history of central adrenal insufficiency, cortical blindness, and multiple brain abnormalities. He has a history of seizures. A homozygous, rare, start loss variant (c.1A>G, p.Met1?) in exon 2 of WARS1 was identified in family 1 with parents as carriers. A homozygous c.1255G>A, p.(Asp419Asn) variant was identified in WARS1 in family 2, with parents as carriers. This variant is present in population databases with a MAF ~ 0.003 but not in the homozygous state. Zebrafish wars1 knockout displayed microcephaly, hearing loss, and musculoskeletal abnormalities, and the homozygous animals do not survive past Day 10

PMID: 35790048 - Bögershausen et al 2022 - 4 individuals from 2 families all with the same missense variant in WARS1 (c.397C>T, p.(R133C)). All 4 had progressive microcephaly with OFC at (-4.2, -4.3, -3.8 and −3.5) at assessment at ages 5, 13, 8 and 7 years. the proband from family 1 had mild ID, the three from family 2 had severe ID and two from family 2 had hypotonia. No seizures or hearing loss was reported. The WARS1 variant negatively impacts protein abundance and is unable to rescue the phenotype of a CRISPR/Cas9 wars1 knockout zebrafish model.

Intellectual disability v9.33 WARS Eleanor Williams gene: WARS was added
gene: WARS was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: WARS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: WARS were set to 34585293; 35790048; 35815345
Phenotypes for gene: WARS were set to Neurodevelopmental disorder with microcephaly and speech delay, with or without brain abnormalities, OMIM:620317; neurodevelopmental disorder with microcephaly and speech delay, with or without brain abnormalities, MONDO:0957218
Review for gene: WARS was set to GREEN
Added comment: Sources: Literature
Intellectual disability v9.31 CRNKL1 Achchuthan Shanmugasundram gene: CRNKL1 was added
gene: CRNKL1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: CRNKL1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CRNKL1 were set to https://doi.org/10.1016/j.ajhg.2025.05.013
Phenotypes for gene: CRNKL1 were set to complex neurodevelopmental disorder, MONDO:0100038
Review for gene: CRNKL1 was set to GREEN
Added comment: There are 10 unrelated patents identified with de novo missense variants in the spliceosomal component CRNKL1, where nine of them harboured one of the two missense variants affecting the same amino acid residue, Arg 267 (p.Arg267Cys & p.Arg267His), while the tenth patient harboured a different variant (p.Arg301Gly). All affected individuals share a common and specific phenotype: profound pre- and post-natal microcephaly (8 of 10 patients), with pontocerebellar hypoplasia (9 patients), seizures (8 patients), and severe intellectual disability (8 patients).

Microinjection of mRNA encoding Crnkl1 variant into a zebrafish model caused a severe lack of brain development accompanied by a significant reduction in proliferating cells and widespread cellular stress, as indicated by p53 staining. RNA sequencing analysis of injected zebrafish embryos showed broad transcriptomic changes, with altered expression of neuronal and cell cycle genes.

This gene has not yet been associated with relevant phenotypes in OMIM or in Gene2Phenotype.
Sources: Literature
Intellectual disability v9.30 NOTCH3 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the association of biallelic LoF variants in NOTCH3 gene with intellectual disability. Hence, this gene can be promoted to green rating in the next GMS update.
Intellectual disability v9.29 NOTCH3 Achchuthan Shanmugasundram gene: NOTCH3 was added
gene: NOTCH3 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: NOTCH3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NOTCH3 were set to 39191170
Phenotypes for gene: NOTCH3 were set to neurodevelopmental disorder, MONDO:0700092
Review for gene: NOTCH3 was set to GREEN
Added comment: 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.

Of these 24 patients from 15 families had developmental delay, ranging from mild or only motor delay in 7 patients to global developmental impairment in 17 patients. 21 patents from 13 families had predominantly severe intellectual disability, of which five had mild ID. Seizures were reported in 10 patients from seven different families.

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.

Biallelic variants in NOTCH3 are not yet associated with any phenotypes in OMIM or in Gene2Phenotype.
Sources: Literature
Intellectual disability v9.27 CELF4 Achchuthan Shanmugasundram gene: CELF4 was added
gene: CELF4 was added to Intellectual disability. Sources: Literature
Q2_25_ promote_green tags were added to gene: CELF4.
Mode of inheritance for gene: CELF4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CELF4 were set to 40108438
Phenotypes for gene: CELF4 were set to neurodevelopmental disorder, MONDO:0700092
Review for gene: CELF4 was set to GREEN
Added comment: PMID:40108438 reported 15 patients with heterozygous missense or loss-of-function variants clustering in the N-terminal of the CELF4 gene. Most patients presented with neurodevelopmental disorders including global developmental delay (12 patients), intellectual disability (8, of which moderate in 2, mild in 3, and severity not defined in 3), seizures (9) and overweight/obesity (10) that began in childhood. Clinical features are similar to the reported celf4-mouse mutant phenotype.

This gene has not yet been associated with relevant phenotypes either in OMIM or in Gene2Phenotype.
Sources: Literature
Intellectual disability v9.24 PDE1B Sarah Dixon gene: PDE1B was added
gene: PDE1B was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: PDE1B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PDE1B were set to PMID: 40492975
Phenotypes for gene: PDE1B were set to hypotonia; ataxia; dystonia; developmental delay; intellectual disability
Penetrance for gene: PDE1B were set to unknown
Review for gene: PDE1B was set to GREEN
Added comment: PMID: 40492975
Biallelic LOF variants in PDE1B identified in seven individuals from five different families
Disorder characterized by hypotonia in infancy, progressing to ataxia and dystonia in early childhood, with developmental delay and intellectual disability
Sources: Literature
Intellectual disability v9.22 MRPL49 Sarah Leigh changed review comment from: Four biallelic MRPL variants have been seen in nine families with Combined oxidative phosphorylation deficiency 60 (OMIM:621195)(PMID: 40043708).
Families F1 & F2 shared a haplotype and the same MRPL variant and families F4 & F5, with the same MRPL variant, although not apparently related, came from the same village. Intellectual disability was apparent in all nine families (mild in one family), primary ovarian insufficiency was seen in 4/5 affected females and bilateral sensorineural hearing loss was evident in 6/9 families (PMID: 40043708)
Sources: Literature; to: Four biallelic MRPL variants have been seen in nine families with Combined oxidative phosphorylation deficiency 60 (OMIM:621195)(PMID: 40043708).
Families F1 & F2 shared a haplotype and the same MRPL variant, and families F4 & F5 (with the same MRPL variant) although not apparently related, came from the same village. Intellectual disability was apparent in all nine families (mild in one family), primary ovarian insufficiency was seen in 4/5 affected females and bilateral sensorineural hearing loss was evident in 6/9 families (PMID: 40043708)
Sources: Literature
Intellectual disability v9.22 MRPL49 Sarah Leigh Marked gene: MRPL49 as ready
Intellectual disability v9.22 MRPL49 Sarah Leigh gene: MRPL49 was added
gene: MRPL49 was added to Intellectual disability. Sources: Literature
Q2_25_ promote_green tags were added to gene: MRPL49.
Mode of inheritance for gene: MRPL49 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MRPL49 were set to 40043708
Phenotypes for gene: MRPL49 were set to Combined oxidative phosphorylation deficiency 60, OMIM:621195; combined oxidative phosphorylation deficiency, MONDO:0000732
Review for gene: MRPL49 was set to GREEN
Added comment: Four biallelic MRPL variants have been seen in nine families with Combined oxidative phosphorylation deficiency 60 (OMIM:621195)(PMID: 40043708).
Families F1 & F2 shared a haplotype and the same MRPL variant and families F4 & F5, with the same MRPL variant, although not apparently related, came from the same village. Intellectual disability was apparent in all nine families (mild in one family), primary ovarian insufficiency was seen in 4/5 affected females and bilateral sensorineural hearing loss was evident in 6/9 families (PMID: 40043708)
Sources: Literature
Intellectual disability v9.21 FBXO22 Achchuthan Shanmugasundram changed review comment from: As reviewed by Julia Baptista, PMID:40215970 reported 16 cases (15 affected children and one foetus) from 14 unrelated families presenting with a pleiotropic syndrome with prenatal onset growth restriction and notable neurodevelopmental delay. They were identified with four distinct homozygous FBXO22 variants with loss-of-function effects segregating with the disease. Intellectual disability was reported in six patients from five families.

This gene has been associated with relevant phenotypes in OMIM (MIM #621184), but not yet in Gene2Phenotype.; to: As reviewed by Julia Baptista, PMID:40215970 reported 16 cases (15 affected children and one foetus) from 14 unrelated families presenting with a pleiotropic syndrome with prominent prenatal onset growth restriction and notable neurodevelopmental delay. They were identified with four distinct homozygous germline FBXO22 variants with loss-of-function effects segregating with the disease. Intellectual disability was reported in seven patients from six families.

This gene has been associated with relevant phenotypes in OMIM (MIM #621184), but not yet in Gene2Phenotype.
Intellectual disability v9.21 RAB3A Sarah Leigh changed review comment from: Hengel et al (PMID: 40166812) report six heterozygous RAB3A variants which appear to be associated with a condition that includes cerebellar ataxia; pyramidal features; neurodevelopmental delay. Five of the variants were only seen in one family each, while (NM_002866.5) c.247C>T (p.Arg83Trp) was seen in 14 members from nine families. The age of onset of phenotypic features ranged from 3 months to adulthood. This gene is appropriate for the Hereditary ataxia with onset in adulthood panel as PMID: 40166812 states "The median age at onset was 26.5 (interquartile range (IQR) 22–32) with gait ataxia as the first symptom in all probands.", In addition, the authors also present supportive functional studies.; to: Hengel et al (PMID: 40166812) report six heterozygous RAB3A variants which appear to be associated with a condition that includes cerebellar ataxia; pyramidal features; neurodevelopmental delay. Five of the variants were only seen in one family each, while (NM_002866.5) c.247C>T (p.Arg83Trp) was seen in 14 members from nine families. The age of onset of phenotypic features ranged from 3 months to adulthood.

The neurodevelopmental disorder associated with variants towards the 3' end of the gene: (NM_002866.5) c.565G>T, p.(Glu189*) and c.628C>T, p.(Gln210*), included global developmental delay and learning disability (PMID: 40166812, table S4).

In addition, the authors also present supportive functional studies for the RAB3A variants.
Intellectual disability v9.21 RAB3A Sarah Leigh Entity copied from Hereditary ataxia with onset in adulthood v8.5
Intellectual disability v9.21 RAB3A Sarah Leigh gene: RAB3A was added
gene: RAB3A was added to Intellectual disability. Sources: Research,Expert Review Amber
Q2_25_ promote_green, Q2_25_ NHS_review tags were added to gene: RAB3A.
Mode of inheritance for gene: RAB3A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RAB3A were set to 36928819; 40166812
Phenotypes for gene: RAB3A were set to RAB3A associated cerebellar ataxia; pyramidal features; neurodevelopmental delay
Penetrance for gene: RAB3A were set to Complete
Intellectual disability v9.18 SMARCA1 Sarah Leigh Phenotypes for gene: SMARCA1 were changed from Coffin-Siris Syndrome; ORPHA1465 to X-linked intellectual disability, MONDO:0100284
Intellectual disability v9.17 SMARCA1 Sarah Leigh Tag Q2_25_ promote_green tag was added to gene: SMARCA1.
Intellectual disability v9.17 SMARCA1 Sarah Leigh Classified gene: SMARCA1 as Amber List (moderate evidence)
Intellectual disability v9.17 SMARCA1 Sarah Leigh Gene: smarca1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.16 SMARCA1 Sarah Leigh reviewed gene: SMARCA1: Rating: GREEN; Mode of pathogenicity: None; Publications: 27479843, 27457812, 33057194, 40316778; Phenotypes: X-linked intellectual disability, MONDO:0100284; Mode of inheritance: None
Intellectual disability v9.16 SMARCA1 Sarah Leigh Publications for gene: SMARCA1 were set to 26539891; 26740508
Intellectual disability v9.15 ATM Arina Puzriakova changed review comment from: Comment on list classification: Tagged for expert review to determine if this Green gene should be demoted on this panel.

Biallelic variants in the ATM gene are associated with Ataxia-telangiectasia, an early-onset progressive cerebellar ataxia which comprises progressive neurologic degeneration, oculocutaneous telangiectasias, sinopulmonary infection, and malignancies. Some patients can display mild cognitive impairment and learning difficulties, but this reflects cognitive decline secondary to neurodegeneration rather than primary ID that is a hallmark of the disorder.; to: Comment on list classification: Tagged for expert review to determine if this Green gene should be demoted on this panel.

Biallelic variants in the ATM gene are associated with Ataxia-telangiectasia, an early-onset progressive cerebellar ataxia which comprises progressive neurologic degeneration, oculocutaneous telangiectasias, sinopulmonary infection, and malignancies. Some patients can display mild cognitive impairment and learning difficulties, but this reflects cognitive decline which is secondary to neurodegeneration rather than a primary ID that is a hallmark of the disorder.
Intellectual disability v9.15 ATM Arina Puzriakova changed review comment from: Comment on list classification: Tagged for expert review to determine if this Green gene should be demoted on this panel.

Biallelic variants in this gene are associated with Ataxia-telangiectasia, an early-onset progressive cerebellar ataxia which comprises progressive neurologic degeneration, oculocutaneous telangiectasias, sinopulmonary infection, and malignancies. Some patients can display mild cognitive impairment and learning difficulties, but this reflects cognitive decline secondary to neurodegeneration.; to: Comment on list classification: Tagged for expert review to determine if this Green gene should be demoted on this panel.

Biallelic variants in the ATM gene are associated with Ataxia-telangiectasia, an early-onset progressive cerebellar ataxia which comprises progressive neurologic degeneration, oculocutaneous telangiectasias, sinopulmonary infection, and malignancies. Some patients can display mild cognitive impairment and learning difficulties, but this reflects cognitive decline secondary to neurodegeneration rather than primary ID that is a hallmark of the disorder.
Intellectual disability v9.15 ATM Arina Puzriakova Added comment: Comment on list classification: Tagged for expert review to determine if this Green gene should be demoted on this panel.

Biallelic variants in this gene are associated with Ataxia-telangiectasia, an early-onset progressive cerebellar ataxia which comprises progressive neurologic degeneration, oculocutaneous telangiectasias, sinopulmonary infection, and malignancies. Some patients can display mild cognitive impairment and learning difficulties, but this reflects cognitive decline secondary to neurodegeneration.
Intellectual disability v9.14 MAP4K4 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to rate this gene as Green at the next GMS panel update - at least 26 individuals from 21 families reported with Rasopathy-like phenotype (PMID: 37126546). Clinical presentation is varied, but most display symptoms of neurodevelopmental conditions with features overlapping those observed in patients with RASopathies. DD/ID was one of the most common features (ID reported in 8/21 cases).
Intellectual disability v9.11 SEL1L Achchuthan Shanmugasundram changed review comment from: PMID:37943610 reported six patients from three unrelated families with a neurodevelopmental disorder involving developmental delay, intellectual disability, facial dysmorphisms, short stature, microcephaly and seizures. Five patients from two families (Saudi Arabian and Moroccan descent) were identified with homozygous SEL1L variants (p.(Gly585Asp) & p.(Met528Arg)), while an unrelated patient of Italian descent was identified with homozygous HRD1 variant. Although there are additional variants reported in Saudi Arabian patient, SEL1L variant was considered as the potential candidate due to its biological relevance as reported in previous studies in mice. The variants were hypomorphic and impaired endoplasmic reticulum (ER)-associated degradation.

PMID:37943617 reported the identification of a homozygous SEL1L variant (p.(Cys141Tyr)) in five patients from a consanguineous Slovakian family. These patients presented with not only ERAD-associated neurodevelopmental disorders with onset in infancy (ENDI) syndromes, but infantile-onset agammaglobulinemia with no mature B cells, resulting in frequent infections and early death. All patients exhibited intellectual disability and were unable to speak words and sentences. Although variant in FAR2 gene was also identified in these patients, Sanger sequencing confirmed the segregation of the FAR2 variant with symptoms in patient 2 and FAR2 function is not linked to neurological disorder or agammaglobulinemia, leading to its exclusion from being causal for these patients.

This gene has been associated with relevant phenotypes in OMIM (MIMs #621067 & #621068), but not yet in Gene2Phenotype.; to: PMID:37943610 reported six patients from three unrelated families with a neurodevelopmental disorder involving developmental delay, intellectual disability, facial dysmorphisms, short stature, microcephaly and seizures. Five patients from two families (Saudi Arabian and Moroccan descent) were identified with homozygous SEL1L variants (p.(Gly585Asp) & p.(Met528Arg)), while an unrelated patient of Italian descent was identified with homozygous HRD1 variant. The variants were hypomorphic and impaired endoplasmic reticulum (ER)-associated degradation.

PMID:37943617 reported the identification of a homozygous SEL1L variant (p.(Cys141Tyr)) in five patients from a consanguineous Slovakian family. These patients presented with not only ERAD-associated neurodevelopmental disorders with onset in infancy (ENDI) syndromes, but infantile-onset agammaglobulinemia with no mature B cells, resulting in frequent infections and early death. All patients exhibited intellectual disability and were unable to speak words and sentences.

This gene has been associated with relevant phenotypes in OMIM (MIMs #621067 & #621068), but not yet in Gene2Phenotype.
Intellectual disability v9.9 SEL1L Achchuthan Shanmugasundram changed review comment from: PMID:37943610 reported six patients from three unrelated families with a neurodevelopmental disorder involving developmental delay, intellectual disability, facial dysmorphisms, short stature, microcephaly and seizures. Five patients from two families (Saudi Arabian and Moroccan descent) were identified with homozygous SEL1L variants (p.(Gly585Asp) & p.(Met528Arg)), while an unrelated patient of Italian descent was identified with homozygous HRD1 variant. Although there are additional variants reported in Saudi Arabian patient, SEL1L variant was considered as the potential candidate due to its biological relevance as reported in previous studies in mice. The variants were hypomorphic and impaired endoplasmic reticulum (ER)-associated degradation.

PMID:37943617 reported the identification of a homozygous SEL1L variant (p.(Cys141Tyr)) in five patients from a consanguineous Slovakian family. These patients presented with not only ERAD-associated neurodevelopmental disorders with onset in infancy (ENDI) syndromes, but infantile-onset agammaglobulinemia with no mature B cells, resulting in frequent infections and early death. All patients exhibited intellectual disability and were unable to speak words and sentences. Although variant in FAR2 gene was also identified in these patients, Sanger sequencing confirmed the segregation of the FAR2 variant with symptoms in patient 2 and FAR2 function is not linked to neurological disorder or agammaglobulinemia (33), leading to its exclusion from being causal for these patients.

This gene has been associated with relevant phenotypes in OMIM (MIMs #621067 & #621068), but not yet in Gene2Phenotype.; to: PMID:37943610 reported six patients from three unrelated families with a neurodevelopmental disorder involving developmental delay, intellectual disability, facial dysmorphisms, short stature, microcephaly and seizures. Five patients from two families (Saudi Arabian and Moroccan descent) were identified with homozygous SEL1L variants (p.(Gly585Asp) & p.(Met528Arg)), while an unrelated patient of Italian descent was identified with homozygous HRD1 variant. Although there are additional variants reported in Saudi Arabian patient, SEL1L variant was considered as the potential candidate due to its biological relevance as reported in previous studies in mice. The variants were hypomorphic and impaired endoplasmic reticulum (ER)-associated degradation.

PMID:37943617 reported the identification of a homozygous SEL1L variant (p.(Cys141Tyr)) in five patients from a consanguineous Slovakian family. These patients presented with not only ERAD-associated neurodevelopmental disorders with onset in infancy (ENDI) syndromes, but infantile-onset agammaglobulinemia with no mature B cells, resulting in frequent infections and early death. All patients exhibited intellectual disability and were unable to speak words and sentences. Although variant in FAR2 gene was also identified in these patients, Sanger sequencing confirmed the segregation of the FAR2 variant with symptoms in patient 2 and FAR2 function is not linked to neurological disorder or agammaglobulinemia, leading to its exclusion from being causal for these patients.

This gene has been associated with relevant phenotypes in OMIM (MIMs #621067 & #621068), but not yet in Gene2Phenotype.
Intellectual disability v9.9 SEL1L Achchuthan Shanmugasundram changed review comment from: PMID:37943610 reported six patients from three unrelated families with a neurodevelopmental disorder involving developmental delay, intellectual disability, facial dysmorphisms, short stature, microcephaly and seizures. Five patients from two families (Saudi Arabian and Moroccan descent) were identified with homozygous SEL1L variants (p.(Gly585Asp) & p.(Met528Arg)), while an unrelated patient of Italian descent was identified with homozygous HRD1 variant. Although there are additional variants reported in Saudi Arabian patient, SEL1L variant was considered as the potential candidate due to its biological relevance as reported in previous studies in mice. The variants were hypomorphic and impaired endoplasmic reticulum (ER)-associated degradation.

PMID:37943617 reported the identification of a homozygous SEL1L variant (p.(Cys141Tyr)) in five patients from a consanguineous Slovakian family. These patients presented with not only ERAD-associated neurodevelopmental disorders with onset in infancy (ENDI) syndromes, but infantile-onset agammaglobulinemia with no mature B cells, resulting in frequent infections and early death. All patients exhibited intellectual disability and were unable to speak words and sentences.

This gene has been associated with relevant phenotypes in OMIM (MIMs #621067 & #621068), but not yet in Gene2Phenotype.; to: PMID:37943610 reported six patients from three unrelated families with a neurodevelopmental disorder involving developmental delay, intellectual disability, facial dysmorphisms, short stature, microcephaly and seizures. Five patients from two families (Saudi Arabian and Moroccan descent) were identified with homozygous SEL1L variants (p.(Gly585Asp) & p.(Met528Arg)), while an unrelated patient of Italian descent was identified with homozygous HRD1 variant. Although there are additional variants reported in Saudi Arabian patient, SEL1L variant was considered as the potential candidate due to its biological relevance as reported in previous studies in mice. The variants were hypomorphic and impaired endoplasmic reticulum (ER)-associated degradation.

PMID:37943617 reported the identification of a homozygous SEL1L variant (p.(Cys141Tyr)) in five patients from a consanguineous Slovakian family. These patients presented with not only ERAD-associated neurodevelopmental disorders with onset in infancy (ENDI) syndromes, but infantile-onset agammaglobulinemia with no mature B cells, resulting in frequent infections and early death. All patients exhibited intellectual disability and were unable to speak words and sentences. Although variant in FAR2 gene was also identified in these patients, Sanger sequencing confirmed the segregation of the FAR2 variant with symptoms in patient 2 and FAR2 function is not linked to neurological disorder or agammaglobulinemia (33), leading to its exclusion from being causal for these patients.

This gene has been associated with relevant phenotypes in OMIM (MIMs #621067 & #621068), but not yet in Gene2Phenotype.
Intellectual disability v9.9 MECP2 Arina Puzriakova Phenotypes for gene: MECP2 were changed from Rett syndrome, 312750Mental retardation, X-linked, syndromic 13, 300055Rett syndrome, preserved speech variant, 312750Encephalopathy, neonatal severe, 300673{Autism susceptibility, X-linked 3}, 300496Angelman syndrome, 105830Mental retardation, X-linked syndromic, Lubs type, 300260; RETT SYNDROME (RTT)[ to Encephalopathy, neonatal severe, OMIM:300673; Intellectual developmental disorder, X-linked syndromic 13, OMIM:300055; Intellectual developmental disorder, X-linked syndromic, Lubs type, OMIM:300260; Rett syndrome, OMIM:312750; Rett syndrome, atypical, OMIM:312750; Rett syndrome, preserved speech variant, OMIM:312750
Intellectual disability v9.8 TAF2 Arina Puzriakova Phenotypes for gene: TAF2 were changed from Mental retardation, autosomal recessive 40, OMIM:615599 to Intellectual developmental disorder, autosomal recessive 40, OMIM:615599
Intellectual disability v9.7 SYNGAP1 Arina Puzriakova Phenotypes for gene: SYNGAP1 were changed from Mental retardation, autosomal dominant 5, 612621; EPILEPTIC ENCEPHALOPATHY to Intellectual developmental disorder, autosomal dominant 5, OMIM:612621
Intellectual disability v8.243 EPB41L3 Julia Baptista gene: EPB41L3 was added
gene: EPB41L3 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: EPB41L3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EPB41L3 were set to 39292993
Phenotypes for gene: EPB41L3 were set to developmental delay; intellectual disability; seizures; hypotonia; neuroregression
Review for gene: EPB41L3 was set to GREEN
Added comment: Six individuals from five unrelated families with global developmental delay, intellectual disability, seizures, hypotonia, neuroregression and delayed myelination. Exome sequencing identified biallelic variants in EPB41L3 in all affected individuals: two nonsense [c.466C>T, p.(R156*); c.2776C>T, p.(R926*)] and three frameshift [c.666delT, p.(F222Lfs*46); c.2289dupC, p.(V764Rfs*19); c.948_949delTG, p.(A317Kfs*33)].
Sources: Literature
Intellectual disability v8.243 EEF1D Julia Baptista gene: EEF1D was added
gene: EEF1D was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: EEF1D was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EEF1D were set to 36576126; 30787422; 38083972; 28097321
Phenotypes for gene: EEF1D were set to Neurodevelopmental disorder; OMIM#621150
Review for gene: EEF1D was set to GREEN
Added comment: Biallelic variants described in at least 5 families from different areas (Syria, Turkey, Oman and China).
Sources: Literature
Intellectual disability v8.243 FBXO22 Julia Baptista gene: FBXO22 was added
gene: FBXO22 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: FBXO22 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FBXO22 were set to 40215970
Phenotypes for gene: FBXO22 were set to neurodevelopmental delay; malformations; OMIM# 621184
Review for gene: FBXO22 was set to GREEN
Added comment: 15 affected children (nine females and six males) and one fetus (16 cases in total) presenting a common core symptomatology of early-onset growth restriction, neurodevelopmental delay, craniofacial abnormalities, and additional poly-malformations (cardiovascular, gastrointestinal, urinal, and endocrinal) (Figure 1A). All individuals belonged to 14 families from four countries of the Greater Middle East region (UAE, KSA, Oman, and Lebanon), of which 12 were identified as consanguineous. Of the 16 cases, three passed away (F7-II:1, F9-II:1, and F13-II:4), and one was a second-trimester termination of pregnancy (TOP) of unknown sex.
Sources: Literature
Intellectual disability v8.243 SEL1L Julia Baptista gene: SEL1L was added
gene: SEL1L was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: SEL1L was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SEL1L were set to 37943610, 37943617
Phenotypes for gene: SEL1L were set to Neurodevelopmental disorder
Review for gene: SEL1L was set to GREEN
Added comment: Biallelic missense variants of SEL1L and HRD1 (or SYVN1) in 6 children from 3 independent families presenting with developmental delay, intellectual disability, microcephaly, facial dysmorphisms, hypotonia, and/or ataxia (Wang et al 2024). Hypomorphic variants.

A biallelic SEL1L variant (p. Cys141Tyr) in 5 patients from a consanguineous Slovakian family reported by Weis et al 2024.

A gene-disease association is now described in OMIM.
Sources: Literature
Intellectual disability v8.241 RNU2-2P Achchuthan Shanmugasundram commented on gene: RNU2-2P: The "new-gene-name" tag has been added as the official HGNC symbol for RNU2-2P is RNU2-2.

In addition, "locus-type-rna-small-nuclear" tag has been added to highlight the biotype for this gene.
Intellectual disability v8.238 RNU2-2P Achchuthan Shanmugasundram changed review comment from: PMID:40210679 reported nine individuals from 100,000 Genomes Project (100KGP) data in the National Genomic Research Library (NGRL) with a neurodevelopmental disorder and with recurrent de novo single-nucleotide variants at nucleotide positions 4 and 35 of RNU2-2 (n.4G>A & n.35A>G).

Monoallelic variants in this gene were also identified in 16 other cases with neurodevelopmental disorder from eight other rare disease collections. All but two of them were confirmed to have a de novo variant and 15 of them had one of the two variants reported from the 100KGP collection. There were no unaffected carriers of either variant. One case had a different variant at position 35 (35A>C).

Detailed clinical information was provided for 15 of these cases, and the disorder is characterised by intellectual disability (ID), autistic behavior, microcephaly, hypotonia, epilepsy and hyperventilation. All cases had ID and global developmental delay, and displayed a severe and complex seizure phenotype.

This gene has not yet been associated with relevant phenotypes either in OMIM or in Gene2Phenotype.; to: PMID:40210679 reported nine individuals from 100,000 Genomes Project (100KGP) data in the National Genomic Research Library (NGRL) with a neurodevelopmental disorder and with recurrent de novo single-nucleotide variants at nucleotide positions 4 and 35 of RNU2-2 (n.4G>A & n.35A>G).

Monoallelic variants in this gene were also identified in 16 other cases with neurodevelopmental disorder from eight other rare disease collections. All but two of them were confirmed to have a de novo variant and 15 of them had one of the two variants reported from the 100KGP collection. There were no unaffected carriers of either variant. One case had a different variant at position 35 (35A>C).

Detailed clinical information was provided for 15 of these cases, and the disorder is characterised by intellectual disability (ID), autistic behaviour, microcephaly, hypotonia, epilepsy and hyperventilation. The phenotype typically manifests from 3 to 6 months of age but is progressive, frequently severe and accompanied by characteristic dysmorphic features. All cases had ID and global developmental delay, and displayed a severe and complex seizure phenotype.

This gene has not yet been associated with relevant phenotypes either in OMIM or in Gene2Phenotype.
Intellectual disability v8.238 RNU2-2P Achchuthan Shanmugasundram changed review comment from: PMID:40210679 reported nine individuals from 100,000 Genomes Project (100KGP) data in the National Genomic Research Library (NGRL) with a neurodevelopmental disorder and with recurrent de novo single-nucleotide variants at nucleotide positions 4 and 35 of RNU2-2 (n.4G>A & n.35A>G).

Monoallelic variants in this gene were also identified in 16 other cases with neurodevelopmental disorder from eight other rare disease collections. All but two of them were confirmed to have a de novo variant and 15 of them had one of the two variants reported from the 100KGP collection. There were no unaffected carriers of either variant. One case had a different variant at position 35 (35A>C).

Detailed clinical information was provided for 15 of these cases, and the disorder is characterised by intellectual disability, autistic behavior, microcephaly, hypotonia, epilepsy and hyperventilation. All cases display a severe and complex seizure phenotype.

This gene has not yet been associated with relevant phenotypes either in OMIM or in Gene2Phenotype.; to: PMID:40210679 reported nine individuals from 100,000 Genomes Project (100KGP) data in the National Genomic Research Library (NGRL) with a neurodevelopmental disorder and with recurrent de novo single-nucleotide variants at nucleotide positions 4 and 35 of RNU2-2 (n.4G>A & n.35A>G).

Monoallelic variants in this gene were also identified in 16 other cases with neurodevelopmental disorder from eight other rare disease collections. All but two of them were confirmed to have a de novo variant and 15 of them had one of the two variants reported from the 100KGP collection. There were no unaffected carriers of either variant. One case had a different variant at position 35 (35A>C).

Detailed clinical information was provided for 15 of these cases, and the disorder is characterised by intellectual disability (ID), autistic behavior, microcephaly, hypotonia, epilepsy and hyperventilation. All cases had ID and global developmental delay, and displayed a severe and complex seizure phenotype.

This gene has not yet been associated with relevant phenotypes either in OMIM or in Gene2Phenotype.
Intellectual disability v8.238 RNU2-2P Achchuthan Shanmugasundram Tag new-gene-name tag was added to gene: RNU2-2P.
Tag locus-type-rna-small-nuclear tag was added to gene: RNU2-2P.
Intellectual disability v8.238 DDX39B Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence (four unrelated cases with missense variants) available for the association. Hence, this gene can be promoted to green rating in the next GMS update.
Intellectual disability v8.237 DDX39B Achchuthan Shanmugasundram changed review comment from: As reviewed by Mike Spiller, PMID:39918047 reported the identification of monoallelic DDX39B variants in six patients from five unrelated families presenting with a neurodevelopmental disorder. Intellectual disability was reported in three of four unrelated patients identified with de novo missense variants, of which ID was severe in two and mild in one. The fourth patient had global developmental delay.

This gene has not yet been associated with relevant phenotypes in OMIM or Gene2Phenotype.; to: As reviewed by Mike Spiller, PMID:39918047 reported the identification of monoallelic DDX39B variants in six patients from five unrelated families presenting with a neurodevelopmental disorder. Intellectual disability was reported in three of four unrelated patients identified with de novo missense variants, of which ID was severe in two and mild in one. The fourth patient had global developmental delay.

The two patients from the same family with splice variant did not present with ID.

This gene has not yet been associated with relevant phenotypes in OMIM or Gene2Phenotype.
Intellectual disability v8.237 DDX39B Achchuthan Shanmugasundram changed review comment from: As reviewed by Mike Spiller, PMID:39918047 reported the identification of monoallelic DDX39B variants in six patients from five unrelated families presenting with a neurodevelopmental disorder. Intellectual disability was reported in three of four patients identified with de novo missense variants, of which ID was severe in two and mild in one. The fourth patient had global developmental delay.

This gene has not yet been associated with relevant phenotypes in OMIM or Gene2Phenotype.; to: As reviewed by Mike Spiller, PMID:39918047 reported the identification of monoallelic DDX39B variants in six patients from five unrelated families presenting with a neurodevelopmental disorder. Intellectual disability was reported in three of four unrelated patients identified with de novo missense variants, of which ID was severe in two and mild in one. The fourth patient had global developmental delay.

This gene has not yet been associated with relevant phenotypes in OMIM or Gene2Phenotype.
Intellectual disability v8.237 DDX39B Achchuthan Shanmugasundram commented on gene: DDX39B: As reviewed by Mike Spiller, PMID:39918047 reported the identification of monoallelic DDX39B variants in six patients from five unrelated families presenting with a neurodevelopmental disorder. Intellectual disability was reported in three of four patients identified with de novo missense variants, of which ID was severe in two and mild in one. The fourth patient had global developmental delay.

This gene has not yet been associated with relevant phenotypes in OMIM or Gene2Phenotype.
Intellectual disability v8.235 CLCN7 Arina Puzriakova Added comment: Comment on publications: PMID: 39994654 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Intellectual disability v8.234 CLCN7 Arina Puzriakova edited their review of gene: CLCN7: Added comment: PMID: 39994654 (2025) - a novel frameshift variant c.175dupA (p.Met59Asnfs*8) in CLCN7 was identified in a family with suspected ADO-II. The proband was homozygous for the variant and presented with intellectual disability, among features of osteopetrosis, deafness, optic atrophy, hepatosplenomegaly, cleft palate and recurrent infection. The variant showed incomplete penetrance in heterozygous family members.

Intellectual disability does not appear to be a typical feature and therefore maintaining the Red rating for now.; Changed publications to: 39994654
Intellectual disability v8.234 TMLHE Arina Puzriakova Added comment: Comment on list classification: Promoting to Amber as two unrelated families have been reported with moderate ID in association with this gene. This gene is otherwise linked to ASD susceptibility and the phenotype in these families may be explained by the more severe consequence (truncating) of their identified variants.

However, caution should be taken in the future if this gene is being considered for a diagnostic panel as pathogenicity remains unclear and it has been listed as non-disease gene.
Intellectual disability v8.233 TMLHE Arina Puzriakova Added comment: Comment on publications: PMID: 39845198 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Intellectual disability v8.232 TRMT1L Arina Puzriakova Added comment: Comment on publications: PMID: 39786990 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Intellectual disability v8.230 TRMT1L Arina Puzriakova gene: TRMT1L was added
gene: TRMT1L was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: TRMT1L was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TRMT1L were set to 39786990
Phenotypes for gene: TRMT1L were set to Early-onset neurodegenerative symptoms
Added comment: PMID: 39786990 (2025) - using GeneMatcher authors identified two siblings with a homozygous missense variant (c.1535C>T, p.(Pro512Leu)) in TRMT1L. Patients exhibited a range of early-onset neurodegenerative symptoms including intellectual disability, distal motor neuropathy, leukodystrophy, generalized hypotonia, and contractures. The variant segregates with the disease in the family and is predicted to be deleterious based upon multiple pathogenicity prediction algorithms.

Additional evidence required prior to making any conclusions about the pathogenicity of this gene and therefore rating Red for now.
Sources: Literature
Intellectual disability v8.229 KCNJ2 Arina Puzriakova Added comment: Comment on publications: PMID: 22155372 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Intellectual disability v8.228 KCNJ2 Arina Puzriakova gene: KCNJ2 was added
gene: KCNJ2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: KCNJ2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: KCNJ2 were set to 22155372
Phenotypes for gene: KCNJ2 were set to Short QT syndrome 3, OMIM:609622
Added comment: PMID: 22155372 (2012) - 8-year-old Japanese girl with a markedly short QT interval and a heterozygous KCNJ2 variant (M301K). Authors noted extracardiac features, including severe intellectual disability and seizures, which they suggested might be attributed to the KCNJ2 variant, but they could not exclude the possibility of other mutated genes.

Intellectual disability is not a typical feature and currently there is not enough evidence to conclusively link KCNJ2. Therefore rating Red until more evidence emerges.
Sources: Literature
Intellectual disability v8.227 VIPAS39 Arina Puzriakova Added comment: Comment on publications: PMID: 39736737 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Intellectual disability v8.226 VIPAS39 Arina Puzriakova reviewed gene: VIPAS39: Rating: AMBER; Mode of pathogenicity: None; Publications: 39736737, 35151346, 26019847; Phenotypes: Arthrogryposis, renal dysfunction, and cholestasis 2, OMIM:613404; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v8.226 VIPAS39 Arina Puzriakova Phenotypes for gene: VIPAS39 were changed from Gene2Phenotype confirmed gene with ID HPO to Arthrogryposis, renal dysfunction, and cholestasis 2, OMIM:613404
Intellectual disability v8.225 WT1 Arina Puzriakova Added comment: Comment on publications: PMID: 39625990 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Intellectual disability v8.224 FUT2 Arina Puzriakova Added comment: Comment on publications: PMID: 39350204 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Intellectual disability v8.223 FUT2 Arina Puzriakova gene: FUT2 was added
gene: FUT2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: FUT2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FUT2 were set to 39350204
Phenotypes for gene: FUT2 were set to Developmental and epileptic encephalopathy
Added comment: PMID: 39350204 (2024) - homozygous missense variant (NC_000019.10:g.48703291C>T) in the FUT2 gene was identified in an infant with vitamin B12-responsive developmental and epileptic encephalopathy and megaloblastic anemia. Although the mechanism of how the FUT2 gene variant affects vitamin B12 absorption is unclear.

Additional evidence is required before conclusively implicating FUT2 in human disease and therefore rating Red for now.
Sources: Literature
Intellectual disability v8.221 EPM2A Arina Puzriakova Added comment: Comment on publications: PMID: 39385815 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Intellectual disability v8.219 TFG Sarah Leigh edited their review of gene: TFG: Added comment: Biallelic TFG variants have been associated with Spastic paraplegia 57, autosomal recessive (OMIM:615658). Five biallelic TFG variants have been associated with OMIM:615658 in nine families from various ethnicities (PMID: 23479643; 27601211; 27492651; 28124177; 29971521; 30467354; 33767317). A range of phenotypic features were reported (table 2 in PMID: 33767317), with spasticity apparent in 8/8 families examined and intellectual disability in 5/9 families.; Changed rating: GREEN
Intellectual disability v8.217 TFG Sarah Leigh Added comment: Comment on publications: PMID: 33767317 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Intellectual disability v8.216 YBX3 Arina Puzriakova Added comment: Comment on publications: PMID:39423228 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Intellectual disability v8.215 YBX3 Arina Puzriakova gene: YBX3 was added
gene: YBX3 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: YBX3 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: YBX3 were set to 39423228
Phenotypes for gene: YBX3 were set to Neurological disorder
Review for gene: YBX3 was set to RED
Added comment: PMID: 39423228 (2024) - functional studies in C. elegans indicate that the Y-Box (YBX) RBP family are involved in memory and cognitive processes. Based on this finding, authors identified two unrelated individuals in the Baylor Genetics dataset with the same heterozygous VUS (c.379A>T (p.Asn127Tyr)) in the YBX3 gene and neurological symptoms. However, phenotypic overlap was limited and there was also a third family with the same variant and a metabolic phenotype. Modelling this variant in worms did lead to memory deficits, however given the clinical heterogeneity among human carriers, there is not enough evidence to draw any conclusions about this gene.
Sources: Literature
Intellectual disability v8.214 ABI2 Achchuthan Shanmugasundram Added comment: Comment on publications: PMID:39774290 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.

PMID:39774290 is a secondary publication and the relevant case described in this publication was originally from the primary publication PMID:28397838.
Intellectual disability v8.213 ABI2 Achchuthan Shanmugasundram gene: ABI2 was added
gene: ABI2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: ABI2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ABI2 were set to 28397838; 39774290
Phenotypes for gene: ABI2 were set to intellectual disability, MONDO:0001071
Review for gene: ABI2 was set to RED
Added comment: PMID:28397838 reported the identification of variants in a cohort of 192 multiplex Pakistani and Iranian consanguineous families with non-syndromic ID by combining microarray genotyping, homozygosity-by-descent (HBD) mapping, copy number variation (CNV) analysis, and whole exome sequencing (WES). This study identified a patient with homozygous loss-of-function variant in ABI2 gene (p.(Arg132Ter)).

This gene has not yet been associated with phenotypes either in OMIM or in Gene2Phenotype.
Sources: Literature
Intellectual disability v8.212 CYFIP1 Achchuthan Shanmugasundram Added comment: Comment on publications: PMID:39774290 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.

PMID:39774290 is a secondary publication and the relevant case described in this publication was originally from the primary publication PMID:37704042.
Intellectual disability v8.211 CYFIP1 Achchuthan Shanmugasundram gene: CYFIP1 was added
gene: CYFIP1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: CYFIP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CYFIP1 were set to 37704042; 39774290
Phenotypes for gene: CYFIP1 were set to intellectual disability, MONDO:0001071
Review for gene: CYFIP1 was set to RED
Added comment: PMID:37704042 reported two individuals from a family with intellectual disability, autism spectrum disorder, spastic tetraparesis, and brain morphology defects. They were identified with compound heterozygous missense variants in the CYFIP1 gene (p.(Ile476Val) and p.(Pro742Leu)).

Functional work from patient fibroblasts showed deficits in actin polymerization. In addition, Drosophila knockin models for these variants exhibited abnormal brain morphology and F-actin loss, and recapitulated the core behavioural symptoms, such as deficits in social interaction and motor coordination.

This gene has not yet been associated with relevant phenotypes either in OMIM or in Gene2Phenotype.
Sources: Literature
Intellectual disability v8.210 C1QC Achchuthan Shanmugasundram Added comment: Comment on publications: PMID:39196411 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Intellectual disability v8.209 C1QC Achchuthan Shanmugasundram gene: C1QC was added
gene: C1QC was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: C1QC was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: C1QC were set to 39196411
Phenotypes for gene: C1QC were set to C1q deficiency 3, OMIM:620322
Review for gene: C1QC was set to RED
Added comment: PMID:39196411 reported 12 patients with C1q deficiency, of which one was identified with homozygous variant in C1QC gene (p.(Arg69Ter)). Intellectual impairment was reported in this patient.
Sources: Literature
Intellectual disability v8.208 C1QA Achchuthan Shanmugasundram changed review comment from: Comment on publications: PMID:39196411 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques; to: Comment on publications: PMID:39196411 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Intellectual disability v8.208 C1QA Achchuthan Shanmugasundram Added comment: Comment on publications: PMID:39196411 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques
Intellectual disability v8.207 C1QA Achchuthan Shanmugasundram gene: C1QA was added
gene: C1QA was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: C1QA was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: C1QA were set to 39196411
Phenotypes for gene: C1QA were set to C1q deficiency 1, OMIM:613652
Review for gene: C1QA was set to RED
Added comment: PMID:39196411 reported 12 patients with C1q deficiency, of which 10 of them were identified with homozygous variants in C1QA gene. Global developmental delay was reported in only one of these ten cases.
Sources: Literature
Intellectual disability v8.205 ATAD2B Arina Puzriakova commented on gene: ATAD2B: PMID: 39313616 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Intellectual disability v8.205 ATAD2B Arina Puzriakova gene: ATAD2B was added
gene: ATAD2B was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: ATAD2B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ATAD2B were set to 39313616
Phenotypes for gene: ATAD2B were set to intellectual disability, MONDO:0001071
Added comment: PMID: 39313616 - two unrelated individuals were identified with biallelic variants in the ATAD2B gene. One patient had an affected sibling with the same genotype and a similar phenotype. A fourth individual with biallelic variants was also identified in GeneDx. All had developmental delay or cognitive impairment but otherwise had distinct phenotypes (with exception of the sibs) (summary in Supplementary Table 6).

Given the lack of phenotypic overlap, more evidence is required to implicate ATAD2B and therefore rating Red until more evidence emerges.
Sources: Literature
Intellectual disability v8.204 ASCC3 Arina Puzriakova commented on gene: ASCC3: PMID: 39286456 (2024) - three additional unrelated families identified with biallelic variants in the ASCC3 gene. All affected individuals had developmental delay and muscle fatigue. Other features included intellectual disability, hypotonia, motor impairment, feeding difficulties, and proximal/truncal muscle weakness.

Review of all reported cases (21 individuals) to date showed clinical heterogeneity, however most patients did exhibit intellectual disability of varying severity which can be the main presenting feature. Overall this supports inclusion of this gene on the panel.
Intellectual disability v8.204 ASCC3 Arina Puzriakova Added comment: Comment on publications: PMID: 39286456 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Intellectual disability v8.202 SUPV3L1 Sarah Leigh changed review comment from: Three SUPV3L1 variants have been reported in two unrelated cases with a syndrome that includes ataxia, spasticity, optic atrophy and skin hypopigmentation (ASOASH) and also intellectual disability (PMID: 35023579;39596606).
The homozygous terminating SUPV3L1 variant (NM_003171.3: c.2215C>T, p.Gln739*) reported in the siblings in PMID: 35023579, was shown to results in reduced expression of the truncated protein in the proband's fibroblasts, resulting in a reduction of the mature ND6 mRNA species and also the accumulation of double-stranded RNA. This effect was partly restored using full-length SUPV3L1 cDNA (PMID: 35023579). This variant and the compound heterozygous SUPV3L1 variants (NM_003171.5: c.272-2A>G and c.1924A>C; p.(Ser642Arg) reported in PMID: 39596606 were each inherited from the parents of the proband (PMID: 35023579;39596606).
Sources: Literature; to: Three SUPV3L1 variants have been reported in two unrelated cases with a syndrome that includes ataxia, spasticity, optic atrophy and skin hypopigmentation (ASOASH) and also intellectual disability (PMID: 35023579;39596606).
The homozygous terminating SUPV3L1 variant (NM_003171.3: c.2215C>T, p.Gln739*) reported in the siblings in PMID: 35023579, was shown to results in reduced expression of the truncated protein in the proband's fibroblasts, resulting in a reduction of the mature ND6 mRNA species and also the accumulation of double-stranded RNA. This effect was partly restored using full-length SUPV3L1 cDNA (PMID: 35023579). This variant and the compound heterozygous SUPV3L1 variants (NM_003171.5: c.272-2A>G and c.1924A>C; p.(Ser642Arg) reported in PMID: 39596606 were each inherited from the parents of the proband (PMID: 35023579;39596606). Supportive functional studies were presented in PMID: 35023579 and 39596606.
Sources: Literature
Intellectual disability v8.202 SUPV3L1 Sarah Leigh Added comment: Comment on publications: PMID: 39596606 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Intellectual disability v8.201 SUPV3L1 Sarah Leigh gene: SUPV3L1 was added
gene: SUPV3L1 was added to Intellectual disability. Sources: Literature
Q1_25_ promote_green tags were added to gene: SUPV3L1.
Mode of inheritance for gene: SUPV3L1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SUPV3L1 were set to 35023579; 39596606
Phenotypes for gene: SUPV3L1 were set to Mitochondrial RNA Helicase SUPV3L1-Associated neurodegenerative syndrome
Review for gene: SUPV3L1 was set to AMBER
Added comment: Three SUPV3L1 variants have been reported in two unrelated cases with a syndrome that includes ataxia, spasticity, optic atrophy and skin hypopigmentation (ASOASH) and also intellectual disability (PMID: 35023579;39596606).
The homozygous terminating SUPV3L1 variant (NM_003171.3: c.2215C>T, p.Gln739*) reported in the siblings in PMID: 35023579, was shown to results in reduced expression of the truncated protein in the proband's fibroblasts, resulting in a reduction of the mature ND6 mRNA species and also the accumulation of double-stranded RNA. This effect was partly restored using full-length SUPV3L1 cDNA (PMID: 35023579). This variant and the compound heterozygous SUPV3L1 variants (NM_003171.5: c.272-2A>G and c.1924A>C; p.(Ser642Arg) reported in PMID: 39596606 were each inherited from the parents of the proband (PMID: 35023579;39596606).
Sources: Literature
Intellectual disability v8.200 MARS2 Achchuthan Shanmugasundram changed review comment from: Comment on publications: PMID:39995633 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.

The patient reported in PMID:39995633 presented with psychomotor developmental delay, growth failure, and generalized skeletal alterations. Genetic analyses showed novel biallelic variants, c.277G > A; p.(Asp93Asn) and c.409C > T; p.(Arg137Cys) in the MARS2 gene. These variants were inherited from the patient's parents, with one variant detected in the mother and the other in the father, both heterozygous.; to: Comment on publications: PMID:39995633 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.

The patient reported in PMID:39995633 presented with psychomotor developmental delay, growth failure, and generalized skeletal alterations. However, this patient was not reported with intellectual disability in the publication.

Genetic analyses showed novel biallelic variants, c.277G > A; p.(Asp93Asn) and c.409C > T; p.(Arg137Cys) in the MARS2 gene. These variants were inherited from the patient's parents, with one variant detected in the mother and the other in the father, both heterozygous.
Intellectual disability v8.200 MARS2 Achchuthan Shanmugasundram Added comment: Comment on publications: PMID:39995633 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.

The patient reported in PMID:39995633 presented with psychomotor developmental delay, growth failure, and generalized skeletal alterations. Genetic analyses showed novel biallelic variants, c.277G > A; p.(Asp93Asn) and c.409C > T; p.(Arg137Cys) in the MARS2 gene. These variants were inherited from the patient's parents, with one variant detected in the mother and the other in the father, both heterozygous.
Intellectual disability v8.200 MARS2 Achchuthan Shanmugasundram Publications for gene: MARS2 were set to 25754315
Intellectual disability v8.199 MARS2 Achchuthan Shanmugasundram reviewed gene: MARS2: Rating: RED; Mode of pathogenicity: None; Publications: 39995633; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v8.198 HNRNPC Achchuthan Shanmugasundram Added comment: Comment on publications: PMID:40004505 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Intellectual disability v8.197 HNRNPC Achchuthan Shanmugasundram changed review comment from: PMID:37541189 reported a cohort of 13 individuals with heterozygous germline variants in HNRNPC gene, including a recurrent de novo in-frame deletion in five individuals (c.850_876del/ p.(Arg284_Asp292del) for HNRNPC-iso1 and c.889_915del/ p.(Arg297_Asp305del) for HNRNPC-iso2). They all presented with a neurodevelopmental disorder characterised by global developmental delay, intellectual disability, behavioural abnormalities, and subtle facial dysmorphic features in most individuals.

PMID:40004505 reported the identification of the missense variant, p.(Arg99Gln) in a patient showing a unique clinical presentation characterized by DD/ID, distinctive facial features, cochlear aplasia, and bilateral colobomatous microphthalmia. This variant was previously reported in an individual in PMID:37541189. The clinical phenotype of this individual fit that of the previously described individual and only partially overlaps with the clinical spectrum of the disease.

This gene has already been associated with relevant phenotypes in OMIM (MIM #620688), but not yet in Gene2Phenotype.
Sources: Literature; to: PMID:37541189 reported a cohort of 13 individuals with heterozygous germline variants in HNRNPC gene, including a recurrent de novo in-frame deletion in five individuals (c.850_876del/ p.(Arg284_Asp292del) for HNRNPC-iso1 and c.889_915del/ p.(Arg297_Asp305del) for HNRNPC-iso2). They all presented with a neurodevelopmental disorder characterised by global developmental delay, intellectual disability, behavioural abnormalities, and subtle facial dysmorphic features in most individuals.

PMID:40004505 reported the identification of the missense variant, p.(Arg99Gln) in a patient showing a unique clinical presentation characterised by DD/ID, distinctive facial features, cochlear aplasia, and bilateral colobomatous microphthalmia. This variant was previously reported in an individual in PMID:37541189. The clinical phenotype of this individual fit that of the previously described individual and only partially overlaps with the clinical spectrum of the disease.

This gene has already been associated with relevant phenotypes in OMIM (MIM #620688), but not yet in Gene2Phenotype.
Sources: Literature
Intellectual disability v8.197 HNRNPC Achchuthan Shanmugasundram gene: HNRNPC was added
gene: HNRNPC was added to Intellectual disability. Sources: Literature
Q1_25_ promote_green tags were added to gene: HNRNPC.
Mode of inheritance for gene: HNRNPC was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: HNRNPC were set to 37541189; 40004505
Phenotypes for gene: HNRNPC were set to Intellectual developmental disorder, autosomal dominant 74, OMIM:620688
Review for gene: HNRNPC was set to GREEN
Added comment: PMID:37541189 reported a cohort of 13 individuals with heterozygous germline variants in HNRNPC gene, including a recurrent de novo in-frame deletion in five individuals (c.850_876del/ p.(Arg284_Asp292del) for HNRNPC-iso1 and c.889_915del/ p.(Arg297_Asp305del) for HNRNPC-iso2). They all presented with a neurodevelopmental disorder characterised by global developmental delay, intellectual disability, behavioural abnormalities, and subtle facial dysmorphic features in most individuals.

PMID:40004505 reported the identification of the missense variant, p.(Arg99Gln) in a patient showing a unique clinical presentation characterized by DD/ID, distinctive facial features, cochlear aplasia, and bilateral colobomatous microphthalmia. This variant was previously reported in an individual in PMID:37541189. The clinical phenotype of this individual fit that of the previously described individual and only partially overlaps with the clinical spectrum of the disease.

This gene has already been associated with relevant phenotypes in OMIM (MIM #620688), but not yet in Gene2Phenotype.
Sources: Literature
Intellectual disability v8.196 VPS33A Sarah Leigh Added comment: Comment on publications: PMID: 39273517 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Intellectual disability v8.194 VPS33A Sarah Leigh gene: VPS33A was added
gene: VPS33A was added to Intellectual disability. Sources: Literature
Q1_25_ promote_green tags were added to gene: VPS33A.
Mode of inheritance for gene: VPS33A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: VPS33A were set to 27547915; 28013294; 31070736; 39273517
Phenotypes for gene: VPS33A were set to Mucopolysaccharidosis-plus syndrome, OMIM:617303; mucopolysaccharidosis-plus syndrome, MONDO:0015012
Review for gene: VPS33A was set to GREEN
Added comment: There are numerous reports of the homozygous VPS33A variant: NM 022916.5: c.1492C > T, p.Arg498Trp in cases of Mucopolysaccharidosis-plus syndrome (OMIM:617303)(PMID: 27547915;28013294;31070736;39273517). Common features of this syndrome include: hepatomegaly, splenomegaly, respiratory difficulties, developmental delay including limited cognitive abilities and various skeletal issues (PMID: 27547915;28013294;31070736;39273517).
Sources: Literature
Intellectual disability v8.193 CRMP1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are three unrelated cases reported with moderate intellectual disability and with monoallelic CRMP1 variants. However, one patient with a different monoallelic CRMP1 variant had normal IQ. Hence, this gene should be rated amber with current evidence.

The 'watchlist' tag has been added to review this gene in light of any new evidence in the future.
Intellectual disability v8.192 CRMP1 Achchuthan Shanmugasundram Added comment: Comment on publications: PMID:39758889 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Intellectual disability v8.191 CRMP1 Achchuthan Shanmugasundram gene: CRMP1 was added
gene: CRMP1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: CRMP1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CRMP1 were set to 36511780; 39758889
Phenotypes for gene: CRMP1 were set to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Review for gene: CRMP1 was set to AMBER
Added comment: PMID:36511780 reported the identification of three different heterozygous de novo variants in the CRMP1 gene (p.(Pro589Leu), p.(Thr427Met) & p.(Phe351Ser)) in three unrelated individuals with a neurodevelopmental disorder presenting with muscular hypotonia, intellectual disability, and/or autism spectrum disorder. ID was moderate in two of them, while IQ was normal in one. There is also functional evidence available for these variants.

PMID:39758889 reported the identification of a novel heterozygous de novo frameshift variant in CRMP1 (p.(Lys586fs)) in a 9-year-old male patient presenting with phenotypes such as autism, language delay, hyperactivity, and learning disabilities. This patient was reported with moderate ID.
Sources: Literature
Intellectual disability v8.190 GAP43 Achchuthan Shanmugasundram Added comment: Comment on publications: PMID:39738362 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Intellectual disability v8.189 GAP43 Achchuthan Shanmugasundram changed review comment from: PMID:39738362 reported the identification of a heterozygous missense variant in the GAP43 gene (p.(Glu146Lys)) in a 15-year-old female patient with moderate intellectual disability, neurodevelopmental disorders, short stature, and skeletal abnormalities such as left-right difference in legs and digital deformities.

The variant GAP43 protein was found to be unstable in neuronal cells and the disruption of Gap43 in mouse embryonic cortical neurons impaired axonal elongation and dendrite formation.

There were six previous cases reported with GAP43 abnormalities (3 involving deletion of a region including GAP43, two siblings with duplication and one SNV). Only one of the siblings with region duplication had moderate ID, while the other sibling and another patient with region deletion had mild ID.
Sources: Literature; to: PMID:39738362 reported the identification of a heterozygous missense variant in the GAP43 gene (p.(Glu146Lys)) in a 15-year-old female patient with moderate intellectual disability, neurodevelopmental disorders, short stature, and skeletal abnormalities such as left-right difference in legs and digital deformities.

The variant GAP43 protein was found to be unstable in neuronal cells and the disruption of Gap43 in mouse embryonic cortical neurons impaired axonal elongation and dendrite formation.

There were six previous cases reported with GAP43 abnormalities (3 involving deletion of a region including GAP43, two siblings with duplication and one SNV). Only one of the siblings with region duplication had moderate ID, while the other sibling and another patient with region deletion had mild ID.

This gene has not yet been associated with phenotypes either in OMIM or in Gene2Phenotype.
Sources: Literature
Intellectual disability v8.189 ERCC4 Sarah Leigh Added comment: Comment on publications: PMID: 39769235 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Intellectual disability v8.188 GAP43 Achchuthan Shanmugasundram changed review comment from: PMID:39738362 reported the identification of a heterozygous missense variant in the GAP43 gene (p.(Glu146Lys)) in a 15-year-old female patient with moderate intellectual disability, neurodevelopmental disorders, short stature, and skeletal abnormalities such as left-right difference in legs and digital deformities.

The variant GAP43 protein was found to be unstable in neuronal cells and the disruption of Gap43 in mouse embryonic cortical neurons impaired axonal elongation and dendrite formation.

There were six previous cases reported with GAP43 abnormalities (4 involving deletion of a region including GAP43, one duplication and one SNV). Only one of these cases with region deletion had moderate ID, while two others had mild ID.
Sources: Literature; to: PMID:39738362 reported the identification of a heterozygous missense variant in the GAP43 gene (p.(Glu146Lys)) in a 15-year-old female patient with moderate intellectual disability, neurodevelopmental disorders, short stature, and skeletal abnormalities such as left-right difference in legs and digital deformities.

The variant GAP43 protein was found to be unstable in neuronal cells and the disruption of Gap43 in mouse embryonic cortical neurons impaired axonal elongation and dendrite formation.

There were six previous cases reported with GAP43 abnormalities (3 involving deletion of a region including GAP43, two siblings with duplication and one SNV). Only one of the siblings with region duplication had moderate ID, while the other sibling and another patient with region deletion had mild ID.
Sources: Literature
Intellectual disability v8.188 GAP43 Achchuthan Shanmugasundram gene: GAP43 was added
gene: GAP43 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: GAP43 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: GAP43 were set to 39738362
Phenotypes for gene: GAP43 were set to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Review for gene: GAP43 was set to RED
Added comment: PMID:39738362 reported the identification of a heterozygous missense variant in the GAP43 gene (p.(Glu146Lys)) in a 15-year-old female patient with moderate intellectual disability, neurodevelopmental disorders, short stature, and skeletal abnormalities such as left-right difference in legs and digital deformities.

The variant GAP43 protein was found to be unstable in neuronal cells and the disruption of Gap43 in mouse embryonic cortical neurons impaired axonal elongation and dendrite formation.

There were six previous cases reported with GAP43 abnormalities (4 involving deletion of a region including GAP43, one duplication and one SNV). Only one of these cases with region deletion had moderate ID, while two others had mild ID.
Sources: Literature
Intellectual disability v8.187 HINT1 Sarah Leigh Added comment: Comment on publications: PMID: 39596683 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Intellectual disability v8.186 LRRC8C Achchuthan Shanmugasundram changed review comment from: Comment on publications: PMID:39623139 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques; to: Comment on publications: PMID:39623139 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Intellectual disability v8.186 LRRC8C Achchuthan Shanmugasundram Added comment: Comment on publications: PMID:39623139 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques
Intellectual disability v8.184 LRRC8C Achchuthan Shanmugasundram gene: LRRC8C was added
gene: LRRC8C was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: LRRC8C was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: LRRC8C were set to 39623139
Phenotypes for gene: LRRC8C were set to TIMES syndrome, OMIM:621056
Mode of pathogenicity for gene: LRRC8C 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: LRRC8C was set to AMBER
Added comment: PMID:39623139 reported two unrelated individuals with a multisystem disorder characterised by considerable phenotypic variability, but with overlapping features including telangiectasia, impaired intellectual development, microcephaly, metaphyseal dysplasia, eye abnormalities, and short stature.

One patient had a 1-bp heterozygous insertion (p.(Leu400IlefsTer8)) in LRRC8C gene, while the other one had a heterozygous missense variant in the same gene (p.(Val390Leu)). There is also evidence from in vitro functional assay available. The evidence also suggests that both variants result in gain-of-function effect.

`This gene has been associated with relevant phenotype in OMIM (MIM #621056), but not yet in Gene2Phenotype.
Sources: Literature
Intellectual disability v8.183 WFS1 Achchuthan Shanmugasundram changed review comment from: PMID:39767643 reported the identification of an ultra-rare, mono-allelic missense variant in the WFS1 gene (p. Asp711Asn) in a nine-year-old girl that showed phenotypic manifestations of intellectual impairment, microcephaly, and epilepsy. There was a positive family history in previous generations for cognitive impairment.; to: PMID:39767643 reported the identification of an ultra-rare, mono-allelic missense variant in the WFS1 gene (p. Asp711Asn) in a nine-year-old girl that showed phenotypic manifestations of intellectual impairment, microcephaly, and epilepsy. There was a positive family history in previous generations for cognitive impairment.

Although there are multiple phenotypes available for this gene in OMIM, mental retardation/ cognitive impairment has been recorded as a clinical manifestation seen in some patients with the autosomal recessive Wolfram syndrome 1 (MIM #222300). However, ID has not been associated with any autosomal dominant syndromes. In addition, ID forms part of a broader phenotype.

Hence, this gene can only be rated red for both monoallelic and biallelic disease associations in this panel.
Intellectual disability v8.183 WFS1 Achchuthan Shanmugasundram Added comment: Comment on publications: PMID:39767643 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Intellectual disability v8.182 LMNA Achchuthan Shanmugasundram Added comment: Comment on publications: PMID:39767643 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Intellectual disability v8.180 LMNA Achchuthan Shanmugasundram changed review comment from: PMID:39767643 reported the identification of a heterozygous missense variant in LMNA gene (p. Glu443Gly) in a 16-year-old boy affected with intellectual impairment, cardiac manifestation, diabetes mellitus, a cataract in the right eye, epilepsy, and skin atrophy on his back. This family showed no positive history of neurodevelopmental disorders (NDDs) in the five previous generations, while one sibling was affected by a NDD phenotype.

There are four cases reported in the Decipher database with sequence variants in LMNA gene (https://www.deciphergenomics.org/gene/LMNA/patient-overlap/snvs), of which the patient with frameshift variant (p.Glu223AspfsTer7) was reported with a number of phenotypes including global developmental delay.; to: PMID:39767643 reported the identification of a heterozygous missense variant in LMNA gene (p. Glu443Gly) in a 16-year-old boy affected with intellectual impairment, cardiac manifestation, diabetes mellitus, a cataract in the right eye, epilepsy, and skin atrophy on his back. This family showed no positive history of neurodevelopmental disorders (NDDs) in the five previous generations, while one sibling was affected by a NDD phenotype.

There are four cases reported in the Decipher database with sequence variants in LMNA gene (https://www.deciphergenomics.org/gene/LMNA/patient-overlap/snvs), of which the patient with frameshift variant (p.Glu223AspfsTer7) was reported with a number of phenotypes including global developmental delay. This variant is annotated to be likely pathogenic and with the contribution of the variant to phenotype is uncertain.
Intellectual disability v8.178 LMNA Achchuthan Shanmugasundram commented on gene: LMNA: PMID:39767643 reported the identification of a heterozygous missense variant in LMNA gene (p. Glu443Gly) in a 16-year-old boy affected with intellectual impairment, cardiac manifestation, diabetes mellitus, a cataract in the right eye, epilepsy, and skin atrophy on his back. This family showed no positive history of neurodevelopmental disorders (NDDs) in the five previous generations, while one sibling was affected by a NDD phenotype.

There are four cases reported in the Decipher database with sequence variants in LMNA gene (https://www.deciphergenomics.org/gene/LMNA/patient-overlap/snvs), of which the patient with frameshift variant (p.Glu223AspfsTer7) was reported with a number of phenotypes including global developmental delay.
Intellectual disability v8.177 HINT1 Sarah Leigh reviewed gene: HINT1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Neuromyotonia and axonal neuropathy, autosomal recessive, OMIM:137200, Gamstorp-Wohlfart syndrome, MONDO:0007646; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v8.176 HINT1 Sarah Leigh Phenotypes for gene: HINT1 were changed from Neuromyotonia and axonal neuropathy, autosomal recessive, 137200 to Neuromyotonia and axonal neuropathy, autosomal recessive, OMIM:137200; Gamstorp-Wohlfart syndrome, MONDO:0007646
Intellectual disability v8.174 DAP3 Achchuthan Shanmugasundram changed review comment from: PMID:39701103 reported the identification of biallelic variants in DAP3 gene in five unrelated individuals presenting with variable clinical presentations ranging from Perrault syndrome (sensorineural hearing loss and ovarian insufficiency) to an early childhood neurometabolic phenotype. All five individuals had bilateral sensorineural hearing loss and the severity was profound in three of them, while not reported in the other two. Severe intellectual disability was reported in one individual and mild ID was reported in two individuals. There is also functional evidence available.

This gene has been associated with relevant phenotypes in OMIM (MIM #621101).
Sources: Literature; to: PMID:39701103 reported the identification of biallelic variants in DAP3 gene in five unrelated individuals presenting with variable clinical presentations ranging from Perrault syndrome (sensorineural hearing loss and ovarian insufficiency) to an early childhood neurometabolic phenotype. All five individuals had bilateral sensorineural hearing loss and the severity was profound in three of them, while not reported in the other two. Severe intellectual disability was reported in one individual and mild ID was reported in two individuals. There is also functional evidence available.

This gene has been associated with relevant phenotypes in OMIM (MIM #621101), but not yet in Gene2Phenotype.
Sources: Literature
Intellectual disability v8.174 PLAT Achchuthan Shanmugasundram changed review comment from: PMID:39574431 reported the identification of three different homozygous truncating variants in PLAT gene in four individuals from three unrelated families. All of them presented with tetraventricular hydrocephalus. Dandy–Walker malformation was reported in three unrelated cases, of which mild intellectual disability was reported in one (family 2). Global developmental delay was reported in another (family 3), but this could partially be explained by a co-occurring Cohen syndrome diagnosis. Mild ID was also reported in the proband from family 1 that did not show Dandy–Walker malformation.

This gene has not yet been associated with any relevant phenotypes in OMIM or in Gene2Phenotype.
Sources: Literature; to: PMID:39574431 reported the identification of three different homozygous truncating variants in PLAT gene in four cases from three unrelated families. All of them presented with tetraventricular hydrocephalus. Dandy–Walker malformation was reported in three unrelated cases (two individuals and one foetus), of which mild intellectual disability was reported in one (family 2). Global developmental delay was reported in another (family 3), but this could partially be explained by a co-occurring Cohen syndrome diagnosis. Mild ID was also reported in the proband from family 1 that did not show Dandy–Walker malformation.

This gene has not yet been associated with any relevant phenotypes in OMIM or in Gene2Phenotype.
Sources: Literature
Intellectual disability v8.174 PLAT Achchuthan Shanmugasundram changed review comment from: PMID:39574431 reported the identification of three different homozygous truncating variants in PLAT gene in four individuals from three unrelated families. All of them presented with tetraventricular hydrocephalus. Dandy–Walker malformation was reported in three unrelated cases, of which mild intellectual disability was reported in two. Global developmental delay was reported in the third one.

This gene has not yet been associated with any relevant phenotypes in OMIM or in Gene2Phenotype.
Sources: Literature; to: PMID:39574431 reported the identification of three different homozygous truncating variants in PLAT gene in four individuals from three unrelated families. All of them presented with tetraventricular hydrocephalus. Dandy–Walker malformation was reported in three unrelated cases, of which mild intellectual disability was reported in one (family 2). Global developmental delay was reported in another (family 3), but this could partially be explained by a co-occurring Cohen syndrome diagnosis. Mild ID was also reported in the proband from family 1 that did not show Dandy–Walker malformation.

This gene has not yet been associated with any relevant phenotypes in OMIM or in Gene2Phenotype.
Sources: Literature
Intellectual disability v8.172 PLAT Achchuthan Shanmugasundram gene: PLAT was added
gene: PLAT was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: PLAT was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PLAT were set to 39574431
Phenotypes for gene: PLAT were set to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Review for gene: PLAT was set to AMBER
Added comment: PMID:39574431 reported the identification of three different homozygous truncating variants in PLAT gene in four individuals from three unrelated families. All of them presented with tetraventricular hydrocephalus. Dandy–Walker malformation was reported in three unrelated cases, of which mild intellectual disability was reported in two. Global developmental delay was reported in the third one.

This gene has not yet been associated with any relevant phenotypes in OMIM or in Gene2Phenotype.
Sources: Literature
Intellectual disability v8.171 IARS2 Achchuthan Shanmugasundram Publications for gene: IARS2 were set to 25130867; 28328135; 39169373
Intellectual disability v8.170 IARS2 Achchuthan Shanmugasundram Phenotypes for gene: IARS2 were changed from Cataracts, growth hormone deficiency, sensory neuropathy, sensorineural hearing loss, and skeletal dysplasia, 616007 to Cataracts, growth hormone deficiency, sensory neuropathy, sensorineural hearing loss, and skeletal dysplasia, OMIM:616007
Intellectual disability v8.170 IARS2 Achchuthan Shanmugasundram Publications for gene: IARS2 were set to 25130867; 28328135
Intellectual disability v8.169 IARS2 Achchuthan Shanmugasundram reviewed gene: IARS2: Rating: RED; Mode of pathogenicity: None; Publications: 39169373; Phenotypes: Cataracts, growth hormone deficiency, sensory neuropathy, sensorineural hearing loss, and skeletal dysplasia, OMIM:616007; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v8.168 DAP3 Achchuthan Shanmugasundram Added comment: Comment on publications: PMID:39701103 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Intellectual disability v8.167 DAP3 Achchuthan Shanmugasundram gene: DAP3 was added
gene: DAP3 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: DAP3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DAP3 were set to 39701103
Phenotypes for gene: DAP3 were set to Perrault syndrome 7, OMIM:621101
Review for gene: DAP3 was set to RED
Added comment: PMID:39701103 reported the identification of biallelic variants in DAP3 gene in five unrelated individuals presenting with variable clinical presentations ranging from Perrault syndrome (sensorineural hearing loss and ovarian insufficiency) to an early childhood neurometabolic phenotype. All five individuals had bilateral sensorineural hearing loss and the severity was profound in three of them, while not reported in the other two. Severe intellectual disability was reported in one individual and mild ID was reported in two individuals. There is also functional evidence available.

This gene has been associated with relevant phenotypes in OMIM (MIM #621101).
Sources: Literature
Intellectual disability v8.165 NHLRC2 Achchuthan Shanmugasundram Added comment: Comment on publications: PMID:39328589 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Intellectual disability v8.164 NHLRC2 Achchuthan Shanmugasundram gene: NHLRC2 was added
gene: NHLRC2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: NHLRC2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NHLRC2 were set to 37188825; 39328589
Phenotypes for gene: NHLRC2 were set to FINCA syndrome, OMIM:618278
Review for gene: NHLRC2 was set to GREEN
Added comment: PMID:37188825 reported 15 patients ranging in age from 22 months to 19 years, from 12 unrelated families with an overlapping phenotype with FINCA syndrome (MIM #618278). They were identified with nine novel NHLRC2 variants via exome sequencing. All these patients presented with moderate to severe global developmental delay and variable disease progression. Seizures, truncal hypotonia and movement disorders were also frequently observed.

PMID:39328589 reported two siblings of Chinese decent with FINCA syndrome and they were identified with the same compound heterozygous variants in NHLRC2 gene. Both of them presented with developmental delay, of which the younger brother was evaluated with a development quotient (DQ) of 39 at four months of age (normal range >85), indicating moderate intellectual disability.

This gene has also been associated with relevant phenotype on the DD panel of Gene2Phenotype, with a definitive rating.
Sources: Literature
Intellectual disability v8.163 DDX39B Mike Spiller gene: DDX39B was added
gene: DDX39B was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: DDX39B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: DDX39B were set to PMID: 39918047
Review for gene: DDX39B was set to GREEN
Added comment: PMID: 39918047 - report 4 de novo missense variants in individuals with phenotypes of ID ranging from mild to severe (2 severe, 1 mild, 1 severity not stated but phenotype of GDD).
Hypotonia, short stature and skeletal abnormalities are also observed frequently.
Variants absent from gnomad, affect highly conserved amino acids in constrained regions of DEAD/DEAH box helicase domain.

Splice variant causing inframe deletion also identified in fifth family (proband and mother), but significance of this unclear as neither has ID.

Supported by functional studies:
Transcriptome profiling shows significant increase in abberant splicing events, consistent with DDX39B role as splicing factor.
Drosophila experiments - overexpression of WT human gene is lethal, but flies overexpressing variants were healthy, suggesting these variants cause loss of / reduced protein function.

Overall good evidence for DEAD box helicase missenses causing an autosomal dominant syndromic ID disorder.
Sources: Literature
Intellectual disability v8.163 AFF2_GCC Sarah Leigh STR: AFF2_GCC was added
STR: AFF2_GCC was added to Intellectual disability. Sources: Literature
STR, NGS Not Validated tags were added to STR: AFF2_GCC.
Mode of inheritance for STR: AFF2_GCC was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for STR: AFF2_GCC were set to 8334699; 8023854; 21739600; 9299237; 11171404; 11923441; 19136466; 2356291
Phenotypes for STR: AFF2_GCC were set to Intellectual developmental disorder, X-linked 109, OMIM:309548; FRAXE intellectual disability, MONDO:0010659
Review for STR: AFF2_GCC was set to GREEN
Added comment: AFF2 transcribed from the forwards strand, which means that the repeated sequence is the forward strand sequence.

AFF2_GCC is on https://gnomad.broadinstitute.org/short-tandem-repeats?dataset=gnomad_r3

AFF2_GCC is on https://stripy.org/database

AFF2_GCC is on DRAGON 4.02.

The coordinates and pathogenic ranges of the sequence repeats were obtained from
https://gnomad.broadinstitute.org/short-tandem-repeats?dataset=gnomad_r3 and DRAGON 4.02/

There is enough evidence for this STR to be green on this panel.

This STR has not been approved by NHS STR working group and is not NGS Not Validated
Sources: Literature
Intellectual disability v8.161 THAP11_CAG Sarah Leigh STR: THAP11_CAG was added
STR: THAP11_CAG was added to Intellectual disability. Sources: Literature
STR, NGS Not Validated tags were added to STR: THAP11_CAG.
Mode of inheritance for STR: THAP11_CAG was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for STR: THAP11_CAG were set to 37148549; 38757579; 39441143
Phenotypes for STR: THAP11_CAG were set to Spinocerebellar ataxia 51, OMIM:620947
Review for STR: THAP11_CAG was set to RED
Added comment: THAP11 transcribed from the forward strand.
THAP11_CAG is not on https://gnomad.broadinstitute.org/short-tandem-repeats?dataset=gnomad_r3
THAP11_CAG is not is not DRAGON 4.02 or other previous versions.
The coordinates and pathogenic ranges of the sequence repeats were obtained from https://stripy.org/database/THAP11

This STR has not been approved by NHS STR working group and is not NGS Not Validated
Sources: Literature
Intellectual disability v8.160 PPP2R2B Sarah Leigh Mode of pathogenicity for gene: PPP2R2B was changed from Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments to None
Intellectual disability v8.158 PPP2R2B Sarah Leigh Added comment: Comment on phenotypes: The PPP2R2B_CAG variant is associated with Spinocerebellar ataxia 12, OMIM:604326
Intellectual disability v8.158 PPP2R2B Sarah Leigh Phenotypes for gene: PPP2R2B were changed from Spinocerebellar ataxia 12, OMIM:604326 to neurodevelopmental syndrome
Intellectual disability v8.157 PPP2R2B Sarah Leigh Added comment: Comment on publications: PMID: 39565297 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Intellectual disability v8.156 HMGXB4 Arina Puzriakova gene: HMGXB4 was added
gene: HMGXB4 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: HMGXB4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HMGXB4 were set to 39166056
Phenotypes for gene: HMGXB4 were set to Intellectual disability, developmental delay, and dysmorphic features
Added comment: PMID: 39166056 (2024) report three affected individuals from a single family with ID/GDD, obesity and dysmorphic facial features. WGS revealed a homozygous frameshift variant (c.1193_1196del; p.(Lys398Argfs*25)) in exon 5 of the HMGXB4 gene which completely segregated with disease. RT-qPCR revealed a substantial decrease in the HMGXB4 gene expression in affected individuals as compared to unaffected individuals of the family.

Rating Red for now as only a single family has been identified to date.
Sources: Literature
Intellectual disability v8.155 NAV3 Sarah Leigh Added comment: Comment on publications: PMID: 39708122 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Intellectual disability v8.153 NAV3 Sarah Leigh gene: NAV3 was added
gene: NAV3 was added to Intellectual disability. Sources: Literature
Q1_25_ promote_green, Q1_25_ expert_review tags were added to gene: NAV3.
Mode of inheritance for gene: NAV3 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: NAV3 were set to 38977784; 39038237; 39708122
Phenotypes for gene: NAV3 were set to recessive neurodevelopmental disorder
Review for gene: NAV3 was set to GREEN
Added comment: At least 11 NAV3 variants have been reported in 11 unrelated families with a neurodevelopmental disorder, with dysmorphism and other features (PMIDs: 38977784;39038237;39708122). The NAV3 variants were homozygous in the affected members of eight of these families, de novo heterozygous NAV3 variants were found in two families (PED4263 & MI01 in PMID: 38977784) and in one case the heterozygous NAV3 variant was inherited from the mother (FM1 in PMID: 38977784). A nav3 knock-zebrafish model resulted in severe morphological defects, microcephaly, impaired neuronal growth, and behavioral impairment, this phenotype was rescued with co-injection of WT NAV3 mRNA, but not pathogenic variant NAV3 mRNA (PMID: 38977784). Varying degrees of intellectual disability was evident in the patients carrying NAV3 variants (severe 2/11, moderate 2/11, mild 7/11)(PMIDs: 38977784;39038237;39708122).
Sources: Literature
Intellectual disability v8.152 TUBGCP2 Arina Puzriakova edited their review of gene: TUBGCP2: Added comment: PMID: 40017707 (2025) - reports a 6-year-old girl with lissencephaly caused by compound heterozygous variants in TUBGCP2 (two paternal missense variants: c.178 C>T, c.538T>C and one maternal exon variant: 2–14 deletion). The patient presented with microcephaly, developmental delay, intellectual disability, and seizures. A literature review of 8 patients (including the reported case) with TUBGCP2 variants showed that all exhibited lissencephaly, microcephaly and developmental delay, with most having intellectual disability, seizures, and dysmorphic facial features.

This publication supports inclusion of the TUBGCP2 gene on the intellectual disability panel at the next GMS panel update.; Changed rating: GREEN
Intellectual disability v8.152 TUBGCP2 Arina Puzriakova Added comment: Comment on publications: PMID: 40017707 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Intellectual disability v8.150 GTF3C3 Arina Puzriakova edited their review of gene: GTF3C3: Added comment: - PMID: 39636576 (2025) - 12 individuals from 7 unrelated families were identified with homozygous or compound heterozygous missense variants in GTF3C3 (8 unpublished individuals combined with newly ascertained information from 4 published individuals). The cohort presented with intellectual disability, variable nonfamilial facial features, motor impairments, seizures, and cerebellar/corpus callosum malformations.

- PMID: 40040844 (2025) - 4 patients from 3 unrelated families with biallelic variants in this gene and microcephaly, developmental delay, intellectual disability, seizures and distinctive dysmorphic facies. Knockout zebrafish recapitulated the key clinical symptoms including microcephaly, brain anomalies and seizure susceptibility.; Changed rating: GREEN; Changed publications to: 39636576, 40040844; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v8.150 GTF3C3 Arina Puzriakova Added comment: Comment on publications: PMID: 40040844 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Intellectual disability v8.148 C12orf66 Arina Puzriakova commented on gene: C12orf66: PMID: 39824192 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Intellectual disability v8.147 C12orf66 Arina Puzriakova gene: C12orf66 was added
gene: C12orf66 was added to Intellectual disability. Sources: Literature
new-gene-name, Q1_25_ promote_green tags were added to gene: C12orf66.
Mode of inheritance for gene: C12orf66 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: C12orf66 were set to 39824192
Phenotypes for gene: C12orf66 were set to Intellectual developmental disorder, autosomal recessive 83, OMIM:621100
Review for gene: C12orf66 was set to GREEN
Added comment: This gene is associated with a relevant phenotype in OMIM (MIM# 621100)

- PMID: 39824192 (2025) - biallelic variants in KICS2 in 11 individuals from 8 families with intellectual disability. All affected individuals had mild to severe intellectual disability, with 8 individuals also presenting with seizures and 3 (2 families) with hearing impairment. Functional studies in cell culture and zebrafish models provided evidence of pathogenicity, showing impaired mTORC1 regulation and effects on ciliogenesis.
Sources: Literature
Intellectual disability v8.146 SPOUT1 Sarah Leigh Added comment: Comment on publications: PMID: 39962046 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Intellectual disability v8.144 SPOUT1 Sarah Leigh gene: SPOUT1 was added
gene: SPOUT1 was added to Intellectual disability. Sources: Literature
Q1_25_ promote_green tags were added to gene: SPOUT1.
Mode of inheritance for gene: SPOUT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SPOUT1 were set to 39962046
Phenotypes for gene: SPOUT1 were set to SPOUT1 Associated Development delay Microcephaly Seizures Short stature
Review for gene: SPOUT1 was set to GREEN
Added comment: PMID: 39962046 reports the association of biallelic SPOUT1 variants with SPOUT1 Associated Development delay Microcephaly Seizures Short stature. In this study, a total of 18 SPOUT1 variants were found in 28 individuals from 21 unrelated families. Intellectual disability was evident in 10/10 families where it could be ascertained, seizures were reported in 16/21 of the families and short stature was seen in 13/15 families where it could be measured.
SPOUT1 variant zebra fish models showed reduction in larval head size with concomitant apoptosis and the human SPOUT1 missense variants were pathogenic in complementation assays in zebrafish (PMID: 39962046).
Sources: Literature
Intellectual disability v8.142 RSPRY1 Arina Puzriakova Added comment: Comment on list classification: At least 5 unrelated families have been reported in the literature with biallelic variants in this gene, presenting with spondyloepimetaphyseal dysplasia. Sufficient to rate Green at the next GMS panel update.
Intellectual disability v8.141 RSPRY1 Arina Puzriakova Added comment: Comment on publications: PMID: 39940902 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Intellectual disability v8.137 DALRD3 Arina Puzriakova Added comment: Comment on publications: PMID: 39482881 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Intellectual disability v8.136 DALRD3 Arina Puzriakova changed review comment from: Second family identified with an individual with a homozygous missense variant in DALRD3 (c.1549C>T, p.(Arg517Cys)) who displayed severe developmental delay, cognitive deficiencies, and multifocal epilepsy. Phenotype was consistent with previously reported cases but less severe which is consistent with the variant types identified. Patient fibroblasts showed reduced levels of DALRD3 protein compared to WT indicating the variant alters the structure of DALRD3.; to: PMID: 39482881 - second family identified with an individual with a homozygous missense variant in DALRD3 (c.1549C>T, p.(Arg517Cys)) who displayed severe developmental delay, cognitive deficiencies, and multifocal epilepsy. Phenotype was consistent with previously reported cases but less severe which is consistent with the variant types identified. Patient fibroblasts showed reduced levels of DALRD3 protein compared to WT indicating the variant alters the structure of DALRD3.
Intellectual disability v8.136 DALRD3 Arina Puzriakova commented on gene: DALRD3: Second family identified with an individual with a homozygous missense variant in DALRD3 (c.1549C>T, p.(Arg517Cys)) who displayed severe developmental delay, cognitive deficiencies, and multifocal epilepsy. Phenotype was consistent with previously reported cases but less severe which is consistent with the variant types identified. Patient fibroblasts showed reduced levels of DALRD3 protein compared to WT indicating the variant alters the structure of DALRD3.
Intellectual disability v8.135 SPAST Sarah Leigh edited their review of gene: SPAST: Added comment: Numerous heterozygous SPAST variants have been associated with Spastic paraplegia 4, autosomal dominant (OMIM:182601). PMID: 39731306 reports five homozygous SPAST variants in nine individuals from six families with spastic paraplegia and neurodegeneration. Amongst the homozygous children, all had lower limb spasticity, 5/6 had upper limb spasticity and 3/6 had severe intellectual disability. Evidence of consanguinity was evident in five of the families and the parents of the homozygous children were heterozygous for the SPAST variant found in the child, these carrier parents were asymptomatic in all but one the families studied.; Changed rating: GREEN; Changed publications to: 39731306; Changed phenotypes to: Spastic paraplegia 4, autosomal dominant, OMIM:182601; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v8.135 PTPMT1 Arina Puzriakova gene: PTPMT1 was added
gene: PTPMT1 was added to Intellectual disability. Sources: Literature
watchlist 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, MONDO:0700092
Review for gene: PTPMT1 was set to AMBER
Added comment: New gene-disease association. Currently not associated with any phenotype in OMIM or G2P.

PMID:39279645 (2025) - 6 individuals from 3 unrelated families identified with biallelic variants in this gene. All patients presented with a complex, neonatal/infantile onset neurological and neurodevelopmental syndrome, however there was variability in the overall clinical presentation between families. Features include developmental delay, microcephaly, facial dysmorphism, epilepsy, spasticity, cerebellar ataxia and nystagmus, sensorineural hearing loss, optic atrophy and bulbar dysfunction. Brain MRI revealed a variable combination of corpus callosum thinning, cerebellar atrophy and white matter changes.

Patient from Family 1 harboured a homozygous missense variant (c.65A>C) while Family 2 and 3 carried the same homozygous variant (c.255G>C) and were shown to share some common ancestry using DNA microarray analysis.

Knockout zebrafish model displayed abnormalities in body size, developmental alterations, decreased total cardiolipin levels and OXPHOS deficiency.

Overall can be classified as Amber on the basis that two families were shown to be distantly related and no specific features were observed universally across all cases (GDD was mild in 5/6 individuals so outside the scope of the ID panel).
Sources: Literature
Intellectual disability v8.134 SPAST Sarah Leigh Phenotypes for gene: SPAST were changed from Spastic paraplegia 4, autosomal dominant, 182601 to Spastic paraplegia 4, autosomal dominant, OMIM:182601; hereditary spastic paraplegia 4, MONDO:0008438
Intellectual disability v8.133 SPAST Sarah Leigh Added comment: Comment on publications: PMID: 39731306 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Intellectual disability v8.131 LSM7 Arina Puzriakova Entity copied from White matter disorders and cerebral calcification - narrow panel v6.9
Intellectual disability v8.130 MARK2 Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: MARK2.
Intellectual disability v8.130 WDR83OS Achchuthan Shanmugasundram Phenotypes for gene: WDR83OS were changed from complex neurodevelopmental disorder, MONDO:0100038; intellectual disability, MONDO:0001071 to Neurodevelopmental disorder with variable familial hypercholanemia, OMIM:621016
Intellectual disability v8.126 XPA Sarah Leigh Added comment: Comment on publications: PMID: 39621777 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Intellectual disability v8.125 XPA Sarah Leigh Phenotypes for gene: XPA were changed from mental retardation; progressive intellectual impariment to Xeroderma pigmentosum, group A, OMIM: 278700
Intellectual disability v8.124 XPA Sarah Leigh changed review comment from: PMID: 39621777 reports 16 XPA variants in 18 patients with Xeroderma pigmentosum, group A (OMIM:278700). Amongst the cohort, the authors were able to classify the patients into three severity groups based on the extent of their neurological abnormalities at age 10 years (8 severe, 6 intermediate and 4 mild). The severe phenotype included developmental delay and mild to profound hearing loss, was associated with terminating variants in exons 3 and 5 of XPA, which resulted in reducing the XPA protein to undetectable levels.; to: PMID: 39621777 reports 16 XPA variants in 18 patients with Xeroderma pigmentosum, group A (OMIM:278700). Amongst the cohort, the authors were able to classify the patients into three severity groups based on the extent of their neurological abnormalities at age 10 years. There were 8 severe, 6 intermediate and 4 mild patients. The severe phenotype included developmental delay and mild to profound hearing loss, and was associated with terminating variants in exons 3 and 5 of XPA, which resulting in undetectable levels of XPA protein.
Intellectual disability v8.124 MAG Sarah Leigh Added comment: Comment on publications: PMID: 39336794 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Intellectual disability v8.122 MAG Sarah Leigh gene: MAG was added
gene: MAG was added to Intellectual disability. Sources: Literature
Q1_25_ promote_green tags were added to gene: MAG.
Mode of inheritance for gene: MAG was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MAG were set to 39336794
Phenotypes for gene: MAG were set to Spastic paraplegia 75, autosomal recessive, OMIM:616680; hereditary spastic paraplegia 75, MONDO:0014729
Review for gene: MAG was set to GREEN
Added comment: AT least six MAG variants have been associated with Spastic paraplegia 75, autosomal recessive, OMIM:616680 in at least five unrelated cases (PMID: 24482476; 26179919; 27606346; 31402626; 39336794). It would appear that intellectual disability is a common feature in cases of OMIM:616680, although this may be mild to moderate.
Sources: Literature
Intellectual disability v8.118 TDP1 Sarah Leigh Added comment: Comment on list classification: This gene remains amber, as there are only two disease associated variants have been reported (PMID: 12244316;31182267;39576382).
Intellectual disability v8.117 TDP1 Sarah Leigh Added comment: Comment on publications: PMID: 39576382 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Intellectual disability v8.116 TDP1 Sarah Leigh Entity copied from Hereditary neuropathy or pain disorder v6.158
Intellectual disability v8.116 TDP1 Sarah Leigh gene: TDP1 was added
gene: TDP1 was added to Intellectual disability. Sources: Expert Review Amber,South West GLH,UKGTN,Emory Genetics Laboratory,Expert list,NHS GMS
founder-effect tags were added to gene: TDP1.
Mode of inheritance for gene: TDP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TDP1 were set to 12244316; 31182267; 39576382
Phenotypes for gene: TDP1 were set to ?Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 1, OMIM:607250
Intellectual disability v8.114 PPP2R5C Sarah Leigh changed review comment from: PMIDs 25972378; 39500882; 39978342 report twenty one PPP2R5C variants in 30 unrelated individuals with macrocephaly, intellectual disability, seizures and hypotonia (PMIDs 39500882 table 1 & 39978342 table 1 ). Most of these heterozygous variants were de novo (there was one case where this could not be established, PMID: 39696819).
Sources: Literature; to: PMIDs 25972378; 39696819; 39978342 report twenty one PPP2R5C variants in 30 unrelated individuals with macrocephaly, intellectual disability, seizures and hypotonia (PMIDs 39696819 table 1 & 39978342 table 1 ). Most of these heterozygous variants were de novo (there was one case where this could not be established, PMID: 39696819).
Intellectual disability v8.114 PPP2R5C Sarah Leigh Added comment: Comment on publications: PMID: 39696819 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Intellectual disability v8.112 PPP2R5C Sarah Leigh gene: PPP2R5C was added
gene: PPP2R5C was added to Intellectual disability. Sources: Literature
Q1_25_ promote_green tags were added to gene: PPP2R5C.
Mode of inheritance for gene: PPP2R5C was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: PPP2R5C were set to 25972378; 39500882; 39978342
Phenotypes for gene: PPP2R5C were set to neurodevelopmental disorder
Review for gene: PPP2R5C was set to GREEN
Added comment: PMIDs 25972378; 39500882; 39978342 report twenty one PPP2R5C variants in 30 unrelated individuals with macrocephaly, intellectual disability, seizures and hypotonia (PMIDs 39500882 table 1 & 39978342 table 1 ). Most of these heterozygous variants were de novo (there was one case where this could not be established, PMID: 39696819).
Sources: Literature
Intellectual disability v8.111 GON4L Sarah Leigh Added comment: Comment on publications: PMID: 39500882 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Intellectual disability v8.110 GON4L Sarah Leigh Phenotypes for gene: GON4L were changed from AUTOSOMAL RECESSIVE MENTAL RETARDATION to prenatal-onset growth impairment and developmental delay
Intellectual disability v8.110 GON4L Sarah Leigh Added comment: Comment on list classification: This gene is rated as amber, as only mild intellectual disability has been associated with GON4L variants (PMID: 39500882).
Intellectual disability v8.109 GON4L Sarah Leigh edited their review of gene: GON4L: Added comment: PMID: 39500882 reports two consanguineous families where children who are homozygous for terminating GON4L variants, have prenatal-onset growth impairment, developmental delay, and mild intellectual disability. The unaffected parents of both children and an unaffected sibling were heterozygous for the GON4L variants identified. Microcephaly was reported in the affected cases, however, it was now severe. Functional studies in gon4lb-knockout and knockdown zebrafish
revealed distinct morphological and size abnormalities, which were reminiscent of the human phenotype. Human wild type GON4L mRNA was able to rescue the craniofacial cartilage phenotypic in zebrafish larvae PMID: 39500882.; Changed rating: AMBER; Changed publications to: 39500882; Changed phenotypes to: prenatal-onset growth impairment and developmental delay; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v8.108 PNPLA8 Sarah Leigh Added comment: Comment on publications: PMID: 39082157 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Intellectual disability v8.106 PNPLA8 Sarah Leigh gene: PNPLA8 was added
gene: PNPLA8 was added to Intellectual disability. Sources: Literature
Q1_25_ promote_green tags were added to gene: PNPLA8.
Mode of inheritance for gene: PNPLA8 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PNPLA8 were set to 39082157
Phenotypes for gene: PNPLA8 were set to ?Mitochondrial myopathy with lactic acidosis, OMIM:251950; mitochondrial myopathy-lactic acidosis-deafness syndrome MONDO:0016825
Review for gene: PNPLA8 was set to GREEN
Added comment: Biallelic PNPLA8 variants have previously been associated with Mitochondrial myopathy with lactic acidosis, (OMIM:251950). PMID: 39082157 reports a study were microcephaly, global delay and seizures are associated with biallelic PNPLA8 variants. Amongst the unrelated individuals studied, 8/11 had severe microcephaly, 9/11 had epileptic seizures and 8/11 had severe global delay and intellectual disability where it could be measured, 3/11 cases died in childhood and affected siblings (but not genotyped) had died in two other families. Using cerebral organoids generated from human induced pluripotent stem cells, the authors were able to assert that the loss of PNPLA8 led to
developmental defects by reducing the number of basal radial glial cells and upper-layer neurons (PMID: 39082157).
Sources: Literature
Intellectual disability v8.105 PLEKHG1 Sarah Leigh Added comment: Comment on publications: PMID: 39202455 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques
Intellectual disability v8.104 PLEKHG1 Sarah Leigh gene: PLEKHG1 was added
gene: PLEKHG1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: PLEKHG1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: PLEKHG1 were set to 39202455; 30659137
Phenotypes for gene: PLEKHG1 were set to Spastic diplegia and psychomotor developmental delay
Review for gene: PLEKHG1 was set to RED
Added comment: PMID: 39202455 reports a de novo heterozygous PLEKHG1 variant (NM_001029884.3 c.370A>G, p.Thr124Ala) in a child with spastic diplegia and psychomotor developmental delay. The child also had cystic fibrosis, due causative CFTR variants inherited from the parents.
A genome-wide association meta-analysis has previously associated the PLEKHG1 locus with white matter hyperintensities (PMID: 30659137).
Sources: Literature
Intellectual disability v8.102 ISCA-37447-Loss Arina Puzriakova Added comment: Comment on mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown has been agreed for the R29 Intellectual disability panel. This would capture both imprinting patterns where there is clinical overlap between Kagami-Ogata and Temple syndrome which are both relevant to this panel.

These disorders are suitable for R27 Paediatric disorders and R69 Hypotonic infant super panels (included via R29)
Intellectual disability v8.101 ARHGEF40 Sarah Leigh Tag watchlist tag was added to gene: ARHGEF40.
Intellectual disability v8.101 ISCA-37447-Loss Arina Puzriakova Region: ISCA-37447-Loss was added
Region: ISCA-37447-Loss was added to Intellectual disability. Sources: ClinGen
Mode of inheritance for Region: ISCA-37447-Loss was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for Region: ISCA-37447-Loss were set to 20585555; 24801763; 27406249; 33579810; 18176563; 28640239
Phenotypes for Region: ISCA-37447-Loss were set to Kagami-Ogata syndrome, OMIM:608149; Temple syndrome, OMIM:616222
Review for Region: ISCA-37447-Loss was set to GREEN
Added comment: Multiple unrelated cases curated in ClinGen - sufficient evidence to add this region (https://search.clinicalgenome.org/kb/gene-dosage/region/ISCA-37447)

DLK1-MEG3 Intergenic Region includes the paternally expressed DLK1 gene, the 2 differentially methylated regions (DMRs) DLK1/MEG3:IG-DMR and MEG3:TSS-DMR, and the 5' end of the maternally expressed gene MEG3 (4 exons).

The phenotype depends on the parental origin: Kagami Ogata syndrome/KOS (maternally derived imprinting) or Temple syndrome/TS (paternally derived imprinting)

Kagami-Ogata syndrome is characterized by typical facial features, skeletal abnormalities (including ""coat-hanger ribs"", and bell-shaped thorax), abdominal wall defects, and developmental delay.

Temple syndrome is a less specific phenotype including intrauterine and postnatal growth restriction, hypotonia, feeding difficulties in infancy, truncal obesity, and small feet and hands.
Sources: ClinGen
Intellectual disability v8.99 ATP11A Sarah Leigh Added comment: Comment on publications: PMID: 39432785 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Intellectual disability v8.97 MARK2 Sarah Leigh Tag Q3_24_promote_green was removed from gene: MARK2.
Intellectual disability v8.97 MARK2 Sarah Leigh reviewed gene: MARK2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v8.97 MARK2 Sarah Leigh Source NHS GMS was added to MARK2.
Source Expert Review Green was added to MARK2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v8.96 GABBR2 Arina Puzriakova Added comment: Comment on publications: PMID: 39028675 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI
Intellectual disability v8.93 TARS2 Sarah Leigh Added comment: Comment on publications: PMID: 39394138 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Intellectual disability v8.93 TARS2 Sarah Leigh Publications for gene: TARS2 were set to 39394138; 33153448; 34508595; 37454282
Intellectual disability v8.92 TARS2 Sarah Leigh Classified gene: TARS2 as Amber List (moderate evidence)
Intellectual disability v8.92 TARS2 Sarah Leigh Gene: tars2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v8.91 TARS2 Sarah Leigh gene: TARS2 was added
gene: TARS2 was added to Intellectual disability. Sources: Literature
Q1_25_ promote_green tags were added to gene: TARS2.
Mode of inheritance for gene: TARS2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TARS2 were set to 39394138; 33153448; 34508595; 37454282
Phenotypes for gene: TARS2 were set to Combined oxidative phosphorylation deficiency 21, OMIM: 615918; combined oxidative phosphorylation defect type 21,NDO:0014398
Review for gene: TARS2 was set to GREEN
Added comment: Numerous biallelic TARS2 variants have been associated with Combined oxidative phosphorylation deficiency 21 (OMIM: 615918) in cases from around the world. A summary of TARS2 variants and associated clinical features is presented in Supplementary Table 1, in PMID: 39394138. There at least 30 variants in 32 cases within 27 families. In eight of the families, the children had died before their second birthdays, all of the cases in the remaining 19 families were in special care, with a maximum age of 27 years. Epilepsy was evident in 15/24 families where an assessment was possible, psychomotor delay was evident in 25/26 families and brain MRI anomalies were apparent in 21/23 families.
Sources: Literature
Intellectual disability v8.90 OPA1 Sarah Leigh Added comment: Comment on publications: PMID: 39233737 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques
Intellectual disability v8.89 FEM1C Julie Evans changed review comment from: Please note that 'two' of the patients with the heterozygous de novo missense variant c.377A>T p.(Asp126Val) in the FEM1C gene are actually the same South West patient who was recruited to the DDD study (PMID 28135719) and 100,000 genomes project.; to: Please note that the 'two' patients with the heterozygous de novo missense variant c.377A>T p.(Asp126Val) in the FEM1C gene are actually the same South West patient who was recruited to the DDD study (PMID 28135719) and 100,000 genomes project.
Intellectual disability v8.89 FEM1C Julie Evans changed review comment from: Please note that 'two' of the patients with the heterozygous de novo missense variant c.376G>C (p.Asp126His) in the FEM1C gene are actually the same South West patient who was recruited to the DDD study (PMID 28135719) and 100,000 genomes project.; to: Please note that 'two' of the patients with the heterozygous de novo missense variant c.377A>T p.(Asp126Val) in the FEM1C gene are actually the same South West patient who was recruited to the DDD study (PMID 28135719) and 100,000 genomes project.
Intellectual disability v8.89 FEM1C Julie Evans changed review comment from: Please note the 'two' patients with the heterozygous de novo missense variant c.376G>C (p.Asp126His) in the FEM1C gene are actually the same South West patient who was recruited to the DDD study and 100,000 genomes project.; to: Please note that 'two' of the patients with the heterozygous de novo missense variant c.376G>C (p.Asp126His) in the FEM1C gene are actually the same South West patient who was recruited to the DDD study (PMID 28135719) and 100,000 genomes project.
Intellectual disability v8.88 OPA1 Sarah Leigh gene: OPA1 was added
gene: OPA1 was added to Intellectual disability. Sources: Literature
Q1_25_ promote_green tags were added to gene: OPA1.
Mode of inheritance for gene: OPA1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: OPA1 were set to 39233737
Phenotypes for gene: OPA1 were set to Optic atrophy plus syndrome, OMIM: 125250
Review for gene: OPA1 was set to GREEN
Added comment: Heterozygous OPA1 variants have been associated with Optic atrophy 1 (OMIM:165500) and Optic atrophy plus syndrome, OMIM: 125250. PMID: 39233737 reports two unrelated cases of OMIM: 125250 with a "prominent neurological phenotype highly resembling clinical and
neuroradiological features of Leigh-like syndrome", including hypotonia and psychomotor delay. Each child had a de novo novel heterozygous OPA1 variant (NM_ 015560.3, c.888T>A, p.Asp296Glu and c.802T>C, p.Tyr268His). The mitochondria in the fibroblasts from these cases appeared to be fragmented with a reduced ATP production compared to controls; additionally, the amount of mtDNA was reduced by about a half in comparison with controls. Complementary studies in yeast suggested that these variants are pathogenic with a possible dominant negative effect (PMID: 39233737).
Sources: Literature
Intellectual disability v8.86 ARHGEF40 Sarah Leigh Classified gene: ARHGEF40 as Amber List (moderate evidence)
Intellectual disability v8.86 ARHGEF40 Sarah Leigh Gene: arhgef40 has been classified as Amber List (Moderate Evidence).
Intellectual disability v8.85 ARHGEF40 Sarah Leigh gene: ARHGEF40 was added
gene: ARHGEF40 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: ARHGEF40 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ARHGEF40 were set to 39838643
Phenotypes for gene: ARHGEF40 were set to developmental delay
Review for gene: ARHGEF40 was set to AMBER
Added comment: Two de novo ARHGEF40 variants have been identified in two individuals with multiple congenital anomalies and developmental delay (PMID: 39838643). The two variants affected the same residue (NM_018071: c.673 C>T, NP_060541: p.Arg225Trp, NM_018071: c.674 G>A, NP_060541: p.Arg225Gln). Both patients had global developmental delay, delayed speech and language development, hypotonia, short stature and impaired hearing.
Sources: Literature
Intellectual disability v8.83 SLC5A7 Arina Puzriakova commented on gene: SLC5A7: Some patients with SLC5A7-related CMS can exhibit developmental delay and cognitive impairment (PMID: 27569547; 39135055; 36840359; 36611016; 33250374). Although this feature is not universal, there are sufficient unrelated cases where cognitive deficit is an defining feature of the early phenotype, to warrant inclusion of SLC5A7 on this panel.
Intellectual disability v8.81 SLC5A7 Arina Puzriakova Added comment: Comment on publications: PMID:39135055 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques
Intellectual disability v8.80 INPP4A Eleanor Williams changed review comment from: More information about previously reported cases and additional cases:

PMID: 21937992 Najmabadi et al 2011 - Report 3 related Iranian probands with moderate intellectual disability and a homozyous 1 bp deletion leading to a frameshift variant in INPP4A:D915fs. No detailed phenotype information, although stated as non-syndromic.

PMIDs: 25338135 - Sheffer et al 2015 - child from healthy consanguineous Arab Moslem parents, found to have hindbrain malformations at 4 months of age. No eye blinking in response to light. Started to have myoclonic seizures at 8 months. The patient had no developmental milestones and was cortically blind. At 15 months, head circumference was 39.5 cm (<3 SD for age). A homozygous frame-shift mutation c.1581 del256, p.Glu528Ilefs*22 in exon 15 of INPP4A was found. It segregated within the family.

PMID: 31978615 - Banihashemi et al 2020 - 5 individuals with severe intellectual disability from an extended Arab Iranian family and patients were born from consanguineous marriages. Patients presented at ages 2-4 years. Brain MRIs were normal. However, EEGs was abnormal due to the presence of generalized slowing waves with no epileptiform discharge. Only IV-2 had myoclonic seizures during infancy. A homozygous nonsense variant INPP4A c.115 C > T; p.Gln39X variant was identified, which segregated with the phenotype in the family (9 unaffected members were either heterozygous or wild type homozygous).

PMID: 36653678 - Hecher et al 2023 - 2-year-old girl whose parents were a healthy consanguineous Turkish couple with microcephaly (OFC of 27.5 cm (− 2.88 z) at birth), severe developmental delay, myoclonic seizures, and pontocerebellar hypoplasia, carrying the novel homozygous INPP4A frameshift variant c.2840del/p.(Gly947Glufs*12) (NM_001134224.2).

There are now 4 families in which homozygous variants in INPP4A are reported in probands with severe intellectual disability. Myoclonic seizures are reported in some patients from an early age, but this is alongside brain abnormalities in 2 cases, suggesting that the seizures are not the only cause for the intellectual disability.; to: More information about previously reported cases and additional cases:

PMID: 21937992 Najmabadi et al 2011 - Report 3 related Iranian probands with moderate intellectual disability and a homozyous 1 bp deletion leading to a frameshift variant in INPP4A:D915fs. No detailed phenotype information, although stated as non-syndromic.

PMIDs: 25338135 - Sheffer et al 2015 - child from healthy consanguineous Arab Moslem parents, found to have hindbrain malformations at 4 months of age. No eye blinking in response to light. Started to have myoclonic seizures at 8 months. The patient had no developmental milestones and was cortically blind. At 15 months, head circumference was 39.5 cm (<3 SD for age). A homozygous frame-shift mutation c.1581 del256, p.Glu528Ilefs*22 in exon 15 of INPP4A was found. It segregated within the family.

PMID: 31978615 - Banihashemi et al 2020 - 5 individuals with severe intellectual disability from an extended Arab Iranian family and patients were born from consanguineous marriages. Patients presented at ages 2-4 years. Brain MRIs were normal. However, EEGs was abnormal due to the presence of generalized slowing waves with no epileptiform discharge. Only IV-2 had myoclonic seizures during infancy. A homozygous nonsense variant INPP4A c.115 C > T; p.Gln39X variant was identified, which segregated with the phenotype in the family (9 unaffected members were either heterozygous or wild type homozygous).

PMID: 36653678 - Hecher et al 2023 - 2-year-old girl whose parents were a healthy consanguineous Turkish couple with microcephaly (OFC of 27.5 cm (− 2.88 z) at birth), severe developmental delay, myoclonic seizures, and pontocerebellar hypoplasia, carrying the novel homozygous INPP4A frameshift variant c.2840del/p.(Gly947Glufs*12) (NM_001134224.2).

There are now 4 families in which homozygous variants in INPP4A are reported in probands with severe intellectual disability. Myoclonic seizures are reported in some patients from an early age, but this is alongside brain abnormalities in 2 cases, suggesting that the seizures are not the only cause for the intellectual disability.

See also review by Medyanik et al 2025 PMID: 39858526.
Intellectual disability v8.78 PTRH2 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the association of biallelic PTRH2 variants with intellectual disability/ global developmental delay. Hence, this gene can be promoted to green rating in the next GMS update.
Intellectual disability v8.76 PTRH2 Achchuthan Shanmugasundram Added comment: Comment on publications: PMID:39176129 and PMID:39766776 papers were identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Intellectual disability v8.75 RUNX1T1 Achchuthan Shanmugasundram Added comment: Comment on publications: PMID:39568205 paper was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Intellectual disability v8.73 RUNX1T1 Achchuthan Shanmugasundram gene: RUNX1T1 was added
gene: RUNX1T1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: RUNX1T1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RUNX1T1 were set to 22644616; 39568205
Phenotypes for gene: RUNX1T1 were set to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Review for gene: RUNX1T1 was set to AMBER
Added comment: PMID:22644616 reported a patient with mild intellectual disability and de novo deletion within the RUNX1T1 gene.

PMID:39568205 reported three unrelated individuals with neurodevelopmental and congenital anomalies and with de novo variants in RUNX1T1 gene. Although delayed speech and language development and delayed fine motor development was reported in all three cases, global developmental delay was only reported in two of them.

This gene has not yet been associated with any relevant phenotypes either in OMIM or in Gene2Phenotype.

Hence, this gene should be rated amber with current evidence.
Sources: Literature
Intellectual disability v8.72 NFIB Achchuthan Shanmugasundram Added comment: Comment on list classification: The patients reported in PMID:30388402 presented with borderline-mild intellectual disability. The severity of ID/ GDD was not reported for the single patient with NFIB variant from PMID:39567597. Hence, the rating should still remain amber with current evidence.
Intellectual disability v8.71 NFIB Achchuthan Shanmugasundram changed review comment from: Comment on publications: PMID:9567597 paper was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.; to: Comment on publications: PMID:39567597 paper was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Intellectual disability v8.71 NFIB Achchuthan Shanmugasundram Added comment: Comment on publications: PMID:9567597 paper was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Intellectual disability v8.65 GPATCH11 Achchuthan Shanmugasundram Added comment: Comment on publications: PMID:39572588 paper was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Intellectual disability v8.64 GPATCH11 Achchuthan Shanmugasundram gene: GPATCH11 was added
gene: GPATCH11 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: GPATCH11 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GPATCH11 were set to 39572588
Phenotypes for gene: GPATCH11 were set to neuronevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Review for gene: GPATCH11 was set to GREEN
Added comment: PMID:39572588 reported 12 individuals from six unrelated families presenting with a syndromic disease and they were identified with biallelic variants in GPATCH11 gene. Intellectual disability was present in three unrelated families, while global developmental delay was reported in all.

This gene has not yet been associated with any relevant phenotypes either in OMIM or in Gene2Phenotype.
Sources: Literature
Intellectual disability v8.63 ITGAV Achchuthan Shanmugasundram Added comment: Comment on list classification: As there are two unrelated cases reported with global developmental delay, this gene can be rated amber with current evidence.
Intellectual disability v8.62 ITGAV Achchuthan Shanmugasundram Added comment: Comment on publications: PMID:39526957 paper was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Intellectual disability v8.61 ITGAV Achchuthan Shanmugasundram gene: ITGAV was added
gene: ITGAV was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: ITGAV was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ITGAV were set to 39526957
Phenotypes for gene: ITGAV were set to syndromic disease, MONDO:0002254
Review for gene: ITGAV was set to AMBER
Added comment: PMID:39526957 reported the identification of biallelic ITGAV variants in two unrelated patients and four foetuses from a third family. The two patients were reported with complex phenotype including global developmental delay, eye and brain abnormalities, inflammatory bowel disease and immune dysregulation. The four foetuses were reported with brain and skull abnormalities. There is also functional evidence in support of the association.

This gene has not yet been associated with any relevant phenotypes either in OMIM or in Gene2Phenotype.
Sources: Literature
Intellectual disability v8.58 NAA20 Achchuthan Shanmugasundram Added comment: Comment on publications: PMID:39814713 paper was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Intellectual disability v8.57 EEFSEC Achchuthan Shanmugasundram changed review comment from: PMID:39753114 reported nine different individuals from eight unrelated families with a selenopathy with early-onset neurodegeneration. Thy were all identified with six different biallelic variants in EEFSEC gene, of which seven families had variants in homozygous state, while one family had variants in compound heterozygous state. They presented with global developmental delay, moderate or severe cognitive impairment, progressive spasticity, ataxia, and seizures. In addition, cerebral MRI primarily demonstrated a cerebellar pathology, including hypoplasia and progressive atrophy.

This gene has not yet been associated with any relevant phenotypes either in OMIM or in Gene2Phenotype.
Sources: Literature; to: PMID:39753114 reported nine different individuals from eight unrelated families with a selenopathy with early-onset neurodegeneration. Thy were all identified with six different biallelic variants in EEFSEC gene, of which seven families had variants in homozygous state, while one family had variants in compound heterozygous state. They presented with global developmental delay, moderate or severe cognitive impairment, progressive spasticity, ataxia, and seizures. In addition, cerebral MRI primarily demonstrated a cerebellar pathology, including hypoplasia and progressive atrophy.

In line with the clinical phenotype, an eEFSec-RNAi Drosophila model displays progressive impairment of motor function, which is reflected in the synaptic defects in this model organisms.

This gene has not yet been associated with any relevant phenotypes either in OMIM or in Gene2Phenotype.
Sources: Literature
Intellectual disability v8.56 EEFSEC Achchuthan Shanmugasundram Added comment: Comment on publications: PMID:39753114 paper was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Intellectual disability v8.54 EEFSEC Achchuthan Shanmugasundram gene: EEFSEC was added
gene: EEFSEC was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: EEFSEC was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EEFSEC were set to 39753114
Phenotypes for gene: EEFSEC were set to neuroseselopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Review for gene: EEFSEC was set to GREEN
Added comment: PMID:39753114 reported nine different individuals from eight unrelated families with a selenopathy with early-onset neurodegeneration. Thy were all identified with six different biallelic variants in EEFSEC gene, of which seven families had variants in homozygous state, while one family had variants in compound heterozygous state. They presented with global developmental delay, moderate or severe cognitive impairment, progressive spasticity, ataxia, and seizures. In addition, cerebral MRI primarily demonstrated a cerebellar pathology, including hypoplasia and progressive atrophy.

This gene has not yet been associated with any relevant phenotypes either in OMIM or in Gene2Phenotype.
Sources: Literature
Intellectual disability v8.50 WDR47 Achchuthan Shanmugasundram Added comment: Comment on publications: PMID:39609633 paper was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Intellectual disability v8.49 WDR47 Achchuthan Shanmugasundram gene: WDR47 was added
gene: WDR47 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: WDR47 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: WDR47 were set to 39609633
Phenotypes for gene: WDR47 were set to neuronevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Review for gene: WDR47 was set to GREEN
Added comment: PMID:39609633 reported seven patients from five unrelated families with either homozygous or compound heterozygous variants in WDR47 gene. They all presented with a complex neurodevelopmental syndrome comprising corpus callosum dysgenesis, microcephaly, intellectual disability and epilepsy. Profound intellectual disability was present in four of five reported families.

This gene has not yet been associated with relevant phenotypes either in OMIM or in Gene2Phenotype.
Sources: Literature
Intellectual disability v8.48 TAOK2 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: As reviewed by Nour Elkhateeb, PMID:39737487 reported 10 individuals with monoallelic TAOK2 variants and with a neurodevelopmemntal disorder. Four of these patients were reported with global developmental delay and eight were reported with intellectual disability/ learning difficulties. Hence, this gene can be promoted to green rating in the next GMS update.; to: Comment on list classification: As reviewed by Nour Elkhateeb, PMID:39737487 reported 10 individuals with monoallelic TAOK2 variants and with a neurodevelopmental disorder. Four of these patients were reported with global developmental delay and eight were reported with intellectual disability/ learning difficulties. Hence, this gene can be promoted to green rating in the next GMS update.
Intellectual disability v8.48 TAOK2 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Nour Elkhateeb, PMID:39737487 reported 10 individuals with monoallelic TAOK2 variants and with a neurodevelopmemntal disorder. Four of these patients were reported with global developmental delay and eight were reported with intellectual disability/ learning difficulties. Hence, this gene can be promoted to green rating in the next GMS update.
Intellectual disability v8.45 TAOK2 Nour Elkhateeb gene: TAOK2 was added
gene: TAOK2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: TAOK2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TAOK2 were set to PMID: 39737487; 29467497
Phenotypes for gene: TAOK2 were set to Developmental delay; Intellectual disability; Speech and language delay; Autism spectrum disorder
Review for gene: TAOK2 was set to GREEN
Added comment: Recent study PMID: 39737487 reporting 10 individuals with varying degrees of Developmental delay, Intellectual disability, Speech and language delay and Autism spectrum disorder as well as other features such as obesity, tall stature and macrocephaly. These individuals had heterozygous missense and truncating TAOK2 variants.
PMID: 29467497 reported individuals with autism and heterozygous missense and truncating TAOK2 variants.
Sources: Literature
Intellectual disability v8.45 PABPC1 Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: PMID:35511136 reported 4 unrelated individuals with de novo PABPC1 variants and with a phenotype of global developmental delay including intellectual disability, movement coordination disorders, seizures, behavioral disorders and mild facial dysmorphisms. There are no biallelic cases reported so far. Hence, the MOI should be updated to "MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted" in the next GMS review.
Intellectual disability v8.43 ARHGAP35 Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: ARHGAP35.
Intellectual disability v8.41 WBP4 Sarah Leigh gene: WBP4 was added
gene: WBP4 was added to Intellectual disability. Sources: Literature
Q4_24_NHS_review, Q4_22_promote_green tags were added to gene: WBP4.
Mode of inheritance for gene: WBP4 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: WBP4 were set to Neurodevelopemental disorder with hypotonia, feeding difficulties, facial dysmorphism, and brain abnormalities, OMIM:620852; neurodevelopmental disorder with hypotonia, feeding difficulties, facial dysmorphism, and brain abnormalities, MONDO:0971043
Review for gene: WBP4 was set to GREEN
Added comment: WBP4 variants have been associated with Neurodevelopemental disorder with hypotonia, feeding difficulties, facial dysmorphism, and brain abnormalities (OMIM:620852). PMID: 37963460 reports four apparently loss of function WBP4 variants in four unrelated cases.
Sources: Literature
Intellectual disability v8.34 RNU4-2 Eleanor Williams edited their review of gene: RNU4-2: Added comment: Additional paper PMID:38991538 Chen et al 2024 supporting the association of RNU4-2 variants with a neurodevelopmental disorder. Data from the 100,000 Genomes Project dataset (used in other studies).; Changed publications to: 38991538
Intellectual disability v8.34 GNAI2 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this to Green at the next GMS panel update. Multiple individuals reported with heterozygous variants supported by functional studies. In PMID:39298586 neurodevelopmental delay in early childhood was reported in 68% of cases, which progressed to ID as patients became older in 53%. Overall patients present with a highly variable phenotype that would be suited to the R27 Paediatic disorders super panel - inclusion on the ID panel would feed into R27.
Intellectual disability v8.33 GNAI2 Arina Puzriakova Mode of pathogenicity for gene: GNAI2 was changed from Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Intellectual disability v8.32 GNAI2 Arina Puzriakova Mode of pathogenicity for gene: GNAI2 was changed from Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Intellectual disability v8.32 GNAI2 Arina Puzriakova Mode of pathogenicity for gene: GNAI2 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
Intellectual disability v8.30 GNAI2 Arina Puzriakova edited their review of gene: GNAI2: Added comment: Ham et al. (2024) (PMID: 39298586) - 20 individuals from 18 unrelated families with heterozygous GOF missense variants in GNAI2 and highly heterogenous clinical presentations. Most commonly observed was disruption of the immune system, with almost 90% of cases exhibiting recurrent, unusual, and/or severe infections. Other features include birth defects, growth abnormalities, neurodevelopmental delay progressing to ID at later stages, brain structural abnormalities and various dysmorphic features. Authors dubbed the syndromic disorder with the acronym MAGIS - Midline malformations of the brain,
Anterior hypopituitarism, Growth retardation, Immunodeficiency/immunodysregulation, Skeletal
abnormalities.; Changed publications to: 31036916, 27787898, 39298586
Intellectual disability v8.30 WDR83OS Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Zornitza Stark, there are nine unrelated families reported with biallelic WDR83OS variants and a neurodevelopmental disorder comprising intellectual disability/ developmental delay. Hence, this gene can be promoted to green rating in the next GMS update.
Intellectual disability v8.28 MARK2 Achchuthan Shanmugasundram Classified gene: MARK2 as Amber List (moderate evidence)
Intellectual disability v8.28 MARK2 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Zornitza Stark, 31 individuals were reported with intellectual disability/ developmental delay and with monoallelic MARK2 variants. ID/ DD was severe in seven, moderate in two, mild and/or borderline in four and unspecified in 17. In addition, functional evidence is also available.

This gene can therefore be promoted to green rating in the next GMS update.
Intellectual disability v8.28 MARK2 Achchuthan Shanmugasundram Gene: mark2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v8.27 MARK2 Achchuthan Shanmugasundram Phenotypes for gene: MARK2 were changed from neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071 to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Intellectual disability v8.26 MARK2 Achchuthan Shanmugasundram Tag Q3_24_promote_green tag was added to gene: MARK2.
Intellectual disability v8.26 MARK2 Achchuthan Shanmugasundram Phenotypes for gene: MARK2 were changed from Neurodevelopmental disorder MONDO:0700092 to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Intellectual disability v8.25 MARK2 Achchuthan Shanmugasundram reviewed gene: MARK2: Rating: GREEN; Mode of pathogenicity: None; Publications: 39419027, 39436150; Phenotypes: neurodevelopmental disorder, MONDO:0700092, intellectual disability, MONDO:0001071; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v8.24 SLC4A10 Arina Puzriakova Added comment: Comment on list classification: This gene is associated with a relevant phenotype in OMIM (MIM# 620746). Over 10 unrelated cases reported in literature with biallelic variants in this gene, presenting with a neurodevelopmental disorder characterised by hypotonia, delayed psychomotor development and intellectual impairment. Microcephaly (<−3 SDS) and epilepsy are also variably observed but there are sufficient to rate as green in the context of these features.

Overall sufficient evidence to promote this gene to Green at the next GMS panel update.
Intellectual disability v8.23 SLC4A10 Arina Puzriakova Phenotypes for gene: SLC4A10 were changed from to Neurodevelopmental disorder with hypotonia and characteristic brain abnormalities, OMIM:620746
Intellectual disability v8.16 LINC01578 Zornitza Stark gene: LINC01578 was added
gene: LINC01578 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: LINC01578 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: LINC01578 were set to 39442041
Phenotypes for gene: LINC01578 were set to Neurodevelopmental disorder, MONDO:0700092, CHASERR-related
Review for gene: LINC01578 was set to GREEN
Added comment: CHASERR (aka LINC01578) encodes a human long noncoding RNA (lncRNA) adjacent to CHD2, a coding gene in which de novo loss-of-function variants cause developmental and epileptic encephalopathy. Three unrelated children reported with a syndromic, early-onset neurodevelopmental disorder, each of whom had a de novo deletion in the CHASERR locus. The children had severe encephalopathy, shared facial dysmorphisms, cortical atrophy, and cerebral hypomyelination - a phenotype that is distinct from the phenotypes of patients with CHD2 haploinsufficiency. CHASERR deletion results in increased CHD2 protein abundance in patient-derived cell lines and increased expression of the CHD2 transcript in cis, indicating bidirectional dosage sensitivity in human disease.
Sources: Literature
Intellectual disability v8.16 MARK2 Zornitza Stark gene: MARK2 was added
gene: MARK2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: MARK2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MARK2 were set to 39419027; 39436150
Phenotypes for gene: MARK2 were set to Neurodevelopmental disorder MONDO:0700092
Review for gene: MARK2 was set to GREEN
Added comment: 31 individuals with autism spectrum disorder (30/31), intellectual disability/developmental delay (100%), motor delay (62%), speech-language problems (100%), seizure/epilepsy (46%), behaviour disorders (ADHD, aggression, anxiety)(74%), and distinctive facial features (narrow face, abnormal or broad forehead, downslanting palpebral fissures, and large or dysplastic ears).

WES/WGS identified 25 LOF and 6 missense variants in MARK2 gene (Microtubule affinity-regulating kinase 2) which contributes to establishing neuronal polarity and developing dendritic spines. LOF variants were de novo (16/25), inherited (4/25), or unk (5/25). All 6 missense variants were de novo and clustered in the kinase or KA1 domains.

The mRNA and protein expression of MARK2 in PBMCs were significantly lower in affected individuals with LOF variants than in the control group. In vitro expression assay of missense variants supported the effect of MARK2 loss. Proband-derived and CRISPR-engineered isogenic induced pluripotent stem cells (iPSCs) showed MARK2 loss leads to early neuronal developmental and functional deficits, including anomalous polarity and disorganization in neural rosettes, as well as imbalanced proliferation and differentiation in neural progenitor cells (NPCs). Mark2+/- mice showed abnormal cortical formation and partition and ASD-like behaviour. Through the use of RNA sequencing (RNA-seq) and lithium treatment, they linked MARK2 loss to downregulation of the WNT/β-catenin signaling pathway and identified lithium as a potential drug for treating MARK2-associated ASD.
Sources: Literature
Intellectual disability v8.14 CCDC88A Arina Puzriakova Added comment: Comment on list classification: There are now at least 7 individuals from 4 unrelated families with biallelic variants in the CCDC88A gene (PMID: 26917597; 30392057; 37798908; 39334473), described to a PEHO-like syndrome with universal features including ID, epilepsy, microcephaly and optic nerve/cerebellar atrophy.

Sufficient unrelated cases with the same phenotype to promote this gene to green at the next GMS panel update.
Intellectual disability v8.13 SLC4A10 Cassandra Smith gene: SLC4A10 was added
gene: SLC4A10 was added to Intellectual disability. Sources: Other
Mode of inheritance for gene: SLC4A10 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC4A10 were set to 37459438; 38054405
Review for gene: SLC4A10 was set to GREEN
Added comment: More than 10 families with biallelic variants reported in SLC4A10, causing a neurodevelopmental disorder including intellectual disability.
Sources: Other
Intellectual disability v8.13 PI4K2A Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Tracy Lester, there are four unrelated cases reported with global developmental delay and/ or profound intellectual disability. Hence, this gene should be promoted to green rating in the next GMS update.
Intellectual disability v8.13 PI4K2A Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Tracy Lester, there are four unrelated cases reported with global developmental delay and/ or profound intellectual disability. Hence, this gene should be promoted to green rating in the next GMS update.
Intellectual disability v8.9 ZFYVE26 Arina Puzriakova Phenotypes for gene: ZFYVE26 were changed from SPASTIC PARAPLEGIA AUTOSOMAL RECESSIVE TYPE 15 (SPG15) to Spastic paraplegia 15, autosomal recessive, OMIM:270700
Intellectual disability v8.6 KIF5B Achchuthan Shanmugasundram changed review comment from: As reviewed by Tracy Lester, there are a total of seven patients reported with missense variants in KIF5B gene from PMIDs: 35342932 and 36018820. Four of these seven patients presented with intellectual disability (two each from the two studies).

This gene has been associated with relevant phenotype in Gene2Phenotype (with 'moderate' rating on the DD panel), but not yet in OMIM.; to: As reviewed by Tracy Lester, there are a total of seven patients reported with missense variants in KIF5B gene from PMIDs: 35342932 and 36018820. Four of these seven patients presented with intellectual disability (two each from the two studies). PMID:36018820 reported the severity of ID as severe for one patient and mild for another, while severity was not recoded in PMID:35342932.

This gene has been associated with relevant phenotype in Gene2Phenotype (with 'moderate' rating on the DD panel), but not yet in OMIM.
Intellectual disability v8.6 PI4K2A Tracy Lester gene: PI4K2A was added
gene: PI4K2A was added to Intellectual disability. Sources: NHS GMS
Mode of inheritance for gene: PI4K2A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PI4K2A were set to 30564627; 35880319; 32418222
Phenotypes for gene: PI4K2A were set to Intellectual disability; developmental delay; seizures
Penetrance for gene: PI4K2A were set to unknown
Review for gene: PI4K2A was set to GREEN
Added comment: At least three cases have been reported with biallelic variants in this gene and a neurodevelopmental disorder
35880319 - Two patients with PI4K2A deficiency (homozygous variants) were identified by exome sequencing, presenting with developmental and epileptic-dyskinetic encephalopathy. Neuroimaging showed corpus callosum dysgenesis, diffuse white matter volume loss, and hypoplastic vermis. In addition to NDD, we observed recurrent infections and death at toddler age.
30564627 - We report a family of Saudi Arabian ancestry with two children presenting with global developmental delay, dystonia, disturbed sleep, and heat intolerance. By genome sequencing, we identified a nonsense variant in the first exon of PI4K2A that was homozygous in both affected individuals and was absent from, or heterozygous in, seven unaffected siblings.
32418222 - a homozygous missense variant of uncertain significance was suggested to be responsible for some features in a case with NDD and metabolic cutis laxa.
Sources: NHS GMS
Intellectual disability v8.5 PLA2G16 Eleanor Williams Entity copied from Hereditary neuropathy or pain disorder v6.19
Intellectual disability v8.5 PLA2G16 Eleanor Williams gene: PLA2G16 was added
gene: PLA2G16 was added to Intellectual disability. Sources: Expert list,Expert Review Amber
new-gene-name, Q3_24_promote_green, Q3_24_NHS_review tags were added to gene: PLA2G16.
Mode of inheritance for gene: PLA2G16 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PLA2G16 were set to 37919452
Phenotypes for gene: PLA2G16 were set to Associated with Lipodystrophy, familial partial, type 9, OMIM:620683; lipodystrophy, familial partial, type 9, MONDO:0958034
Intellectual disability v7.67 MSL2 Arina Puzriakova Phenotypes for gene: MSL2 were changed from neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071 to Karayol-Borroto-Haghshenas neurodevelopmental syndrome, OMIM:620985
Intellectual disability v7.65 TBCE Eleanor Williams Phenotypes for gene: TBCE were changed from Kenny-Caffey syndrome-1, 244460Hypoparathyroidism-retardation-dysmorphism syndrome, 241410; KENNY-CAFFEY SYNDROME TYPE 1 (KCS1) to Kenny-Caffey syndrome, type 1, OMIM:244460; autosomal recessive Kenny-Caffey syndrome, MONDO:0009486; Hypoparathyroidism-retardation-dysmorphism syndrome, OMIM:241410; hypoparathyroidism-retardation-dysmorphism syndrome, MONDO:0009426
Intellectual disability v7.64 TRMT5 Arina Puzriakova changed review comment from: Comment on list classification: New gene added to the panel by Alexander Rossor (UCL Institute of Neurology). There is sufficient evidence to promote this gene to Green at the next GMS panel update.

Associated with relevant phenotype in OMIM, but not associated with phenotype in G2P. At least 3 variants reported in at least three cases, together with supportive functional studies.

Phenotype is characterised as a highly variable multisystemic disorder, ranging from hypotonia and GDD in infancy to exercise intolerance and muscle weakness in early adulthood. Peripheral neuropathy is a universal feature in all cases. Various other neurological features such as spasticity, cerebellar signs and seizures, and involvement of other organ systems, including the heart, pancreas, and kidney may also be observed.; to: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update.

Associated with relevant phenotype in OMIM, but not associated with phenotype in G2P. At least 3 variants reported in at least three cases, together with supportive functional studies.

Phenotype is characterised as a highly variable multisystemic disorder, ranging from hypotonia and GDD in infancy to exercise intolerance and muscle weakness in early adulthood. Peripheral neuropathy is a universal feature in all cases. Various other neurological features such as spasticity, cerebellar signs and seizures, and involvement of other organ systems, including the heart, pancreas, and kidney may also be observed.
Intellectual disability v7.64 TRMT5 Arina Puzriakova Entity copied from Hereditary neuropathy or pain disorder v5.88
Intellectual disability v7.64 TRMT5 Arina Puzriakova gene: TRMT5 was added
gene: TRMT5 was added to Intellectual disability. Sources: Expert list,Expert Review Amber
Q3_24_promote_green, Q3_24_NHS_review tags were added to gene: TRMT5.
Mode of inheritance for gene: TRMT5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TRMT5 were set to 35342985; 26189817; 29021354
Phenotypes for gene: TRMT5 were set to Peripheral neuropathy with variable spasticity, exercise intolerance, and developmental delay, OMIM:616539
Penetrance for gene: TRMT5 were set to Complete
Intellectual disability v7.61 KIF5B Tracy Lester gene: KIF5B was added
gene: KIF5B was added to Intellectual disability. Sources: NHS GMS
Mode of inheritance for gene: KIF5B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KIF5B were set to 36018820; 35342932
Phenotypes for gene: KIF5B were set to kyphomelic dysplasia; hypotonia; developmental delay; intellectual disability
Penetrance for gene: KIF5B were set to unknown
Review for gene: KIF5B was set to AMBER
Added comment: PMID: 35342932 - 3 de novo missense variants reported in 4 subjects with a syndromic skeletal disorder characterized by kyphomelic dysplasia, hypotonia and DD/ID
PMID: 36018820 - 3 more missense variants reported in individuals with a clinically wide phenotypic spectrum ranging from dilated cardiomyopathy with adult-onset ophthalmoplegia and progressive skeletal myopathy to a neurodevelopmental condition characterized by severe hypotonia with or without seizures. In vitro and in vivo analyses provide evidence that the identified disease-associated KIF5B variants disrupt lysosomal, autophagosome and mitochondrial organization, and impact cilium biogenesis. All variants, and one of the previously reported missense changes, were shown to affect multiple developmental processes in zebrafish.
Sources: NHS GMS
Intellectual disability v7.61 GNAI2 Dmitrijs Rots reviewed gene: GNAI2: 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: PMID: 39298586; Phenotypes: Immunodefficiency with multisystemic presentation; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v7.61 DDX17 Hannah Knight gene: DDX17 was added
gene: DDX17 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: DDX17 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: DDX17 were set to PMID: 39405200
Phenotypes for gene: DDX17 were set to Intellectual disability; delayed speech and language; motor delay
Review for gene: DDX17 was set to GREEN
Added comment: PMID: 39405200 (2024) - new paper identified 11 patients with de novo, monoallelic variants in DDX17 and neurodevelopmental phenotypes + experimental evidence
Sources: Literature
Intellectual disability v7.60 DHRSX Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There is sufficient evidence available (three unrelated families) for the promotion of this gene to green rating in the next GMS update.; to: Comment on list classification: There are three unrelated families reported with intellectual disability and hence there is sufficient evidence available for the promotion of this gene to green rating in the next GMS update.
Intellectual disability v7.57 DHRSX Achchuthan Shanmugasundram changed review comment from: PMID:38821050 reported the identification of biallelic missense variants in DHRSX gene in four patients from three unrelated families with a congenital disorder of glycosylation. They displayed distinct facial features, severe neurological involvement including hypotonia, scoliosis, contractures, profound intellectual disability, epilepsy, and sensorineural hearing loss. These patients also experienced severe failure to thrive (requiring tube feeding); variable respiratory insufficiency; and involvement of the eyes, the gastrointestinal system, and other organs.

This gene has not yet been associated with any relevant phenotypes in OMIM or in Gene2Phenotype.; to: PMID:38821050 reported the identification of biallelic missense variants in DHRSX gene in four patients from three unrelated families with a congenital disorder of glycosylation. They displayed distinct facial features, severe neurological involvement including hypotonia, scoliosis, contractures, profound intellectual disability, epilepsy, and sensorineural hearing loss. These patients also experienced severe failure to thrive (requiring tube feeding); variable respiratory insufficiency; and involvement of the eyes, the gastrointestinal system, and other organs.

This gene has not yet been associated with any relevant phenotypes in OMIM or in Gene2Phenotype.
Intellectual disability v7.56 XYLT1 Sarah Leigh edited their review of gene: XYLT1: Added comment: There is enough evidence for XYLT1_GGC to be green on this panel. At least ten patients from at least eight families have either homozygous or compound heterozygous (with other XYLT1 variants) XYLT1_GGC expansions (PMID: 22711505;30554721).; Changed rating: GREEN
Intellectual disability v7.53 LRRC7 Achchuthan Shanmugasundram changed review comment from: PMID:39256359 identified 33 individuals with heterozygous missense or loss-of-function variants in LRRC7 and presenting with a neurodevelopmental disorder. This is a syndromic disorder characterised by intellectual disability, developmental delay, autism, attention deficit hyperactivity disorder (ADHD) and other behavioural features, including aggressiveness and impulsivity. There is also functional evidence available for the missense variants.; to: PMID:39256359 identified 33 individuals with heterozygous missense or loss-of-function variants in LRRC7 and presenting with a neurodevelopmental disorder. This is a syndromic disorder characterised by intellectual disability, developmental delay, autism, attention deficit hyperactivity disorder (ADHD) and other behavioural features, including aggressiveness and impulsivity. There is also functional evidence available for the missense and truncating variants that support LoF mechanism of disease.
Intellectual disability v7.52 LRRC7 Achchuthan Shanmugasundram Phenotypes for gene: LRRC7 were changed from neurodevelopmental abnormality; intelelctual disability; autism; abnormal earting behaviours to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Intellectual disability v7.50 YIF1B Arina Puzriakova Added comment: Comment on phenotypes: Relevant phenotype has now been added to OMIM - Kaya-Barakat-Masson syndrome, OMIM:619125
Intellectual disability v7.50 YIF1B Arina Puzriakova Phenotypes for gene: YIF1B were changed from Central hypotonia; Failure to thrive; Microcephaly; Global developmental delay; Intellectual disability; Seizures; Spasticity; Abnormality of movement to Kaya-Barakat-Masson syndrome, OMIM:619125
Intellectual disability v7.48 TTC5 Arina Puzriakova Added comment: Comment on phenotypes: Relevant phenotype has now been added to OMIM - Neurodevelopmental disorder with cerebral atrophy and variable facial dysmorphism, OMIM:619244
Intellectual disability v7.48 TTC5 Arina Puzriakova Phenotypes for gene: TTC5 were changed from Central hypotonia; Global developmental delay; Intellectual disability; Abnormality of nervous system morphology; Microcephaly; Abnormality of the face; Behavioral abnormality; Abnormality of the genitourinary system to Neurodevelopmental disorder with cerebral atrophy and variable facial dysmorphism, OMIM:619244
Intellectual disability v7.47 TMEM94 Arina Puzriakova Phenotypes for gene: TMEM94 were changed from Intellectual developmental disorder with cardiac defects and dysmorphic facies, 618316; Global developmental delay; Intellectual disability; Abnormal heart morphology; Abnormality of head or neck to Intellectual developmental disorder with cardiac defects and dysmorphic facies, OMIM:618316
Intellectual disability v7.46 RBSN Arina Puzriakova Added comment: Comment on phenotypes: Phenotypes have now been added to OMIM for this gene - Kariminejad-Reversade neurodevelopmental syndrome, OMIM:620937 and Myelofibrosis, congenital, with anemia, neutropenia, developmental delay, and ocular abnormalities, OMIM:620939
Intellectual disability v7.46 RBSN Arina Puzriakova Phenotypes for gene: RBSN were changed from intellectual disability, MONDO:0001071 to Kariminejad-Reversade neurodevelopmental syndrome, OMIM:620937; Myelofibrosis, congenital, with anemia, neutropenia, developmental delay, and ocular abnormalities, OMIM:620939
Intellectual disability v7.43 CXorf56 Arina Puzriakova Phenotypes for gene: CXorf56 were changed from ?Mental retardation, X-linked 107, 301013 to Intellectual developmental disorder, X-linked 107, OMIM:301013
Intellectual disability v7.39 PRKACB Achchuthan Shanmugasundram changed review comment from: PMID:39095811 reported the identification of a de novo missense variant in PRKACB on ES re-analysis in an individual with intellectual disability, refractory focal epilepsy, spasticity, periventricular nodular heterotopia, a common atrium / AVSD, polydactyly and several tumours.; to: PMID:39095811 paper was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.

This paper reported the identification of a de novo missense variant in PRKACB on ES re-analysis in an individual with intellectual disability, refractory focal epilepsy, spasticity, periventricular nodular heterotopia, a common atrium / AVSD, polydactyly and several tumours.
Intellectual disability v7.39 PSMC5 Achchuthan Shanmugasundram changed review comment from: PMID:38776958 reported seven unrelated individuals with four different heterozygous variants (three missense and one nonsense) presenting with a neurodevelopmental disorder. Intellectual disability was present in all cases with being severe in two, moderate in three, borderline in one and severity not reported in one.

This gene has been associated with relevant phenotype in Gene2Phenotype ('moderate' rating on the DD panel), but not yet in OMIM.; to: PMID:38776958 paper was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.

This paper reported seven unrelated individuals with four different heterozygous variants (three missense and one nonsense) presenting with a neurodevelopmental disorder. Intellectual disability was present in all cases with being severe in two, moderate in three, borderline in one and severity not reported in one.

This gene has been associated with relevant phenotype in Gene2Phenotype ('moderate' rating on the DD panel), but not yet in OMIM.
Intellectual disability v7.39 LRRC7 Andrew Mumford gene: LRRC7 was added
gene: LRRC7 was added to Intellectual disability. Sources: Expert Review,Literature
Mode of inheritance for gene: LRRC7 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: LRRC7 were set to (PMID: 36928819):(PMID: 39256359)
Phenotypes for gene: LRRC7 were set to neurodevelopmental abnormality; intelelctual disability; autism; abnormal earting behaviours
Penetrance for gene: LRRC7 were set to Complete
Review for gene: LRRC7 was set to GREEN
Added comment: The association between monoallelic rare LoF variants in LRRC7 and disease class 'intellectual disability' in 100KGP participants was reported first in in 2023 (PMID 36928819).

Detailed phenotype descriptions of the nine pedigrees in the 100KGP discovery collection plus a further sixteen pedigrees in a multicentre european case collection were subsequently published in 2024 (33 affected cases in total; PMID 39256359). This paper confirms functional impact of observed variants on synaptic targeting of the encoded protein Densin-180 in a manner consistent with human phenotype.
Sources: Expert Review, Literature
Intellectual disability v7.35 PRKACB Achchuthan Shanmugasundram changed review comment from: Comment on list classification: Three of five unrelated cases reported with PRKACB variants had intellectual disability, of which one had mild ID. Hence, it should still be rated amber. The 'watchlist' tag has been added to look out for new evidence in the future.; to: Comment on list classification: In total, three of five unrelated cases reported with PRKACB variants had intellectual disability, of which one had mild ID. Hence, it should still be rated amber. The 'watchlist' tag has been added to look out for new evidence in the future.
Intellectual disability v7.35 PRKACB Achchuthan Shanmugasundram Added comment: Comment on list classification: Three of five unrelated cases reported with PRKACB variants had intellectual disability, of which one had mild ID. Hence, it should still be rated amber. The 'watchlist' tag has been added to look out for new evidence in the future.
Intellectual disability v7.34 PRKACB Achchuthan Shanmugasundram changed review comment from: PMID:39095811 reported the identification of a de novo missense variant in PRKACB on ES re-analysis in an individual with intellectual disability, refractory focal epilepsy, spasticity, periventricular nodular heterotopia, a common atrium / AVSD, polydactyly and several tumours.; to: PMID:39095811 reported the identification of a de novo missense variant in PRKACB on ES re-analysis in an individual with intellectual disability, refractory focal epilepsy, spasticity, periventricular nodular heterotopia, a common atrium / AVSD, polydactyly and several tumours.
Intellectual disability v7.34 PRKACB Achchuthan Shanmugasundram changed review comment from: PMID:39095811 reported the identification of a de novo missense variant in PRKACB on ES re-analysis in an individual with intellectual disability, refractory focal epilepsy, spasticity, periventricular nodular heterotopia, a common atrium / AVSD, polydactyly and several tumours; to: PMID:39095811 reported the identification of a de novo missense variant in PRKACB on ES re-analysis in an individual with intellectual disability, refractory focal epilepsy, spasticity, periventricular nodular heterotopia, a common atrium / AVSD, polydactyly and several tumours.
Intellectual disability v7.34 PSMC5 Achchuthan Shanmugasundram changed review comment from: PMID:38776958 reported seven unrelated individuals with four different heterozygous variants (three missense and one nonsense) presenting with a neurodevelopmental disorder. Intellectual disability was present in all cases with being severe in two, moderate in three, borderline in one and severity not reported in one).

This gene has been associated with relevant phenotype in Gene2Phenotype ('moderate' rating on the DD panel), but not yet in OMIM.; to: PMID:38776958 reported seven unrelated individuals with four different heterozygous variants (three missense and one nonsense) presenting with a neurodevelopmental disorder. Intellectual disability was present in all cases with being severe in two, moderate in three, borderline in one and severity not reported in one.

This gene has been associated with relevant phenotype in Gene2Phenotype ('moderate' rating on the DD panel), but not yet in OMIM.
Intellectual disability v7.33 PSMC5 Achchuthan Shanmugasundram changed review comment from: PMID:38776958 reported seven unrelated individuals with four different heterozygous variants (three missense and one nonsense) presenting with a neurodevelopmental disorder. Intellectual disability was present in all cases with being severe in two, moderate in three, borderline in one and not mentioned in one).

This gene has been associated with relevant phenotype in Gene2Phenotype ('moderate' rating on the DD panel), but not yet in OMIM.; to: PMID:38776958 reported seven unrelated individuals with four different heterozygous variants (three missense and one nonsense) presenting with a neurodevelopmental disorder. Intellectual disability was present in all cases with being severe in two, moderate in three, borderline in one and severity not reported in one).

This gene has been associated with relevant phenotype in Gene2Phenotype ('moderate' rating on the DD panel), but not yet in OMIM.
Intellectual disability v7.31 BORCS8 Achchuthan Shanmugasundram gene: BORCS8 was added
gene: BORCS8 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: BORCS8 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BORCS8 were set to 38128568
Phenotypes for gene: BORCS8 were set to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Review for gene: BORCS8 was set to GREEN
Added comment: PMID:38128568 reported five patients from three unrelated families with homozygous or compound heterozygous loss of function missense and PTC variants in BORCS8 gene. All of them (5/5) presented with hypotonia, failure to thrive, global developmental delay, profound intellectual disability, muscle weakness and atrophy and dysmorphic features, while spasticity was present in 4/5 patients, and microcephaly, seizures and scoliosis were present in 3/5 patients. Optic atrophy was reported in all four patients assessed.

Zebrafish knockout of the orthologous brocs8 causes decreased brain and eye size, neuromuscular anomalies and impaired locomotion, recapitulating some of the key traits of the human phenotype. In addition, functional evidence from HEK293T cells were reported for both missense and PTC variants.

This gene has been associated with relevant phenotype in Gene2Phenotype ('moderate' rating on the DD panel), but not yet associated with any phenotypes in OMIM.
Sources: Literature
Intellectual disability v7.30 ZNRF3 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are only two patients reported with moderate intellectual disability and hence the evidence is currently not sufficient for green rating.
Intellectual disability v7.29 ZNRF3 Achchuthan Shanmugasundram gene: ZNRF3 was added
gene: ZNRF3 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: ZNRF3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ZNRF3 were set to 39168120
Phenotypes for gene: ZNRF3 were set to complex neurodevelopmental disorder, MONDO:0100038
Review for gene: ZNRF3 was set to AMBER
Added comment: PMID:39168120 reported 12 individuals from 11 families with heterozygous de novo variants in ZNRF3 gene (the variant was inherited only in the son of a father-son pair) and presented with various phenotypes.

Eight of these individuals harboured missense variants and displayed a complex neurodevelopmental disorder, of which missense variants clustered in the RING ligase domain are associated with macrocephalic NDD. In contrast, four individuals harbouring de novo truncating or de novo or inherited large in-frame deletion variants presented with non-NDD phenotypes, including heart, adrenal, or nephrotic problems. Overall, 4 individuals had congenital heart defects, 2 had moderate intellectual disability and 2 had microcephaly. There is also supporting functional evidence available from in vitro assays.

This gene has not yet been associated with any relevant phenotypes either in OMIM or in Gene2Phenotype.
Sources: Literature
Intellectual disability v7.28 RNU2-2P Eleanor Williams gene: RNU2-2P was added
gene: RNU2-2P was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: RNU2-2P was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Review for gene: RNU2-2P was set to RED
Added comment: PRE-PRINT article https://doi.org/10.1101/2024.09.03.24312863

Greene et al 2024 - report 15 cases in which recurrent germline variants in RNU2-2P are found in patients with a severe neurodevelopmental disorder.

9 cases were from the 100,000 Genomes Project, all of which were annotated with Intellectual disability and displayed severe epilepsy usually from the first few months of life. Among these 9 two recurrent variants were found; n.4G>A and n.35A>G. Trio sequencing of 4/5 of the cases with n.4G>A and 3/4 of the cases with n.35A>G showed that the variants were de novo in all cases.

A variant with a different alternate allele at nucleotide 35, n.35A>T, was identified in
8 unaffected participants but further analysis suggests that this is a recurring somatic mosaic
variant.

A further 6 cases were identified in additional datasets of patients with neurodevelopmental abnormalities with de novo variants and no unaffected carriers of either variant; 4 cases had n.4G>A, 1 case had n.35A>G and 1 case had a different alternate allele, n.35A>C.

RNU2-2P is currently annotated as a pseudogene in Ensembl, but there is evidence that it is a transcribed gene from PMID.: 35288589
Sources: Literature
Intellectual disability v7.23 CTNND2 Arina Puzriakova Added comment: Comment on list classification: Upgraded from Red to Amber following discussion with the Genomics England clinical team.

There are multiple papers and cases in decipher of patients with intragenic deletions in CTNND2; however, almost all have mild or borderline ID (often isolated). Some variants are inherited from parents with mildly low/normal IQ. Deletion size is thought to correlate with severity of mental impairment.

Rationale for upgrading to Amber, is that smaller intragenic deletions in CTNND2 would not be picked up the region that encompasses this gene (ISCA-37390-Loss) as they fall below the 60% overlap threshold. However, mild ID is not within the scope of the panel and the only cases with SNVs have a slightly different phenotype (myoclonus, but they were missense and could be acting in a different mechanism).

This gene has recently been signed off for GMS use via the DDG2P panel (v4.8) meaning it will be applied to any patients referred under the R27 Paediatric disorders super panel.
Intellectual disability v7.20 DPP6 Sarah Leigh changed review comment from: DPP6 variants have been associated with Intellectual developmental disorder, autosomal dominant 33 in OMIM (#: 616311), but not with a phenotype in Gen2Phen. To date two monoallelic variants have been associated with OMIM: 616311 in two unrelated families, where the affected individuals all had microcephaly and intellectual disability (PMID:23832105). Various Dpp6 knock-down mouse models, showed that these mice had significantly lower body and brain weights in comparison to wildtype and displayed behaviours characteristic of reduced learning abilities and impaired memory (PMID: 21943606; 23832105; 29651237).
The ClinGen Gene-Disease Validity score for this gene is "Disputed" (https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_3d41cebe-5490-419d-882d-4f3c6856be07-2021-05-05T160000.000Z), therefore, this gene will remain amber.; to: DPP6 variants have been associated with Intellectual developmental disorder, autosomal dominant 33 in OMIM (#: 616311), but not with a phenotype in Gen2Phen. To date two monoallelic variants have been associated with OMIM: 616311 in two unrelated families, where the affected individuals all had microcephaly and intellectual disability (PMID:23832105). Various Dpp6 knock-down mouse models, showed that these mice had significantly lower body and brain weights in comparison to wildtype and displayed behaviours characteristic of reduced learning abilities and impaired memory (PMID: 21943606; 23832105; 29651237).
The ClinGen Gene-Disease Validity score for this gene is "Disputed" (https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_3d41cebe-5490-419d-882d-4f3c6856be07-2021-05-05T160000.000Z), therefore, this gene will remain red.
Intellectual disability v7.20 DPP6 Sarah Leigh changed review comment from: DPP6 variants have been associated with Intellectual developmental disorder, autosomal dominant 33 in OMIM (#: 616311), but not with a phenotype in Gen2Phen. To date two monoallelic variants have been associated with OMIM: 616311 in two unrelated families, where the affected individuals all had microcephaly and intellectual disability (PMID:23832105). Various Dpp6 knock-down mouse models, showed that these mice had significantly lower body and brain weights in comparison to wildtype and displayed behaviours characteristic of reduced learning abilities and impaired memory (PMID: 21943606; 23832105; 29651237).; to: DPP6 variants have been associated with Intellectual developmental disorder, autosomal dominant 33 in OMIM (#: 616311), but not with a phenotype in Gen2Phen. To date two monoallelic variants have been associated with OMIM: 616311 in two unrelated families, where the affected individuals all had microcephaly and intellectual disability (PMID:23832105). Various Dpp6 knock-down mouse models, showed that these mice had significantly lower body and brain weights in comparison to wildtype and displayed behaviours characteristic of reduced learning abilities and impaired memory (PMID: 21943606; 23832105; 29651237).
The ClinGen Gene-Disease Validity score for this gene is "Disputed" (https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_3d41cebe-5490-419d-882d-4f3c6856be07-2021-05-05T160000.000Z), therefore, this gene will remain amber.
Intellectual disability v7.20 DPP6 Sarah Leigh Added comment: Comment on list classification: Although only two DPP6 variants have so far been associated with OMIM:616311 (PMID:23832105), I feel that the mouse model evidence from three studies provides evidence to support the association between DPP6 variants and microcephaly and intellectual disability (PMID: 21943606; 23832105; 29651237).
Intellectual disability v7.18 DPP6 Sarah Leigh edited their review of gene: DPP6: Added comment: DPP6 variants have been associated with Intellectual developmental disorder, autosomal dominant 33 in OMIM (#: 616311), but not with a phenotype in Gen2Phen. To date two monoallelic variants have been associated with OMIM: 616311 in two unrelated families, where the affected individuals all had microcephaly and intellectual disability (PMID:23832105). Various Dpp6 knock-down mouse models, showed that these mice had significantly lower body and brain weights in comparison to wildtype and displayed behaviours characteristic of reduced learning abilities and impaired memory (PMID: 21943606; 23832105; 29651237).; Changed rating: GREEN
Intellectual disability v7.18 PLEKHG2 Sarah Leigh changed review comment from: Three biallelic PLEKHG2 missense variants have been identified in three unrelated families with individuals who have neurological disorders (PMID: 26539891, 26573021, 34326120).; to: Three biallelic PLEKHG2 missense variants have been identified in three unrelated families, in individuals who have Leukodystrophy and acquired microcephaly with or without dystonia (OMIM:616763)(PMID: 26539891, 26573021, 34326120). Segregation of the variant and the condition has been demonstrated in two of these families (PMID: 26573021, 34326120) and functional studies show that although PLEKHG2 gene expression is not affected, the resultant variant peptide has a reduced effect (PMID: 26573021, 35203342).
Intellectual disability v7.18 FOSL2 Dmitrijs Rots changed review comment from: Already in OMIM as Aplasia cutis-enamel dysplasia syndrome. PMID: 36197437 described 10 cases with truncating variants in the last exon of FOSL2.
Sources: Literature; to: Already in OMIM as Aplasia cutis-enamel dysplasia syndrome. PMID: 36197437 described 10 cases with NDD and aplasia cutis and truncating variants in the last exon of FOSL2.
Sources: Literature
Intellectual disability v7.18 FOSL2 Dmitrijs Rots gene: FOSL2 was added
gene: FOSL2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: FOSL2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FOSL2 were set to PMID: 36197437
Phenotypes for gene: FOSL2 were set to Aplasia cutis-enamel dysplasia syndrome
Mode of pathogenicity for gene: FOSL2 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: FOSL2 was set to GREEN
Added comment: Already in OMIM as Aplasia cutis-enamel dysplasia syndrome. PMID: 36197437 described 10 cases with truncating variants in the last exon of FOSL2.
Sources: Literature
Intellectual disability v7.14 CIAO1 Sarah Leigh Entity copied from Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v4.37
Intellectual disability v7.14 CIAO1 Sarah Leigh gene: CIAO1 was added
gene: CIAO1 was added to Intellectual disability. Sources: Literature,Expert Review Amber
Q3_24_promote_green, Q3_24_NHS_review tags were added to gene: CIAO1.
Mode of inheritance for gene: CIAO1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CIAO1 were set to 38950322
Phenotypes for gene: CIAO1 were set to CIAO1 associated neuromuscular disorder
Intellectual disability v7.13 FIBP Sarah Leigh changed review comment from: FIBP variants have been associated with Thauvin-Robinet-Faivre syndrome in OMIM (OMIM:617107) and Gen2Phen rate this gene as having a moderate association with FIBP-related overgrowth syndrome with developmental delay (Thauvin-Robinet-Faivre syndrome). To date, three biallelic FIBP variants have been reported in three unrelated patients with Thauvin-Robinet-Faivre syndrome, the variant segregated with the condition in each of these families (PMID: 26660953; 27183861; 37876348).; to: FIBP variants have been associated with Thauvin-Robinet-Faivre syndrome in OMIM (OMIM:617107) and Gen2Phen rate this gene as having a moderate association with FIBP-related overgrowth syndrome with developmental delay (Thauvin-Robinet-Faivre syndrome). To date, three biallelic FIBP variants have been reported in three unrelated patients with Thauvin-Robinet-Faivre syndrome, the variant segregated with the condition in each of these families (PMID: 26660953; 27183861; 37876348). The variant reported in PMID: 37876348 & 37218527 may result in a frameshift and termination, if the wild type splice site is used. However, if the splice site in the duplicated sequence is used, the variant may not be pathogenic as the coding sequence would not altered, expression studies would reveal the mechanism.
Intellectual disability v7.11 CRELD1 Dmitrijs Rots gene: CRELD1 was added
gene: CRELD1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: CRELD1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CRELD1 were set to PMID: 37947183
Review for gene: CRELD1 was set to GREEN
Added comment: The papers reports:
Biallelic variants in CRELD1 were found in 18 participants from 14 families. Affected individuals displayed an array of phenotypes involving developmental delay, early-onset epilepsy, and hypotonia, with about half demonstrating cardiac arrhythmias and some experiencing recurrent infections.
Sources: Literature
Intellectual disability v7.11 SRPK3 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Zornitza Stark, PMID:39073169 reported nine individuals from 5 unrelated families reported with SRPK3 variants and X-linked intellectual disability. Of eight patients from four families that were ascertained postnatally, seven from three families had ID, while the eighth patient was reported with global developmental delay. The ninth case that was ascertained prenatally, had a complex structural brain phenotype.

This gene has not yet been associated with any relevant phenotypes either in OMIM or in Gene2Phenotype.

As there is sufficient evidence available for the association of this gene to ID, this gene should be promoted to green rating in the next GMS update.
Intellectual disability v7.9 HDAC3 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Zornitza Stark, PMID:39047730 reported the identification of de novo missense variants in HDAC3 gene in six unrelated individuals with neurodevelopmental disorder. Intellectual disability of varying severity was present in five of six patients (severe and moderate ID in two each and mild ID in one).

This gene has not yet been associated with relevant phenotypes either in OMIM or in Gene2Phenotype.

This gene should be promoted to green rating in the next GMS update.
Intellectual disability v7.7 RBBP5 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Zornitza Stark, PMID:39036895 reported five unrelated cases with five different heterozygous RBBP5 variants, of which four patients had developmental delay and intellectual disability (3 with severe ID and one with mild ID).

This gene has not yet been associated with relevant phenotypes wither in OMIM or in Gene2Phenotype.

This gene can be promoted to green rating in the next GMS update.
Intellectual disability v7.7 RBBP5 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Zornitza Stark, PMID:39036895 reported five unrelated cases with five different heterozygous RBBP5 variants, of which four patients had developmental delay and intellectual disability (3 with severe ID and one with mild ID).

This gene has not yet been associated with relevant phenotypes wither in OMIM or in Gene2Phenotype.

This gene can be promoted to green rating in the next GMS update.
Intellectual disability v7.5 PCBP2 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Zornitza Stark, there were three unrelated cases reported with three different variants in PMID:38965372. One of them had borderline ID, one had mild ID and two had delayed motor and speech development.

This gene has been associated with relevant phenotype in Gene2Phenotype (with 'limited' rating on the DD panel), but not yet in OMIM.

Hence, this gene can only be rated amber with current evidence.
Intellectual disability v7.2 ATXN7L3 Sarah Leigh gene: ATXN7L3 was added
gene: ATXN7L3 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: ATXN7L3 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ATXN7L3 were set to 38753057; 33731875
Phenotypes for gene: ATXN7L3 were set to syndromic neurodevelopmental disorder
Review for gene: ATXN7L3 was set to GREEN
Added comment: ATXN7L3 variants are not associated with a phenotype in OMIM or Gen2Phen. PMID: 38753057 reports five monoallelic ATXN7L3 variants in nine unrelated cases. The variants were de novo, where this could be established (8/9 cases). Common features in the cases were: global developmental delay (8/9), dysmorphic features (7/9), hypotonia (7/9), strabismus (4/6), abnormal brain MRI (6/8). ATXN7L3 protein levels were reduced and deubiquitylation was impaired, resulting in increased levels of histone H2Bub1 in the fibroblasts of an affected individual carrying the recurrent variant: NM_001382309.1: c.340C>T; p.(Arg114Ter). This finding was consistent with the increased H2Bub1 levels in Atxn7l3-null mouse embryos, who have developmental delay and embryonic lethality (PMID: 33731875).
Sources: Literature
Intellectual disability v6.77 PCBP2 Zornitza Stark gene: PCBP2 was added
gene: PCBP2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: PCBP2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PCBP2 were set to 38965372
Phenotypes for gene: PCBP2 were set to neurodevelopmental disorder MONDO:0700092, PCBP2-related
Review for gene: PCBP2 was set to GREEN
Added comment: Three individuals reported with de novo variants and DD/ASD.
Sources: Literature
Intellectual disability v6.77 RBBP5 Zornitza Stark gene: RBBP5 was added
gene: RBBP5 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: RBBP5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RBBP5 were set to 39036895
Phenotypes for gene: RBBP5 were set to neurodevelopmental disorder MONDO:0700092, RBBP5-related
Review for gene: RBBP5 was set to GREEN
Added comment: Five individuals reported, four of whom had de novo variants. Four had DD/ID; other more variable features included short stature, microcephaly, SNHL, seizures and hypotonia.
Sources: Literature
Intellectual disability v6.77 HDAC3 Zornitza Stark gene: HDAC3 was added
gene: HDAC3 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: HDAC3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: HDAC3 were set to 39047730
Phenotypes for gene: HDAC3 were set to Neurodevelopmental disorder, MONDO:0700092, HDAC3-related
Added comment: Six individuals with de novo missense variants in this gene and variable NDD phenotypes, including ID, seizures. Supportive functional data.
Sources: Literature
Intellectual disability v6.77 SRPK3 Zornitza Stark gene: SRPK3 was added
gene: SRPK3 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: SRPK3 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: SRPK3 were set to 39073169
Phenotypes for gene: SRPK3 were set to Neurodevelopmental disorder, MONDO:0700092, SRPK3-related
Review for gene: SRPK3 was set to GREEN
Added comment: PMID 39073169: 9 individuals from 5 unrelated families reported with 4 missense and 1 putative truncating variant and a neurodevelopmental phenotype. The 8 patients ascertained postnatally shared common clinical features including intellectual disability, agenesis of the corpus callosum, abnormal eye movement, and ataxia. A ninth case, ascertained prenatally, had a complex structural brain phenotype. Supportive animal model data (mouse and zebrafish).
Sources: Literature
Intellectual disability v6.77 RNU7-1 Sarah Leigh Tag locus-type-rna-small-nuclear tag was added to gene: RNU7-1.
Intellectual disability v6.74 MAPKAPK5 Achchuthan Shanmugasundram Phenotypes for gene: MAPKAPK5 were changed from Neurocardiofaciodigital syndrome, OMIM:619869 to Neurocardiofaciodigital syndrome, OMIM:619869
Intellectual disability v6.73 MAPKAPK5 Achchuthan Shanmugasundram Phenotypes for gene: MAPKAPK5 were changed from Developmental delay, variable brain anomalies, congenital heart defects, dysmorphism to Neurocardiofaciodigital syndrome, OMIM:619869
Intellectual disability v6.71 MAPKAPK5 Achchuthan Shanmugasundram reviewed gene: MAPKAPK5: Rating: GREEN; Mode of pathogenicity: None; Publications: 35575217, 36581449; Phenotypes: Neurocardiofaciodigital syndrome, OMIM:619869; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v6.70 IREB2 Achchuthan Shanmugasundram Phenotypes for gene: IREB2 were changed from Neurodegeneration, early-onset, with choreoathetoid movements and microcytic anemia, MIM#618451 to Neurodegeneration, early-onset, with choreoathetoid movements and microcytic anemia, OMIM:618451
Intellectual disability v6.68 IREB2 Achchuthan Shanmugasundram changed review comment from: PMID:35602653 reported a 7-year-old male patient with compound heterozygous missense variants in IREB2 gene and with clinical manifestations including a profound global neurodevelopmental delay and dystonia.

This gene has been associated with relevant phenotypes in OMIM (MIM #618451) and Gene2Phenotype (with 'moderate' rating on the ID panel).; to: PMID:35602653 reported a 7-year-old male patient with compound heterozygous missense variants in IREB2 gene and with clinical manifestations including a profound global neurodevelopmental delay and dystonia.

This gene has been associated with relevant phenotypes in OMIM (MIM #618451) and Gene2Phenotype (with 'moderate' rating on the DD panel).
Intellectual disability v6.68 IREB2 Achchuthan Shanmugasundram reviewed gene: IREB2: Rating: GREEN; Mode of pathogenicity: None; Publications: 35602653; Phenotypes: Neurodegeneration, early-onset, with choreoathetoid movements and microcytic anemia, OMIM:618451; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v6.68 GEMIN4 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are 12 unrelated families and three different GEMIN4 variants reported in the literature. Hence, this gene can be promoted to green rating in the next GMS update.
Intellectual disability v6.67 GEMIN4 Achchuthan Shanmugasundram Phenotypes for gene: GEMIN4 were changed from Neurodevelopmental disorder with microcephaly, cataracts, and renal abnormalities, 617913 to Neurodevelopmental disorder with microcephaly, cataracts, and renal abnormalities, OMIM:617913
Intellectual disability v6.65 GEMIN4 Achchuthan Shanmugasundram changed review comment from: PMID:35861185 provided a retrospective review of 16 patients from 11 unrelated Saudi consanguineous families with GEMIN4 variants., of which five patients were previously reported. Only two missense homozygous pathogenic variants (p.Pro105Leu and p.Trp818Arg) were reported in these patients, which suggests founder effect. All patients shared global developmental delay with variable ophthalmological, renal, and skeletal manifestations.

PMID:35052432 reported the identification of a novel homozygous variant (p.His147Arg) in two siblings from a consanguineous Saudi family. Both of them presented with global developmental delay, seizures, microcephaly and cataract.; to: PMID:35861185 provided a retrospective review of 16 patients from 11 unrelated Saudi consanguineous families with GEMIN4 variants., of which five patients were previously reported. Only two missense homozygous pathogenic variants (p.Pro105Leu and p.Trp818Arg) were reported in these patients, which suggests founder effect. All patients shared global developmental delay with variable ophthalmological, renal, and skeletal manifestations.

PMID:35052432 reported the identification of a novel homozygous variant (p.His147Arg) in two siblings from a consanguineous Saudi family. Both of them presented with global developmental delay, seizures, microcephaly and cataract.

This gene has been associated with relevant phenotypes in OMIM (MIM #617913) and Gene2Phenotype (with 'strong' rating on the DD panel).
Intellectual disability v6.65 GEMIN4 Achchuthan Shanmugasundram reviewed gene: GEMIN4: Rating: GREEN; Mode of pathogenicity: None; Publications: 35052432, 35861185; Phenotypes: Neurodevelopmental disorder with microcephaly, cataracts, and renal abnormalities, OMIM:617913; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v6.64 GABBR1 Achchuthan Shanmugasundram gene: GABBR1 was added
gene: GABBR1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: GABBR1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: GABBR1 were set to 36103875
Phenotypes for gene: GABBR1 were set to Neurodevelopmental disorder with language delay and variable cognitive abnormalities, OMIM:620502
Review for gene: GABBR1 was set to AMBER
Added comment: PMID:36103875 reported the identification of monoallelic de novo variants in four unrelated individuals presenting with motor and/or language delay, ranging from mild to severe, and in one case, epilepsy. Intellectual disability was present in two of four individuals, whereas ID was not documented in one patient.

This gene has been associated with relevant phenotypes in OMIM (MIM #620502) and Gene2Phenotype (with 'moderate' rating on the DD panel).
Sources: Literature
Intellectual disability v6.62 FZR1 Achchuthan Shanmugasundram changed review comment from: PMID:31318984 reported the identification of a novel heterozygous missense FZR1 variant (c.560A>G/ p.Asp187Gly) in a 4-year-old boy, born from non-consanguineous Spanish parents, who presents with severe antenatal microcephaly, global developmental delay, and refractory epilepsy. There is some functional evidence available for this variant.

PMID:34788397 reported the identification of three de novo missense FZR1 variants (c.559G>A/ p.Asp187Asn, c.999C>G/ p.Asn333Lys & c.999C>A/ p.Asn333Lys) in three unrelated individuals from different descents (Turkish, Moroccan and Afghan) presenting with childhood-onset generalized epilepsy, intellectual disability, and mild ataxia.

This gene has been associated with relevant phenotypes in OMIM (MIM #620145) and Gene2Phenotype (with 'strong' rating on the DD panel).
Sources: Literature; to: PMID:31318984 reported the identification of a novel heterozygous missense FZR1 variant (c.560A>G/ p.Asp187Gly) in a 4-year-old boy, born from non-consanguineous Spanish parents, who presents with severe antenatal microcephaly, global developmental delay, and refractory epilepsy. There is some functional evidence available for this variant.

PMID:34788397 reported the identification of three de novo missense FZR1 variants (c.559G>A/ p.Asp187Asn, c.999C>G/ p.Asn333Lys & c.999C>A/ p.Asn333Lys) in three unrelated individuals from different descents (Turkish, Moroccan and Afghan) presenting with childhood-onset generalized epilepsy, intellectual disability, and mild ataxia. There is functional evidence available for variants reported in this study.

This gene has been associated with relevant phenotypes in OMIM (MIM #620145) and Gene2Phenotype (with 'strong' rating on the DD panel).
Sources: Literature
Intellectual disability v6.62 FZR1 Achchuthan Shanmugasundram gene: FZR1 was added
gene: FZR1 was added to Intellectual disability. Sources: Literature
Q3_24_promote_green tags were added to gene: FZR1.
Mode of inheritance for gene: FZR1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FZR1 were set to 31318984; 34788397
Phenotypes for gene: FZR1 were set to Developmental and epileptic encephalopathy 109, OMIM:620145
Review for gene: FZR1 was set to GREEN
Added comment: PMID:31318984 reported the identification of a novel heterozygous missense FZR1 variant (c.560A>G/ p.Asp187Gly) in a 4-year-old boy, born from non-consanguineous Spanish parents, who presents with severe antenatal microcephaly, global developmental delay, and refractory epilepsy. There is some functional evidence available for this variant.

PMID:34788397 reported the identification of three de novo missense FZR1 variants (c.559G>A/ p.Asp187Asn, c.999C>G/ p.Asn333Lys & c.999C>A/ p.Asn333Lys) in three unrelated individuals from different descents (Turkish, Moroccan and Afghan) presenting with childhood-onset generalized epilepsy, intellectual disability, and mild ataxia.

This gene has been associated with relevant phenotypes in OMIM (MIM #620145) and Gene2Phenotype (with 'strong' rating on the DD panel).
Sources: Literature
Intellectual disability v6.60 FUK Achchuthan Shanmugasundram Added comment: Comment on list classification: There are four unrelated families reported with ID (severe in three families and mild in one). Hence, this gene can be promoted to green rating in the next GMS update.
Intellectual disability v6.58 FRA10AC1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are six unrelated families reported with biallelic FRA10AC1 variants and intellectual disability and/ or global developmental delay. Hence, this gene can be promoted to green rating in the next GMS update.
Intellectual disability v6.57 FRA10AC1 Achchuthan Shanmugasundram gene: FRA10AC1 was added
gene: FRA10AC1 was added to Intellectual disability. Sources: Literature
Q3_24_promote_green tags were added to gene: FRA10AC1.
Mode of inheritance for gene: FRA10AC1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FRA10AC1 were set to 34694367; 35871492; 35821753
Phenotypes for gene: FRA10AC1 were set to Neurodevelopmental disorder with growth retardation, dysmorphic facies, and corpus callosum abnormalities, OMIM:620113
Review for gene: FRA10AC1 was set to GREEN
Added comment: PMID:34694367 reported the identification of homozygous FRA10AC1 variants in five individuals from three unrelated consanguineous Arabic families with a neurodevelopmental disorder. The two unrelated patients from two different families with loss-of-function variants (g.4656_7575del and c.561_562insTTTA/ p.Ser188Phefs*6) presented with developmental delay, profound intellectual disability (ID), and no speech, while three siblings from the third family with the c.494_496delAAG (p.Glu165del) variant had borderline to mild ID. There is some functional evidence available for the p.Glu165del variant, which shows that this variant impacts intrinsic stability of FRA10AC1 but does not affect its nuclear localisation.

PMID:35871492 reported the identification of a homozygous nonsense variant (c.328C>T/ p.Arg110Ter) in two sisters from a consanguineous family. They presented with global developmental delay, growth impairment, congenital malformations and facial dysmorphism. Another patient identified from the DECIPHER database was also reported with a ~13kb homozygous deletion encompassing exons 1-3 and with global developmental delay.

PMID:35821753 reported the identification of a homozygous LOF nonsense variant (c.481C>T/ p.Arg161Ter) in two siblings from a highly consanguineous Arab family. They presented with dysmorphic features, failure to thrive, global developmental delay, generalized hypotonia, feeding problems, and congenital heart disease.

This gene has been associated with relevant phenotypes in OMIM (MIM #620113) and Gene2Phenotype ('strong' rating on the DD panel).
Sources: Literature
Intellectual disability v6.54 B9D1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are three unrelated individuals reported with Joubert syndrome, where intellectual disability or global developmental delay is part of the phenotype. Hence, this gene can be promoted to green rating in the next GMS update.
Intellectual disability v6.52 TBC1D7 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Frances Elmslie, PMID:36669495 reported an additional case with compound heterozygous variants (identified via trio RNA-Seq) and presenting with a neurodevelopmental disorder involving mild intellectual disability.

Hence, this gene can be promoted to green rating with the current evidence (three unrelated cases and functional studies) in the next GMS update.
Intellectual disability v6.50 RNU4-2 Arina Puzriakova changed review comment from: Greene et al. 2024 (PMID: 38821540) reported on 73 unrelated cases with a neurodevelopmental disorder associated with heterozygous variants in the RNU4-2 gene, overlapping findings in PMID:38645094 (still currently in preprint). Participants were identified through their enrolment in various cohorts including the 100,000 Genomes Project, NHSE Genomic Medicine Service (GMS), and NIHR BioResource.

Almost all variants were acquired de novo, with the exception of one variant that was inherited from an affected mother and 16 probands with unknown inheritance due to lack of parental genotype data.
Variants cluster in two regions of RNU4-2 (n.62–70 and n.73–79) but the majority of cases harboured a recurrent variant, n.64_65insT.

Clinical presentation was predominantly characterised by intellectual disability, but other observed features include microcephaly, proportionate short stature, hypotonia, seizures and motor delay.; to: Greene et al. 2024 (PMID: 38821540) reported on 73 unrelated cases with a neurodevelopmental disorder associated with heterozygous variants in the RNU4-2 gene, overlapping findings in PMID: 38645094 (still currently in preprint). Participants were identified through their enrolment in various cohorts including the 100,000 Genomes Project, NHSE Genomic Medicine Service (GMS), and NIHR BioResource.

Almost all variants were acquired de novo, with the exception of one variant that was inherited from an affected mother and 16 probands with unknown inheritance due to lack of parental genotype data.
Variants cluster in two regions of RNU4-2 (n.62–70 and n.73–79) but the majority of cases harboured a recurrent variant, n.64_65insT.

Clinical presentation was predominantly characterised by intellectual disability, but other observed features include microcephaly, proportionate short stature, hypotonia, seizures and motor delay.
Intellectual disability v6.50 RNU4-2 Arina Puzriakova changed review comment from: Comment on list classification: The two papers (PMID: 38821540; 38645094) corroborate mutual findings and report over 100 unrelated individuals with a clinically overlapping neurological disorder and variants the non-coding gene RNU4-2.

Overall there is sufficient evidence to promote this gene to Green status at the next GMS panel update.; to: Comment on list classification: Multiple individuals have been identified in PMID: 38821540 with a clinically overlapping neurological disorder and variants the non-coding gene RNU4-2. Additional cases with mutual findings have also been reported in PMID: 38645094, corroborating this gene-disease association - however, PMID: 38645094 is still in preprint at this time.

Overall there is sufficient evidence to promote this gene to Green status at the next GMS panel update.
Intellectual disability v6.50 RNU4-2 Arina Puzriakova changed review comment from: Second paper by Greene et al. 2024 (PMID: 38821540) reported on 73 unrelated cases with a neurodevelopmental disorder associated with heterozygous variants in the RNU4-2 gene, overlapping findings with the PMID: 38645094 paper (still currently in preprint). Participants were identified through their enrolment in various cohorts including the 100,000 Genomes Project, NHSE Genomic Medicine Service (GMS), and NIHR BioResource.

Almost all variants were acquired de novo, with the exception of one variant that was inherited from an affected mother and 16 probands with unknown inheritance due to lack of parental genotype data.
Variants cluster in two regions of RNU4-2 (n.62–70 and n.73–79) but the majority of cases harboured a recurrent variant, n.64_65insT.

Clinical presentation was predominantly characterised by intellectual disability, but other observed features include microcephaly, proportionate short stature, hypotonia, seizures and motor delay.; to: Greene et al. 2024 (PMID: 38821540) reported on 73 unrelated cases with a neurodevelopmental disorder associated with heterozygous variants in the RNU4-2 gene, overlapping findings in PMID:38645094 (still currently in preprint). Participants were identified through their enrolment in various cohorts including the 100,000 Genomes Project, NHSE Genomic Medicine Service (GMS), and NIHR BioResource.

Almost all variants were acquired de novo, with the exception of one variant that was inherited from an affected mother and 16 probands with unknown inheritance due to lack of parental genotype data.
Variants cluster in two regions of RNU4-2 (n.62–70 and n.73–79) but the majority of cases harboured a recurrent variant, n.64_65insT.

Clinical presentation was predominantly characterised by intellectual disability, but other observed features include microcephaly, proportionate short stature, hypotonia, seizures and motor delay.
Intellectual disability v6.49 FEM1B Achchuthan Shanmugasundram changed review comment from: Comment on list classification: As recently reviewed by Zornitza Stark, five unrelated individuals are reported with a syndromic neurodevelopmental disorder and identified with the same missense variant p.Arg126Gln. All five individuals presented with global developmental delay and all four patients tested for intellectual disability had ID.

This gene has not yet been associated with any phenotypes either in OMIM or in Gene2Phenotype.

Although only one variant was reported, there is functional evidence available for this variant. Hence, this gene can be promoted to green rating in the next GMS update.; to: Comment on list classification: As recently reviewed by Zornitza Stark, five unrelated individuals were reported with a syndromic neurodevelopmental disorder and identified with the same missense variant p.Arg126Gln. All five individuals presented with global developmental delay and all four patients tested for intellectual disability had ID.

This gene has not yet been associated with any phenotypes either in OMIM or in Gene2Phenotype.

Although only one variant was reported, there is functional evidence available for this variant. Hence, this gene can be promoted to green rating in the next GMS update.
Intellectual disability v6.49 FEM1B Achchuthan Shanmugasundram changed review comment from: Comment on list classification: As recently reviewed by Zornitza Stark, five unrelated individuals are reported with a syndromic neurodevelopmental disorder and identified with the same missense variant p.Arg126Gln.

Although only one variant was reported, there is functional evidence available for this variant. Hence, this gene can be promoted to green rating in the next GMS update.; to: Comment on list classification: As recently reviewed by Zornitza Stark, five unrelated individuals are reported with a syndromic neurodevelopmental disorder and identified with the same missense variant p.Arg126Gln. All five individuals presented with global developmental delay and all four patients tested for intellectual disability had ID.

This gene has not yet been associated with any phenotypes either in OMIM or in Gene2Phenotype.

Although only one variant was reported, there is functional evidence available for this variant. Hence, this gene can be promoted to green rating in the next GMS update.
Intellectual disability v6.49 FEM1B Achchuthan Shanmugasundram Added comment: Comment on list classification: As recently reviewed by Zornitza Stark, five unrelated individuals are reported with a syndromic neurodevelopmental disorder and identified with the same missense variant p.Arg126Gln.

Although only one variant was reported, there is functional evidence available for this variant. Hence, this gene can be promoted to green rating in the next GMS update.
Intellectual disability v6.44 ADGRL1 Achchuthan Shanmugasundram edited their review of gene: ADGRL1: Added comment: PMID:35907405 reported the identification of monoallelic ADGRL1 variants in ten individuals with a neurodevelopmental disorder comprising developmental delay, intellectual disability, attention deficit hyperactivity and autism spectrum disorders, and epilepsy. This includes a case that was previously reported in PMID:30504930. Mild/ moderate intellectual disability was reported in five of these ten cases.

This gene has been associated with relevant phenotype in OMIM (MIM #620065), but not yet in Gene2Phenotype.; Changed publications to: 30504930, 35907405
Intellectual disability v6.42 KCNB2 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: As reviewed by Zornitza Stark, PMID:38503299 reported seven unrelated individuals with monoallelic KCNB2 variants and neurodevelopmental disorder, of which six of them had intellectual disability.; to: Comment on list classification: As reviewed by Zornitza Stark, PMID:38503299 reported seven unrelated individuals with monoallelic KCNB2 variants and neurodevelopmental disorder, of which six of them had intellectual disability.

This gene has not yet been associated with relevant phenotypes either in OMIM or in Gene2Phenotype.
Intellectual disability v6.42 KCNB2 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Zornitza Stark, PMID:38503299 reported seven unrelated individuals with monoallelic KCNB2 variants and neurodevelopmental disorder, of which six of them had intellectual disability.
Intellectual disability v6.38 PLXNB2 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reported in PMID:38458752 and reviewed by Claire Smith, there are six patients from four different families (from a total of eight patients from six families) reported with intellectual disability. Hence, this gene can be promoted to green rating in the next GMS update.
Intellectual disability v6.38 PLXNB2 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reported in PMID:38458752 and reviewed by Claire Smith, there are six patients from four different families (from a total of eight patients from six families) reported with intellectual disability. Hence, this gene can be promoted to green rating in the next GMS update.
Intellectual disability v6.37 PLXNB2 Achchuthan Shanmugasundram Phenotypes for gene: PLXNB2 were changed from amelogenesis imperfecta, MONDO:0019507; sensorineural hearing loss disorder, MONDO:0020678; intellectual disability, MONDO:0001071 to amelogenesis imperfecta, MONDO:0019507; sensorineural hearing loss disorder, MONDO:0020678; intellectual disability, MONDO:0001071
Intellectual disability v6.37 PLXNB2 Achchuthan Shanmugasundram Phenotypes for gene: PLXNB2 were changed from amelogenesis imperfecta, MONDO:0019507; sensorineural hearing loss disorder, MONDO:0020678; intellectual disability, MONDO:0001071 to amelogenesis imperfecta, MONDO:0019507; sensorineural hearing loss disorder, MONDO:0020678; intellectual disability, MONDO:0001071
Intellectual disability v6.37 PLXNB2 Achchuthan Shanmugasundram Phenotypes for gene: PLXNB2 were changed from amelogenesis imperfecta, MONDO:0019507; sensorineural hearing loss disorder, MONDO:0020678; intellectual disability, MONDO:0001071 to amelogenesis imperfecta, MONDO:0019507; sensorineural hearing loss disorder, MONDO:0020678; intellectual disability, MONDO:0001071
Intellectual disability v6.37 PLXNB2 Achchuthan Shanmugasundram Phenotypes for gene: PLXNB2 were changed from amelogenesis imperfecta, MONDO:0019507; sensorineural hearing loss disorder, MONDO:0020678; intellectual disability, MONDO:0001071 to amelogenesis imperfecta, MONDO:0019507; sensorineural hearing loss disorder, MONDO:0020678; intellectual disability, MONDO:0001071
Intellectual disability v6.37 PLXNB2 Achchuthan Shanmugasundram Phenotypes for gene: PLXNB2 were changed from Syndromic disease MONDO:0002254, PLXNB2 -related to amelogenesis imperfecta, MONDO:0019507; sensorineural hearing loss disorder, MONDO:0020678; intellectual disability, MONDO:0001071
Intellectual disability v6.36 PLXNB2 Achchuthan Shanmugasundram reviewed gene: PLXNB2: Rating: GREEN; Mode of pathogenicity: None; Publications: 38458752; Phenotypes: amelogenesis imperfecta, MONDO:0019507, sensorineural hearing loss disorder, MONDO:0020678, intellectual disability, MONDO:0001071; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v6.35 CAMK2D Achchuthan Shanmugasundram gene: CAMK2D was added
gene: CAMK2D was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: CAMK2D was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CAMK2D were set to 38272033
Phenotypes for gene: CAMK2D were set to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Added comment: PMID:38272033 reported eight unrelated individuals with monoallelic CAMK2D variants and presenting with a neurodevelopmental disorder. Clinical phenotypes include intellectual disability (ID), delayed speech, behavioral problems and dilated cardiomyopathy.

The majority of the variants tested lead to a gain of function (GoF), which appears to cause both neurological problems and dilated cardiomyopathy. In contrast, loss-of-function (LoF) variants appear to induce only neurological symptoms.

ID was reported in all seven individuals tested for ID, where ID was mild in 2, moderate to severe in 1, severe in 3 and profound in 1 patient.

This gene has been associated with relevant phenotype in Gene2Phenotype ('moderate' rating on the DD panel), but not yet in OMIM.
Sources: Literature
Intellectual disability v6.34 EZH1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the association of both monoallelic and biallelic EZH1 variants to intellectual disability with green rating. Hence, this gene should be promoted to green in the next GMS update.
Intellectual disability v6.33 EZH1 Achchuthan Shanmugasundram changed review comment from: PMID:37433783 reported 19 individuals from 14 unrelated families with a neurodevelopmental disorder manifested early in life as global motor, speech and cognitive delay leading to intellectual disability, usually non-progressive and co-occurring with dysmorphic facial features. Nine individuals from seven families were identified with monoallelic variants and ten individuals from seven families were identified with biallelic variants.

This gene has been associated with relevant phenotypes in Gene2Phenotype (both monoallelic and biallelic disorders rated 'moderate' on the DD panel), but not yet in OMIM.
Sources: Literature; to: PMID:37433783 reported 19 individuals from 14 unrelated families with a neurodevelopmental disorder manifested early in life as global motor, speech and cognitive delay leading to intellectual disability, usually non-progressive and co-occurring with dysmorphic facial features. Nine individuals from seven families were identified with monoallelic variants and ten individuals from seven families were identified with biallelic variants.

Functional studies have shown that some missense EZH1 variants lead to gain of function with increased methyltransferase activity and biallelic variants impair EZH1 expression leading to loss of function effects.

This gene has been associated with relevant phenotypes in Gene2Phenotype (both monoallelic and biallelic disorders rated 'moderate' on the DD panel), but not yet in OMIM.
Sources: Literature
Intellectual disability v6.33 EZH1 Achchuthan Shanmugasundram gene: EZH1 was added
gene: EZH1 was added to Intellectual disability. Sources: Literature
Q2_24_promote_green tags were added to gene: EZH1.
Mode of inheritance for gene: EZH1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: EZH1 were set to 37433783
Phenotypes for gene: EZH1 were set to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Mode of pathogenicity for gene: EZH1 was set to Other
Review for gene: EZH1 was set to GREEN
Added comment: PMID:37433783 reported 19 individuals from 14 unrelated families with a neurodevelopmental disorder manifested early in life as global motor, speech and cognitive delay leading to intellectual disability, usually non-progressive and co-occurring with dysmorphic facial features. Nine individuals from seven families were identified with monoallelic variants and ten individuals from seven families were identified with biallelic variants.

This gene has been associated with relevant phenotypes in Gene2Phenotype (both monoallelic and biallelic disorders rated 'moderate' on the DD panel), but not yet in OMIM.
Sources: Literature
Intellectual disability v6.32 YWHAE Achchuthan Shanmugasundram changed review comment from: PMID:36999555 reported three individuals with sequence variants in YWHAE gene and six individuals with deletion variants (1 intragenic deletion and 5 large deletions encompassing YWHEA but not PAFAH1B1). In addition, five patients were previously reported with deletion variants. Only one of the three individuals with sequence variants had mild intellectual disability, while five of 12 patients with deletion variants had mild to severe intellectual disability.
Sources: Literature; to: PMID:36999555 reported three individuals with sequence variants in YWHAE gene and six individuals with deletion variants (1 intragenic deletion and 5 large deletions encompassing YWHEA but not PAFAH1B1). In addition, five patients were previously reported with deletion variants. Only one of three individuals with sequence variants had mild intellectual disability, while five of 12 patients with deletion variants had mild to severe intellectual disability.
Sources: Literature
Intellectual disability v6.32 YWHAE Achchuthan Shanmugasundram gene: YWHAE was added
gene: YWHAE was added to Intellectual disability. Sources: Literature
cnv tags were added to gene: YWHAE.
Mode of inheritance for gene: YWHAE was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: YWHAE were set to 36999555
Phenotypes for gene: YWHAE were set to neurodevelopmental disorder, MONDO:0700092
Review for gene: YWHAE was set to RED
Added comment: PMID:36999555 reported three individuals with sequence variants in YWHAE gene and six individuals with deletion variants (1 intragenic deletion and 5 large deletions encompassing YWHEA but not PAFAH1B1). In addition, five patients were previously reported with deletion variants. Only one of the three individuals with sequence variants had mild intellectual disability, while five of 12 patients with deletion variants had mild to severe intellectual disability.
Sources: Literature
Intellectual disability v6.31 STX1A Achchuthan Shanmugasundram Added comment: Comment on list classification: There are six unrelated cases reported with monoallelic variants and two siblings reported with biallelic variants. Hence, the MOI was set to 'MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted'. The rating should be updated to green in the next GMS update.
Intellectual disability v6.31 STX1A Achchuthan Shanmugasundram Added comment: Comment on list classification: There are six unrelated cases reported with monoallelic variants and two siblings reported with biallelic variants. Hence, the MOI was set to 'MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted'. The rating should be updated to green in the next GMS update.
Intellectual disability v6.31 STX1A Achchuthan Shanmugasundram Added comment: Comment on list classification: There are six unrelated cases reported with monoallelic variants and two siblings reported with biallelic variants. Hence, the MOI was set to 'MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted'. The rating should be updated to green in the next GMS update.
Intellectual disability v6.30 STX1A Achchuthan Shanmugasundram Added comment: Comment on list classification: There are six unrelated cases reported with monoallelic variants and two siblings reported with biallelic variants. Hence, the MOI was set to 'MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted'. The rating should be updated to green in the next GMS update.
Intellectual disability v6.29 STX1A Achchuthan Shanmugasundram gene: STX1A was added
gene: STX1A was added to Intellectual disability. Sources: Literature
Q2_24_promote_green tags were added to gene: STX1A.
Mode of inheritance for gene: STX1A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: STX1A were set to 36564538
Phenotypes for gene: STX1A were set to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Review for gene: STX1A was set to GREEN
Added comment: PMID:36564538 reported the identification of monoallelic STX1A variants in six unrelated individuals (five of them de novo and one unknown) and biallelic variants in two related individuals. All of them presented with a neurodevelopmental disorder and had intellectual disability (Both homozygous individuals had moderate ID, three heterozygous individuals had severe ID. one had profound ID and two had moderate ID).

This gene has been associated with relevant phenotype in Gene2Phenotype (with 'moderate' rating on the DD panel), but has not yet been associated with phenotypes in OMIM.
Sources: Literature
Intellectual disability v6.27 WDR5 Achchuthan Shanmugasundram gene: WDR5 was added
gene: WDR5 was added to Intellectual disability. Sources: Literature
Q2_24_promote_green tags were added to gene: WDR5.
Mode of inheritance for gene: WDR5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: WDR5 were set to 36408368
Phenotypes for gene: WDR5 were set to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Mode of pathogenicity for gene: WDR5 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: WDR5 was set to GREEN
Added comment: PMID:36408368 reported the identification of six different de novo missense variants in 11 affected individuals with a neurodevelopmental disorder with a broad spectrum of additional features, including epilepsy, aberrant growth parameters, skeletal and cardiac abnormalities. 9 of 11 probands have intellectual disability (five with moderate ID, three with mild ID and one with borderline ID).

In vivo and in vitro functional studies suggested that loss-of-function is not the mechanism of disease. However, the mechanism of disease is yet to be established.

This gene has been associated with relevant phenotype in Gene2Phenotype (with 'moderate' rating on the DD panel), but not associated with phenotypes in OMIM.
Sources: Literature
Intellectual disability v6.25 FAM177A1 Achchuthan Shanmugasundram gene: FAM177A1 was added
gene: FAM177A1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: FAM177A1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FAM177A1 were set to 25558065; 38767059
Phenotypes for gene: FAM177A1 were set to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Review for gene: FAM177A1 was set to GREEN
Added comment: PMID:25558065 reported a study of 143 multiplex consanguineous families, on which a homozygous frameshift variant in FAM177A1 gene was identified in a family with four affected siblings with intellectual disability, dolicocephaly, obesity, and macrocephaly. The variant segregated with all 4 affected siblings and parents were confirmed heterozygous carriers.

PMID:38767059 reported five individuals from three unrelated families with biallelic loss of function variants in FAM177A1 gene. They presented with clinical manifestations including global developmental delay, intellectual disability, seizures, behavioural abnormalities, hypotonia, gait disturbance, and macrocephaly.

This gene has not yet been associated with relevant phenotypes either in OMIM or in Gene2Phenotype.
Sources: Literature
Intellectual disability v6.18 RNU4-2 Arina Puzriakova Added comment: Comment on list classification: The two papers (PMID: 38821540; 38645094) corroborate mutual findings and report over 100 unrelated individuals with a clinically overlapping neurological disorder and variants the non-coding gene RNU4-2.

Overall there is sufficient evidence to promote this gene to Green status at the next GMS panel update.
Intellectual disability v6.17 RNU4-2 Arina Puzriakova Tag locus-type-rna-small-nuclear tag was added to gene: RNU4-2.
Tag Q2_24_promote_green tag was added to gene: RNU4-2.
Intellectual disability v6.16 ITSN1 John Taylor gene: ITSN1 was added
gene: ITSN1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: ITSN1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ITSN1 were set to Bruel et al., 2021 (PMID: 34707297):
Phenotypes for gene: ITSN1 were set to autism spectrum disorders; intellectual disability; epilepsy.
Penetrance for gene: ITSN1 were set to unknown
Review for gene: ITSN1 was set to GREEN
gene: ITSN1 was marked as current diagnostic
Added comment: Bruel et al 2021 (PMID: 34707297):
Recent studies in large cohorts of subjects with neurodevelopmental disorders have identified de novo variants in ITSN1 gene thereby suggesting that this gene is involved in the development of such disorders.

A worldwide collaboration identified ten novel patients from eight families with heterozygous truncating or missense variants in ITSN1 gene. All patients underwent detailed phenotypic and genetic assessment and data was collected and shared by healthcare givers.

In addition, four previously published patients from large meta-analysis studies were included.
In total, 7/14 patients presented a de novo variant in ITSN1. Frameshift, nonsense and splice site variants would be consistent with haploinsufficiency. gnomADv4.1 indicates the ITSN1 gene is intolerant to LoF variants and Decipher indicates a high haploinsufficiency index score.

All patients showed neurodevelopmental disorders from autism spectrum disorders (90%), intellectual disability (86%), and epilepsy (30%). Minor and inconstant dysmorphic features were observed. Gastro-intestinal problems including constipation, diarrhoea, and gastroesophageal reflux was reported in some patients. Intellectual disability (IQ test) was reported to range from mild to moderate. In two families, the ITSN1 variant was inherited from a paucisymptomatic father, who were reported to present with ADHD, or learning difficulties and autistic features. Patients 8,9, and 10 (Bruel et al., 2021) inherited the familial nonsense variant from their father (learning difficulties and autistic features) and one unaffected sibling was not found to have the variant.
Sources: Literature
Intellectual disability v6.16 ANO4 Sarah Leigh commented on gene: ANO4: To date, no phenotype has been associated with ANO4 variants in OMIM, Gen2Phen or Mondo.
Intellectual disability v6.14 ANO4 Sarah Leigh gene: ANO4 was added
gene: ANO4 was added to Intellectual disability. Sources: Literature
Q2_24_promote_green, Q2_24_MOI tags were added to gene: ANO4.
Mode of inheritance for gene: ANO4 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ANO4 were set to 38744284
Mode of pathogenicity for gene: ANO4 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: ANO4 was set to GREEN
Added comment: PMID: 38744284 reports five de novo ANO4 missense variants in patients (I1–I5) with a phenotype that includes intellectual disability, developmental and epileptic or epileptic encephalopathy (DEE/EE) and hypotonia. A further two ANO4 missenses variants were observed, one had been inherited from unaffected mother (patient F7) and with a penetrance of 73% in members of a large pedigree with a milder phenotype (PMID: 38744284: Supplementary figure S2). Febrile seizures plus (GEFS+) or temporal lobe epilepsy were associated with these inherited variants. A dominant negative mechanism was proposed by Yang et al (PMID: 38744284) as a result of functional studies of one of the variants causing DEE/EE and one causing GEFS+.
Sources: Literature
Intellectual disability v6.12 ARF3 Eleanor Williams Tag gene-checked tag was added to gene: ARF3.
Intellectual disability v6.12 MAST3 Sarah Leigh Entity copied from Early onset or syndromic epilepsy v5.10
Intellectual disability v6.12 MAST3 Sarah Leigh gene: MAST3 was added
gene: MAST3 was added to Intellectual disability. Sources: Expert Review Amber,Literature
Q2_24_promote_green, Q2_24_MOI tags were added to gene: MAST3.
Mode of inheritance for gene: MAST3 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: MAST3 were set to 34185323; 35095415
Mode of pathogenicity for gene: MAST3 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Intellectual disability v6.11 ARF3 Achchuthan Shanmugasundram Tag Q4_23_promote_green was removed from gene: ARF3.
Intellectual disability v6.11 FAR1 Achchuthan Shanmugasundram Tag to_be_confirmed_NHSE was removed from gene: FAR1.
Intellectual disability v6.11 FAR1 Sarah Leigh commented on gene: FAR1: The mode of inheritance of this gene has been updated to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.
Intellectual disability v6.11 ARF3 Sarah Leigh reviewed gene: ARF3: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v6.10 FAR1 Achchuthan Shanmugasundram Source NHS GMS was added to FAR1.
Mode of inheritance for gene FAR1 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Intellectual disability v6.10 ARF3 Achchuthan Shanmugasundram Source Expert Review Green was added to ARF3.
Source NHS GMS was added to ARF3.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v6.9 DPP6 Arina Puzriakova Phenotypes for gene: DPP6 were changed from autosomal dominant microcephaly and mental retardation; Mental retardation, autosomal dominant 33, 616311 to Intellectual developmental disorder, autosomal dominant 33, OMIM:616311
Intellectual disability v6.7 CASP2 Arina Puzriakova Phenotypes for gene: CASP2 were changed from neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071 to Intellectual developmental disorder, autosomal recessive 80, with variant lissencephaly, OMIM:620653
Intellectual disability v6.5 ISCA-46743-Loss Arina Puzriakova changed review comment from: The rating of this region has been updated to Green and the mode of inheritance set to 'X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)' following NHS Genomic Medicine Service approval. Evidence: multiple unrelated cases curated in ClinGen plus several others - sufficient evidence for this region. Phenotype: syndromic intellectual disability (congenital anomalies, behavioural problems and facial dysmorphism), seizures in about 30%. Modulated phenotype in females is reported.; to: The rating of this region has been updated to Green and the mode of inheritance set to 'X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)' following NHS Genomic Medicine Service approval. Evidence: two cases (PMID: 30158690; 33758131) with intragenic STAG2 deletions but listed as sufficient evidence in ClinGen. Region encompasses STAG2 and some of XIAP. Phenotype: holoprosencephaly and/or developmental delay/ID based on LOF of STAG2 gene. Affected females are reported.
Intellectual disability v5.558 Arina Puzriakova Panel name changed from Intellectual disability - microarray and sequencing to Intellectual disability
List of related panels changed from Coarse facial features including Coffin-Siris-like disorders; ID; Moderate; severe or profound intellectual disability; Schizophrenia plus additional features; Intellectual disability - microarray; fragile X and sequencing; Intellectual disability; R29 to Coarse facial features including Coffin-Siris-like disorders; ID; Moderate; severe or profound intellectual disability; Schizophrenia plus additional features; Intellectual disability - microarray; fragile X and sequencing; Intellectual disability - microarray and sequencing; R29
Intellectual disability v5.557 ADGRL1 Dmitrijs Rots gene: ADGRL1 was added
gene: ADGRL1 was added to Intellectual disability - microarray and sequencing. Sources: Literature
Mode of inheritance for gene: ADGRL1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ADGRL1 were set to PubMed: 35907405
Phenotypes for gene: ADGRL1 were set to Developmental delay, behavioral abnormalities, and neuropsychiatric disorders
Review for gene: ADGRL1 was set to GREEN
Added comment: More than 10 cases described in PubMed: 35907405
Sources: Literature
Intellectual disability v5.555 DOCK4 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Zornitza Stark, PMID:38526744 reported seven unrelated individuals with heterozygous variants and with developmental delay or intellectual disability, of which four had ID. Three of them with ID had heterozygous variants, while one had compound heterozygous variants. There is also some functional evidence available.

Hence, this gene can be promoted to green rating in the next GMS review.
Intellectual disability v5.552 GTF3C5 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: As reviewed by Zornitza Stark, PMID:35503477 reported a proband with profound developmental delay and PMID:38520561 reported three families with syndromic intellectual disability (ID was mild in one family). There is also functional evidence and evidence from zebrafish model in support of the disease association.

Hence, the gene can be promoted to green rating in the next GMS review.; to: Comment on list classification: As reviewed by Zornitza Stark, PMID:35503477 reported a proband with profound developmental delay and PMID:38520561 reported three families with syndromic intellectual disability (ID was mild in one family). There is also functional evidence and evidence from zebrafish model in support of the disease association.

Hence, this gene can be promoted to green rating in the next GMS review.
Intellectual disability v5.552 GTF3C5 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Zornitza Stark, PMID:35503477 reported a proband with profound developmental delay and PMID:38520561 reported three families with syndromic intellectual disability (ID was mild in one family). There is also functional evidence and evidence from zebrafish model in support of the disease association.

Hence, the gene can be promoted to green rating in the next GMS review.
Intellectual disability v5.548 IGF1 Arina Puzriakova Phenotypes for gene: IGF1 were changed from Growth retardation with deafness and mental retardation due to IGF1 deficiency, 608747; INSULIN-LIKE GROWTH FACTOR I DEFICIENCY (IGF1 DEFICIENCY) to Insulin-like growth factor I deficiency, OMIM:608747
Intellectual disability v5.543 PCNT Arina Puzriakova Phenotypes for gene: PCNT were changed from Microcephalic osteodysplastic primordial dwarfism, type II, 210720 -3; MICROCEPHALIC OSTEODYSPLASTIC PRIMORDIAL DWARFISM, TYPE II to Microcephalic osteodysplastic primordial dwarfism, type II, OMIM:210720
Intellectual disability v5.542 RNU4ATAC Arina Puzriakova Phenotypes for gene: RNU4ATAC were changed from Gene2Phenotype confirmed gene with ID HPO to Lowry-Wood syndrome, OMIM:226960; Microcephalic osteodysplastic primordial dwarfism, type I, OMIM:210710; Roifman syndrome, OMIM:616651
Intellectual disability v5.540 XRCC4 Arina Puzriakova Phenotypes for gene: XRCC4 were changed from PRIMORDIAL DWARFISM to Short stature, microcephaly, and endocrine dysfunction, OMIM:616541
Intellectual disability v5.536 FEM1B Zornitza Stark edited their review of gene: FEM1B: Added comment: Five individuals reported now with same recurrent missense variant, NM_015322.5:c.377G>A NP_056137.1:p.(Arg126Gln). Affected individuals shared a severe neurodevelopmental disorder with behavioral phenotypes and a variable set of malformations, including brain anomalies, clubfeet, skeletal abnormalities, and facial dysmorphism. Overexpression of the the FEM1BR126Q variant but not FEM1B wild-type protein, during mouse brain development, resulted in delayed neuronal migration of the target cells.; Changed rating: GREEN; Changed publications to: 31036916, 38465576; Changed phenotypes to: Syndromic disease MONDO:0002254, FEM1B-related
Intellectual disability v5.536 RNU4-2 Zornitza Stark gene: RNU4-2 was added
gene: RNU4-2 was added to Intellectual disability - microarray and sequencing. Sources: Literature
Mode of inheritance for gene: RNU4-2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RNU4-2 were set to 38645094
Phenotypes for gene: RNU4-2 were set to Neurodevelopmental disorder, MONDO:0700092, RNU4-2 related
Review for gene: RNU4-2 was set to GREEN
Added comment: Over 100 individuals reported with NND and heterozygous variants in a 18 bp region of RNU4-2 mapping to two structural elements in the U4/U6 snRNA duplex (the T-loop and Stem III). The vast majority of individuals (77.3%) have the same highly recurrent single base-pair insertion (n.64_65insT). Variants in this region likely explain 0.41% of individuals with NDD.
Sources: Literature
Intellectual disability v5.535 GLI3 Arina Puzriakova Phenotypes for gene: GLI3 were changed from Greig cephalopolysyndactyly syndrome, 175700Pallister-Hall syndrome, 146510Polydactyly, preaxial, type IV, 174700Polydactyly, postaxial, types A1 and B, 174200{Hypothalamic hamartomas, somatic}, 241800; GREIG CEPHALOPOLYSYNDACTYLY SYNDROME to Greig cephalopolysyndactyly syndrome, OMIM:175700; Pallister-Hall syndrome, OMIM:146510
Intellectual disability v5.533 GLI3 Arina Puzriakova Added comment: Comment on list classification: Reassessed in view of the Red review by Tracy Lester on this Green gene

Rarely, individuals with Greig cephalopolysyndactyly syndrome or GLI3-Related Pallister-Hall syndrome have been found to have intellectual disability (PMID: 12414818; 14708104; 14608643; 34296525). This is usually observed in the most severely affected individuals and those with large deletions encompassing GLI3. The majority of patients have normal psychomotor development or only some mild delays. All GLI3-related disorders are more likely to be recognised in context of other features such as skeletal abnormalities.

Overall, I therefore agree that this gene could be demoted to Amber at the next GMS panel update.
Intellectual disability v5.532 KCNB2 Zornitza Stark gene: KCNB2 was added
gene: KCNB2 was added to Intellectual disability - microarray and sequencing. Sources: Literature
Mode of inheritance for gene: KCNB2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KCNB2 were set to 38503299
Phenotypes for gene: KCNB2 were set to neurodevelopmental disorder MONDO:0700092, KCNB2-related
Review for gene: KCNB2 was set to GREEN
Added comment: 7 individuals, all missense
5 de novo + 1x inherited from father who has hypotonia + 1x from asymptomatic father

2/5 MRI anomalies
2/5 cardiac anomalies
2/7 urogenital anomalies
7/7 with ID
2/7 epilepsy
2/7 hypotonia
Sources: Literature
Intellectual disability v5.532 GTF3C5 Zornitza Stark gene: GTF3C5 was added
gene: GTF3C5 was added to Intellectual disability - microarray and sequencing. Sources: Literature
Mode of inheritance for gene: GTF3C5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GTF3C5 were set to 38520561; 35503477
Phenotypes for gene: GTF3C5 were set to neurodevelopmental disorder MONDO:0700092, GTF3C5-related
Review for gene: GTF3C5 was set to GREEN
Added comment: 4 families/probands with syndromic ID. Loss of function is the expected mechanism.
PMID: 38520561 - Biallelic variants identified (3 missense & 1 stopgain) in 4 individuals from 3 families presenting with multisystem developmental syndrome including the features: growth retardation, developmental delay, intellectual disability, dental anomalies, cerebellar malformations, delayed bone age, skeletal anomalies, and facial dysmorphism. Gene-disease relationship supported by: reduced protein expression in patient cells, yeast assays, and a zebrafish model
PMID: 35503477 - 1 proband with biallelic missense variants and hypomelanosis of Ito, seizures, growth retardation, abnormal brain MRI, developmental delay, and facial dysmorphism
Sources: Literature
Intellectual disability v5.532 DOCK4 Zornitza Stark gene: DOCK4 was added
gene: DOCK4 was added to Intellectual disability - microarray and sequencing. Sources: Literature
Mode of inheritance for gene: DOCK4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: DOCK4 were set to 38526744
Phenotypes for gene: DOCK4 were set to DOCK4-related neurodevelopmental disorder (MONDO:0060490)
Review for gene: DOCK4 was set to GREEN
Added comment: 7 unrelated individuals reported with heterozygous variants (missense or null variants) in DOCK4. The individuals either had ID or DD between mild and moderate with brain abnormalities. Two of the individuals are reportedly compound heterozygous.

Functional assay neuro-2A Dock4 knockout cells by using the Alt-R CRISPR-Cas9 system utilizing two different guide RNAs (ko1 and ko2) and one nonspecific control guide RNA (C: control). The assay depicted the loss of function mechanism in the presence of either p.Arg853Leu and p.Asp946_Lys1966delinsValSer* (described as 945VS).
Sources: Literature
Intellectual disability v5.532 PLXNB2 Zornitza Stark gene: PLXNB2 was added
gene: PLXNB2 was added to Intellectual disability - microarray and sequencing. Sources: Literature
Mode of inheritance for gene: PLXNB2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PLXNB2 were set to 38458752
Phenotypes for gene: PLXNB2 were set to Syndromic disease MONDO:0002254, PLXNB2 -related
Review for gene: PLXNB2 was set to GREEN
Added comment: 8 individuals from 6 families with core features of amelogenesis imperfecta and sensorineural hearing loss. Intellectual disability, ocular disease, ear developmental abnormalities and lymphoedema were also present in multiple cases. WES and WGS identified biallelic pathogenic variants in PLXNB2 (missense, nonsense, splice and a multiexon deletion variants). Variants segregated with disease.

PLXNB2 is a large transmembrane semaphorin receptor protein, and semaphorin-plexin signalling controls cellular interactions that are critical during development as well as in adult life stages. Plxnb2 expression was detected in differentiating ameloblasts in mice. Human phenotype overlaps with that seen in Plxnb2 knockout mice.
Sources: Literature
Intellectual disability v5.532 CEP295 Zornitza Stark gene: CEP295 was added
gene: CEP295 was added to Intellectual disability - microarray and sequencing. Sources: Expert Review
Mode of inheritance for gene: CEP295 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CEP295 were set to 38154379
Phenotypes for gene: CEP295 were set to Seckel syndrome 11, OMIM # 620767
Added comment: 4 children from 2 unrelated families with Seckel-like syndrome - severe primary microcephaly, short stature, developmental delay, intellectual disability, facial deformities, and abnormalities of fingers and toes. WES identified biallelic pathogenic variants in CEP295 gene (p(Q544∗) and p(R1520∗); p(R55Efs∗49) and p(P562L)).

Patient-derived fibroblasts and CEP295-depleted U2OS and RPE1 cells were used to clarify the underlying mechanisms. Depletion of CEP295 resulted in a decrease in the numbers of centrioles and centrosomes and triggered p53-dependent G1 cell cycle arrest. Loss of CEP295 caused extensive primary ciliary defects in both patient-derived fibroblasts and RPE1 cells. The results from complementary experiments revealed that the wild-type CEP295, but not the mutant protein, can correct the developmental defects of the centrosome/centriole and cilia in the patient-derived skin fibroblasts.
Sources: Expert Review
Intellectual disability v5.532 SMAD3 Achchuthan Shanmugasundram changed review comment from: Two out of six cases with single nucleotide variants from DECIPHER database (https://www.deciphergenomics.org/gene/SMAD3/patient-overlap/snvs )were reported with global developmental delay. However, intellectual disability or global developmental delay were not reported as clinical presentations in patients with Loeys-Dietz syndrome 3 (MIM #613795).; to: Two out of six cases with single nucleotide variants from DECIPHER database (https://www.deciphergenomics.org/gene/SMAD3/patient-overlap/snvs) were reported with global developmental delay. However, intellectual disability or global developmental delay were not reported as clinical presentations in patients with Loeys-Dietz syndrome 3 (MIM #613795). Hence the rating should remain amber with current evidence.
Intellectual disability v5.531 GAN Arina Puzriakova changed review comment from: Comment on list classification: Biallelic variants in the GAN gene cause giant axonal neuropathy, characterised by abnormalities in the peripheral and central nervous systems. Though extent of CNS involvement can vary, intellectual disability has been reported in at least 3 unrelated cases to date (PMID: 18595793; 19231187). Therefore, this gene should be promoted to Green at the next GMS panel update.; to: Comment on list classification: Biallelic variants in the GAN gene cause giant axonal neuropathy, characterised by abnormalities in the peripheral and central nervous systems. Though extent of CNS involvement can vary, intellectual disability has been reported in at least 3 unrelated cases (PMID: 18595793; 19231187). Therefore, this gene should be promoted to Green at the next GMS panel update.
Intellectual disability v5.530 GAN Arina Puzriakova Added comment: Comment on list classification: Biallelic variants in the GAN gene cause giant axonal neuropathy, characterised by abnormalities in the peripheral and central nervous systems. Though extent of CNS involvement can vary, intellectual disability has been reported in at least 3 unrelated cases to date (PMID: 18595793; 19231187). Therefore, this gene should be promoted to Green at the next GMS panel update.
Intellectual disability v5.525 SEPHS1 Arina Puzriakova gene: SEPHS1 was added
gene: SEPHS1 was added to Intellectual disability - microarray and sequencing. Sources: Literature
Q2_24_promote_green tags were added to gene: SEPHS1.
Mode of inheritance for gene: SEPHS1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SEPHS1 were set to 38531365
Phenotypes for gene: SEPHS1 were set to Neurodevelopmental disorder, MONDO:0700092
Review for gene: SEPHS1 was set to GREEN
Added comment: Mullegama et al. (2024) reported 9 individuals from 8 families with developmental delay, growth and feeding problems, hypotonia, and dysmorphic features, all with heterozygous missense variants in SEPHS1. Eight individuals shared different missense variants at the same p.Arg371 residue in SEPHS1 (p.Arg371Trp, p.Arg371Gln, and p.Arg371Gly); seven of these variants were confirmed as de novo (one unknown). Functional studies showed that variants at the Arg371 residue impact direct protein-protein interactions of SEPSH1 and enhance cell proliferation by modulating ROS homeostasis.
Sources: Literature
Intellectual disability v5.524 ADA Arina Puzriakova Phenotypes for gene: ADA were changed from Severe combined immunodeficiency due to ADA deficiency, 102700; Adenosine deaminase deficiency, partial, 102700 to Severe combined immunodeficiency due to ADA deficiency, OMIM:102700; Adenosine deaminase deficiency, partial, OMIM:102700
Intellectual disability v5.523 FRYL Arina Puzriakova Added comment: Comment on list classification: Rating Amber as overall the evidence is borderline. Only one recent study (PMID:38479391) has reported an disease association for FRYL, with variable phenotypes and results from functional studies, as well as variants in other genes in several cases. Additional studies are required to conclusively corroborate causality (added watchlist tag).
Intellectual disability v5.522 FRYL Arina Puzriakova gene: FRYL was added
gene: FRYL was added to Intellectual disability - microarray and sequencing. Sources: Literature
watchlist tags were added to gene: FRYL.
Mode of inheritance for gene: FRYL was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FRYL were set to 38479391
Phenotypes for gene: FRYL were set to Neurodevelopmental disorder, MONDO:0700092
Review for gene: FRYL was set to AMBER
Added comment: New association linking this gene to disease which is not yet listed in OMIM or Gene2Phenotype. There are no sequence variants in Decipher and ClinVar shows only a single pathogenic frameshift variant (c.1224del, p.Lys409fs) for FRYL-associated neurodevelopmental disorder, amongst multiple SNVs which are mostly missense VUS or B/LB.

Pan et al., 2024 (PMID: 38479391) reported 14 individuals with heterozygous variant in FRYL who presented with DD/ID, dysmorphic features, and other congenital anomalies in multiple systems. Except for DD/ID which was the only universal feature, observed phenotypes were variable and nonspecific.

Variants were confirmed de novo in all except one individual (duo testing excluded paternal inheritance although it was present at low frequency in gnomAD). Variant types include missense (5), fs/stop-gain (8) and canonical splice (1). Modelling 4/5 patient missense variants using flies showed that only one serves as a severe LoF variant, two others behave as partial LoF variants, and one variant had no functional impact (only variant not confirmed as de novo indicating this is a VUS). Four individuals also had P/LP variants in other genes (SF3B4, DHCR7, SLC6A19, SDHA) which could at least partially explain their phenotypes, and a further four harboured additional VUSs.
Sources: Literature
Intellectual disability v5.520 DENND5B Sarah Leigh gene: DENND5B was added
gene: DENND5B was added to Intellectual disability - microarray and sequencing. Sources: Literature
Mode of inheritance for gene: DENND5B was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: DENND5B were set to 38387458
Phenotypes for gene: DENND5B were set to DENND5B associated neurodevelopmental disorder
Review for gene: DENND5B was set to GREEN
Added comment: DENND5B variants have not previously been associated with a phenotype in OMIM, Gen2Phen or MONDO. PMID: 38387458 reports five de novo missense variants in five unrelated cases. The carriers of these DENND5B variants have a neurodevelopmental disorder, which is characterized by psychomotor delay (5/5 cases), intellectual disability, ranging from severe to mild (3/5 cases, although one of the negative cases was a 2 year old child, who was considered to be too young to make the assessment, although the DD/intellectual disability phenotype was considered to be moderate in this case), epilepsy (2/5 cases) and hypotonia (4/5 cases). The authors of PMID: 38387458 also report the functional effects of the DENND5B variants, which revealed defective intracellular vesicle trafficking, with significant impairment of lipid uptake and distribution. They conclude that this effect is likely to be caused by the predicted disruption of protein folding in the variant DENND5B peptide.
Sources: Literature
Intellectual disability v5.517 TBC1D2B Sarah Leigh Phenotypes for gene: TBC1D2B were changed from Global developmental delay; Intellectual disability; Seizures; Gingival overgrowth; Behavioral abnormality; Abnormality of the mandible; Abnormality of brain morphology; Abnormality of the eye; Hearing abnormality to Neurodevelopmental disorder with seizures and gingival overgrowth, OMIM:619323; neurodevelopmental disorder with seizures and gingival overgrowth, MONDO:0859148
Intellectual disability v5.515 ASCC3 Arina Puzriakova Phenotypes for gene: ASCC3 were changed from AUTOSOMAL RECESSIVE MENTAL RETARDATION to Intellectual developmental disorder, autosomal recessive 81, OMIM:620700
Intellectual disability v5.514 PTRHD1 Arina Puzriakova Added comment: Comment on phenotypes: Gene-checked tag removed as this gene now has a relevant phenotype listed in OMIM (Neurodevelopmental disorder with early-onset parkinsonism and behavioral abnormalities, OMIM:620747)
Intellectual disability v5.514 PTRHD1 Arina Puzriakova Phenotypes for gene: PTRHD1 were changed from Intellectual disability; Parkinsonism to Neurodevelopmental disorder with early-onset parkinsonism and behavioral abnormalities, OMIM:620747
Intellectual disability v5.512 BRD4 Arina Puzriakova Phenotypes for gene: BRD4 were changed from Intellectual disability; Microcephaly; Abnormal heart morphology; Abnormality of the face to Cornelia de Lange syndrome 6, OMIM:620568
Intellectual disability v5.510 CAPRIN1 Arina Puzriakova Added comment: Comment on phenotypes: Gene-checked tag removed as this gene now has a phenotype listed in OMIM (Neurodegeneration, childhood-onset, with cerebellar ataxia and cognitive decline, OMIM:620636)
Intellectual disability v5.510 CAPRIN1 Arina Puzriakova Phenotypes for gene: CAPRIN1 were changed from Global developmental delay; Delayed speech and language development; Intellectual disability; Autistic behaviour; Seizures to Neurodegeneration, childhood-onset, with cerebellar ataxia and cognitive decline, OMIM:620636
Intellectual disability v5.506 SRCAP Arina Puzriakova Phenotypes for gene: SRCAP were changed from Floating-Harbor syndrome, 136140; FLOATING-HARBOR SYNDROME to Developmental delay, hypotonia, musculoskeletal defects, and behavioral abnormalities, OMIM:619595; Floating-Harbor syndrome, OMIM:136140
Intellectual disability v5.505 ABHD5 Arina Puzriakova Phenotypes for gene: ABHD5 were changed from Chanarin-Dorfman syndrome, 275630; CHANARIN-DORFMAN SYNDROME (CDS) to Chanarin-Dorfman syndrome, OMIM:275630
Intellectual disability v5.504 STAMBP Arina Puzriakova Phenotypes for gene: STAMBP were changed from MICROCEPHALY CAPILLARY MALFORMATION (MIC-CAP) SYNDROME to Microcephaly-capillary malformation syndrome, OMIM:614261
Intellectual disability v5.502 CLEC16A Sarah Leigh edited their review of gene: CLEC16A: Added comment: Heterozygous CLEC16A variants have been identified as a genetic risk factor for several autoimmune disorders and for Parkinson disease (PMID: 37175930). PMID: 36538041 reports the neurological effect of homozygous terminating CLEC16A variants in two families. In family 1, the first child died at 5 months, he had progressive microcephaly, failure to thrive and cranial CT showed brain atrophy, dilatation of both central and peripheral liquor spaces, hypoplasia of the corpus callosum (no genetic testing was done), the third pregnancy was terminated (17 weeks of gestation) after prenatal ultrasound showed ventriculomegaly, agenesis of corpus callosum (no genetic testing was done), the fourth pregnancy was also terminated (22 weeks of gestation) as the prenatal ultrasound showed agenesis of corpus callosum. This fetus was homozygous for NM_001243403.1(CLEC16A):c.2062 + 5G > A, RT-PRC showed that this variant resulted in the deletion of exon 19 and a frame shift. Both parents and an unaffected sibling were heterozygous for this variant. In family 2, a single affected child was homozygous for NM_001243403.1(CLEC16A):c.-4_12del, p.Met1fs*. This child had progressive microcephaly, failure to thrive, severe global developmental delay, global brain atrophy and died at 6 years. There is no genetic data from the parents or unaffected siblings in Family 2. PMID: 37175930, also presents zebrafish experiments, where mutagenesis of
clec16a by CRISPR–Cas9 resulted in accumulated acidic/phagolysosome compartments, in neurons
and microglia, and dysregulated mitophagy. This was rescued by wild type CLEC16A, but not by the C-terminal truncated variant. The authors conclude that dysregulation of CLEC16A-mediated endosomal sorting is associated with neurodegeneration.; Changed rating: GREEN; Changed publications to: 36538041; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v5.499 ZFHX3 Sarah Leigh edited their review of gene: ZFHX3: Added comment: Personal communication from Nour Elkhateeb (Clinical Fellow in Genomics, Genomics England): we have data about 12 individuals with nonsense/frameshift/exon deletions in ZFHX3. Five of the variants are located in exon 9/10 or exon 9, which has been shown to harbour the highest density of pathogenic variants (PMID: 38412861). Eleven of these cases presented with developmental delay / intellectual disability and a range of other features, including dysmorphology, seizures and failure to thrive.; Changed publications to: 38412861
Intellectual disability v5.498 ZFHX3 Sarah Leigh gene: ZFHX3 was added
gene: ZFHX3 was added to Intellectual disability - microarray and sequencing. Sources: Literature
Mode of inheritance for gene: ZFHX3 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ZFHX3 were set to 38412861; 38035881; 37292950
Phenotypes for gene: ZFHX3 were set to syndromic intellectual disability
Intellectual disability v5.497 SPATA5 Arina Puzriakova Phenotypes for gene: SPATA5 were changed from Epilepsy, hearing loss, and mental retardation syndrome, 616577 to Neurodevelopmental disorder with hearing loss, seizures, and brain abnormalities, OMIM:616577
Intellectual disability v5.496 SNF8 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are three unrelated cases with intellectual disability and hence this gene can be promoted to green rating in the next GMS review.
Intellectual disability v5.495 SNF8 Achchuthan Shanmugasundram changed review comment from: PMID:38423010 reported nine individuals from six families presenting with a spectrum of neurodevelopmental/ neurodegenerative features caused by biallelic variants in SNF8. The phenotypic spectrum included four individuals with severe developmental and epileptic encephalopathy with leukoencephalopathy and early death in three of those cases. Two individuals died too young to develop epilepsy. A second cohort shows a milder phenotype with intellectual disability, childhood-onset optic atrophy, or ataxia. All mildly affected individuals shared the same hypomorphic variant, c.304G>A (p.Val102Ile) as compound heterozygous. Functional studies using fibroblasts derived from patients and zebrafish model showed loss of function as the disease mechanism.
Sources: Literature; to: PMID:38423010 reported nine individuals from six families presenting with a spectrum of neurodevelopmental/ neurodegenerative features caused by biallelic variants in SNF8.

The phenotypic spectrum included four individuals with severe developmental and epileptic encephalopathy with leukoencephalopathy and early death in three of those cases. Two individuals died too young to develop epilepsy. A second cohort shows a milder phenotype with intellectual disability, childhood-onset optic atrophy, or ataxia. All mildly affected individuals shared the same hypomorphic variant, c.304G>A (p.Val102Ile) as compound heterozygous.

Functional studies using fibroblasts derived from patients and zebrafish model showed loss of function as the disease mechanism.

This gene has not yet been associated with any phenotypes either in OMIM or in Gene2Phenotype.
Sources: Literature
Intellectual disability v5.495 SNF8 Achchuthan Shanmugasundram gene: SNF8 was added
gene: SNF8 was added to Intellectual disability - microarray and sequencing. Sources: Literature
Mode of inheritance for gene: SNF8 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SNF8 were set to 38423010
Phenotypes for gene: SNF8 were set to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Review for gene: SNF8 was set to GREEN
Added comment: PMID:38423010 reported nine individuals from six families presenting with a spectrum of neurodevelopmental/ neurodegenerative features caused by biallelic variants in SNF8. The phenotypic spectrum included four individuals with severe developmental and epileptic encephalopathy with leukoencephalopathy and early death in three of those cases. Two individuals died too young to develop epilepsy. A second cohort shows a milder phenotype with intellectual disability, childhood-onset optic atrophy, or ataxia. All mildly affected individuals shared the same hypomorphic variant, c.304G>A (p.Val102Ile) as compound heterozygous. Functional studies using fibroblasts derived from patients and zebrafish model showed loss of function as the disease mechanism.
Sources: Literature
Intellectual disability v5.493 DYNC2H1 Arina Puzriakova commented on gene: DYNC2H1: - PMID: 22589734 (2012) - A 29 Mb deletion encompassing DYNC2H1 was found in one patient with syndromic hirschsprung disease which included moderate mental retardation, mild hydrocephalus, microcephaly, cardiomyopathy and congenital hypotonia. Other candidate genes in this region include CNTN5 and CARD17. Skeletal findings that are typical for DYNC2H1 are not reported.

Comment on publications: PMID: 22589734 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques
Intellectual disability v5.491 ZNFX1 Sarah Leigh edited their review of gene: ZNFX1: Added comment: ZNFX1 variants are associated with Immunodeficiency 91 and hyperinflammation (OMIM:619644). Neurological involvement has been observed in at least 11 patients with OMIM:619644 (PMID:33876776;33872655). Of these, four had seizures, three had developmental regression, and one had developmental delay. The incidence of neurological involvement could be higher, but the mortality of affected children is high; in PMID:33872655 11/15 cases were deceased, with seven of these not surviving to 3 months of age.; Changed rating: GREEN
Intellectual disability v5.491 ZNFX1 Sarah Leigh gene: ZNFX1 was added
gene: ZNFX1 was added to Intellectual disability - microarray and sequencing. Sources: Literature
Mode of inheritance for gene: ZNFX1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZNFX1 were set to 33876776; 33872655
Phenotypes for gene: ZNFX1 were set to Immunodeficiency 91 and hyperinflammation, OMIM:619644; immunodeficiency 91 and hyperinflammation, MONDO:0030491
Review for gene: ZNFX1 was set to AMBER
Added comment: Sources: Literature
Intellectual disability v5.490 SRPX2 Arina Puzriakova Phenotypes for gene: SRPX2 were changed from Rolandic epilepsy, mental retardation, and speech dyspraxia, 300643 -3; ROLANDIC EPILEPSY WITH SPEECH DYSPRAXIA AND MENTAL RETARDATION X-LINKED (RESDX) to ?Rolandic epilepsy, impaired intellectual development, and speech dyspraxia, OMIM:300643
Intellectual disability v5.489 SMARCAL1 Arina Puzriakova Phenotypes for gene: SMARCAL1 were changed from Gene2Phenotype confirmed gene with ID HPO to Schimke immunoosseous dysplasia, OMIM:242900
Intellectual disability v5.488 SMARCAL1 Arina Puzriakova Publications for gene: SMARCAL1 were set to
Intellectual disability v5.487 SMARCAL1 Arina Puzriakova edited their review of gene: SMARCAL1: Changed phenotypes to: Schimke immunoosseous dysplasia, OMIM:242900
Intellectual disability v5.487 SMARCAL1 Arina Puzriakova reviewed gene: SMARCAL1: Rating: ; Mode of pathogenicity: None; Publications: 28796785, 20301550; Phenotypes: ; Mode of inheritance: None
Intellectual disability v5.487 ZFX Sarah Leigh changed review comment from: A single ZFX variant has been associated with a neurodevelopmental disorder, that has a Rett syndrome-like phenotype disorder, in a 14 year old male. The ZFX variant was allelic with another X-linked variant in SHROOM4. These variants were inherited from the mother, who had random X inactivation pattern (PMID: 26740508).
PMID: 38325380 reports 11 ZFX variants in 18 subjects from 16 unrelated families (14 males and 4 females) with an X-linked neurodevelopmental disorder with recurrent facial gestalt. Seven variants were truncating and the remaining were missense variants within the Zinc finger array. In the pedigree of family 6 (figure 3, PMID: 38325380), it was apparent that there were female carriers of the ZFX variant (GRCh38 chrX: 24229396A>G, c.2438A>G, p.Tyr774Cys) with hyperparathyroidism and two affected males and one affected female, with the neurodevelopmental disorder. It appeared that skewed X-inactivation in the female carriers was responsible for the different phenotypic features. The association between ZFX variants and a novel neurodevelopmental disorder, was further supported by functional studies showing altered transcriptional activity in missense variants and altered behavior in a zebrafish loss-of-function model.; to: To date, germline variants in ZFX have not been associated with a phenotype in OMIM or Gen2Phen.
A single ZFX variant has been associated with a neurodevelopmental disorder, that has a Rett syndrome-like phenotype disorder, in a 14 year old male. The ZFX variant was allelic with another X-linked variant in SHROOM4. These variants were inherited from the mother, who had random X inactivation pattern (PMID: 26740508).
PMID: 38325380 reports 11 ZFX variants in 18 subjects from 16 unrelated families (14 males and 4 females) with an X-linked neurodevelopmental disorder with recurrent facial gestalt. Seven variants were truncating and the remaining were missense variants within the Zinc finger array. In the pedigree of family 6 (figure 3, PMID: 38325380), it was apparent that there were female carriers of the ZFX variant (GRCh38 chrX: 24229396A>G, c.2438A>G, p.Tyr774Cys) with hyperparathyroidism and two affected males and one affected female, with the neurodevelopmental disorder. It appeared that skewed X-inactivation in the female carriers was responsible for the different phenotypic features. The association between ZFX variants and a novel neurodevelopmental disorder, was further supported by functional studies showing altered transcriptional activity in missense variants and altered behavior in a zebrafish loss-of-function model.
Intellectual disability v5.485 AFF2 Arina Puzriakova Phenotypes for gene: AFF2 were changed from Mental retardation, X-linked, FRAXE type, 309548; FRAXE Syndrome; FRAGILE X-E MENTAL RETARDATION SYNDROME (FRAXE) to Intellectual developmental disorder, X-linked 109, OMIM:309548; Fragile XE syndrome (FRAXE)
Intellectual disability v5.483 PPP2R2B Arina Puzriakova edited their review of gene: PPP2R2B: Added comment: - PMID: 25356899 (2014) - missense variant (c.413G>C, p.Arg138Pro) in the PPP2R2B gene identified in a 7-year-old boy with moderate ID, intractable seizures and autistic features. Otherwise limited information provided.

Comment on publications: PMID: 25356899 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques; Changed publications to: 25356899; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v5.483 NXF5 Arina Puzriakova Added comment: Comment on list classification: Maintaining Red rating as evidence linking this gene to ID is not definitive since patient variants have involved multiple genes and no cases of SNVs in the NXF5 gene have been reported.
Intellectual disability v5.482 NXF5 Arina Puzriakova Added comment: Comment on publications: PMID: 23675524 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques
Intellectual disability v5.480 NHEJ1 Arina Puzriakova Phenotypes for gene: NHEJ1 were changed from Severe combined immunodeficiency with microcephaly, growth retardation, and sensitivity to ionizing radiation to Severe combined immunodeficiency with microcephaly, growth retardation, and sensitivity to ionizing radiation, OMIM:611291
Intellectual disability v5.479 KIRREL3 Arina Puzriakova Added comment: Comment on publications: New publication added - PMID:25902260. This paper was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques

Provides review of cases in literature and functional studies demonstrating brain expressed proteins that interact with the KIRREL3 using yeast two-hybrid screening supporting a link to neurological and cognitive disorders. They also show KIRREL3 localisation to the Golgi complex and synaptic secretary vesicles.
Intellectual disability v5.478 KIF26B Arina Puzriakova Phenotypes for gene: KIF26B were changed from to Progressive microcephaly, pontocerebellar hypoplasia, and arthrogryposis
Intellectual disability v5.477 INTS1 Arina Puzriakova Phenotypes for gene: INTS1 were changed from Neurodevelopmental disorder with cataracts, poor growth, and dysmorphic facies, 618571; Hypotonia; Global developmental delay; Cataract; Abnormality of the skeletal system to Neurodevelopmental disorder with cataracts, poor growth, and dysmorphic facies, OMIM:618571
Intellectual disability v5.475 INTS8 Arina Puzriakova Phenotypes for gene: INTS8 were changed from to ?Neurodevelopmental disorder with cerebellar hypoplasia and spasticity, OMIM:618572
Intellectual disability v5.474 EFNB1 Arina Puzriakova Added comment: Comment on list classification: Upgrading from Red to Amber as a literature search did reveal evidence to suggest that some individuals may develop intellectual deficits. However, in most affected cases this was a mild presentation and there are more prominent and recognisable features observed in the general group of EFNB1-related cases which are more likely to inform diagnostic testing (e.g. craniosynostosis and clefting).
Intellectual disability v5.473 EFNB1 Arina Puzriakova Added comment: Comment on publications: PMID: 25679214 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques
Intellectual disability v5.462 CLIC2 Arina Puzriakova Phenotypes for gene: CLIC2 were changed from Mental retardation, X-linked, syndromic 32, 300886 to Intellectual developmental disorder, X-linked syndromic 32 , OMIM:300886
Intellectual disability v5.461 ARHGEF6 Arina Puzriakova changed review comment from: PMID: 22511880 (2012) - a variant in the ARHGEF6 gene (p.I444N) was identified in a male patient with autism. However, this individual harboured variants in other genes (UBE3B) that were likely to explain their phenotype so conclusions about the consequence of the ARHGEF6 variant cannot be made in this case.

Comment on publications: PMID: 22511880 (2012) was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques; to: PMID: 22511880 (2012) - a variant in the ARHGEF6 gene (p.I444N) was identified in a male patient with autism. However, this individual harboured variants in other genes (UBE3B) that were likely to explain their phenotype so conclusions about the consequence of the ARHGEF6 variant cannot be made in this case.

Comment on publications: PMIDs: 22511880 (2012) and 26177020 (2015) were identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques
Intellectual disability v5.461 ARHGEF6 Arina Puzriakova Publications for gene: ARHGEF6 were set to 21989057; 20861843; 17304053; 11017088; 26177020; 22511880
Intellectual disability v5.461 ARHGEF6 Arina Puzriakova Publications for gene: ARHGEF6 were set to 21989057; 20861843; 17304053; 11017088; 26177020
Intellectual disability v5.460 ARHGEF6 Arina Puzriakova commented on gene: ARHGEF6: PMID: 22511880 (2012) - a variant in the ARHGEF6 gene (p.I444N) was identified in a male patient with autism. However, this individual harboured variants in other genes (UBE3B) that were likely to explain their phenotype so conclusions about the consequence of the ARHGEF6 variant cannot be made in this case.

Comment on publications: PMID: 22511880 (2012) was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques
Intellectual disability v5.460 ARHGEF6 Arina Puzriakova Publications for gene: ARHGEF6 were set to 21989057; 20861843; 17304053; 11017088
Intellectual disability v5.459 ARHGEF6 Arina Puzriakova Phenotypes for gene: ARHGEF6 were changed from Mental retardation, X-linked 46, 300436; Mental Retardation, X-linked; MENTAL RETARDATION X-LINKED TYPE 46 to Intellectual developmental disorder, X-linked 46, OMIM:300436
Intellectual disability v5.457 CAMSAP1 Achchuthan Shanmugasundram gene: CAMSAP1 was added
gene: CAMSAP1 was added to Intellectual disability - microarray and sequencing. Sources: Literature
Mode of inheritance for gene: CAMSAP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CAMSAP1 were set to 36283405
Phenotypes for gene: CAMSAP1 were set to Cortical dysplasia, complex, with other brain malformations 12, OMIM:620316
Review for gene: CAMSAP1 was set to GREEN
Added comment: Seven children from five unrelated families were identified with either homozygous or compound heterozygous CAMSAP1 variants and were reported with a severe neurodevelopmental disorder apparent from infancy. Clinical features of the syndrome include a characteristic craniofacial appearance, primary microcephaly, lissencephaly, agenesis or severe hypogenesis of the corpus callosum, severe or profound global developmental delay, cortical visual impairment, and seizures.

This gene has been associated with relevant phenotypes in both OMIM (MIM #620316) and in Gene2Phenotype (with 'moderate' rating in the DD panel).
Sources: Literature
Intellectual disability v5.450 DHX37 Sarah Leigh changed review comment from: Comment on mode of inheritance: The mode of inheritance for DHX37 on the Intellectual disability panel should be biallelic as monoallelic variant have not been associated with intellectual disability.; to: Comment on mode of inheritance: The mode of inheritance for DHX37 on the Intellectual disability panel should be biallelic as monoallelic variants have not been associated with intellectual disability.
Intellectual disability v5.449 ABCC9 Tracy Lester edited their review of gene: ABCC9: Added comment: This gene is currently green for monoallelic inheritance but the associated review relates to cases with biallelic inheritance. The MOI for this gene should be amended to biallelic only. Monoallelic variants are associated with Cantu syndrome which is not primarily an ID disorder or DCM.; Changed rating: GREEN
Intellectual disability v5.449 DHX37 Sarah Leigh Added comment: Comment on mode of inheritance: The mode of inheritance for DHX37 on the Intellectual disability panel should be biallelic as monoallelic variant have not been associated with intellectual disability.
Intellectual disability v5.448 DHX37 Sarah Leigh edited their review of gene: DHX37: Added comment: Biallelic DHX37 variants have been associated with Neurodevelopmental disorder with brain anomalies and with or without vertebral or cardiac anomalies (OMIM:618731). Five DHX37 variants have been reported in three unrelated cases of OMIM:618731. Zebra fish models, support the role of DHX37 variants in aberrant behaviors (PMID: 24027265); Changed rating: GREEN; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v5.448 ABCC9 Sarah Leigh Added comment: Comment on mode of pathogenicity: Loss of function variants do cause the phenotype of Intellectual disability and myopathy syndrome (OMIM:619719) , which is relevant to this panel.
Intellectual disability v5.446 ABCC9 Sarah Leigh Phenotypes for gene: ABCC9 were changed from Cardiomyopathy, dilated, 10, 608569; Atrial fibrillation, familial, 12, 614050; Hypertrichotic osteochondrodysplasia, 239850; CANTU SYNDROME HYPERTRICHOTIC OSTEOCHONDRODYSPLASIA to Intellectual disability and myopathy syndrome, OMIM:619719; intellectual disability and myopathy syndrome, MONDO:0859224
Intellectual disability v5.445 ABCC9 Sarah Leigh changed review comment from: Seven homozygous loss of function ABCC9 variants have been reported in seven unrelated cases of Intellectual disability and myopathy syndrome (OMIM:619719)(PMID: 31575858; 38217872). In vivo studies of abcc9 LoF in zebrafish, revealed an exacerbated motor response to pentylenetetrazole, a pro-convulsive drug, consistent with impaired neurodevelopment associated with an increased seizure susceptibility.(PMID: 38217872).; to: Seven homozygous loss of function ABCC9 variants have been reported in seven unrelated cases of Intellectual disability and myopathy syndrome (OMIM:619719)(PMID: 31575858; 38217872). In vivo studies of abcc9 LoF in zebrafish, revealed an exacerbated motor response to pentylenetetrazole, a pro-convulsive drug, consistent with impaired neurodevelopment associated with an increased seizure susceptibility.(PMID: 38217872). Heterozygous parents of the cases, did not show a consistent phenotype, although intrauterine death was reported in two families (PMID: 38217872). In family 4 the fetus was homozygous for c.1858C>T, p.(Arg620Ter) and in family 8 the parents were both heterozygous for c.2140_2141del, p.(Leu714SerfsTer7), but analysis of the fetus was not possible.
Intellectual disability v5.442 MADD Sarah Leigh edited their review of gene: MADD: Added comment: Comments from Karen Stals (Royal Devon and Exeter Hospital), 4 Dec 2023: Apnoea a presenting feature in 13/14 patients with MADD-related disorder with biallelic MADD variants in Schneeberger et al 2020 PMID: 32761064. Identified biallelic variants in this gene in a patient with a consistent phenotype.; Changed rating: GREEN; Changed publications to: 32761064
Intellectual disability v5.442 KIRREL3 Sarah Leigh Phenotypes for gene: KIRREL3 were changed from Mental retardation, autosomal dominant 4, 612581; MENTAL RETARDATION AUTOSOMAL DOMINANT TYPE 4 (MRD4) to Intellectual developmental disorder, autosomal dominant 4, OMIM:612581; intellectual disability, autosomal dominant 4, MONDO:0012947
Intellectual disability v5.441 KIRREL3 Sarah Leigh changed review comment from: At least 15 missense KIRREL3 variants have been reported in 17 unrelated cases with a neurodevelopmental disorder, that includes intellectual disability ranging from mild to severe (PMID: 19012874; 29271092; 33853164; 33853164). Table 1 in PMID: 37605258, lists KIRREL3 variants and demonstrates that the variants maybe either de novo (9/16) or inherited from one of the parents (7/9). (PMID: 37605258). The KIRREL3 variants are either absent from control databases or are present at a very low frequency.; to: At least 12 missense KIRREL3 variants have been reported in 12 unrelated cases with a neurodevelopmental disorder, that includes intellectual disability ranging from mild to severe (PMID: 29271092; 33853164; 33853164). Table 1 in PMID: 37605258, reviews KIRREL3 variants and demonstrates that the variants maybe either de novo (4/11) or inherited from one of the parents (7/11)(mode of inheritance was unknown for one of the variants). The KIRREL3 variants are either absent from controls or are present at a very low frequency. However, the three variants reported in PMID: 19012874, were shown to be present in publicly databases at a high frequency (see KIRREL3 OMIM entry).
Intellectual disability v5.433 TUSC3 Arina Puzriakova Phenotypes for gene: TUSC3 were changed from Mental retardation, autosomal recessive 7, 611093; MENTAL RETARDATION AUTOSOMAL RECESSIVE TYPE 7 (MRT7) to Intellectual developmental disorder, autosomal recessive 7, OMIM:611093
Intellectual disability v5.431 CC2D1A Arina Puzriakova Phenotypes for gene: CC2D1A were changed from Mental retardation, autosomal recessive 3, 608443; MENTAL RETARDATION AUTOSOMAL RECESSIVE TYPE 3 (MRT3) to Intellectual developmental disorder, autosomal recessive 3, OMIM:608443
Intellectual disability v5.430 RARS Arina Puzriakova Publications for gene: RARS were set to 31814314; 28905880; 24777941; 30500859
Intellectual disability v5.429 RARS Arina Puzriakova Phenotypes for gene: RARS were changed from Cerebral hypomyelination; Global developmental delay; Intellectual disability; Seizures; Cerebral atrophy; Nystagmus; Ataxia; Feeding difficulties to Leukodystrophy, hypomyelinating, 9, OMIM:616140
Intellectual disability v5.427 ASPM Arina Puzriakova Phenotypes for gene: ASPM were changed from Microcephaly 5, primary, autosomal recessive, 608716; PRIMARY AUTOSOMAL RECESSIVE MICROCEPHALY to Microcephaly 5, primary, autosomal recessive, OMIM:608716
Intellectual disability v5.426 RARS Arina Puzriakova Publications for gene: RARS were set to 31814314; 28905880; 24777941
Intellectual disability v5.424 WDR62 Arina Puzriakova Phenotypes for gene: WDR62 were changed from Microcephaly, Cortical Malformations, and Mental Retardation; Microcephaly 2, primary, autosomal recessive, with or without cortical malformations, 604317; MICROCEPHALY CORTICAL MALFORMATIONS AND MENTAL RETARDATION (MCMMR) to Microcephaly 2, primary, autosomal recessive, with or without cortical malformations, OMIM:604317
Intellectual disability v5.422 MCPH1 Arina Puzriakova Phenotypes for gene: MCPH1 were changed from genetic heterogeneity Microcephaly 1, primary, autosomal recessive, 251200; MICROCEPHALY PRIMARY TYPE 1 (MCPH1) to Microcephaly 1, primary, autosomal recessive, OMIM:251200
Intellectual disability v5.421 HSD17B10 Arina Puzriakova Added comment: Comment on mode of inheritance: Should be updated from 'XL, biallelic in females' to 'XL, monoallelic in females' as female patients harbouring heterozygous variants have been described. Some carrier females shown to have mild to moderate developmental delay or intellectual disability (PMIDs: 12112118; 16148061; 22127393; 34765396)
Intellectual disability v5.419 HSD17B10 Arina Puzriakova Phenotypes for gene: HSD17B10 were changed from 17-beta-hydroxysteroid dehydrogenase X deficiency, 300438Mental retardation, X-linked syndromic 10, 300220Mental retardation, X-linked 17/31, microduplication, 300705; 2-METHYL-3-HYDROXYBUTYRYL-COA DEHYDROGENASE DEFICIENCY (MHBD DEFICIENCY) to HSD10 mitochondrial disease, OMIM:300438
Intellectual disability v5.411 LGI3 Achchuthan Shanmugasundram changed review comment from: PMID:35948005 reported sixteen individuals from eight unrelated families with loss-of-function (LoF) bi-allelic variants in LGI3. All of them exhibited a potentially clinically recognizable peripheral nerve hyperexcitability syndrome (PNHS) trait characterized by global developmental delay, intellectual disability, distal deformities with diminished reflexes, visible facial myokymia, and distinctive electromyographic features suggestive of motor nerve instability. All sixteen patients had global developmental delay and all thirteen tested patients had mild or moderate intellectual disability. Lgi3-null mice showed reduced and mis-localized Kv1 channel complexes in myelinated peripheral axons.

This gene has been associated with relevant phenotype in OMIM (MIM #620007), but not yet in Gene2Phenotype.
Sources: Literature; to: PMID:35948005 reported sixteen individuals from eight unrelated families with loss-of-function (LoF) bi-allelic variants in LGI3. All of them exhibited a potentially clinically recognizable peripheral nerve hyperexcitability syndrome (PNHS) trait characterized by global developmental delay, intellectual disability, distal deformities with diminished reflexes, visible facial myokymia, and distinctive electromyographic features suggestive of motor nerve instability. All sixteen patients had global developmental delay and all thirteen tested patients had mild or moderate intellectual disability.

Lgi3-null mice showed reduced and mis-localized Kv1 channel complexes in myelinated peripheral axons.

This gene has been associated with relevant phenotypes in OMIM (MIM #620007), but not yet in Gene2Phenotype.
Sources: Literature
Intellectual disability v5.410 LGI3 Achchuthan Shanmugasundram gene: LGI3 was added
gene: LGI3 was added to Intellectual disability - microarray and sequencing. Sources: Literature
Mode of inheritance for gene: LGI3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LGI3 were set to 35948005
Phenotypes for gene: LGI3 were set to Intellectual developmental disorder with muscle tone abnormalities and distal skeletal defects, OMIM:620007
Review for gene: LGI3 was set to GREEN
Added comment: PMID:35948005 reported sixteen individuals from eight unrelated families with loss-of-function (LoF) bi-allelic variants in LGI3. All of them exhibited a potentially clinically recognizable peripheral nerve hyperexcitability syndrome (PNHS) trait characterized by global developmental delay, intellectual disability, distal deformities with diminished reflexes, visible facial myokymia, and distinctive electromyographic features suggestive of motor nerve instability. All sixteen patients had global developmental delay and all thirteen tested patients had mild or moderate intellectual disability. Lgi3-null mice showed reduced and mis-localized Kv1 channel complexes in myelinated peripheral axons.

This gene has been associated with relevant phenotype in OMIM (MIM #620007), but not yet in Gene2Phenotype.
Sources: Literature
Intellectual disability v5.409 KCNA3 Gavin Ryan gene: KCNA3 was added
gene: KCNA3 was added to Intellectual disability - microarray and sequencing. Sources: Expert Review
Mode of inheritance for gene: KCNA3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KCNA3 were set to PMID: 37964487
Phenotypes for gene: KCNA3 were set to Intellectual disability; Developmental Delay; Epilepsy
Penetrance for gene: KCNA3 were set to unknown
Review for gene: KCNA3 was set to GREEN
Added comment: Soldovieri et al identified 14 de novo missense variants in KCNA3 gene. The majority of individuals presented with ID, developmental delay, and epilepsy, amongst other features. Functional studies showed loss-of-function effects for some variants and possible gain-of-function for others. One of these variants has also been identified in NHS GMS WGS patient with consistent features.
Sources: Expert Review
Intellectual disability v5.409 BAZ2B Dmitrijs Rots gene: BAZ2B was added
gene: BAZ2B was added to Intellectual disability - microarray and sequencing. Sources: Literature
Mode of inheritance for gene: BAZ2B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: BAZ2B were set to PMID: 31999386
Phenotypes for gene: BAZ2B were set to developmental delay, intellectual disability and autism spectrum disorder
Review for gene: BAZ2B was set to GREEN
Added comment: BAZ2B gene is intolerant to LoF variants in population (pLI=1) and PMID: 31999386 described that de novo LoF variants are statistically enriched among NDD cases & summarize 10 cases. Enough evidence for the green rating.
Sources: Literature
Intellectual disability v5.409 MTSS1L Achchuthan Shanmugasundram edited their review of gene: MTSS1L: Changed phenotypes to: Intellectual developmental disorder with ocular anomalies and distinctive facial features, OMIM:620086
Intellectual disability v5.407 PRX Arina Puzriakova Phenotypes for gene: PRX were changed from Dejerine-Sottas disease, 145900; Charcot-Marie-Tooth disease, type 4F, 614895 to Charcot-Marie-Tooth disease, type 4F, OMIM:614895; Dejerine-Sottas disease, OMIM:145900
Intellectual disability v5.402 ACBD6 Arina Puzriakova edited their review of gene: ACBD6: Added comment: - PMID: 21937992 (2011) - single individuals with a p.G22fs variant in the ACBD6 gene, presenting with mild ID, microcephaly, facial dysmorphism, spasticity. Limited additional information.

- PMID: 32108178 (2020) - two unrelated individuals with neurodevelopmental disorder (moderate ID is noted but otherwise limited clinical information) and carrying homozygous LoF variants in the ACBD6 gene (1 frameshift, 1 canonical splice). One individual also carried an allelic homozygous variant in the PRDX6 gene (unlikely but unknown disease consequence). Skin-derived patient fibroblasts showed reduced ACBD6 expression and N-myristoylation deficiency.

- PMID: 36457943 (2023) - two Thai siblings presenting with profound ID, morbid obesity, pancytopenia with severe recurrent infections, diabetes mellitus, cirrhosis, and renal failure, leading to deaths in their early 30s. Sequencing showed a novel homozygous single bp duplication (c.360dup; p.Leu121Thrfs*27) in the ACBD6 gene. Parents were heterozygous carriers.

- PMID: 37951597 (2023) - 45 previously undiagnosed individuals from 28 families with a neurodevelopmental syndrome including a complex and progressive movement disorder phenotype. Cardinal clinical features include moderate-to-severe GDD/ID (45/45), facial dysmorphism (38/40), HC <2nd percentile (21/31), weight >50th percentile (20/34), mild cerebellar ataxia (35/41), limb spasticity/hypertonia (31/41), gait abnormalities (33/35), dystonia (30/32) and variable epilepsy (13/29).

Homozygous ACBD6 variants were identified by WES in all cases, including 18 predicted LoF, 1 missense and 1 inframe insertion. Knockout studies in zebrafish recapitulate clinical features reported in patients such as movement disorders, seizures, and facial dysmorphology, while inactivation of acbd6 in X. tropicalis predominantly caused embryo death while surviving tadpoles demonstrated microcephaly, reduced movement, eye abnormalities, and brain structure differences.; Changed rating: GREEN; Changed publications to: 21937992, 32108178, 36457943, 37951597; Changed phenotypes to: Neurodevelopmental disorder, MONDO:0700092; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v5.402 ACBD6 Arina Puzriakova Added comment: Comment on publications: PMID: 32108178 (2020) paper was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques
Intellectual disability v5.400 ACBD6 Sarah Leigh edited their review of gene: ACBD6: Added comment: ACBD6 variants have not been associated with a phenotype in OMIM, and as an autosomal recessive condition with Limited strength in Gen2Phen. Three variants have been reported in three unrelated cases with intellectual disability, however, in one of these carriers the ACBD6 variant was allelic with PRDX6 gene c.136del; p.(ValCysfs*23), therefore the contribution of the ACBD6 variant to intellectual disability is uncertain in this case (PMID: 21937992, 32108178).; Changed rating: AMBER
Intellectual disability v5.399 RPL10 Achchuthan Shanmugasundram Phenotypes for gene: RPL10 were changed from Mental retardation, X-linked, syndromic, 35, 300998 to Intellectual developmental disorder, X-linked syndromic 35, OMIM:300998
Intellectual disability v5.396 RPL10 Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: As reviewed by Sarah Leigh and Dmitrijs Rots, all the cases reported previously in literature and recently in PMID:35876338 were males with hemizygous RPL10 variants. The females were carriers and showed fully skewed X inactivation of the mutation-bearing X chromosomes.

In addition, this gene has been associated with relevant phenotypes in both OMIM (MIM #300998) and Gene2Phenotype (with 'definitive' rating on the DD panel). The MOI has been recorded as 'X-linked recessive' in OMIM.

The MOI should therefore be updated 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' in the next GMS review.
Intellectual disability v5.395 RELN Achchuthan Shanmugasundram changed review comment from: Comment on mode of inheritance: The MOI should be updated from "BIALLELIC, autosomal or pseudoautosomal"to "BOTH monoallelic and biallelic, autosomal or pseudoautosomal" as there are three unrelated cases with monoallelic RELN variants and intellectual disability reported in the literature.; to: Comment on mode of inheritance: The MOI should be updated from "BIALLELIC, autosomal or pseudoautosomal" to "BOTH monoallelic and biallelic, autosomal or pseudoautosomal" in the next GMS review as there are three unrelated cases with monoallelic RELN variants and intellectual disability reported in the literature.
Intellectual disability v5.395 RELN Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: The MOI should be updated from "BIALLELIC, autosomal or pseudoautosomal"to "BOTH monoallelic and biallelic, autosomal or pseudoautosomal" as there are three unrelated cases with monoallelic RELN variants and intellectual disability reported in the literature.
Intellectual disability v5.389 CLDN11 Achchuthan Shanmugasundram gene: CLDN11 was added
gene: CLDN11 was added to Intellectual disability - microarray and sequencing. Sources: Literature
Mode of inheritance for gene: CLDN11 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CLDN11 were set to 33313762
Phenotypes for gene: CLDN11 were set to Leukodystrophy, hypomyelinating, 22, OMIM:619328
Review for gene: CLDN11 was set to GREEN
Added comment: PMID:33313762 reported three unrelated individuals with early-onset spastic movement disorder, expressive speech disorder and eye abnormalities including hypermetropia. These patients exhibit global developmental delay, particularly motor and speech delay. Intellectual disability was maximally mild in two of three individuals and the intelligence is in a low-normal range in third individual, although IQ testing was not performed in them.

Two different heterozygous de novo stop-loss variants were identified in these patients. One of the variants did not lead to a loss of CLDN11 expression on RNA level in fibroblasts indicating this transcript is not subject to nonsense-mediated decay and most likely translated into an extended protein.

This gene has been associated with hypomyelinating leukodystrophy in OMIM, which includes global developmental delay and impaired intellectual development (mild) as clinical presentations. However, this gene has not yet been associated with phenotypes in Gene2Phenotype.
Sources: Literature
Intellectual disability v5.388 RARB Achchuthan Shanmugasundram Mode of pathogenicity for gene: RARB was changed from None to None
Intellectual disability v5.388 RARB Achchuthan Shanmugasundram Mode of pathogenicity for gene: RARB was changed from None to None
Intellectual disability v5.387 RARB Achchuthan Shanmugasundram Mode of pathogenicity for gene: RARB was changed from None to None
Intellectual disability v5.388 RARB Achchuthan Shanmugasundram Mode of pathogenicity for gene: RARB was changed from None to None
Intellectual disability v5.388 RARB Achchuthan Shanmugasundram Mode of pathogenicity for gene: RARB was changed from None to None
Intellectual disability v5.388 RARB Achchuthan Shanmugasundram Mode of pathogenicity for gene: RARB was changed from None to None
Intellectual disability v5.387 RARB Achchuthan Shanmugasundram Mode of pathogenicity for gene: RARB was changed from None to None
Intellectual disability v5.387 RARB Achchuthan Shanmugasundram Mode of pathogenicity for gene: RARB was changed from Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments to None
Intellectual disability v5.386 RARB Achchuthan Shanmugasundram Publications for gene: RARB were set to 17506106; 24075189; 25457163; 27120018; 30281527; 30880327
Intellectual disability v5.386 RARB Achchuthan Shanmugasundram Publications for gene: RARB were set to 17506106; 24075189; 25457163; 27120018; 30281527; 30880327
Intellectual disability v5.386 RARB Achchuthan Shanmugasundram Publications for gene: RARB were set to 17506106; 24075189; 25457163; 27120018; 30281527; 30880327
Intellectual disability v5.385 RARB Achchuthan Shanmugasundram Publications for gene: RARB were set to 17506106; 24075189; 25457163; 27120018; 30281527; 30880327
Intellectual disability v5.385 RARB Achchuthan Shanmugasundram Publications for gene: RARB were set to 24075189
Intellectual disability v5.384 RARB Achchuthan Shanmugasundram Phenotypes for gene: RARB were changed from Microphthalmia, syndromic 12, OMIM:615524; neurodevelopmental disorder, MONDO:0700092 to Microphthalmia, syndromic 12, OMIM:615524; neurodevelopmental disorder, MONDO:0700092
Intellectual disability v5.384 RARB Achchuthan Shanmugasundram Phenotypes for gene: RARB were changed from Microphthalmia, syndromic 12, OMIM:615524; neurodevelopmental disorder, MONDO:0700092 to Microphthalmia, syndromic 12, OMIM:615524; neurodevelopmental disorder, MONDO:0700092
Intellectual disability v5.383 RARB Achchuthan Shanmugasundram Phenotypes for gene: RARB were changed from MICROPHTHALMIA AND DIAPHRAGMATIC HERNIA to Microphthalmia, syndromic 12, OMIM:615524; neurodevelopmental disorder, MONDO:0700092
Intellectual disability v5.381 RARB Achchuthan Shanmugasundram Mode of pathogenicity for gene: RARB was changed from to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Intellectual disability v5.380 COX11 Sarah Leigh commented on gene: COX11: The three unrelated case of Mitochondrial complex IV deficiency, nuclear type 23 (OMIM:620275) so far reported, all had significant cognitive impairment and 2/3 of the cases had hypotonia (PMID: 36030551;38068960).
Intellectual disability v5.380 YARS Achchuthan Shanmugasundram changed review comment from: As reviewed by Sarah Leigh, none of the previously reported cases presented with intellectual disability, although the family reported in PMID:30304524 had expressive language delay and the older brother reported in PMID:27633801 had mild delays.

As reviewed by Dmitrijs Rots, all 12 patients from six families identified with homozygous p.Arg367Trp variant had neurodevelopmental phenotype including intellectual disability. As all these families were identified with the same homozygous variant, the rating should remain amber. However, 'watchlist' tag has been added to review this gene in future with any new evidence.; to: As reviewed by Sarah Leigh, none of the previously reported cases presented with intellectual disability, although the family reported in PMID:30304524 had expressive language delay and the older brother reported in PMID:27633801 had mild delays.

As reviewed by Dmitrijs Rots, all 12 patients from six families identified with homozygous p.Arg367Trp variant had neurodevelopmental phenotype including intellectual disability. As all these families were identified with the same homozygous variant, the rating should remain amber.
Intellectual disability v5.380 YARS Achchuthan Shanmugasundram reviewed gene: YARS: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Infantile-onset multisystem neurologic, endocrine, and pancreatic disease 2, OMIM:619418; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v5.380 COX11 Sarah Leigh gene: COX11 was added
gene: COX11 was added to Intellectual disability - microarray and sequencing. Sources: NHS GMS,Expert Review Amber
Q4_23_promote_green tags were added to gene: COX11.
Mode of inheritance for gene: COX11 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COX11 were set to 36030551; 38068960
Phenotypes for gene: COX11 were set to Mitochondrial complex IV deficiency, nuclear type 23, OMIM:620275; Mitochondrial complex IV deficiency, nuclear type 23, MONDO:0859520
Intellectual disability v5.379 CLCN6 Sarah Leigh Added comment: Comment on mode of pathogenicity: PMID 33217309 reports gain of function associated with CLCN6 variants.
Intellectual disability v5.377 CLCN6 Sarah Leigh edited their review of gene: CLCN6: Added comment: Review copied from Neuronal ceroid lipofuscinosis panel: PMID 33217309: Three unrelated families reported with recurrent GOF de novo c.1658A>G (p.Tyr553Cys) and severe developmental delay with pronounced generalized hypotonia, respiratory insufficiency, and variable neurodegeneration and diffusion restriction in cerebral peduncles, midbrain, and/or brainstem in MRI scans. Previously, monoallelic variants reported in 3 families with BPEI, but functional data/segregation not compelling. Mouse knockout model has features of NCL (Zornitza Stark (Australian Genomics), 9 Dec 2020).; Changed rating: GREEN; 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
Intellectual disability v5.377 CLCN6 Sarah Leigh gene: CLCN6 was added
gene: CLCN6 was added to Intellectual disability - microarray and sequencing. Sources: Other
Mode of inheritance for gene: CLCN6 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CLCN6 were set to 29667327; 26658788; 25794116; 21107136; 33217309; 16950870
Phenotypes for gene: CLCN6 were set to Neurodegeneration, childhood-onset, hypotonia, respiratory insufficiency and brain imaging abnormalities OMIM:619173
Review for gene: CLCN6 was set to RED
Added comment: Sources: Other
Intellectual disability v5.375 ASL Eleanor Williams Phenotypes for gene: ASL were changed from Argininosuccinic aciduria 207900 to Argininosuccinic aciduria, OMIM:207900; argininosuccinic aciduria, MONDO:0008815
Intellectual disability v5.374 COG3 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: As reviewed by Zornitza Stark, there are two unrelated cases reported with biallelic COG3 variants and hence this gene should be rated amber with current evidence.; to: Comment on list classification: As reviewed by Zornitza Stark, there are two unrelated families reported with biallelic COG3 variants and hence this gene should be rated amber with current evidence.
Intellectual disability v5.374 COG3 Achchuthan Shanmugasundram gene: COG3 was added
gene: COG3 was added to Intellectual disability - microarray and sequencing. Sources: Literature,Expert Review Amber
Mode of inheritance for gene: COG3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COG3 were set to 37711075
Phenotypes for gene: COG3 were set to Congenital disorder of glycosylation, type IIbb, OMIM:620546
Intellectual disability v5.373 SGSM3 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: As reviewed by Zornitza Stark, there are eight families reported with the same variant from the same Ashkenazi Jewish ancestry and the variant co-segregated with the disease in all family members.

The 'founder-effect' tag has been added as 1 in 52 Ashkenazi Jews carry the variant.; to: Comment on list classification: As reviewed by Zornitza Stark, there are eight families reported with the same variant from the same Ashkenazi Jewish ancestry and the variant co-segregated with the disease in all family members. This gene should therefore be rated amber with the current evidence.

The 'founder-effect' tag has been added as 1 in 52 Ashkenazi Jews carry the variant.
Intellectual disability v5.373 SGSM3 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Zornitza Stark, there are eight families reported with the same variant from the same Ashkenazi Jewish ancestry and the variant co-segregated with the disease in all family members.

The 'founder-effect' tag has been added as 1 in 52 Ashkenazi Jews carry the variant.
Intellectual disability v5.373 SGSM3 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Zornitza Stark, there are eight families reported with the same variant from the same Ashkenazi Jewish ancestry and the variant co-segregated with the disease in all family members.

The 'founder-effect' tag has been added as 1 in 52 Ashkenazi Jews carry the variant.
Intellectual disability v5.371 SHQ1 Sarah Leigh gene: SHQ1 was added
gene: SHQ1 was added to Intellectual disability - microarray and sequencing. Sources: Literature,Expert Review Amber
Q4_23_promote_green tags were added to gene: SHQ1.
Mode of inheritance for gene: SHQ1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SHQ1 were set to 34542157; 29178645; 36810590; 36847845; 36416405; 37475611; 36189577
Phenotypes for gene: SHQ1 were set to ?Dystonia 35, childhood-onset, OMIM:619921; dystonia 35, childhood-onset, MONDO:0030958; Neurodevelopmental disorder with dystonia and seizures, OMIM:619922; neurodevelopmental disorder with dystonia and seizures, MONDO:0859258
Intellectual disability v5.369 TRPC5 Sarah Leigh changed review comment from: To date, TRPC5 variants have not been associated with a phenotype in OMIM, however, Gen2Phen lists TRPC5 as having an Limited association with the phenotype of TRPC5-related neurodevelopmental disorder. Six TRPC5 have been reported to be associated with a neurodevelopmental disorder, which has a range of phenotypic features, including intellectual disability and autism spectrum disorder (PMIDs: 36323681;33504798;28191890;23033978).; to: To date, TRPC5 variants have not been associated with a phenotype in OMIM, however, Gen2Phen lists TRPC5 as having an Limited association with the phenotype of TRPC5-related neurodevelopmental disorder. Six TRPC5 variants have been reported to be associated with a neurodevelopmental disorder, which has a range of phenotypic features, including intellectual disability and autism spectrum disorder (PMIDs: 36323681;33504798;28191890;23033978).
Intellectual disability v5.369 TRPC5 Sarah Leigh Added comment: Comment on list classification: This gene is rated amber, despite six published variants being reported in unrelated cases with a neurodevelopmental disorder, this is because it is unclear in the publications, how many of these cases actually have intellectual disability.
Intellectual disability v5.368 TRPC5 Sarah Leigh commented on gene: TRPC5: To date, TRPC5 variants have not been associated with a phenotype in OMIM, however, Gen2Phen lists TRPC5 as having an Limited association with the phenotype of TRPC5-related neurodevelopmental disorder. Six TRPC5 have been reported to be associated with a neurodevelopmental disorder, which has a range of phenotypic features, including intellectual disability and autism spectrum disorder (PMIDs: 36323681;33504798;28191890;23033978).
Intellectual disability v5.366 AGPAT3 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Zornitza Stark, only one family was reported so far with AGPAT3 biallelic variants and intellectual disability. In addition, functional evidence is also available, Hence, this gene should be rated amber.
Intellectual disability v5.362 C20orf24 Arina Puzriakova Added comment: Comment on list classification: New gene added by Hannah Knight. Biallelic LoF variant identified in a patient with craniofacial dysmorphism, skeletal anomalies, and impaired intellectual development syndrome. Authors suggested possible low penetrance due to two relatives with heterozygous variant and cleft lip and/or palate (PMID: 35614220).

Rating Red as only a single family reported to date. In OMIM the relationship between the phenotype and gene is provisional.
Intellectual disability v5.360 MTF1 Sarah Leigh changed review comment from: Comment on publications: PMID: 23033978 reports MTF1: NM_005955.2 c.333del p.(Thr112Hisfs*26) as a de novo variant in a patient with severe ID, who also carries a maternally inherited TRPC5 NM_012471.2 c.1999C>A p.(Pro667Thr) variant (tables S3 & S10).; to: Comment on publications: PMID: 23033978 reports MTF1: NM_005955.2 c.333del p.(Thr112Hisfs*26) as a de novo variant in a patient with severe ID, who also carries a maternally inherited TRPC5 NM_012471.2 c.1999C>A p.(Pro667Thr) variant (tables S3, S9 & S10).
Intellectual disability v5.360 TRPC5 Sarah Leigh Added comment: Comment on publications: PMID: 23033978 reports MTF1: NM_005955.2 c.333del p.(Thr112Hisfs*26) as a de novo variant in a patient with severe ID, who also carries a maternally inherited TRPC5 NM_012471.2 c.1999C>A p.(Pro667Thr) variant (tables S3, S9 & S10).
Intellectual disability v5.359 MTF1 Sarah Leigh Added comment: Comment on publications: PMID: 23033978 reports MTF1: NM_005955.2 c.333del p.(Thr112Hisfs*26) as a de novo variant in a patient with severe ID, who also carries a maternally inherited TRPC5 NM_012471.2 c.1999C>A p.(Pro667Thr) variant (tables S3 & S10).
Intellectual disability v5.357 TRPC5 Sarah Leigh gene: TRPC5 was added
gene: TRPC5 was added to Intellectual disability - microarray and sequencing. Sources: DD-Gene2Phenotype,Expert Review Red
Mode of inheritance for gene: TRPC5 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: TRPC5 were set to 36323681
Phenotypes for gene: TRPC5 were set to TRPC5-related neurodevelopmental disorder
Intellectual disability v5.355 CDK16 Sarah Leigh Added comment: Comment on phenotypes: Intellectual disability, MONDO:0001071 is the phenotype listed for CDK16 in Gene2Phen (2nd January 2024)
Intellectual disability v5.354 CDK16 Sarah Leigh edited their review of gene: CDK16: Added comment: To date, CDK16 variants have not been associated with a phenotype in OMIM, but have a limited association with intellectual disability (ID) in Gen2Phen. Four CDK16 variants have been associated with a spectrum of phenotypic features, including ID (n= 3), autism spectrum disorder (n= 3), seizures (n= 2) and spacity (n= 2)(PMID:36323681, 31981491, 25644381).; Changed rating: GREEN
Intellectual disability v5.353 ACACA Sarah Leigh Entity copied from Likely inborn error of metabolism - targeted testing not possible v4.83
Intellectual disability v5.353 ACACA Sarah Leigh gene: ACACA was added
gene: ACACA was added to Intellectual disability - microarray and sequencing. Sources: Expert Review Amber,Literature
Q4_23_promote_green, Q4_23_NHS_review tags were added to gene: ACACA.
Mode of inheritance for gene: ACACA was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ACACA were set to 6114432; 34552920; 36709796
Phenotypes for gene: ACACA were set to Acetyl-CoA carboxylase deficiency, OMIM: 613933
Intellectual disability v5.351 FAR1 Achchuthan Shanmugasundram Tag Q2_21_expert_review was removed from gene: FAR1.
Tag Q2_21_MOI was removed from gene: FAR1.
Intellectual disability v5.347 PSMC3 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There is sufficient evidence available for the association of monoallelic variants in this gene with hearing loss and hence this gene can be promoted to green rating in the next GMS review.; to: Comment on list classification: This gene can be promoted to green rating in the next GMS review.
Intellectual disability v5.347 PSMC3 Achchuthan Shanmugasundram changed review comment from: Comment on mode of inheritance: There is sufficient evidence for the association of monoallelic variants from this gene with intellectual disability. However, there is only one family reported with biallelic variants. Hence, the MOI is set as "MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted".; to: Comment on mode of inheritance: There is sufficient evidence available for the association of monoallelic variants from this gene with intellectual disability. However, there is only one family reported with biallelic variants. Hence, the MOI is set as "MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted".
Intellectual disability v5.347 PSMC3 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There is sufficient evidence available for the association of monoallelic variants in this gene with hearing loss and hence this gene can be promoted to green rating in the next GMS review.; to: Comment on list classification: There is sufficient evidence available for the association of monoallelic variants in this gene with hearing loss and hence this gene can be promoted to green rating in the next GMS review.
Intellectual disability v5.347 PSMC3 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: This gene can be promoted to green rating at the next GMS review.; to: Comment on list classification: There is sufficient evidence available for the association of monoallelic variants in this gene with hearing loss and hence this gene can be promoted to green rating in the next GMS review.
Intellectual disability v5.347 PSMC3 Achchuthan Shanmugasundram changed review comment from: PMID:32500975 - Three individuals from a single extended consanguineous Turkish pedigree was reported with early-onset and rapidly progressive deafness, early-onset cataract, severe developmental delay, severely impaired intellectual development, subcutaneous calcifications and peripheral neuropathy. There were identified with homozygous variant in PSMC3 gene (c.1127 + 337A>G). Functional studies in patient fibroblast cells suggested that the patient PSMC3 variant is responsible for proteasome failure affecting protein homeostasis under stress conditions. This is also supported by evidence from zebrafish models, where PSMC3 knockout has reproduced the human phenotype with inner ear development anomalies as well as cataracts.

PMID:37256937 - 23 individuals with neurodevelopmental disorder were identified with 15 different de novo missense variants. Apart from one child (patient 2), all others had developmental delay characterised by speech delay (19/19) alone or with intellectual disability (16/18) and motor delay (15/19). In addition, structural modeling as well as proteomic and transcriptomic analyses of T cells derived from patients with PSMC3 variants implicated the PSMC3 variants in proteasome dysfunction through disruption of substrate translocation, induction of proteotoxic stress, and alterations in proteins controlling developmental and innate immune program.

The phenotype caused by recessive PSMC3 variants has been reported in OMIM (MIM #619354), but not in Gene2Phenotype. However, the phenotype caused by dominant variants has not yet been reported in either resources.; to: PMID:32500975 - Three individuals from a single extended consanguineous Turkish pedigree was reported with early-onset and rapidly progressive deafness, early-onset cataract, severe developmental delay, severely impaired intellectual development, subcutaneous calcifications and peripheral neuropathy. They were identified with homozygous variant in PSMC3 gene (c.1127 + 337A>G). Functional studies in patient fibroblast cells suggested that the patient PSMC3 variant is responsible for proteasome failure affecting protein homeostasis under stress conditions. This is also supported by evidence from zebrafish models, where PSMC3 knockout has reproduced the human phenotype with inner ear development anomalies as well as cataracts.

PMID:37256937 - 23 individuals with neurodevelopmental disorder were identified with 15 different de novo missense variants. Apart from one child (patient 2), all others had developmental delay characterised by speech delay (19/19) alone or with intellectual disability (16/18) and motor delay (15/19). In addition, structural modeling as well as proteomic and transcriptomic analyses of T cells derived from patients with PSMC3 variants implicated the PSMC3 variants in proteasome dysfunction through disruption of substrate translocation, induction of proteotoxic stress, and alterations in proteins controlling developmental and innate immune program.

The phenotype caused by recessive PSMC3 variants has been reported in OMIM (MIM #619354), but not in Gene2Phenotype. However, the phenotype caused by dominant variants has not yet been reported in either resources.
Intellectual disability v5.347 PSMC3 Achchuthan Shanmugasundram changed review comment from: PMID:32500975 - Three individuals from a single extended consanguineous Turkish pedigree was reported with early-onset and rapidly progressive deafness, early-onset cataract, severe developmental delay, severely impaired intellectual development, subcutaneous calcifications and peripheral neuropathy. There were identified with homozygous variant in PSMC3 gene (c.1127 + 337A>G). Functional studies in patient fibroblast cells suggested that the patient PSMC3 variant is responsible for proteasome failure affecting protein homeostasis under stress conditions. This is also supported by evidence from zebrafish models, where PSMC3 knockout has reproduced the human phenotype with inner ear development anomalies as well as cataracts.

PMID:37256937 - 23 individuals with neurodevelopmental disorder was identified with 15 different de novo missense variants. Apart from one child (patient 2), all others had developmental delay characterised by speech delay (19/19) alone or with intellectual disability (16/18) and motor delay (15/19). In addition, structural modeling as well as proteomic and transcriptomic analyses of T cells derived from patients with PSMC3 variants implicated the PSMC3 variants in proteasome dysfunction through disruption of substrate translocation, induction of proteotoxic stress, and alterations in proteins controlling developmental and innate immune program.

The phenotype caused by recessive PSMC3 variants has been reported in OMIM (MIM #619354), but not in Gene2Phenotype. However, the phenotype caused by dominant variants has not yet been reported in either resources.; to: PMID:32500975 - Three individuals from a single extended consanguineous Turkish pedigree was reported with early-onset and rapidly progressive deafness, early-onset cataract, severe developmental delay, severely impaired intellectual development, subcutaneous calcifications and peripheral neuropathy. There were identified with homozygous variant in PSMC3 gene (c.1127 + 337A>G). Functional studies in patient fibroblast cells suggested that the patient PSMC3 variant is responsible for proteasome failure affecting protein homeostasis under stress conditions. This is also supported by evidence from zebrafish models, where PSMC3 knockout has reproduced the human phenotype with inner ear development anomalies as well as cataracts.

PMID:37256937 - 23 individuals with neurodevelopmental disorder were identified with 15 different de novo missense variants. Apart from one child (patient 2), all others had developmental delay characterised by speech delay (19/19) alone or with intellectual disability (16/18) and motor delay (15/19). In addition, structural modeling as well as proteomic and transcriptomic analyses of T cells derived from patients with PSMC3 variants implicated the PSMC3 variants in proteasome dysfunction through disruption of substrate translocation, induction of proteotoxic stress, and alterations in proteins controlling developmental and innate immune program.

The phenotype caused by recessive PSMC3 variants has been reported in OMIM (MIM #619354), but not in Gene2Phenotype. However, the phenotype caused by dominant variants has not yet been reported in either resources.
Intellectual disability v5.346 TEFM Achchuthan Shanmugasundram gene: TEFM was added
gene: TEFM was added to Intellectual disability - microarray and sequencing. Sources: Literature
Mode of inheritance for gene: TEFM was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TEFM were set to 36823193
Phenotypes for gene: TEFM were set to Combined oxidative phosphorylation deficiency 58, OMIM:620451
Intellectual disability v5.342 NSD2 Sarah Leigh Phenotypes for gene: NSD2 were changed from Intrauterine growth retardation; Growth delay; Microcephaly; Muscular hypotonia; Neurodevelopmental delay; Intellectual disability; No OMIM number to Rauch-Steindl syndrome, OMIM:619695; Rauch-Steindl syndrome, MONDO:0859219
Intellectual disability v5.341 C20orf24 Hannah Knight gene: C20orf24 was added
gene: C20orf24 was added to Intellectual disability - microarray and sequencing. Sources: Literature
Mode of inheritance for gene: C20orf24 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: C20orf24 were set to 35614220
Phenotypes for gene: C20orf24 were set to ?Craniofacial dysmorphism, skeletal anomalies, and impaired intellectual development syndrome 2
Added comment: HGNC Approved Gene Symbol: RAB5IF
PMID: 35614220 (2022) identified a homozygous nonsense variant (p.W25X) in a Turkish boy previously reported by PMID: 24194475 to have bilateral cleft lip, complete cleft palate, moderate to severe intellectual delay and dysmorphic features. FHx of cleft lip/cleft palate as well in relatives who were heterozygous for the reported variant
Sources: Literature
Intellectual disability v5.341 CASP2 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Dmitrijs Rots, there are at least three unrelated families reported with biallelic CASP2 variants and intellectual disability/ global developmental delay. Hence, this gene can be promoted to green rating in the next GMS review.
Intellectual disability v5.341 CASP2 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Dmitrijs Rots, there are at least three unrelated families reported with biallelic CASP2 variants and intellectual disability/ global developmental delay. Hence, this gene can be promoted to green rating in the next GMS review.
Intellectual disability v5.341 CASP2 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Dmitrijs Rots, there are at least three unrelated families reported with biallelic CASP2 variants and intellectual disability/ global developmental delay. Hence, this gene can be promoted to green rating in the next GMS review.
Intellectual disability v5.340 CASP2 Achchuthan Shanmugasundram Phenotypes for gene: CASP2 were changed from Autosomal recessive mental retardation to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Intellectual disability v5.338 ZBTB47 Sarah Leigh commented on gene: ZBTB47: The opinion of Helen Brittain (Genomics England, Clinical Fellow), was that ZBTB47 should be green on the Intellectual disability and Early onset or syndromic epilepsy panels.
Intellectual disability v5.338 ZBTB47 Sarah Leigh edited their review of gene: ZBTB47: Added comment: ZBTB47 variants have not been associated with a phenotype in OMIM, Gen2Phen or MONDO. PMID: 37743782 reports five unrelated patients with de novo missense variants in ZBTB47 (c.2039A>G, p.(Glu680Gly) in one patient and c.1429G>A, p.(Glu477Lys) in four others), with a phenotype that included developmental delay, intellectual disability, seizures, hypotonia, gait abnormalities, and variable movement abnormalities.; Changed rating: GREEN
Intellectual disability v5.337 CLEC16A Dmitrijs Rots gene: CLEC16A was added
gene: CLEC16A was added to Intellectual disability - microarray and sequencing. Sources: Literature
Mode of inheritance for gene: CLEC16A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CLEC16A were set to PMID: 36538041
Phenotypes for gene: CLEC16A were set to severe neurodevelopmental disorder including microcephaly, brain atrophy, corpus callosum dysgenesis, and growth retardation
Penetrance for gene: CLEC16A were set to Complete
Review for gene: CLEC16A was set to GREEN
Added comment: Two independent cases reported PMID: 36538041with biallelic variants and functional evidence. Sufficient for the green rating.
Sources: Literature
Intellectual disability v5.336 VCP Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Zornitza Stark, there is sufficient evidence available for adding this gene with green rating in the next GMS update.
Intellectual disability v5.332 RAP1B Achchuthan Shanmugasundram changed review comment from: PMID:35451551 - New patient reported with mild intellectual disability, bicuspid aortic valve, dilation of aortic root and ascending aorta, hearing loss, and long‐standing thrombocytopenia with lymphopenia. A novel, missense RAP1B variant (p.Ala59Gly) has been identified in this patient. This variant is on the neighbouring amino acid to one of the previously reported variants (p.Gly60Arg). This variant is confirmed de novo and not in gnomAD; to: PMID:35451551 - New patient reported with mild intellectual disability, bicuspid aortic valve, dilation of aortic root and ascending aorta, hearing loss, and long‐standing thrombocytopenia with lymphopenia. A novel, missense RAP1B variant (p.Ala59Gly) has been identified in this patient. This variant is on the neighbouring amino acid to one of the previously reported variants (p.Gly60Arg). This variant is confirmed de novo and not in gnomAD.

This gene has been associated with relevant phenotype in Gene2Phenotype database (with 'limited' rating in the DD panel), but not yet been associated with phenotypes in OMIM.
Intellectual disability v5.332 SGSM3 Zornitza Stark gene: SGSM3 was added
gene: SGSM3 was added to Intellectual disability - microarray and sequencing. Sources: Literature
Mode of inheritance for gene: SGSM3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SGSM3 were set to 37833060
Phenotypes for gene: SGSM3 were set to Neurodevelopmental disorder (MONDO:0700092), SGSM3-related
Review for gene: SGSM3 was set to AMBER
Added comment: PMID: 37833060
- 13 patients from 8 families of Ashkenazi Jewish origin all had the same homozygous frameshift variant (c.981dup). Predicted to cause NMD. The variant co-segregated with disease in all available family members. The affected individuals displayed mild global developmental delay and mild to moderate intellectual disability. Additional features observed included hypotonia, behavioural challenges and short stature. Considered a founder variant (1 in 52 Ashkenazi Jews carry the variant). Also present in other populations but no homozygotes in gnomAD.
Sources: Literature
Intellectual disability v5.332 AGPAT3 Zornitza Stark gene: AGPAT3 was added
gene: AGPAT3 was added to Intellectual disability - microarray and sequencing. Sources: Literature
Mode of inheritance for gene: AGPAT3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AGPAT3 were set to 37821758
Phenotypes for gene: AGPAT3 were set to Neurodevelopmental disorder (MONDO#0700092), AGPAT3-related
Review for gene: AGPAT3 was set to AMBER
Added comment: - Single consanguineous family with four individuals with severe intellectual disability and retinitis pigmentosa
- All affected individuals were homozygous for a nonsense variant in AGPAT3, healthy unaffected individuals who were tested were heterozygous for the variant
- Overexpression of mutant transcript revealed absence of AGPAT3 protein compared to WT transcript via Western blot analysis
- KO AGPAT3 mouse demonstrated impaired neuronal migration
Sources: Literature
Intellectual disability v5.332 VCP Zornitza Stark gene: VCP was added
gene: VCP was added to Intellectual disability - microarray and sequencing. Sources: Literature
Mode of inheritance for gene: VCP was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: VCP were set to 37883978
Phenotypes for gene: VCP were set to Neurodevelopmental disorder (MONDO: 0700092)
Review for gene: VCP was set to GREEN
Added comment: 13 unrelated individuals with childhood onset ID/DD disorder including macrocephaly, hypotonia and dysmorphic features. Non-specific / mild MRI findings.
12 de novo - 1 inherited
Sources: Literature
Intellectual disability v5.330 MYCN Sarah Leigh Added comment: Comment on mode of pathogenicity: Gain-of-function MYCN variants have been reported (PMID: 30573562; 37710961) where the phenotypic features are to an extent opposite the phenotype of Feingold syndrome 1 (OMIM:164280) caused by loss-of-function MYCN variants.
Intellectual disability v5.328 MAST4 Sarah Leigh edited their review of gene: MAST4: Added comment: MAST4 variants have not been associated with a phenotype in OMIM, Gen2Phen or MONDO to date. PMID: 36910266 reports three de novo heterozygous MAST4 missense variants in four unrelated cases, with a neurodevelopmental disorder, including cognitive delay/intellectual disability and PMID: 33057194 reports four heterozygous MAST4 missense variants in four unrelated cases and a terminating variant in an additional case, from a cohort of 31,058 parent-offspring trios of individuals with developmental disorders. Between these two publications there are five missense MAST4 variants and one terminating variant. Variant c.4412C>T (p.Thr1471Ile) was seen in three unrelated cases.; Changed rating: GREEN
Intellectual disability v5.325 RBL2 Sarah Leigh edited their review of gene: RBL2: Added comment: RBL2 variants have been associated with Brunet-Wagner neurodevelopmental syndrome (OMIM:619690) but not with phenotype in Gen2Phen. To date six RBL2 variants have been reported in four unrelated cases of OMIM:619690 (PMIDs: 32105419; 33980986).; Changed rating: GREEN; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v5.322 FAM111A Sarah Leigh changed review comment from: Intellectual disability is not a feature of Gracile bone dysplasia (OMIM: 602361) or Kenny-Caffey syndrome, type 2 (OMIM: 127000)(PMID: 23684011;23996431;25529582).; to: Intellectual disability is not a feature of Gracile bone dysplasia (OMIM: 602361) or Kenny-Caffey syndrome, type 2 (OMIM: 127000)(PMID: 23684011;23996431;25529582).
PMID: 34382758 reports an autosomal recessive case of Kenny-Caffey Syndrome Type 2. The proband had inherited FAM111A variants from his healthy parents (paternal heterozygous missense
variant c.976T>A (p.L326I) and maternal heterozygous
in-frame deletion variant c.1714_1716del (p.Ile572del,
rs779963813)).
Intellectual disability v5.320 ARF3 Achchuthan Shanmugasundram Tag watchlist was removed from gene: ARF3.
Intellectual disability v5.320 ARF3 Achchuthan Shanmugasundram Classified gene: ARF3 as Amber List (moderate evidence)
Intellectual disability v5.320 ARF3 Achchuthan Shanmugasundram Gene: arf3 has been classified as Amber List (Moderate Evidence).
Intellectual disability v5.319 ARF3 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: ARF3.
Intellectual disability v5.319 ARF3 Achchuthan Shanmugasundram Publications for gene: ARF3 were set to 34346499; 36369169
Intellectual disability v5.319 ARF3 Achchuthan Shanmugasundram Publications for gene: ARF3 were set to 34346499
Intellectual disability v5.318 ARF3 Achchuthan Shanmugasundram reviewed gene: ARF3: Rating: GREEN; Mode of pathogenicity: None; Publications: 36369169; Phenotypes: neurodevelopmental disorder, MONDO:0700092, intellectual disability, MONDO:0001071; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v5.315 MYCN Zornitza Stark edited their review of gene: MYCN: Added comment: PMID 37710961: Three individuals now reported with gain-of-function missense variants (identical variant in two individuals) and somewhat opposing phenotype cf Feingold. Clinical presentation includes megalencephaly, hypoplastic corpus callosum, postaxial polydactyly, intellectual disability and motor delay. Knock-in mouse model showed morphological manifestations in multiple tissues including digits, female reproductive system and kidney.; Changed publications to: 21224895, 8470948, 37710961; Changed phenotypes to: Feingold syndrome 1, Megalencephaly, intellectual disability, Neurodevelopmental disorder (MONDO:0700092), MYCN-related
Intellectual disability v5.315 MAST4 Zornitza Stark gene: MAST4 was added
gene: MAST4 was added to Intellectual disability - microarray and sequencing. Sources: Literature
Mode of inheritance for gene: MAST4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MAST4 were set to 36910266; 33057194
Phenotypes for gene: MAST4 were set to neurodevelopmental disorder MONDO:0700092, MAST4-related
Review for gene: MAST4 was set to GREEN
Added comment: 9 individuals with de novo missense variants and ID reported altogether.

PMID: 36910266 - 4 affecteds from unrelated families, all de novo missense

2x borderline microcephaly (-2SD)
2x gross motor delay
2x dysmorphism
4x ID + seizures
3x abnormal brain MRI findings

PMID: 33057194 - 5x de novos, 4x missense + 1x PTC
Cohort of individuals with severe developmental disorder
individual phenotypic information not provided


Recurrent variants are Thr1471Ile (3x) and Ser1181Phe)
Sources: Literature
Intellectual disability v5.315 ZBTB47 Zornitza Stark gene: ZBTB47 was added
gene: ZBTB47 was added to Intellectual disability - microarray and sequencing. Sources: Literature
Mode of inheritance for gene: ZBTB47 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ZBTB47 were set to 37743782
Phenotypes for gene: ZBTB47 were set to Neurodevelopmental disorder (MONDO#0700092), ZBTB47-related
Review for gene: ZBTB47 was set to GREEN
Added comment: PMID 37743782:
- 5 individuals with de novo missense variants, 4/5 have a recurring p.Gly477Lys. Probands have intellectual disability (5/5), seizures (5/5), hypotonia (5/5), gait abnormalities, and variable movement abnormalities (5/5).
- Missense variants are positioned close to His and Cys residues involved in forming C2H2 zinc fingers.
- No functional studies performed
Sources: Literature
Intellectual disability v5.315 MT-ND4 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing was removed from gene: MT-ND4.
Intellectual disability v5.315 MT-ND1 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing was removed from gene: MT-ND1.
Intellectual disability v5.315 MT-ATP6 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing was removed from gene: MT-ATP6.
Intellectual disability v5.315 ERI1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are four unrelated cases with biallelic null ERI1 variants and mild intellectual disability. Hence, this gene can be promoted to green rating in the next GMS review.
Intellectual disability v5.314 ERI1 Achchuthan Shanmugasundram gene: ERI1 was added
gene: ERI1 was added to Intellectual disability - microarray and sequencing. Sources: Literature
Mode of inheritance for gene: ERI1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ERI1 were set to 36208065; 37352860
Phenotypes for gene: ERI1 were set to intellectual disability, MONDO:0001071
Review for gene: ERI1 was set to GREEN
Added comment: PMID:36208065 reported a female patient with a homozygous nonsense variant in ERI1 gene and with mild intellectual disability (ID), eyelid ptosis, and anomalies in her hands and feet (brachydactyly, clinodactyly, dysplastic/short nail of halluces, brachytelephalangy, short metacarpals, and toe syndactyly).

PMID:37352860 reported eight patients from seven unrelated families with compound heterozygous variants in ERI1 gene, of which four patients had missense variants, three had null variants and one had missense and PTC variants. The patients with missense variants had a more severe severe spondyloepimetaphyseal dysplasia, syndactyly, brachydactyly/clinodactyly/camptodactyly. The patients with null variants had mild ID and digit anomalies including brachydactyly/clinodactyly/camptodactyly. The patient with both missense and PTC variants had phenotype with short stature, syndactyly, brachydactyly/clinodactyly/camptodactyly, and delayed motor milestones and speech and generalised hypotonia.

This gene has not yet been reported with relevant phenotypes either in OMIM or in Gene2Phenotype.
Sources: Literature
Intellectual disability v5.307 SRSF1 Achchuthan Shanmugasundram gene: SRSF1 was added
gene: SRSF1 was added to Intellectual disability - microarray and sequencing. Sources: Literature
Mode of inheritance for gene: SRSF1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SRSF1 were set to 37071997
Phenotypes for gene: SRSF1 were set to Neurodevelopmental disorder with dysmorphic facies and behavioral abnormalities, OMIM:620489
Review for gene: SRSF1 was set to GREEN
Added comment: There are 17 individuals from 16 different families were reported with 15 different monoallelic variants (mostly de novo) in SRSF1 gene. They were reported with a neurodevelopmental disorder mainly comprising neurological abnormalities such as intellectual disability/ developmental delay, motor delay, speech delay, and behavioural disorders and facial dysmorphisms. Intellectual disability was present in 16 of 17 individuals (3 severe, 2 moderate, 3 mild to moderate, 3 mild, 1 borderline and 4 unknown severity), while the remaining one had learning disability.

Functional testing of a subset of variants in Drosophila supported pathogenicity in most, but 2 missense variants showed no functional effect and were classified VUS.

This gene has already been associated with neurodevelopmental disorder in both OMIM (MIM #620489) and Gene2Phenotype ('limited' rating in the DD panel).
Sources: Literature
Intellectual disability v5.305 ZMYM3 Arina Puzriakova Phenotypes for gene: ZMYM3 were changed from X-linked mental retardation to Intellectual developmental disorder, X-linked 112, OMIM:301111
Intellectual disability v5.304 WIPI2 Arina Puzriakova Phenotypes for gene: WIPI2 were changed from ?Intellectual developmental disorder with short stature and variable skeletal anomalies 618453 to Intellectual developmental disorder with short stature and variable skeletal anomalies, OMIM:618453
Intellectual disability v5.301 TAF2 Arina Puzriakova Phenotypes for gene: TAF2 were changed from Mental retardation, autosomal recessive 40, 615599 to Mental retardation, autosomal recessive 40, OMIM:615599
Intellectual disability v5.300 SARS Arina Puzriakova Tag Q1_23_promote_green was removed from gene: SARS.
Intellectual disability v5.300 PRKAR1B Arina Puzriakova Phenotypes for gene: PRKAR1B were changed from Global developmental delay; Intellectual disability; Autism; Attention deficit hyperactivity disorder; Aggressive behavior; Abnormality of movement; Upslanted palpebral fissure to Marbach-Schaaf neurodevelopmental syndrome, OMIM:619680
Intellectual disability v5.299 PRKAR1B Arina Puzriakova Tag watchlist was removed from gene: PRKAR1B.
Tag Q2_23_promote_green was removed from gene: PRKAR1B.
Intellectual disability v5.298 MTSS1L Arina Puzriakova Phenotypes for gene: MTSS1L were changed from Global developmental delay; Intellectual disability; Ophthalmological anomalies; Microcephaly; Mild facial dysmorphisms to Intellectual developmental disorder with ocular anomalies and distinctive facial features, OMIM:620086
Intellectual disability v5.297 MED11 Arina Puzriakova Phenotypes for gene: MED11 were changed from MED11-associated neurodevelopmental disorder to Neurodegeneration with developmental delay, early respiratory failure, myoclonic seizures, and brain abnormalities, OMIM:620327
Intellectual disability v5.295 KDM5A Arina Puzriakova Phenotypes for gene: KDM5A were changed from AUTOSOMAL RECESSIVE MENTAL RETARDATION; autism spectrum disorder, MONDO:0005258; intellectual disability, MONDO:0001071 to autism spectrum disorder, MONDO:0005258; intellectual disability, MONDO:0001071
Intellectual disability v5.294 IQSEC2 Arina Puzriakova Phenotypes for gene: IQSEC2 were changed from Mental retardation, X-linked 1, 309530; non-syndromic X-linked intellectual disability; Rett like phenotype in males; MENTAL RETARDATION X-LINKED TYPE 1 (MRX1) to Intellectual developmental disorder, X-linked 1, OMIM:309530
Intellectual disability v5.293 INTS11 Arina Puzriakova Phenotypes for gene: INTS11 were changed from Complex neurodevelopmental disorder, MONDO:0100038 to Neurodevelopmental disorder with motor and language delay, ocular defects, and brain abnormalities, OMIM:620428
Intellectual disability v5.286 SARS Arina Puzriakova commented on gene: SARS: The rating of this gene has been updated to Green following NHS Genomic Medicine Service approval.
Intellectual disability v5.286 PRKAR1B Arina Puzriakova reviewed gene: PRKAR1B: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v5.286 SARS Arina Puzriakova Source NHS GMS was added to SARS.
Source Expert Review Green was added to SARS.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v5.286 PRKAR1B Arina Puzriakova Source NHS GMS was added to PRKAR1B.
Source Expert Review Green was added to PRKAR1B.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v5.285 RAB5C Achchuthan Shanmugasundram changed review comment from: Comment on list classification: As reviewed by Zornitza Stark, there is sufficient evidence for this gene to be promoted to green rating at the next GMS update.; to: Comment on list classification: As reviewed by Zornitza Stark, there is sufficient evidence (12 unrelated cases) for this gene to be promoted to green rating at the next GMS update.
Intellectual disability v5.285 RAB5C Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Zornitza Stark, there is sufficient evidence for this gene to be promoted to green rating at the next GMS update.
Intellectual disability v5.284 ESAM Achchuthan Shanmugasundram changed review comment from: As reviewed by Julia Baptista, PMID:36996813 reported the identification of biallelic ESAM variants in 13 individuals from eight unrelated families, which included four foetuses. All nine born individuals had profound global developmental delay/ unspecified intellectual disability, epilepsy, absent or severely delayed speech, varying degrees of spasticity, ventriculomegaly, and ICH/ cerebral calcifications, the latter being also observed in the foetuses.

This gene has been associated with relevant phenotypes in OMIM (MIM #620371), but not yet in Gene2Phenotype.; to: As reviewed by Julia Baptista, PMID:36996813 reported the identification of biallelic ESAM variants in 13 individuals from eight unrelated families, which included four foetuses. All nine live-born individuals had profound global developmental delay/ unspecified intellectual disability, epilepsy, absent or severely delayed speech, varying degrees of spasticity, ventriculomegaly, and ICH/ cerebral calcifications, the latter being also observed in the foetuses.

This gene has been associated with relevant phenotypes in OMIM (MIM #620371), but not yet in Gene2Phenotype.
Intellectual disability v5.281 PPP1R3F Achchuthan Shanmugasundram Added comment: Comment on list classification: There are at least nine patients reported with intellectual disability and with hemizygious PPP1R3F variants and hence this gene should be promoted to green rating at the next GMS review.
Intellectual disability v5.281 PPP1R3F Achchuthan Shanmugasundram Added comment: Comment on list classification: There are at least nine patients reported with intellectual disability and with hemizygious PPP1R3F variants and hence this gene should be promoted to green rating at the next GMS review.
Intellectual disability v5.281 PPP1R3F Achchuthan Shanmugasundram Added comment: Comment on list classification: There are at least nine patients reported with intellectual disability and with hemizygious PPP1R3F variants and hence this gene should be promoted to green rating at the next GMS review.
Intellectual disability v5.281 PPP1R3F Achchuthan Shanmugasundram Added comment: Comment on list classification: There are at least nine patients reported with intellectual disability and with hemizygious PPP1R3F variants and hence this gene should be promoted to green rating at the next GMS review.
Intellectual disability v5.281 PPP1R3F Achchuthan Shanmugasundram Added comment: Comment on list classification: There are at least nine patients reported with intellectual disability and with hemizygious PPP1R3F variants and hence this gene should be promoted to green rating at the next GMS review.
Intellectual disability v5.281 PPP1R3F Achchuthan Shanmugasundram Added comment: Comment on list classification: There are at least nine patients reported with intellectual disability and with hemizygious PPP1R3F variants and hence this gene should be promoted to green rating at the next GMS review.
Intellectual disability v5.276 NR2F2 Achchuthan Shanmugasundram changed review comment from: This gene is an established gene for congenital heart defects (MIM #615779) and disorder of sexual differentiation (MIM #618901). This gene has been associated with these two phenotypes in both OMIM and Gene2Phenotype.

PMID:29663647 - An 11-month old boy was reported with global developmental delay, dysmorphic features, coarctation of the aorta, and ventricular septal defect and was identified with pathogenic NR2F2 variant.

PMID:37500725 - 16 previously unreported unrelated individuals (and a mildly affected mosaic mother of one of them) with rare heterozygous variants (majority are de novo variants) were reviewed in this publication and they had variable clinical presentations including intrauterine growth restriction (IUGR), CHD, CDH, genital anomalies, DSD, developmental delays, hypotonia, feeding difficulties, failure to thrive, congenital and acquired microcephaly, dysmorphic facial features, renal failure, hearing loss, strabismus, asplenia, and vascular malformations. All 14 for whom data is available had motor delays and 13 had speech delay. One of them had global developmental delay, one had mild intellectual disability and four had learning disabilities.; to: This gene is an established gene for congenital heart defects (MIM #615779) and disorder of sexual differentiation (MIM #618901). This gene has been associated with these two phenotypes in both OMIM and Gene2Phenotype. Some patients with CHD (MIM #615779) are reported with developmental delays in the OMIM record.

PMID:29663647 - An 11-month old boy was reported with global developmental delay, dysmorphic features, coarctation of the aorta, and ventricular septal defect and was identified with pathogenic NR2F2 variant.

PMID:37500725 - 16 previously unreported unrelated individuals (and a mildly affected mosaic mother of one of them) with rare heterozygous variants (majority are de novo variants) were reviewed in this publication and they had variable clinical presentations including intrauterine growth restriction (IUGR), CHD, CDH, genital anomalies, DSD, developmental delays, hypotonia, feeding difficulties, failure to thrive, congenital and acquired microcephaly, dysmorphic facial features, renal failure, hearing loss, strabismus, asplenia, and vascular malformations. All 14 for whom data is available had motor delays and 13 had speech delay. One of them had global developmental delay, one had mild intellectual disability and four had learning disabilities.
Intellectual disability v5.276 NR2F2 Achchuthan Shanmugasundram changed review comment from: This gene is an established gene for congenital heart defects (MIM #615779) and disorder of sexual differentiation (MIM #618901).

PMID:29663647 - An 11-month old boy was reported with global developmental delay, dysmorphic features, coarctation of the aorta, and ventricular septal defect and was identified with pathogenic NR2F2 variant.

PMID:37500725 - 16 previously unreported unrelated individuals (and a mildly affected mosaic mother of one of them) with rare heterozygous variants (majority are de novo variants) were reviewed in this publication and they had variable clinical presentations including intrauterine growth restriction (IUGR), CHD, CDH, genital anomalies, DSD, developmental delays, hypotonia, feeding difficulties, failure to thrive, congenital and acquired microcephaly, dysmorphic facial features, renal failure, hearing loss, strabismus, asplenia, and vascular malformations. All 14 for whom data is available had motor delays and 13 had speech delay. One of them had global developmental delay, one had mild intellectual disability and four had learning disabilities.; to: This gene is an established gene for congenital heart defects (MIM #615779) and disorder of sexual differentiation (MIM #618901). This gene has been associated with these two phenotypes in both OMIM and Gene2Phenotype.

PMID:29663647 - An 11-month old boy was reported with global developmental delay, dysmorphic features, coarctation of the aorta, and ventricular septal defect and was identified with pathogenic NR2F2 variant.

PMID:37500725 - 16 previously unreported unrelated individuals (and a mildly affected mosaic mother of one of them) with rare heterozygous variants (majority are de novo variants) were reviewed in this publication and they had variable clinical presentations including intrauterine growth restriction (IUGR), CHD, CDH, genital anomalies, DSD, developmental delays, hypotonia, feeding difficulties, failure to thrive, congenital and acquired microcephaly, dysmorphic facial features, renal failure, hearing loss, strabismus, asplenia, and vascular malformations. All 14 for whom data is available had motor delays and 13 had speech delay. One of them had global developmental delay, one had mild intellectual disability and four had learning disabilities.
Intellectual disability v5.274 NR2F2 Achchuthan Shanmugasundram commented on gene: NR2F2: This gene is an established gene for congenital heart defects (MIM #615779) and disorder of sexual differentiation (MIM #618901).

PMID:29663647 - An 11-month old boy was reported with global developmental delay, dysmorphic features, coarctation of the aorta, and ventricular septal defect and was identified with pathogenic NR2F2 variant.

PMID:37500725 - 16 previously unreported unrelated individuals (and a mildly affected mosaic mother of one of them) with rare heterozygous variants (majority are de novo variants) were reviewed in this publication and they had variable clinical presentations including intrauterine growth restriction (IUGR), CHD, CDH, genital anomalies, DSD, developmental delays, hypotonia, feeding difficulties, failure to thrive, congenital and acquired microcephaly, dysmorphic facial features, renal failure, hearing loss, strabismus, asplenia, and vascular malformations. All 14 for whom data is available had motor delays and 13 had speech delay. One of them had global developmental delay, one had mild intellectual disability and four had learning disabilities.
Intellectual disability v5.271 MT-ND4 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing tag was added to gene: MT-ND4.
Intellectual disability v5.271 MT-ND1 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing tag was added to gene: MT-ND1.
Intellectual disability v5.271 MT-ATP6 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing tag was added to gene: MT-ATP6.
Intellectual disability v5.271 PPP1R3F Zornitza Stark gene: PPP1R3F was added
gene: PPP1R3F was added to Intellectual disability - microarray and sequencing. Sources: Literature
Mode of inheritance for gene: PPP1R3F was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: PPP1R3F were set to 37531237
Phenotypes for gene: PPP1R3F were set to Neurodevelopmental Disorder, MONDO:0700092,PPP1R3F-related
Review for gene: PPP1R3F was set to GREEN
Added comment: 13 unrelated hemizygous individuals reported with functional evidence
Sources: Literature
Intellectual disability v5.271 RAB5C Zornitza Stark gene: RAB5C was added
gene: RAB5C was added to Intellectual disability - microarray and sequencing. Sources: Literature
Mode of inheritance for gene: RAB5C was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RAB5C were set to 37552066
Phenotypes for gene: RAB5C were set to Neurodevelopmental disorder MONDO:0700092, RAB5C-related
Review for gene: RAB5C was set to GREEN
Added comment: 12 individuals with nine different heterozygous de novo variants in RAB5C.
9 with missense, 1 inframe duplication and 2 stop-gains (clinically more severe).
All have mild-severe ID, 4/12 have epilepsy, 6/12 have macrocephaly (more than 3 SD).
Sources: Literature
Intellectual disability v5.271 NR2F2 Katherine Lachlan reviewed gene: NR2F2: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 37500725; Phenotypes: intrauterine growth restriction (IUGR), CHD, CDH, genital anomalies, DSD, developmental delays, hypotonia, feeding difficulties, failure to thrive, congenital and acquired microcephaly, dysmorphic facial features, renal failure, hearing loss, strabismus, asplenia, vascular malformations; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v5.271 ESAM Julia Baptista gene: ESAM was added
gene: ESAM was added to Intellectual disability - microarray and sequencing. Sources: Literature,Expert Review
Mode of inheritance for gene: ESAM was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ESAM were set to PMID: 36996813
Phenotypes for gene: ESAM were set to severe ID; seizures, spasticity
Review for gene: ESAM was set to GREEN
Added comment: Lecca et al 2023 reported thirteen patients from eight unrelated families with biallelic loss of function variants (nonsense, frameshift, canonical splice site, all predicted to result in a transcript targeted for nonsense-mediated decay). Protein staining assays in one of the brain fetal samples confirmed loss the loss of protein.
The phenotype reported in this cohort is of a severe neurodevelopmental disorder with brain anomalies (calcifications, hydrocephalus, enlarged ventricles, cerebral atrophy, etc), and dysmorphic features.
Sources: Literature, Expert Review
Intellectual disability v5.271 TP63 Arina Puzriakova Phenotypes for gene: TP63 were changed from Ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome; 3, 604292; Split-hand/foot malformation 4, 605289; Hay-Wells syndrome, 106260; ADULT syndrome, 103285; Limb-mammary syndrome, 603543; Rapp-Hodgkin syndrome, 129400; Orofacial cleft 8, 129400 to ADULT syndrome, OMIM:103285; Ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome 3, OMIM:604292; Hay-Wells syndrome, OMIM:106260; Limb-mammary syndrome, OMIM:603543; Orofacial cleft 8, OMIM:618149; Rapp-Hodgkin syndrome, OMIM:129400; Split-hand/foot malformation 4, OMIM:605289
Intellectual disability v5.270 ERMARD Achchuthan Shanmugasundram Classified gene: ERMARD as Red List (low evidence)
Intellectual disability v5.270 ERMARD Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Arina Puzriakova, this gene has been demoted from amber to red.
Intellectual disability v5.270 ERMARD Achchuthan Shanmugasundram Gene: ermard has been classified as Red List (Low Evidence).
Intellectual disability v5.270 ERMARD Achchuthan Shanmugasundram Classified gene: ERMARD as Red List (low evidence)
Intellectual disability v5.270 ERMARD Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Arina Puzriakova, this gene has been demoted from amber to red.
Intellectual disability v5.270 ERMARD Achchuthan Shanmugasundram Gene: ermard has been classified as Red List (Low Evidence).
Intellectual disability v5.270 ERMARD Achchuthan Shanmugasundram Classified gene: ERMARD as Red List (low evidence)
Intellectual disability v5.270 ERMARD Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Arina Puzriakova, this gene has been demoted from amber to red.
Intellectual disability v5.270 ERMARD Achchuthan Shanmugasundram Gene: ermard has been classified as Red List (Low Evidence).
Intellectual disability v5.269 ERMARD Achchuthan Shanmugasundram Classified gene: ERMARD as Red List (low evidence)
Intellectual disability v5.269 ERMARD Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Arina Puzriakova, this gene has been demoted to red.
Intellectual disability v5.269 ERMARD Achchuthan Shanmugasundram Gene: ermard has been classified as Red List (Low Evidence).
Intellectual disability v5.269 ERMARD Achchuthan Shanmugasundram Classified gene: ERMARD as Red List (low evidence)
Intellectual disability v5.269 ERMARD Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Arina Puzriakova, this gene has been demoted to red.
Intellectual disability v5.269 ERMARD Achchuthan Shanmugasundram Gene: ermard has been classified as Red List (Low Evidence).
Intellectual disability v5.268 U2AF2 Celia Duff-Farrier changed review comment from: Literature evidence Ref1-5, identification of affected patients in the diagnostic setting (CVA database, 19:55661148:C>T ) and further accounts in open access databases (ClinVar and LOVD), make this gene suitable for clinical review and upgrading to a green gene status on relevant panels. It is associated with a phenotype encompassing dysmorphism, epilepsy, developmental delay, intellectual disability, and brain malformation Ref1-5. There is a recent publication that proposes an extension of this phenotype to include hypomyelination leukodystrophy Ref6. A loss of function mechanism has been suggested, associated with disruption of RNA recognition motifs required for the function of U2AF2 as a pre-mRNA splicing factor Ref4. At least one recurrent pathogenic variant has been identified by this review U2AF2 c.445C>T p.(Arg149Trp). U2AF2 is constrained for missense in gnomAD Z=4.71.
total variants reported
1) De novo U2AF2 (NM_007279.3:c.445C>T p.(Arg149Trp)) recurrent variant; 1x patient in Hiraide (PubMed: 34112922), 1x patient in Kittock (PubMed: 37092751), 2x patients in Kaplanis (Pubmed: 33057194), 7x patients in the Leiden Open Variation Database (LOVD, https://www.lovd.nl/), 1x patient in house BGL and 4x additional on CVA
2) De novo U2AF2 c.603G>T; 1 patient in Wang 2023 (PubMed: 36747105)
3) De novo U2AF2 c.470C>T p.Pro157Leu) in Kuroda (PubMed: 37134193)
4) 9x additional pathogenic or likely pathogenic variants on LOVD
5) 2x additional likely pathogenic variants on ClinVar

References
1.       PubMed: 28135719 McRae (2017)-DDD data
2.       PubMed: 31785789 Turner (2019)-DDD data
3.       PubMed: 34112922 Hiraide (2021) de novo U2AF2 c.445C>T p.R149W
4.       PubMed: 36747105 Wang (2023) de novo U2AF2 c.603G>T, p.163_201del
5.       PubMed: 37092751 Kittock (2023) de novo U2AF2 c.445C>T p.R149W
Possible emerging phenotype of hypomyelinating leukodystrophy
6.       PubMed: 37134193 Kuroda (2023); to: Literature evidence Ref1-5, identification of affected patients in the diagnostic setting (CVA database, 19:55661148:C>T ) and further accounts in open access databases (ClinVar and LOVD), make this gene suitable for clinical review and upgrading to a green gene status on relevant panels. It is associated with a phenotype encompassing dysmorphism, epilepsy, developmental delay, intellectual disability, and brain malformation Ref1-5. There is a recent publication that proposes an extension of this phenotype to include hypomyelination leukodystrophy Ref6. A loss of function mechanism has been suggested, associated with disruption of RNA recognition motifs required for the function of U2AF2 as a pre-mRNA splicing factor Ref4. At least one recurrent pathogenic variant has been identified by this review U2AF2 c.445C>T p.(Arg149Trp). U2AF2 is constrained for missense in gnomAD Z=4.71.
total variants/patients identified
1) De novo U2AF2 (NM_007279.3:c.445C>T p.(Arg149Trp)) recurrent variant; 1x patient in Hiraide (PubMed: 34112922), 1x patient in Kittock (PubMed: 37092751), 2x patients in Kaplanis (Pubmed: 33057194), 7x patients in the Leiden Open Variation Database (LOVD, https://www.lovd.nl/), 1x patient in house BGL and 4x additional on CVA
2) De novo U2AF2 c.603G>T; 1 patient in Wang 2023 (PubMed: 36747105)
3) De novo U2AF2 c.470C>T p.Pro157Leu) in Kuroda (PubMed: 37134193)
4) 9x additional pathogenic or likely pathogenic variants on LOVD
5) 2x additional likely pathogenic variants on ClinVar
6) We are collaborating with a researcher in the USA with a cohort of 40+ cases.


References
1.       PubMed: 28135719 McRae (2017)-DDD data
2.       PubMed: 31785789 Turner (2019)-DDD data
3.       PubMed: 34112922 Hiraide (2021) de novo U2AF2 c.445C>T p.R149W
4.       PubMed: 36747105 Wang (2023) de novo U2AF2 c.603G>T, p.163_201del
5.       PubMed: 37092751 Kittock (2023) de novo U2AF2 c.445C>T p.R149W
Possible emerging phenotype of hypomyelinating leukodystrophy
6.       PubMed: 37134193 Kuroda (2023)
Intellectual disability v5.268 NEUROG1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are four unrelated cases reported with global developmental delay/ intellectual disability. Hence, this gene can be promoted to green rating in the next GMS review.
Intellectual disability v5.268 NEUROG1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are four unrelated cases reported with global developmental delay/ intellectual disability. Hence, this gene can be promoted to green rating in the next GMS review.
Intellectual disability v5.268 NEUROG1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are four unrelated cases reported with global developmental delay/ intellectual disability. Hence, this gene can be promoted to green rating in the next GMS review.
Intellectual disability v5.263 UQCRB Arina Puzriakova Phenotypes for gene: UQCRB were changed from Mitochondrial complex III deficiency, nuclear type 3, 615158 to Mitochondrial complex III deficiency, nuclear type 3, OMIM:615158
Intellectual disability v5.260 ATP6V0C Achchuthan Shanmugasundram Phenotypes for gene: ATP6V0C were changed from Epilepsy, early-onset, 3, with or without developmental delay, OMIM:620465 to Epilepsy, early-onset, 3, with or without developmental delay, OMIM:620465
Intellectual disability v5.260 ATP6V0C Achchuthan Shanmugasundram Phenotypes for gene: ATP6V0C were changed from Epilepsy, early-onset, 3, with or without developmental delay, OMIM:620465 to Epilepsy, early-onset, 3, with or without developmental delay, OMIM:620465
Intellectual disability v5.261 ATP6V0C Achchuthan Shanmugasundram Phenotypes for gene: ATP6V0C were changed from Epilepsy, early-onset, 3, with or without developmental delay, OMIM:620465 to Epilepsy, early-onset, 3, with or without developmental delay, OMIM:620465
Intellectual disability v5.261 ATP6V0C Achchuthan Shanmugasundram Phenotypes for gene: ATP6V0C were changed from Epilepsy, early-onset, 3, with or without developmental delay, OMIM:620465 to Epilepsy, early-onset, 3, with or without developmental delay, OMIM:620465
Intellectual disability v5.261 ATP6V0C Achchuthan Shanmugasundram Phenotypes for gene: ATP6V0C were changed from Epilepsy, early-onset, 3, with or without developmental delay, OMIM:620465 to Epilepsy, early-onset, 3, with or without developmental delay, OMIM:620465
Intellectual disability v5.261 ATP6V0C Achchuthan Shanmugasundram Phenotypes for gene: ATP6V0C were changed from Epilepsy, early-onset, 3, with or without developmental delay, OMIM:620465 to Epilepsy, early-onset, 3, with or without developmental delay, OMIM:620465
Intellectual disability v5.260 ATP6V0C Achchuthan Shanmugasundram Phenotypes for gene: ATP6V0C were changed from Epilepsy, early-onset, 3, with or without developmental delay, OMIM:620465 to Epilepsy, early-onset, 3, with or without developmental delay, OMIM:620465
Intellectual disability v5.260 ATP6V0C Achchuthan Shanmugasundram Phenotypes for gene: ATP6V0C were changed from Epilepsy; Intellectual Disability; microcephaly to Epilepsy, early-onset, 3, with or without developmental delay, OMIM:620465
Intellectual disability v5.257 ATP6V0C Achchuthan Shanmugasundram changed review comment from: 17 of 32 total patients had impaired intellectual development.; to: PMID:36074901 - 16 of 27 patients identified with monoallelic ATP6V0C variants, including a patient each from PMID:24623842 and PMID:33190975 had impaired intellectual development, while 21 patients had developmental delay.

PMID:37161035 - One of three patients identified with monoallelic ATP6V0C variant had impaired intellectual development and language delay, while another had developmental delay and speech delay.

This gene has been associated with relevant phenotypes in OMIM (MIM #620465) and Gene2Phenotype (with 'strong' rating in the DD panel).
Intellectual disability v5.257 ATP6V0C Achchuthan Shanmugasundram reviewed gene: ATP6V0C: Rating: GREEN; Mode of pathogenicity: None; Publications: 33190975, 35600075, 36074901, 37161035; Phenotypes: Epilepsy, early-onset, 3, with or without developmental delay, OMIM:620465; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v5.257 PTCH1 Arina Puzriakova Phenotypes for gene: PTCH1 were changed from Basal cell nevus syndrome, 109400Basal cell carcinoma, somatic, 605462Holoprosencephaly-7, 610828; HOLOPROSENCEPHALY-7 to Holoprosencephaly 7, OMIM:610828
Intellectual disability v5.256 NEUROG1 Julia Baptista gene: NEUROG1 was added
gene: NEUROG1 was added to Intellectual disability - microarray and sequencing. Sources: Literature
Mode of inheritance for gene: NEUROG1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NEUROG1 were set to 36647078; 33439489; 23419067; 26077850
Phenotypes for gene: NEUROG1 were set to developmental delay; behavioural problems; cranial dysinnervation; absent corneal reflex
Review for gene: NEUROG1 was set to GREEN
Added comment: Five affected individuals from four independently reported families (Middle Eastern, Portuguese, Indian and Turkish backgrounds) with biallelic microdeletion, missense, nonsense or frameshift variants.

Affected individuals present at birth or in early infancy with corneal opacities due to absent blinking, sensorineural deafness associated with hypoplastic or malformed cochlea and hypoplasia or agenesis of CN VIII was reported. Developmental delay, poor speech, autistic behavior and dysmorphic facial features were also present.
Sources: Literature
Intellectual disability v5.255 CMIP Tord Jonson changed review comment from: CMIP (MANE Select NM_198390) loss of function-variants (deletions) have been reported in two studies that describes patients with syndromic ASD and co-morbid gastrointestinal issues. See Van der Aa et al., 2012, Haploinsufficiency of CMIP in a girl with autism spectrum disorder and developmental delay due to a de novo deletion on chromosome 16q23.2 (PMID: 22689534); and Luo et al., 2017, CMIP haploinsufficiency in two patients with autism spectrum disorder and co-occurring gastrointestinal issues (PMID: 28504353). In addition, we have observed a local case with a de novo deletion encompassing only the genes CMIP and GAN in a patient with gastrostomy, intellectual disability, autism, ADHD and seizures.
Sources: Other; to: CMIP (MANE Select NM_198390) loss of function-variants (deletions) have been reported in two studies that describes patients with syndromic ASD and co-morbid gastrointestinal issues. See Van der Aa et al., 2012, Haploinsufficiency of CMIP in a girl with autism spectrum disorder and developmental delay due to a de novo deletion on chromosome 16q23.2 (PMID: 22689534); and Luo et al., 2017, CMIP haploinsufficiency in two patients with autism spectrum disorder and co-occurring gastrointestinal issues (PMID: 28504353). In addition, we have observed a local case with a de novo deletion encompassing only the genes CMIP and GAN in a patient with gastrostomy, intellectual disability, autism, ADHD and seizures.
Intellectual disability v5.255 CMIP Tord Jonson gene: CMIP was added
gene: CMIP was added to Intellectual disability - microarray and sequencing. Sources: Other
Mode of inheritance for gene: CMIP was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CMIP were set to PMID: 22689534; 28504353
Phenotypes for gene: CMIP were set to HP:0012759; HP:0000717; HP:0007018; HP:0001250; HP:0011471
Penetrance for gene: CMIP were set to unknown
Review for gene: CMIP was set to GREEN
gene: CMIP was marked as current diagnostic
Added comment: CMIP (MANE Select NM_198390) loss of function-variants (deletions) have been reported in two studies that describes patients with syndromic ASD and co-morbid gastrointestinal issues. See Van der Aa et al., 2012, Haploinsufficiency of CMIP in a girl with autism spectrum disorder and developmental delay due to a de novo deletion on chromosome 16q23.2 (PMID: 22689534); and Luo et al., 2017, CMIP haploinsufficiency in two patients with autism spectrum disorder and co-occurring gastrointestinal issues (PMID: 28504353). In addition, we have observed a local case with a de novo deletion encompassing only the genes CMIP and GAN in a patient with gastrostomy, intellectual disability, autism, ADHD and seizures.
Sources: Other
Intellectual disability v5.255 PABPC1 Sarah Leigh edited their review of gene: PABPC1: Added comment: PABPC1 variants have not been associated with a phenotype in OMIM, Gen2Phen or MONDO. PMID: 35511136 reports four de novo PABPC1 variants in four unrelated cases with a phenotype of global DD, movement coordination disorders,
seizures, behavioral disorders and mild facial dysmorphisms. Intellectual disability ranged in the cases from profound (1/4), IQ: 61 (1/4) and IQ: 79 (2/4). Seizures were apparent in the all of the three cases where it was assessed.
Molecular modeling of the variants suggested that they would result in a reduced binding affinity to the messenger RNA metabolism-related protein - PAIP2. This predicted effect was seen in coimmunoprecipitation assays between variant PABPC1 and PAIP2 (PMID: 35511136). Further functional studies in PMID: 35511136, showed that the proliferation of neural progenitor cells in Pabpc1 knockdown mouse embryo brains were decreased, this effect was rescued by the wild-type Pabpc1, but not by the variants c.1691A>G (p.Glu564Gly) or c.1709T>C (p.Ile570Thr).
Other variants were identified in 3/4 cases in PMID: 35511136, two of these had a ACMG VUS classification (RBBP4: c.845A>G, p.(Asn282Ser), IGF2R: c.1850G>A p.Cys617Tyr), while the third variant was monoallelic, whereas bialleic variants in this gene are associated with disease (KDM5B: c.2265dupA, p.(Tyr755*))(PMID: 35511136, table 1).; Changed rating: GREEN
Intellectual disability v5.254 CLCNKA Sarah Leigh Phenotypes for gene: CLCNKA were changed from Bartter syndrome, type 4b, digenic, 613090; Infantile Bartter syndrome with sensorineural deafness, intellectual disability to Bartter syndrome, type 4b, digenic, OMIM:613090; Bartter disease type 4B, MONDO:0000909
Intellectual disability v5.253 CLCNKA Sarah Leigh Added comment: Comment on mode of inheritance: Digenic CLCNKA & CLCNKB variants are associated with Bartter syndrome, type 4b, digenic (OMIM:613090)(PMID: 15044642;18310267;32488762). The current GMS rare disease bioinformatic pipeline does not allow for interpretation of digenic events.
Intellectual disability v5.252 CLCNKB Sarah Leigh Added comment: Comment on mode of inheritance: The mode of inheritance for CLCNKB should be BIALLELIC, autosomal or pseudoautosomal. Although digenic CLCNKB & CLCNKA variants are associated with Bartter syndrome, type 4b, digenic (OMIM:613090), the current GMS rare disease bioinformatic pipeline does not allow for interpretation of digenic events.
Intellectual disability v5.251 MKL2 Achchuthan Shanmugasundram Added comment: Comment on list classification: As there are only two unrelated cases reported so far, this gene should be rated amber for now.
Intellectual disability v5.247 MKL2 Achchuthan Shanmugasundram commented on gene: MKL2: PMID:37013900 - Two unrelated paediatric cases with de novo variants in MKL2 gene (p.Arg103Gly & p.Ala91Pro) were reported with mild dysmorphic features, severe intellectual disability, global developmental delays, speech apraxia, and impulse control issues. Functional studies in a Drosophila model suggest a gain of function disease mechanism.
Intellectual disability v5.247 MKL2 Achchuthan Shanmugasundram reviewed gene: MKL2: Rating: AMBER; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: 37013900; Phenotypes: neurodevelopmental disorder, MONDO:0700092; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v5.247 ATG4D Achchuthan Shanmugasundram Added comment: Comment on list classification: There are two unrelated cases with mild cognitive impairment and hence this gene should be rated amber with the current evidence.
Intellectual disability v5.246 ATG4D Achchuthan Shanmugasundram changed review comment from: PMID:36765070 - Three individuals from two different families were reported with a neurodevelopmental disorder and identified with compound heterozygous variants in ATG4D gene (family 1: :c.266G>A/ p.Ser89Asn & c.839A>G/ p.Tyr280Cys; family 2: c.1310_1328del/ p.Asp437Alafs*37 & c.1066G>A/ p.Asp356Asn). Patient from family 1 and one of two patients from family 2 had mild cognitive impairment.

This gene has been associated with relevant phenotypes in Gene2Phenotype (with 'limited' rating in the DD panel), but not yet in OMIM.; to: PMID:36765070 - Three individuals from two different families were reported with a neurodevelopmental disorder and identified with compound heterozygous variants in ATG4D gene (family 1: :c.266G>A/ p.Ser89Asn & c.839A>G/ p.Tyr280Cys; family 2: c.1310_1328del/ p.Asp437Alafs*37 & c.1066G>A/ p.Asp356Asn). Patient from family 1 and one of two patients from family 2 had mild cognitive impairment. Based on the clinical, bioinformatic, and functional data, the authors also concluded that bi-allelic loss-of-function variants in ATG4D contribute to the pathogenesis of syndromic neurodevelopmental disorder.

This gene has been associated with relevant phenotypes in Gene2Phenotype (with 'limited' rating in the DD panel), but not yet in OMIM.
Intellectual disability v5.246 ATG4D Achchuthan Shanmugasundram changed review comment from: PMID:36765070 - Three individuals from two different families were reported with a neurodevelopmental disorder and identified with compound heterozygous variants in ATG4D gene (family 1: :c.266G>A/ p.Ser89Asn & c.839A>G/ p.Tyr280Cys; family 2: c.1310_1328del/ p.Asp437Alafs*37 & c.1066G>A/ p.Asp356Asn). Patient from family 1 and one of two patients from family 2 had cognitive impairment.

This gene has been associated with relevant phenotypes in Gene2Phenotype (with 'limited' rating in the DD panel), but not yet in OMIM.; to: PMID:36765070 - Three individuals from two different families were reported with a neurodevelopmental disorder and identified with compound heterozygous variants in ATG4D gene (family 1: :c.266G>A/ p.Ser89Asn & c.839A>G/ p.Tyr280Cys; family 2: c.1310_1328del/ p.Asp437Alafs*37 & c.1066G>A/ p.Asp356Asn). Patient from family 1 and one of two patients from family 2 had mild cognitive impairment.

This gene has been associated with relevant phenotypes in Gene2Phenotype (with 'limited' rating in the DD panel), but not yet in OMIM.
Intellectual disability v5.246 ATG4D Achchuthan Shanmugasundram Phenotypes for gene: ATG4D were changed from neurodevelopmental disorder characterized by speech and motor impairment to neurodevelopmental disorder, MONDO:0700092
Intellectual disability v5.243 PSMC3 Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: There is sufficient evidence for the association of monoallelic variants from this gene with intellectual disability. However, there is only one family reported with biallelic variants. Hence, the MOI is set as "MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted".
Intellectual disability v5.243 PSMC3 Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: There is sufficient evidence for the association of monoallelic variants from this gene with intellectual disability. However, there is only one family reported with biallelic variants. Hence, the MOI is set as "MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted".
Intellectual disability v5.243 PSMC3 Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: There is sufficient evidence for the association of monoallelic variants from this gene with intellectual disability. However, there is only one family reported with biallelic variants. Hence, the MOI is set as "MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted".
Intellectual disability v5.242 PSMC3 Achchuthan Shanmugasundram Phenotypes for gene: PSMC3 were changed from ?Deafness, cataract, impaired intellectual development, and polyneuropathy, OMIM:619354; neurodevelopmental disorder, MONDO:0700092 to ?Deafness, cataract, impaired intellectual development, and polyneuropathy, OMIM:619354; neurodevelopmental disorder, MONDO:0700092
Intellectual disability v5.242 PSMC3 Achchuthan Shanmugasundram Phenotypes for gene: PSMC3 were changed from ?Deafness, cataract, impaired intellectual development, and polyneuropathy, OMIM:619354; neurodevelopmental disorder, MONDO:0700092 to ?Deafness, cataract, impaired intellectual development, and polyneuropathy, OMIM:619354; neurodevelopmental disorder, MONDO:0700092
Intellectual disability v5.242 PSMC3 Achchuthan Shanmugasundram Phenotypes for gene: PSMC3 were changed from ?Deafness, cataract, impaired intellectual development, and polyneuropathy, OMIM:619354; neurodevelopmental disorder, MONDO:0700092 to ?Deafness, cataract, impaired intellectual development, and polyneuropathy, OMIM:619354; neurodevelopmental disorder, MONDO:0700092
Intellectual disability v5.242 PSMC3 Achchuthan Shanmugasundram Phenotypes for gene: PSMC3 were changed from ?Deafness, cataract, impaired intellectual development, and polyneuropathy, OMIM:619354; neurodevelopmental disorder, MONDO:0700092 to ?Deafness, cataract, impaired intellectual development, and polyneuropathy, OMIM:619354; neurodevelopmental disorder, MONDO:0700092
Intellectual disability v5.242 PSMC3 Achchuthan Shanmugasundram Phenotypes for gene: PSMC3 were changed from ?Deafness, cataract, impaired intellectual development, and polyneuropathy, OMIM:619354; neurodevelopmental disorder, MONDO:0700092 to ?Deafness, cataract, impaired intellectual development, and polyneuropathy, OMIM:619354; neurodevelopmental disorder, MONDO:0700092
Intellectual disability v5.242 PSMC3 Achchuthan Shanmugasundram Phenotypes for gene: PSMC3 were changed from ?Deafness, cataract, impaired intellectual development, and polyneuropathy, OMIM:619354; neurodevelopmental disorder, MONDO:0700092 to ?Deafness, cataract, impaired intellectual development, and polyneuropathy, OMIM:619354; neurodevelopmental disorder, MONDO:0700092
Intellectual disability v5.242 PSMC3 Achchuthan Shanmugasundram Phenotypes for gene: PSMC3 were changed from ?Deafness, cataract, impaired intellectual development, and polyneuropathy, OMIM:619354; neurodevelopmental disorder, MONDO:0700092 to ?Deafness, cataract, impaired intellectual development, and polyneuropathy, OMIM:619354; neurodevelopmental disorder, MONDO:0700092
Intellectual disability v5.242 PSMC3 Achchuthan Shanmugasundram Phenotypes for gene: PSMC3 were changed from ?Deafness, cataract, impaired intellectual development, and polyneuropathy, OMIM:619354; neurodevelopmental disorder, MONDO:0700092 to ?Deafness, cataract, impaired intellectual development, and polyneuropathy, OMIM:619354; neurodevelopmental disorder, MONDO:0700092
Intellectual disability v5.242 PSMC3 Achchuthan Shanmugasundram Phenotypes for gene: PSMC3 were changed from ?Deafness, cataract, impaired intellectual development, and polyneuropathy, OMIM:619354; neurodevelopmental disorder, MONDO:0700092 to ?Deafness, cataract, impaired intellectual development, and polyneuropathy, OMIM:619354; neurodevelopmental disorder, MONDO:0700092
Intellectual disability v5.241 PSMC3 Achchuthan Shanmugasundram Phenotypes for gene: PSMC3 were changed from neurodevelopmental delay to ?Deafness, cataract, impaired intellectual development, and polyneuropathy, OMIM:619354; neurodevelopmental disorder, MONDO:0700092
Intellectual disability v5.239 PSMC3 Achchuthan Shanmugasundram reviewed gene: PSMC3: Rating: GREEN; Mode of pathogenicity: None; Publications: 32500975, 37256937; Phenotypes: ?Deafness, cataract, impaired intellectual development, and polyneuropathy, OMIM:619354, neurodevelopmental disorder, MONDO:0700092; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v5.238 KCNH5 Achchuthan Shanmugasundram Mode of pathogenicity for gene: KCNH5 was changed from Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Intellectual disability v5.238 KCNH5 Achchuthan Shanmugasundram Mode of pathogenicity for gene: KCNH5 was changed from Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Intellectual disability v5.238 KCNH5 Achchuthan Shanmugasundram Mode of pathogenicity for gene: KCNH5 was changed from Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Intellectual disability v5.237 KCNH5 Achchuthan Shanmugasundram Mode of pathogenicity for gene: KCNH5 was changed from to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Intellectual disability v5.235 CLCNKB Sarah Leigh Phenotypes for gene: CLCNKB were changed from Bartter syndrome, type 3, 607364Bartter syndrome, type 4b, digenic, 613090; BARTTER SYNDROME TYPE 4B to Bartter syndrome, type 3, OMIM:607364; Bartter disease type 3, MONDO:0011822; Bartter syndrome, type 4b, digenic, OMIM:613090; Bartter disease type 4B, MONDO:0000909
Intellectual disability v5.234 LETM1 Sarah Leigh changed review comment from: LETM1 variants has been associated with Neurodegeneration, childhood-onset, with multisystem involvement due to mitochondrial dysfunction, OMIM:620089 and as moderate Gen2Phen gene for LETM1-related neurodevelopmental disorder.
PMID: 36055214 reports 10 LETM1 variants in 18 patients from 11 unrelated families with childhood-onset neurodegeneration with multisystem involvement, many of whom were gathered using the GeneMatcher Program. The most common clinical features of this cohort, where an assessment could be made, were: mitochondrial respiratory complex deficiencies 11/11 (100%), global developmental delay / intellectual disability 17/18 (94%), bilateral sensorineural hearing loss 11/14 (78%) , impaired vision 10/10 (100%), cerebellar ataxia 7/9 (78%), seizures 10/15 (67%), hypotonia 11/18 (61%) (PMID: 36055214, figure 1c).; to: LETM1 variants have been associated with Neurodegeneration, childhood-onset, with multisystem involvement due to mitochondrial dysfunction, OMIM:620089 and as moderate Gen2Phen gene for LETM1-related neurodevelopmental disorder.
PMID: 36055214 reports 10 LETM1 variants in 18 patients from 11 unrelated families with childhood-onset neurodegeneration with multisystem involvement, many of whom were gathered using the GeneMatcher Program. The most common clinical features of this cohort, where an assessment could be made, were: mitochondrial respiratory complex deficiencies 11/11 (100%), global developmental delay / intellectual disability 17/18 (94%), bilateral sensorineural hearing loss 11/14 (78%) , impaired vision 10/10 (100%), cerebellar ataxia 7/9 (78%), seizures 10/15 (67%), hypotonia 11/18 (61%) (PMID: 36055214, figure 1c).
Intellectual disability v5.233 SLC22A5 Sarah Leigh changed review comment from: Comment on mode of inheritance: The mode of inheritance for SLC22A5 variants should be BOTH Monoallelic and Biallelic. Although, most of the evidence for symptoms associated SLC22A5 are seen in a patients with biallelic variants (HGNC:10969, OMIM:603377, Gen2Phen, Orphanet:118781, ClinGen), a few individuals heterozygous for SLC22A5 variants have been seen with a milder phenotype (PMID: 10545605; 11261427).; to: Comment on mode of inheritance: The mode of inheritance for SLC22A5 variants should be BIALLELIC, autosomal or pseudoautosomal. Although, heterozygous SLC22A5 variants have been seen in a few cases, these are detectable biochemically and are not associated with clear clinical presentation (PMID: 10545605; 11261427).
Intellectual disability v5.232 RPS6KA3 Arina Puzriakova Added comment: Comment on mode of inheritance: Should be updated from XLR to XLD (monoallelic variants in females may cause disease) at the next GMS panel update as several affected female carriers have been reported. ID in female carriers can range from mild to severe which is within the scope of the panel (PMIDs: 12210291; 12030896; 12558110; 17318637). This would also match the current MOI on other GMS panels and OMIM.
Intellectual disability v5.231 RPS6KA3 Arina Puzriakova Phenotypes for gene: RPS6KA3 were changed from Coffin-Lowry syndrome, 303600Mental retardation, X-linked 19, 300844; COFFIN-LOWRY SYNDROME (CLS) to Coffin-Lowry syndrome, OMIM:303600; Intellectual developmental disorder, X-linked 19, OMIM:300844
Intellectual disability v5.230 KCNH5 Dmitrijs Rots reviewed gene: KCNH5: 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: PMID: 36307226, 35874597; Phenotypes: Neurodevelopmental disorder and Epilepsy; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v5.230 LETM1 Sarah Leigh Entity copied from Ataxia and cerebellar anomalies - narrow panel v4.27
Intellectual disability v5.230 LETM1 Sarah Leigh gene: LETM1 was added
gene: LETM1 was added to Intellectual disability - microarray and sequencing. Sources: Expert Review Amber,Expert Review
Q3_23_promote_green, Q3_23_MOI tags were added to gene: LETM1.
Mode of inheritance for gene: LETM1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LETM1 were set to 36055214; 33815143
Phenotypes for gene: LETM1 were set to Neurodegeneration, childhood-onset, with multisystem involvement due to mitochondrial dysfunction, OMIM:620089
Intellectual disability v5.227 SLC22A5 Sarah Leigh Added comment: Comment on mode of inheritance: The mode of inheritance for SLC22A5 variants should be BOTH Monoallelic and Biallelic. Although, most of the evidence for symptoms associated SLC22A5 are seen in a patients with biallelic variants (HGNC:10969, OMIM:603377, Gen2Phen, Orphanet:118781, ClinGen), a few individuals heterozygous for SLC22A5 variants have been seen with a milder phenotype (PMID: 10545605; 11261427).
Intellectual disability v5.226 SLC22A5 Sarah Leigh Phenotypes for gene: SLC22A5 were changed from Carnitine deficiency, systemic primary, 212140 to Carnitine deficiency, systemic primary, OMIM:212140; systemic primary carnitine deficiency disease, MONDO:0008919
Intellectual disability v5.224 AGTPBP1 Achchuthan Shanmugasundram changed review comment from: PMID:30420557 reported the identification of either homozygous or compound heterozygous variants in AGTPBP1 gene in 13 individuals from 10 unrelated families with infantile‐onset neurodegeneration. Impaired intellectual development was severe in several patients: Two had severe cognitive delay, one had profound cognitive delay, five had no speech and four had no visual recognition. In addition, functional studies with mouse models have recapitulated the human phenotype.

This gene has been associated with relevant phenotypes in both OMIM (MIM #618276) and Gene2Phenotype (on DD panel with 'definitive' rating).
Sources: Literature; to: PMID:30420557 reported the identification of either homozygous or compound heterozygous variants in AGTPBP1 gene in 13 individuals from 10 unrelated families with infantile‐onset neurodegeneration. Impaired intellectual development was severe in several patients: Two had severe cognitive delay, one had profound cognitive delay, five had no speech and four had no visual recognition. In addition, functional studies with mouse models have recapitulated the human phenotype.

This gene has been associated with relevant phenotypes in both OMIM (MIM #618276) and Gene2Phenotype (on DD panel with 'definitive' rating).
Sources: Literature
Intellectual disability v5.224 AGTPBP1 Achchuthan Shanmugasundram changed review comment from: PMID:30420557 reported the identification of either homozygous or compound heterozygous variants in AGTPBP1 gene in 13 individuals from 10 unrelated families with infantile‐onset neurodegeneration. Impaired intellectual development was severe, and several patients were unable to speak or have eye contact.

This gene has been associated with relevant phenotypes in both OMIM (MIM #618276) and Gene2Phenotype (on DD panel with 'definitive' rating).
Sources: Literature; to: PMID:30420557 reported the identification of either homozygous or compound heterozygous variants in AGTPBP1 gene in 13 individuals from 10 unrelated families with infantile‐onset neurodegeneration. Impaired intellectual development was severe in several patients: Two had severe cognitive delay, one had profound cognitive delay, five had no speech and four had no visual recognition. In addition, functional studies with mouse models have recapitulated the human phenotype.

This gene has been associated with relevant phenotypes in both OMIM (MIM #618276) and Gene2Phenotype (on DD panel with 'definitive' rating).
Sources: Literature
Intellectual disability v5.224 AGTPBP1 Achchuthan Shanmugasundram gene: AGTPBP1 was added
gene: AGTPBP1 was added to Intellectual disability - microarray and sequencing. Sources: Literature
Mode of inheritance for gene: AGTPBP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AGTPBP1 were set to 30420557
Phenotypes for gene: AGTPBP1 were set to Neurodegeneration, childhood-onset, with cerebellar atrophy, OMIM:618276
Review for gene: AGTPBP1 was set to GREEN
Added comment: PMID:30420557 reported the identification of either homozygous or compound heterozygous variants in AGTPBP1 gene in 13 individuals from 10 unrelated families with infantile‐onset neurodegeneration. Impaired intellectual development was severe, and several patients were unable to speak or have eye contact.

This gene has been associated with relevant phenotypes in both OMIM (MIM #618276) and Gene2Phenotype (on DD panel with 'definitive' rating).
Sources: Literature
Intellectual disability v5.222 PIP5K1C Achchuthan Shanmugasundram gene: PIP5K1C was added
gene: PIP5K1C was added to Intellectual disability - microarray and sequencing. Sources: Literature
Mode of inheritance for gene: PIP5K1C was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PIP5K1C were set to 37451268
Phenotypes for gene: PIP5K1C were set to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Review for gene: PIP5K1C was set to GREEN
Added comment: Three de novo heterozygous missense variants in PIP5K1C (p.Glu146Lys, p.Tyr205Cys & p.Tyr221Cys) were identified in nine unrelated children exhibiting intellectual disability, developmental delay, acquired microcephaly, seizures, visual abnormalities, and dysmorphic features. Intellectual disability was reported in all nine children and seizures were present in seven children, of which three had developmental and epileptic encephalopathy. In addition, there is functional evidence available, which includes an in vivo zebrafish model that recapitulates the human phenotype (developmental defects affecting the forebrain, including the eyes, as well as craniofacial abnormalities) (PMID:37451268).

This gene has been associated with another phenotype (Lethal congenital contractural syndrome 3, MIM #611369) in both OMIM and Gene2Phenotype, but not yet associated with this neurodevelopmental disorders in either databases.
Sources: Literature
Intellectual disability v5.220 TMEM63B Achchuthan Shanmugasundram gene: TMEM63B was added
gene: TMEM63B was added to Intellectual disability - microarray and sequencing. Sources: Literature
Mode of inheritance for gene: TMEM63B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TMEM63B were set to 37421948
Phenotypes for gene: TMEM63B were set to developmental and epileptic encephalopathy, MONDO:0100062
Review for gene: TMEM63B was set to GREEN
Added comment: PMID:37421948 - 17 unrelated individuals with severe early-onset developmental and epileptic encephalopathy (DEE), intellectual disability, and severe motor and cortical visual impairment were identified with ten distinct heterozygous variants inTMEM63B. The variants occurred de novo in 16/17 individuals for whom parental DNA was available and either missense or in-frame. All individuals had global developmental delay, with moderate-to-profound intellectual disability and severe motor impairment.
Sources: Literature
Intellectual disability v5.218 DHX9 Achchuthan Shanmugasundram gene: DHX9 was added
gene: DHX9 was added to Intellectual disability - microarray and sequencing. Sources: Literature
Mode of inheritance for gene: DHX9 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: DHX9 were set to 37467750
Phenotypes for gene: DHX9 were set to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Review for gene: DHX9 was set to GREEN
Added comment: PMID:37467750 - 17 unrelated individuals were identified with de novo, ultra-rare, heterozygous missense or loss-of-function DHX9 variants, of which 14 individuals were reported with a neurodevelopmental disorder (NDD) and three were reported with Charcot-Marie-Tooth disease (CMT). All 14 cases with NDD had developmental delay, of which eight were reported with intellectual disability (4 severe, 1 moderate, 3 mild). Two cases did not have ID, one had borderline ID and three cases were too young (0-5 years old).
Sources: Literature
Intellectual disability v5.216 CNOT9 Achchuthan Shanmugasundram gene: CNOT9 was added
gene: CNOT9 was added to Intellectual disability - microarray and sequencing. Sources: Literature
Mode of inheritance for gene: CNOT9 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CNOT9 were set to 37092538
Phenotypes for gene: CNOT9 were set to intellectual disability, MONDO:0001071
Review for gene: CNOT9 was set to GREEN
Added comment: PMID:37092538 - Seven unrelated individuals with de novo variants in CNOT9 gene (one individual each with variants p.Arg46Gly, p.Pro131Leu and p.Arg227His and four individuals with p.Arg292Trp) were reported with a neurodevelopmental disorder. All affected persons have intellectual disability (three severe, three mild and one unclassified) and five of them have seizures.

This gene has not yet been associated with relevant phenotypes either in OMIM or in Gene2Phenotype.
Sources: Literature
Intellectual disability v5.215 SLC30A9 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are six unrelated families with Intellectual disability/ global developmental delay reported with biallelic variants in this gene. Hence, this gene can be promoted to Green at the next major update.
Intellectual disability v5.215 SLC30A9 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are six unrelated families with Intellectual disability/ global developmental delay reported with biallelic variants in this gene. Hence, this gene can be promoted to Green at the next major update.
Intellectual disability v5.215 SLC30A9 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There are six unrelated families with Intellectual disability/ global developmental delay reported with biallelic variants in this gene. Hence, this gene can be promoted to Green at the next major update.; to: Comment on list classification: There are six unrelated families with Intellectual disability/ global developmental delay reported with biallelic variants in this gene. Hence, this gene can be promoted to Green at the next major update.
Intellectual disability v5.215 SLC30A9 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There are six unrelated families with Intellectual disability/ global developmental delay reported with biallelic variants in this gene. Hence, this gene can be promoted to Green at the next major update.; to: Comment on list classification: There are six unrelated families with Intellectual disability/ global developmental delay reported with biallelic variants in this gene. Hence, this gene can be promoted to Green at the next major update.
Intellectual disability v5.215 SLC30A9 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are six unrelated families with Intellectual disability/ global developmental delay reported with biallelic variants in this gene. Hence, this gene can be promoted to Green at the next major update.
Intellectual disability v5.215 SLC30A9 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are six unrelated families with Intellectual disability/ global developmental delay reported with biallelic variants in this gene. Hence, this gene can be promoted to Green at the next major update.
Intellectual disability v5.211 DAGLA Achchuthan Shanmugasundram Mode of pathogenicity for gene: DAGLA was changed from Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Intellectual disability v5.211 DAGLA Achchuthan Shanmugasundram Mode of pathogenicity for gene: DAGLA was changed from Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Intellectual disability v5.211 DAGLA Achchuthan Shanmugasundram Mode of pathogenicity for gene: DAGLA was changed from Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Intellectual disability v5.211 DAGLA Achchuthan Shanmugasundram Mode of pathogenicity for gene: DAGLA was changed from Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Intellectual disability v5.211 DAGLA Achchuthan Shanmugasundram Mode of pathogenicity for gene: DAGLA was changed from Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Intellectual disability v5.210 DAGLA Achchuthan Shanmugasundram Mode of pathogenicity for gene: DAGLA was changed from Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Intellectual disability v5.210 DAGLA Achchuthan Shanmugasundram Mode of pathogenicity for gene: DAGLA was changed from Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Intellectual disability v5.210 DAGLA Achchuthan Shanmugasundram Mode of pathogenicity for gene: DAGLA was changed from Other to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Intellectual disability v5.209 DAGLA Achchuthan Shanmugasundram edited their review of gene: DAGLA: 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
Intellectual disability v5.209 DAGLA Achchuthan Shanmugasundram changed review comment from: As reviewed by Irina Ziravecka, there are nine children from eight unrelated families reported with heterozygous de novo variants in DAGLA gene and presenting with a neuro-ocular phenotype characterized by developmental delay, ataxia and complex oculomotor abnormality. Of these nine children, five had intellectual disability and one had low average IQ. In addition, the functional data suggests potential mechanisms include DAGLA haploinsufficiency at the plasma membrane or dominant negative effect (PMID:35737950).; to: As reviewed by Irina Ziravecka, there are nine children from eight unrelated families reported with heterozygous de novo variants in DAGLA gene and presenting with a neuro-ocular phenotype characterized by developmental delay, ataxia and complex oculomotor abnormality. Of these nine children, five had intellectual disability and one had low average IQ. In addition, the functional data suggests potential mechanisms include DAGLA haploinsufficiency at the plasma membrane or dominant negative effect (PMID:35737950).

This gene has not yet been associated with any relevant phenotypes either in OMIM or in Gene2Phenotype.
Intellectual disability v5.208 DAGLA Achchuthan Shanmugasundram Added comment: Comment on list classification: There are more than 3 unrelated cases associating monoallelic variants in this gene to intellectual disability. Hence, this gene can be promoted to Green rating at the next GMS update.
Intellectual disability v5.208 DAGLA Achchuthan Shanmugasundram Added comment: Comment on list classification: There are more than 3 unrelated cases associating monoallelic variants in this gene to intellectual disability. Hence, this gene can be promoted to Green rating at the next GMS update.
Intellectual disability v5.208 DAGLA Achchuthan Shanmugasundram Added comment: Comment on list classification: There are more than 3 unrelated cases associating monoallelic variants in this gene to intellectual disability. Hence, this gene can be promoted to Green rating at the next GMS update.
Intellectual disability v5.208 DAGLA Achchuthan Shanmugasundram Added comment: Comment on list classification: There are more than 3 unrelated cases associating monoallelic variants in this gene to intellectual disability. Hence, this gene can be promoted to Green rating at the next GMS update.
Intellectual disability v5.207 DAGLA Achchuthan Shanmugasundram Added comment: Comment on list classification: There are more than 3 unrelated cases associating monoallelic variants in this gene to intellectual disability. Hence, this gene can be promoted to Green rating at the next GMS update.
Intellectual disability v5.207 DAGLA Achchuthan Shanmugasundram Added comment: Comment on list classification: There are more than 3 unrelated cases associating monoallelic variants in this gene to intellectual disability. Hence, this gene can be promoted to Green rating at the next GMS update.
Intellectual disability v5.207 DAGLA Achchuthan Shanmugasundram Added comment: Comment on list classification: There are more than 3 unrelated cases associating monoallelic variants in this gene to intellectual disability. Hence, this gene can be promoted to Green rating at the next GMS update.
Intellectual disability v5.205 DAGLA Achchuthan Shanmugasundram changed review comment from: As reviewed by Irina Ziravecka, there are nine children from eight unrelated families reported with heterozygous de novo variants in DAGLA gene and presenting with a neuro-ocular phenotype characterized by developmental delay, ataxia and complex oculomotor abnormality. Of these nine children, five had intellectual disability and one had low average IQ (PMID:35737950).; to: As reviewed by Irina Ziravecka, there are nine children from eight unrelated families reported with heterozygous de novo variants in DAGLA gene and presenting with a neuro-ocular phenotype characterized by developmental delay, ataxia and complex oculomotor abnormality. Of these nine children, five had intellectual disability and one had low average IQ. In addition, the functional data suggests potential mechanisms include DAGLA haploinsufficiency at the plasma membrane or dominant negative effect (PMID:35737950).
Intellectual disability v5.205 DAGLA Achchuthan Shanmugasundram changed review comment from: As reviewed by Irina Ziravecka, there are nine children from eight unrelated families reported with heterozygous variants in DAGLA gene and presenting with a neuro-ocular phenotype characterized by developmental delay, ataxia and complex oculomotor abnormality. Of these nine children, five had intellectual disability and one had low average IQ (PMID:35737950).; to: As reviewed by Irina Ziravecka, there are nine children from eight unrelated families reported with heterozygous de novo variants in DAGLA gene and presenting with a neuro-ocular phenotype characterized by developmental delay, ataxia and complex oculomotor abnormality. Of these nine children, five had intellectual disability and one had low average IQ (PMID:35737950).
Intellectual disability v5.205 BUB1 Arina Puzriakova Phenotypes for gene: BUB1 were changed from Congenital microcephaly; Global developmental delay; Intellectual disability; Abnormal heart morphology; Growth delay to Microcephaly 30, primary, autosomal recessive, OMIM:620183
Intellectual disability v5.204 DAGLA Irina Ziravecka gene: DAGLA was added
gene: DAGLA was added to Intellectual disability - microarray and sequencing. Sources: Literature
Mode of inheritance for gene: DAGLA was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: DAGLA were set to PMID: 35737950
Phenotypes for gene: DAGLA were set to developmental delay; ataxia; complex oculomotor abnormality
Mode of pathogenicity for gene: DAGLA was set to Other
Review for gene: DAGLA was set to GREEN
Added comment: PMID: 35737950 - nine children from eight families with heterozygous, de novo truncating variants in the last exon of DAGLA with a neuro-ocular phenotype.
Sources: Literature
Intellectual disability v5.204 PTPA Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Konstantinos Varvagiannis, there are two unrelated cases with intellectual disability and hence this gene should be rated amber.
Intellectual disability v5.203 PTPA Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Konstantinos Varvagiannis, there are two unrelated cases with intellectual disability and hence this gene should be rated amber.
Intellectual disability v5.203 PTPA Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Konstantinos Varvagiannis, there are two unrelated cases with intellectual disability and hence this gene should be rated amber.
Intellectual disability v5.203 PTPA Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Konstantinos Varvagiannis, there are two unrelated cases with intellectual disability and hence this gene should be rated amber.
Intellectual disability v5.201 PTPA Achchuthan Shanmugasundram Phenotypes for gene: PTPA were changed from Intellectual disability; Parkinsonism to Intellectual disability, MONDO:0001071
Intellectual disability v5.200 FOXR1 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Zornitza Stark, there is one case with global developmental delay and supporting functional evidence including mouse model. Hence, this gene should be rated amber.
Intellectual disability v5.200 FOXR1 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: As reviewed by Zornitza Stark, there is one case with global developmental delay and supporting functional evidence including mouse model. Hence, this gene should be rated amber.; to: Comment on list classification: As reviewed by Zornitza Stark, there is one case with global developmental delay supported by functional evidence including mouse model. Hence, this gene should be rated amber.
Intellectual disability v5.200 FOXR1 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Zornitza Stark, there is one case with global developmental delay and supporting functional evidence including mouse model. Hence, this gene should be rated amber.
Intellectual disability v5.199 FOXR1 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Zornitza Stark, there is one case with global developmental delay and supporting functional evidence including mouse model. Hence, this gene should be rated amber.
Intellectual disability v5.200 FOXR1 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Zornitza Stark, there is one case with global developmental delay and supporting functional evidence including mouse model. Hence, this gene should be rated amber.
Intellectual disability v5.199 FOXR1 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Zornitza Stark, there is one case with global developmental delay and supporting functional evidence including mouse model. Hence, this gene should be rated amber.
Intellectual disability v5.199 FOXR1 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Zornitza Stark, there is one case with global developmental delay and supporting functional evidence including mouse model. Hence, this gene should be rated amber.
Intellectual disability v5.199 FOXR1 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Zornitza Stark, there is one case with global developmental delay and supporting functional evidence including mouse model. Hence, this gene should be rated amber.
Intellectual disability v5.199 FOXR1 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Zornitza Stark, there is one case with global developmental delay and supporting functional evidence including mouse model. Hence, this gene should be rated amber.
Intellectual disability v5.196 KDM6B Sarah Leigh Phenotypes for gene: KDM6B were changed from Neurodevelopmental disorder with coarse facies and mild distal skeletal abnormalities, 618505 to Neurodevelopmental disorder with coarse facies and mild distal skeletal abnormalities, OMIM:618505; neurodevelopmental disorder with coarse facies and mild distal skeletal abnormalities, MONDO:0032790
Intellectual disability v5.194 DALRD3 Arina Puzriakova Added comment: Comment on list classification: New gene added by Konstantinos Varvagiannis. Rating Amber as this is a good candidate gene but only a single family has been reported to date with variants. Additional evidence needed prior to adding the gene as diagnostic-grade.
Intellectual disability v5.191 PSMC3 Dmitrijs Rots gene: PSMC3 was added
gene: PSMC3 was added to Intellectual disability - microarray and sequencing. Sources: Literature
Mode of inheritance for gene: PSMC3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PSMC3 were set to PMID: 37256937
Phenotypes for gene: PSMC3 were set to neurodevelopmental delay
Mode of pathogenicity for gene: PSMC3 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: PSMC3 was set to GREEN
Added comment: 23 individuals with NDD due to 15 different de novo missense variants in PMID: 37256937.
Sources: Literature
Intellectual disability v5.191 MKL2 Dmitrijs Rots gene: MKL2 was added
gene: MKL2 was added to Intellectual disability - microarray and sequencing. Sources: Literature
Mode of inheritance for gene: MKL2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MKL2 were set to PMID:37013900
Phenotypes for gene: MKL2 were set to neurodevelopmental phenotype with dysmorphic features
Mode of pathogenicity for gene: MKL2 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: MKL2 was set to GREEN
Added comment: 2 cases with de novo missense GoF variants in MRTFB (previously known as MKL2) + functional evidence
Sources: Literature
Intellectual disability v5.190 EIF4A2 Sarah Leigh gene: EIF4A2 was added
gene: EIF4A2 was added to Intellectual disability - microarray and sequencing. Sources: Literature
Q3_23_promote_green tags were added to gene: EIF4A2.
Mode of inheritance for gene: EIF4A2 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: EIF4A2 were set to 36528028
Phenotypes for gene: EIF4A2 were set to Neurodevelopmental disorder
Review for gene: EIF4A2 was set to GREEN
Added comment: EIF4A2 has not been associated with a phenotype in OMIM, Gen2Phen or Mondo at the time of reporting. PMID: 36528028 reports the findings of an international collaboration through Matchmaker Exchange, where EIF4A2 variants are found in cases with neurodevelopmental disorder characterized by intellectual disability, hypotonia, and epilepsy. A total of 15 EIF4A2 variants have been reported in PMID: 36528028, with 12 variants occurring as de novo monoallelic in 12 individuals and 3 as biallelic in two unrelated cases (one as homozygote and the other as compound heterozygous). Severe intellectual was seen in 6/10 unrelated cases where an assessment was made, epilepsy was evident in 10/14 unrelated cases and 13/14 cases had hyptonia. Functional studies were also presented and it would appear that both loss and gain functions maybe associated with EIF4A2 variants.
Sources: Literature
Intellectual disability v5.188 TTI1 Sarah Leigh gene: TTI1 was added
gene: TTI1 was added to Intellectual disability - microarray and sequencing. Sources: Literature
Mode of inheritance for gene: TTI1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TTI1 were set to 36724785
Phenotypes for gene: TTI1 were set to neurodevelopmental disorder with microcephaly
Review for gene: TTI1 was set to GREEN
Added comment: TTI1 has not previously been associated with a phenotype in OMIM, Gen2Phen or MONDO. At least 2 variants have been reported. PMID: 36724785 reported 15 TTI1 variants as either homozygotes (2 families) or compound heterozygotes (7 families) in cases with a neurodevelopmental disorder with microcephaly. In all cases the parents were heterozygous carriers of the TTI1 variant identified in the affected child. Development delay was observed in all of the families (9/9), moderate to severe intellectual disability was evident in all families where it could be assessed (8/8) and severe microcephaly was present in members of 5/9 families. Supportive functional results were also presented.
Sources: Literature
Intellectual disability v5.187 TSPOAP1 Sarah Leigh gene: TSPOAP1 was added
gene: TSPOAP1 was added to Intellectual disability - microarray and sequencing. Sources: Literature,Expert Review Amber
Mode of inheritance for gene: TSPOAP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TSPOAP1 were set to 33539324
Phenotypes for gene: TSPOAP1 were set to Dystonia, intellectual disability and cerebellar atrophy
Intellectual disability v5.183 GRM7 Achchuthan Shanmugasundram gene: GRM7 was added
gene: GRM7 was added to Intellectual disability - microarray and sequencing. Sources: Literature
Mode of inheritance for gene: GRM7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GRM7 were set to 2248644; 32286009
Phenotypes for gene: GRM7 were set to Neurodevelopmental disorder with seizures, hypotonia, and brain abnormalities, OMIM:618922
Review for gene: GRM7 was set to GREEN
Added comment: PMID:32286009 reported eleven individuals from six unrelated families identified with three different biallelic variants and presenting with a neurodevelopmental disorder comprising severe to profound global developmental delays, intellectual disability, seizures, hypotonia, microcephaly and brain abnormalities. This is also supported by functional evidence from knockout mouse models, where absence of metabotropic glutamate receptor 7 alters the phenotypes within the domains of social behavior, associative learning, motor function, epilepsy and sleep (PMID:32248644).

This gene has also been associated with relevant phenotypes in both OMIM (MIM #618922) and in Gene2Phenotype (with 'strong' rating in the DD panel).
Sources: Literature
Intellectual disability v5.182 CCDC82 Achchuthan Shanmugasundram changed review comment from: As reviewed by Konstantinos Varvagiannis, there is more than three unrelated cases with biallelic variants in CCDC82 presenting with a neurodevelopmental disorder comprising intellectual disability/ global developmental delay. Hence, this gene should be rated GREEN at the next GMS review.; to: As reviewed by Konstantinos Varvagiannis, there are more than three unrelated cases with biallelic variants in CCDC82 presenting with a neurodevelopmental disorder comprising intellectual disability/ global developmental delay. Hence, this gene should be rated GREEN at the next GMS review.
Intellectual disability v5.181 CCDC82 Achchuthan Shanmugasundram Phenotypes for gene: CCDC82 were changed from Global developmental delay; Intellectual disability; Spastic paraparesis to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Intellectual disability v5.180 CCDC82 Achchuthan Shanmugasundram commented on gene: CCDC82: As reviewed by Konstantinos Varvagiannis, there is more than three unrelated cases with biallelic variants in CCDC82 presenting with a neurodevelopmental disorder comprising intellectual disability/ global developmental delay. Hence, this gene should be rated GREEN at the next GMS review.
Intellectual disability v5.179 UBE3C Achchuthan Shanmugasundram Added comment: Comment on list classification: There are two unrelated cases associating biallelic variants in UBE3C gene with intellectual disability. Hence, this gene should be rated AMBER.
Intellectual disability v5.179 UBE3C Achchuthan Shanmugasundram Added comment: Comment on list classification: There are two unrelated cases associating biallelic variants in UBE3C gene with intellectual disability. Hence, this gene should be rated AMBER.
Intellectual disability v5.178 UBE3C Achchuthan Shanmugasundram gene: UBE3C was added
gene: UBE3C was added to Intellectual disability - microarray and sequencing. Sources: Literature
Mode of inheritance for gene: UBE3C was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: UBE3C were set to 36401616
Phenotypes for gene: UBE3C were set to Neurodevelopmental disorder with absent speech and movement and behavioral abnormalities, OMIM:620270
Review for gene: UBE3C was set to AMBER
Added comment: PMID:36401616 reported three patients from two unrelated families with homozygous variants in UBE3C gene and presenting with syndromic neurodevelopmental, seizure, and movement disorders and neurobehavioral phenotypes. All three patients had severe intellectual disability. The RNA studies in some patients with LoF variants provided evidence for the LoF effect.
Sources: Literature
Intellectual disability v5.175 HECTD4 Achchuthan Shanmugasundram gene: HECTD4 was added
gene: HECTD4 was added to Intellectual disability - microarray and sequencing. Sources: Literature
Mode of inheritance for gene: HECTD4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HECTD4 were set to 36401616
Phenotypes for gene: HECTD4 were set to Neurodevelopmental disorder with seizures, spasticity, and complete or partial agenesis of the corpus callosum, OMIM:620250
Review for gene: HECTD4 was set to GREEN
Added comment: PMID:36401616 reported seven patients from five unrelated families with either homozygous (3 families) or compound heterozygous variants (2 families) in HECTD4 gene and presenting with syndromic neurodevelopmental, seizure, and movement disorders and neurobehavioral phenotypes. All seven patients had severe (4 cases) or moderate (3 cases) intellectual disability.
Sources: Literature
Intellectual disability v5.171 TRA2B Achchuthan Shanmugasundram changed review comment from: This gene has already been associated with phenotypes in Gene2Phenotype (with 'moderate' rating in the DD panel), but not in OMIM.
Sources: Literature; to: PMID:36549593 reported 12 individuals from 11 unrelated families identified with 11 different heterozygous variants in TRA2B gene. The variants arose de novo in 10 families, while the variant was inherited from father to son in one family. 6 variants were expected to disrupt the translation start site in exon 1 (start-loss variants), 3 were expected to disrupt the splicing process at the exon 2/3 boundary (splice-affecting variants), and the remaining 2 were expected to produce a premature stop codon (truncating variants).

These patients presented with a neurodevelopmental disorder comprising developmental delay/ intellectual disability (in all patients), axial or global hypotonia (10 patients), delayed motor milestones (all patients), behavioural issues (8 patients), speech impairment (9 patients), epilepsy (7 patients, initial presentation as infantile spasms in 6 and unclassified epileptic encephalopathy in 1), brain abnormalities (10 patients) and microcephaly (5 patients). The degree of ID was severe to profound for 6 individuals, moderate to severe for 2 and mild to moderate for 3.

In addition, functional studies in mice showed that heterozygous knockout mice developed normal, while complete knockout mice cannot develop embryonically.

This gene has already been associated with phenotypes in Gene2Phenotype (with 'moderate' rating in the DD panel), but not in OMIM.
Sources: Literature
Intellectual disability v5.171 TRA2B Achchuthan Shanmugasundram gene: TRA2B was added
gene: TRA2B was added to Intellectual disability - microarray and sequencing. Sources: Literature
Mode of inheritance for gene: TRA2B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TRA2B were set to 36549593
Phenotypes for gene: TRA2B were set to neurodevelopmental disorder, MONDO:0700092; epilepsy, MONDO:0005027
Review for gene: TRA2B was set to GREEN
Added comment: This gene has already been associated with phenotypes in Gene2Phenotype (with 'moderate' rating in the DD panel), but not in OMIM.
Sources: Literature
Intellectual disability v5.170 ATG4D Dmitrijs Rots gene: ATG4D was added
gene: ATG4D was added to Intellectual disability - microarray and sequencing. Sources: Literature
Mode of inheritance for gene: ATG4D was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ATG4D were set to 36765070
Phenotypes for gene: ATG4D were set to neurodevelopmental disorder characterized by speech and motor impairment
Review for gene: ATG4D was set to GREEN
Added comment: Morimoto et al., described 3 cases from 2 families with ATG4D biallelic variants and provided some functional evidence.
No data about homozygous or compound heterozygous with two rare variants in ATG4D in gnomAD database.
Sources: Literature
Intellectual disability v5.166 CLDN5 Achchuthan Shanmugasundram changed review comment from: PMID: 36477332 identified de novo heterozygous missense variants in CLDN5 in fifteen unrelated patients who presented with a shared constellation of features including developmental delay, seizures (primarily infantile onset focal epilepsy), microcephaly and a recognizable pattern of pontine atrophy and brain calcifications.
Sources: Literature; to: PMID:36477332 reported the identification of de novo heterozygous missense variants in CLDN5 in 15 unrelated patients who presented with a number of clinical features including developmental delay including intellectual disability, seizures (primarily infantile onset focal epilepsy), microcephaly and a recognisable pattern of pontine atrophy and brain calcifications. All seven living patients over four years of age were reported to have intellectual disability.

In addition, functional studies from zebrafish model also provided parallel evidence that CLDN5 variants cause a neurodevelopmental disorder involving disruption of the blood brain barrier and impaired neuronal function.

This gene has been associated with relevant phenotypes in Gene2Phenotype (CLDN5-related neurodevelopmental disorder with 'limited' rating in the DD panel), but not in OMIM.
Sources: Literature
Intellectual disability v5.166 CLDN5 Achchuthan Shanmugasundram gene: CLDN5 was added
gene: CLDN5 was added to Intellectual disability - microarray and sequencing. Sources: Literature
Mode of inheritance for gene: CLDN5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CLDN5 were set to 36477332
Phenotypes for gene: CLDN5 were set to epilepsy, MONDO:0005027
Review for gene: CLDN5 was set to GREEN
Added comment: PMID: 36477332 identified de novo heterozygous missense variants in CLDN5 in fifteen unrelated patients who presented with a shared constellation of features including developmental delay, seizures (primarily infantile onset focal epilepsy), microcephaly and a recognizable pattern of pontine atrophy and brain calcifications.
Sources: Literature
Intellectual disability v5.163 TCEAL1 Achchuthan Shanmugasundram changed review comment from: PMID:36368327 reported seven unrelated individuals with de novo variants (2 nonsense, 2 frameshift, 2 CNVs & 1 missense variants) in TCEAL1 gene and presenting with an X-linked dominant neurodevelopmental disorder. All these seven individuals had intellectual disability (mild to severe). The other major clinical presentations include hypotonia, abnormal gait, speech impairment, autistic-like behavior, and mildly dysmorphic facial features.

This gene is associated with relevant phenotypes in OMIM (MIM #301094), but not in Gene2Phenotype.
Sources: Literature; to: PMID:36368327 reported seven unrelated individuals with de novo variants (2 nonsense, 2 frameshift, 2 CNVs & 1 missense variants) in TCEAL1 gene and presenting with an X-linked dominant neurodevelopmental disorder. All these seven individuals had intellectual disability (mild to severe). The other major clinical presentations include hypotonia, abnormal gait, speech impairment, autistic-like behaviour, and mildly dysmorphic facial features.

This gene is associated with relevant phenotypes in OMIM (MIM #301094), but not in Gene2Phenotype.
Sources: Literature
Intellectual disability v5.163 TCEAL1 Achchuthan Shanmugasundram gene: TCEAL1 was added
gene: TCEAL1 was added to Intellectual disability - microarray and sequencing. Sources: Literature
Mode of inheritance for gene: TCEAL1 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: TCEAL1 were set to 36368327
Phenotypes for gene: TCEAL1 were set to Neurodevelopmental disorder with gait disturbance, dysmorphic facies and behavioral abnormalities, X-linked, OMIM:301094
Review for gene: TCEAL1 was set to GREEN
Added comment: PMID:36368327 reported seven unrelated individuals with de novo variants (2 nonsense, 2 frameshift, 2 CNVs & 1 missense variants) in TCEAL1 gene and presenting with an X-linked dominant neurodevelopmental disorder. All these seven individuals had intellectual disability (mild to severe). The other major clinical presentations include hypotonia, abnormal gait, speech impairment, autistic-like behavior, and mildly dysmorphic facial features.

This gene is associated with relevant phenotypes in OMIM (MIM #301094), but not in Gene2Phenotype.
Sources: Literature
Intellectual disability v5.162 FEM1C Achchuthan Shanmugasundram changed review comment from: Comment on list classification: This gene should be rated AMBER as there are two unrelated cases of intellectual disability reported (one in literature and another from Diagnostic Discovery initiative).; to: Comment on list classification: This gene should be rated AMBER as there are two unrelated cases of intellectual disability (one in literature and another from Diagnostic Discovery initiative).
Intellectual disability v5.162 FEM1C Achchuthan Shanmugasundram Added comment: Comment on list classification: This gene should be rated AMBER as there are two unrelated cases of intellectual disability reported (one in literature and another from Diagnostic Discovery initiative).
Intellectual disability v5.161 FEM1C Achchuthan Shanmugasundram changed review comment from: This gene should be rated RED as there is only one clear case of intellectual disability reported in literature.

PMID:36336956 reported a 9 year-old boy with severe global developmental delay, lack of speech, pyramidal signs and limb ataxia and identified with a heterozygous de novo missense variant c.376G>C (p.Asp126His) in the FEM1C gene. Cognitive assessment performed at 9 years of age showed that he has moderate intellectual disability.

De novo variant in the same residue (p.Asp126Val) has also been associated with an uncharacterised developmental disorder in PMID:28135719.

An additional case with a diagnostically reported de novo variant in this gene and a compatible phenotype including intellectual disability and ataxia was identified in the internal Genomics England Clinical Variant Archive (CVA) by the Diagnostic Discovery initiative.

This gene has not yet been associated with relevant phenotypes in OMIM or in Gene2Phenotype.
Sources: Literature; to: PMID:36336956 reported a 9 year-old boy with severe global developmental delay, lack of speech, pyramidal signs and limb ataxia and identified with a heterozygous de novo missense variant c.376G>C (p.Asp126His) in the FEM1C gene. Cognitive assessment performed at 9 years of age showed that he has moderate intellectual disability.

De novo variant in the same residue (p.Asp126Val) has also been associated with an uncharacterised developmental disorder in PMID:28135719.

An additional case with a diagnostically reported de novo variant in this gene and a compatible phenotype including intellectual disability and ataxia was identified in the internal Genomics England Clinical Variant Archive (CVA) by the Diagnostic Discovery initiative.

This gene has not yet been associated with relevant phenotypes in OMIM or in Gene2Phenotype.
Sources: Literature
Intellectual disability v5.161 FEM1C Achchuthan Shanmugasundram changed review comment from: This gene should be rated RED as there is only one clear case of intellectual disability reported in literature.

PMID:36336956 reported a 9 year-old boy with severe global developmental delay, lack of speech, pyramidal signs and limb ataxia and identified with a heterozygous de novo missense variant c.376G>C (p.Asp126His) in the FEM1C gene. Cognitive assessment performed at 9 years of age showed that he has moderate intellectual disability.

De novo variant in the same residue (p.Asp126Val) has also been associated with an uncharacterised developmental disorder in PMID:28135719.

This gene has not yet been associated with relevant phenotypes in OMIM or in Gene2Phenotype.
Sources: Literature; to: This gene should be rated RED as there is only one clear case of intellectual disability reported in literature.

PMID:36336956 reported a 9 year-old boy with severe global developmental delay, lack of speech, pyramidal signs and limb ataxia and identified with a heterozygous de novo missense variant c.376G>C (p.Asp126His) in the FEM1C gene. Cognitive assessment performed at 9 years of age showed that he has moderate intellectual disability.

De novo variant in the same residue (p.Asp126Val) has also been associated with an uncharacterised developmental disorder in PMID:28135719.

An additional case with a diagnostically reported de novo variant in this gene and a compatible phenotype including intellectual disability and ataxia was identified in the internal Genomics England Clinical Variant Archive (CVA) by the Diagnostic Discovery initiative.

This gene has not yet been associated with relevant phenotypes in OMIM or in Gene2Phenotype.
Sources: Literature
Intellectual disability v5.160 POU3F2 Sarah Leigh gene: POU3F2 was added
gene: POU3F2 was added to Intellectual disability - microarray and sequencing. Sources: Literature
Q2_23_promote_green tags were added to gene: POU3F2.
Mode of inheritance for gene: POU3F2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: POU3F2 were set to 37207645
Phenotypes for gene: POU3F2 were set to neurodevelopmental delay with hyperphagic obesity
Review for gene: POU3F2 was set to GREEN
Added comment: Not associated with a phenotype in OMIM, Gen2Phen or MONDO. PMID: 37207645 reports eight POU3F2 variants in the unrelated cases of neurodevelopmental delay with hyperphagic obesity, with no other variants detected in other candidate genes. Intellectual disability was apparent in 6/7 of these cases from infancy to early childhood. The remaining variant : NM_005604.4 c.135C>A, p.Tyr45* was found in a mother and son, where the son was classified as having intellectual disability, the mother did not. Excluding the mother and son, all of the remaining cases carrying POU3F2 variants had neurodevelopmental delay.
Sources: Literature
Intellectual disability v5.157 ETFB Sarah Leigh Phenotypes for gene: ETFB were changed from GLUTARIC ACIDURIA TYPE 2B to Glutaric acidemia IIB, OMIM:231680; multiple acyl-CoA dehydrogenase deficiency, MONDO:0009282
Intellectual disability v5.156 ETFA Sarah Leigh Phenotypes for gene: ETFA were changed from GLUTARIC ACIDURIA TYPE 2A to Glutaric acidemia IIA, OMIM:231680; multiple acyl-CoA dehydrogenase deficiency, MONDO:0009282
Intellectual disability v5.155 NUP214 Eleanor Williams commented on gene: NUP214: After consultation with the Genomics England clinical team it has been decided that there is just enough evidence to promote this gene to green as there are 4 unrelated families and developmental delay is reported in all.
Intellectual disability v5.155 FILIP1 Achchuthan Shanmugasundram changed review comment from: PMID:36344539 reported a single male with biallelic variant in FILIP1 (c.2665C > T/ p.Arg889Ter) gene and presenting with distal arthrogryposis and mild learning disability.

PMID:37163662 reported five individuals from four unrelated families with four different biallelic variants in FILIP1 gene. The main symptoms in childhood included delayed motor milestones (all four families), delayed speech development (three families), intellectual disability (three families), contractures (2 families), clubfeet (2 families) and microcephaly (2 families). As one of the patients died at the age of 13 months, intellectual disability and speech delay were not evaluated.

This gene has not been associated with relevant phenotypes either in OMIM or in Gene2Phenotype.
Sources: Literature; to: PMID:36344539 reported a single male with biallelic variant in FILIP1 (c.2665C > T/ p.Arg889Ter) gene and presenting with distal arthrogryposis and mild learning disability.

PMID:37163662 reported five individuals from four unrelated families with four different biallelic variants in FILIP1 gene. The main symptoms in childhood included delayed motor milestones (all four families), delayed speech development (three families), intellectual disability (three families), contractures (2 families), clubfeet (2 families) and microcephaly (2 families). As one of the patients died at the age of 13 months, intellectual disability and speech delay were not evaluated.

This gene has not yet been associated with relevant phenotypes either in OMIM or in Gene2Phenotype.
Sources: Literature
Intellectual disability v5.153 FILIP1 Achchuthan Shanmugasundram changed review comment from: Sources: Literature; to: PMID:36344539 reported a single male with biallelic variant in FILIP1 (c.2665C > T/ p.Arg889Ter) gene and presenting with distal arthrogryposis and mild learning disability.

PMID:37163662 reported five individuals from four unrelated families with four different biallelic variants in FILIP1 gene. The main symptoms in childhood included delayed motor milestones (all four families), delayed speech development (three families), intellectual disability (three families), contractures (2 families), clubfeet (2 families) and microcephaly (2 families). As one of the patients died at the age of 13 months, intellectual disability and speech delay were not evaluated.

This gene has not been associated with relevant phenotypes either in OMIM or in Gene2Phenotype.
Sources: Literature
Intellectual disability v5.153 FILIP1 Achchuthan Shanmugasundram gene: FILIP1 was added
gene: FILIP1 was added to Intellectual disability - microarray and sequencing. Sources: Literature
Mode of inheritance for gene: FILIP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FILIP1 were set to 36344539; 37163662
Phenotypes for gene: FILIP1 were set to intellectual disability, MONDO:0001071
Review for gene: FILIP1 was set to GREEN
Added comment: Sources: Literature
Intellectual disability v5.150 PRKACB Arina Puzriakova Phenotypes for gene: PRKACB were changed from Postaxial hand polydactyly; Postaxial foot polydactyly; Common atrium; Atrioventricular canal defect; Narrow chest; Abnormality of the teeth; Intellectual disability to Cardioacrofacial dysplasia 2, OMIM:619143
Intellectual disability v5.143 ZMYND8 Achchuthan Shanmugasundram edited their review of gene: ZMYND8: Added comment: As reviewed by Konstantinos Varvagiannis, PMID:35916866 reported intellectual disability in10 out of 11 unrelated cases, of which one patient had profound ID and two had moderate ID.

This gene has not yet been associated with phenotypes in OMIM, but has been reported in Gene2Phenotype (with 'moderate' rating in the DD panel).; Changed phenotypes to: intellectual disability, MONDO:0001071
Intellectual disability v5.140 ZMYND15 Achchuthan Shanmugasundram Phenotypes for gene: ZMYND15 were changed from Delayed speech and language development; Motor delay; Intellectual disability; Abnormality of cardiovascular system morphology; Hearing abnormality; Abnormality of vision; Abnormality of the face; Seizures to ?Spermatogenic failure 14 OMIM:615842
Intellectual disability v5.137 PRSS12 Achchuthan Shanmugasundram changed review comment from: Comment on gene classification - This gene should remain as Green rating as there are four unrelated cases and two different variants reported.

PMID:12459588 - Two unrelated families with the same variant (4bp homozygous deletion) and with intellectual disability. Although the cases were thought to be unrelated, they had the same haplotype across the PRSS12 locus, suggesting either distant consanguinity or a founder effect in the Algerian population.

PMID:25529582 - Two unrelated cases with homozygous c.2389C>T/ p.Arg797Cys variants and with severe intellectual disability reported in the Deciphering Developmental Disorders (DDD) study.

In addition, this gene has been associated with intellectual disability in both OMIM (MIM #249500) and Gene2Phenotype (with 'Definitive' rating in the DD panel).; to: Comment on gene classification - This gene should remain as Green as there are four unrelated cases and two different variants reported.

PMID:12459588 - Two unrelated families with the same variant (4bp homozygous deletion) and with intellectual disability. Although the cases were thought to be unrelated, they had the same haplotype across the PRSS12 locus, suggesting either distant consanguinity or a founder effect in the Algerian population.

PMID:25529582 - Two unrelated cases with homozygous c.2389C>T/ p.Arg797Cys variants and with severe intellectual disability reported in the Deciphering Developmental Disorders (DDD) study.

In addition, this gene has been associated with intellectual disability in both OMIM (MIM #249500) and Gene2Phenotype (with 'Definitive' rating in the DD panel).
Intellectual disability v5.137 PRSS12 Achchuthan Shanmugasundram changed review comment from: PMID:12459588 - Two unrelated families with the same variant (4bp homozygous deletion) and with intellectual disability. Although the cases were thought to be unrelated, they had the same haplotype across the PRSS12 locus, suggesting either distant consanguinity or a founder effect in the Algerian population.

PMID:25529582 - Two unrelated cases with homozygous c.2389C>T/ p.Arg797Cys variants and with severe intellectual disability reported in the Deciphering Developmental Disorders (DDD) study.

In addition, this gene has been associated with intellectual disability in both OMIM (MIM #249500) and Gene2Phenotype (with 'Definitive' rating in the DD panel).; to: Comment on gene classification - This gene should remain as Green rating as there are four unrelated cases and two different variants reported.

PMID:12459588 - Two unrelated families with the same variant (4bp homozygous deletion) and with intellectual disability. Although the cases were thought to be unrelated, they had the same haplotype across the PRSS12 locus, suggesting either distant consanguinity or a founder effect in the Algerian population.

PMID:25529582 - Two unrelated cases with homozygous c.2389C>T/ p.Arg797Cys variants and with severe intellectual disability reported in the Deciphering Developmental Disorders (DDD) study.

In addition, this gene has been associated with intellectual disability in both OMIM (MIM #249500) and Gene2Phenotype (with 'Definitive' rating in the DD panel).
Intellectual disability v5.137 PRSS12 Achchuthan Shanmugasundram changed review comment from: PMID:12459588 - Two unrelated families with the same variant (4bp homozygous deletion) and with intellectual disability. Although the cases were thought to be unrelated, they had the same haplotype across the PRSS12 locus, suggesting either distant consanguinity or a founder effect in the Algerian population.

PMID:25529582 - Two unrelated cases with homozygous c.2389C>T/ p.Arg797Cys variants and with severe intellectual disability reported in the Deciphering Developmental Disorders (DDD) study.

In addition, this gene has been associated with intellectual disability in both OMIM (MIM #249500) and Gene2Phenotype (with 'Definitive' rating in the DD panel).; to: PMID:12459588 - Two unrelated families with the same variant (4bp homozygous deletion) and with intellectual disability. Although the cases were thought to be unrelated, they had the same haplotype across the PRSS12 locus, suggesting either distant consanguinity or a founder effect in the Algerian population.

PMID:25529582 - Two unrelated cases with homozygous c.2389C>T/ p.Arg797Cys variants and with severe intellectual disability reported in the Deciphering Developmental Disorders (DDD) study.

In addition, this gene has been associated with intellectual disability in both OMIM (MIM #249500) and Gene2Phenotype (with 'Definitive' rating in the DD panel).
Intellectual disability v5.135 MAN2C1 Achchuthan Shanmugasundram commented on gene: MAN2C1: As reviewed by Konstantinos Varvagiannis, there are three unrelated cases reported with intellectual disability in PMID:35045343.

In addition, this gene has been associated with relevant phenotypes in both OMIM (MIM #619775) and Gene2Phenotype (with 'strong' rating in DD panel).
Intellectual disability v5.135 FAAH2 Achchuthan Shanmugasundram changed review comment from: As reviewed already, there are two cases reported in PMIDs: 25885783 & 34645488. Additional cases were reported in PMIDs: 20655035 & 23352160, however without much clinical details. Hence, the rating should remain amber.; to: As reviewed already, there are two cases reported in PMIDs: 25885783 & 34645488. Additional cases were reported in PMIDs: 20655035 & 23352160, however without much clinical details. Hence, the rating should remain amber.

This gene has not yet been associated with relevant phenotypes either in OMIM or in Gene2Phenotype.
Intellectual disability v5.131 ITPR1 Arina Puzriakova Phenotypes for gene: ITPR1 were changed from Gillespie syndrome 206700 to Gillespie syndrome, OMIM:206700; Spinocerebellar ataxia 15, OMIM:606658; Spinocerebellar ataxia 29, congenital nonprogressive, OMIM:117360
Intellectual disability v5.130 ITPR1 Arina Puzriakova Added comment: Comment on mode of inheritance: Should be updated from 'biallelic' to 'both mono- and biallelic' at the next GMS panel update inline with the review by Tracy Lester. Although not observed in all, some patients do exhibit cognitive deficits which may be an early and severe feature. There are sufficient unrelated cases with heterozygous variants and ID (associated with either Gillespie or SCA) to warrant including this MOI on this panel.
Intellectual disability v5.123 ENTPD1 Achchuthan Shanmugasundram changed review comment from: As reviewed by Konstantinos Varvagiannis, PMID:35471564 reported 27 cases from 17 families with a complex childhood-onset neurodevelopmental disorder characterised by intellectual disability/ developmental delay and spastic paraplegia in all individuals, white matter abnormalities in 12 individuals and epilepsy in 7 individuals.

In addition, this gene has been associated with autosomal recessive intellectual developmental disorder in Gene2phenotype with 'limited' rating and ID has been included as part of the SPG64 phenotype in OMIM. ; to: As reviewed by Konstantinos Varvagiannis, PMID:35471564 reported 27 cases from 17 families with biallelic variants in ENTPD1 and with a complex childhood-onset neurodevelopmental disorder characterised by intellectual disability/ developmental delay and spastic paraplegia in all individuals, white matter abnormalities in 12 individuals and epilepsy in 7 individuals.

PMID:35758610 reported two siblings with biallelic variants in ENTPD1. The proband was mildly intellectually disabled and her brother was moderately clinically disabled based on clinical observations.

In addition, this gene has been associated with autosomal recessive intellectual developmental disorder in Gene2phenotype with 'limited' rating and ID has been included as part of the SPG64 phenotype in OMIM.
Intellectual disability v5.123 COASY Sarah Leigh Phenotypes for gene: COASY were changed from Neurodegeneration with brain iron accumulation 6, OMIM:615643; neurodegeneration with brain iron accumulation 6, MONDO:0014290 to Neurodegeneration with brain iron accumulation 6, OMIM:615643; neurodegeneration with brain iron accumulation 6, MONDO:0014290; Pontocerebellar hypoplasia, type 12, OMIM:618266; pontocerebellar hypoplasia, type 12, MONDO:0032643
Intellectual disability v5.121 ENTPD1 Achchuthan Shanmugasundram changed review comment from: As reviewed by Konstantinos Varvagiannis, PMID35471564 reported 27 cases from 17 families with a complex childhood-onset neurodevelopmental disorder characterised by intellectual disability/ developmental delay and spastic paraplegia in all individuals, white matter abnormalities in 12 individuals and epilepsy in 7 individuals.

In addition, this gene has been associated with autosomal recessive intellectual developmental disorder in Gene2phenotype with 'limited' rating and ID has been included as part of the SPG64 phenotype in OMIM. ; to: As reviewed by Konstantinos Varvagiannis, PMID:35471564 reported 27 cases from 17 families with a complex childhood-onset neurodevelopmental disorder characterised by intellectual disability/ developmental delay and spastic paraplegia in all individuals, white matter abnormalities in 12 individuals and epilepsy in 7 individuals.

In addition, this gene has been associated with autosomal recessive intellectual developmental disorder in Gene2phenotype with 'limited' rating and ID has been included as part of the SPG64 phenotype in OMIM.
Intellectual disability v5.120 ENTPD1 Achchuthan Shanmugasundram changed review comment from: As reviewed by Konstantinos Varvagiannis, PMID35471564 reported 27 cases from 17 families with a complex childhood-onset neurodevelopmental disorder characterised by intellectual disability/ developmental delay and spastic paraplegia in all individuals, white matter abnormalities in 12 individuals and epilepsy in 7 individuals.

In addition, this gene has been associated with autosomal recessive intellectual developmental disorder in Gene2phenotype with 'limited' rating and ID has been includes as part of the SPG64 phenotype in OMIM. ; to: As reviewed by Konstantinos Varvagiannis, PMID35471564 reported 27 cases from 17 families with a complex childhood-onset neurodevelopmental disorder characterised by intellectual disability/ developmental delay and spastic paraplegia in all individuals, white matter abnormalities in 12 individuals and epilepsy in 7 individuals.

In addition, this gene has been associated with autosomal recessive intellectual developmental disorder in Gene2phenotype with 'limited' rating and ID has been included as part of the SPG64 phenotype in OMIM.
Intellectual disability v5.120 ENTPD1 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: As reviewed by Konstantinos Varvagiannis, PMID35471564 reported 27 cases from 17 families with a complex childhood-onset neurodevelopmental disorder characterised by intellectual disability/ developmental delay and spastic paraplegia in all individuals, white matter abnormalities in 12 individuals and epilepsy in 7 individuals. Hence, this gene can be promoted to Green in the next major update.; to: As reviewed by Konstantinos Varvagiannis, PMID35471564 reported 27 cases from 17 families with a complex childhood-onset neurodevelopmental disorder characterised by intellectual disability/ developmental delay and spastic paraplegia in all individuals, white matter abnormalities in 12 individuals and epilepsy in 7 individuals.

In addition, this gene has been associated with autosomal recessive intellectual developmental disorder in Gene2phenotype with 'limited' rating and ID has been includes as part of the SPG64 phenotype in OMIM.
Intellectual disability v5.119 ENTPD1 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Konstantinos Varvagiannis, PMID35471564 reported 27 cases from 17 families with a complex childhood-onset neurodevelopmental disorder characterised by intellectual disability/ developmental delay and spastic paraplegia in all individuals, white matter abnormalities in 12 individuals and epilepsy in 7 individuals. Hence, this gene can be promoted to Green in the next major update.
Intellectual disability v5.118 ENTPD1 Achchuthan Shanmugasundram reviewed gene: ENTPD1: Rating: GREEN; Mode of pathogenicity: None; Publications: 35471564; Phenotypes: Spastic paraplegia 64, autosomal recessive, OMIM:615683; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v5.117 RNF13 Arina Puzriakova Phenotypes for gene: RNF13 were changed from Cortical visual impairment; Epileptic encephalopathy, early infantile, 73, 618379; Failure to thrive; Seizures; Congenital microcephaly; Abnormal muscle tone; Feeding difficulties; Intellectual disability; Global developmental delay; Sensorineural hearing impairment to Developmental and epileptic encephalopathy 73, OMIM:618379
Intellectual disability v5.115 CHMP3 Arina Puzriakova gene: CHMP3 was added
gene: CHMP3 was added to Intellectual disability - microarray and sequencing. Sources: Literature
Mode of inheritance for gene: CHMP3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CHMP3 were set to 35710109
Phenotypes for gene: CHMP3 were set to Complex spastic quadriplegia associated with developmental delay and seizures
Added comment: Cohen-Barak et al., 2022 (PMID: 35710109) reported on a consanguineous family, in which five individuals presented with intellectual and progressive motor disabilities, seizures and spastic quadriplegia, associated with a homozygous variant in CHMP3. Patient derived fibroblasts expressed ultrastructural and molecular features of impaired autophagy, partially rescued by ectopic expression of WT-CHMP3.
Sources: Literature
Intellectual disability v5.110 GRIN2B Arina Puzriakova Phenotypes for gene: GRIN2B were changed from Mental Retardation, Dominant; Mental retardation, autosomal dominant 6, 613970; AUTISM to Intellectual developmental disorder, autosomal dominant 6, with or without seizures, OMIM:613970; Developmental and epileptic encephalopathy 27, OMIM:616139
Intellectual disability v5.108 LHX2 Sarah Leigh gene: LHX2 was added
gene: LHX2 was added to Intellectual disability - microarray and sequencing. Sources: Literature
Q2_23_promote_green tags were added to gene: LHX2.
Mode of inheritance for gene: LHX2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: LHX2 were set to 37057675
Phenotypes for gene: LHX2 were set to neurodevelopmental disorder
Review for gene: LHX2 was set to GREEN
Added comment: Not associated with a phenotype in OMIM, Gen2Phen or MONDO. PMID: 37057675 reports 17 predominanly de novo LHX2 variants in a panel of patients with a variable neurodevelopmental disorder. Haploinsufficiency and functional studies are supportive of a loss-of-function pathogenic action of the reported LHX2 variants.
Sources: Literature
Intellectual disability v5.107 ITPR1 Tracy Lester edited their review of gene: ITPR1: Added comment: PMID:29925855 - All 7 EOA patients with ITPR1 de novo variants (3 from cohort #1; 4 from cohort #2) presented with infantile onset cerebellar ataxia starting before the age of 2 years, including delayed motor milestones (Table 2). Cognitive deficits of variable degree were observed in 3 out of 4 patients where this information was available, reaching from only mild dyscalculia (P2) to severe intellectual disability with a speech vocabulary of only a few words (P7 at age 12 years). In contrast, patient P1 showed normal intelligence with an IQ of 97.

PMID:27108797 - Here, we report that both recessive and dominant ITPR1 mutations cause Gillespie syndrome. ITPR1 is a predominant isoform in the brain among the three types of ITPRs and is strongly expressed in cerebellar Purkinje cells.31 Mice with complete homozygosity for Itpr1 ablation suffer from severe epilepsy and ataxia and die either in utero or before weaning.32 Consistently, ITPR1 mutations have been reported to cause cerebellar diseases including late-onset spinocerebellar ataxia type 15 (SCA15 [MIM: 606658]),33 congenital nonprogressive spinocerebellar ataxia and mild cognitive impairment (SCA29 [MIM: 117360]),34 infantile-onset cerebellar ataxia with mild cognitive deficit,35 and childhood-onset ataxic cerebellar palsy with moderate intellectual disability36 (see ITPR1 schematic diagram in Figure 3A).
Affected individuals had similar iris anomalies and neonatal ataxia with progressive cerebellar atrophy (Figure 2). Moderate to severe intellectual disabilities were noted in the three individuals with recessive mutations (F1:II1, F2:II1, and F3:II1; Table 1). In contrast, the affected individual F4:II1 aged 18 years and harboring the de novo c.7687_7689del mutation was reported to have normal intelligence (Table 1).

As de novo variants are associated with ID/DD the inheritance should be updated to be BOTH AD and AR.; Set current diagnostic: yes
Intellectual disability v5.107 ITPR1 Tracy Lester reviewed gene: ITPR1: Rating: GREEN; Mode of pathogenicity: None; Publications: 29925855, 27108797; Phenotypes: developmental delay, intellectual disability, hypotonia, ataxia, cerebellar malformatons; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v5.105 SLC32A1 Achchuthan Shanmugasundram changed review comment from: PMID:36073542 reported four unrelated patients with four different de novo missense variants in SLC32A1 gene reported with global developmental delay, moderate-to-severe intellectual disability, infantile-onset epilepsy within the first 18 months of life, and a choreiform, dystonic, or dyskinetic movement disorder.

In silico modeling and functional analyses showed that these variants can impair GABAergic neurotransmission through at least two mechanisms, by affecting synaptic vesicle filling and by altering synaptic short-term plasticity.
Sources: Literature; to: PMID:36073542 reported four unrelated patients with four different de novo missense variants in SLC32A1 gene reported with global developmental delay, moderate-to-severe intellectual disability, infantile-onset epilepsy within the first 18 months of life, and a choreiform, dystonic, or dyskinetic movement disorder.

In silico modeling and functional analyses showed that these variants can impair GABAergic neurotransmission through at least two mechanisms, by affecting synaptic vesicle filling and by altering synaptic short-term plasticity.

Although this gene has not yet been associated with phenotypes in OMIM, it has been added to Gene2Phenotype with 'moderate' rating in the DD panel.

Sources: Literature
Intellectual disability v5.105 SLC32A1 Achchuthan Shanmugasundram gene: SLC32A1 was added
gene: SLC32A1 was added to Intellectual disability - microarray and sequencing. Sources: Literature
Mode of inheritance for gene: SLC32A1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SLC32A1 were set to 36073542
Phenotypes for gene: SLC32A1 were set to developmental and epileptic encephalopathy, MONDO:0100062
Review for gene: SLC32A1 was set to GREEN
Added comment: PMID:36073542 reported four unrelated patients with four different de novo missense variants in SLC32A1 gene reported with global developmental delay, moderate-to-severe intellectual disability, infantile-onset epilepsy within the first 18 months of life, and a choreiform, dystonic, or dyskinetic movement disorder.

In silico modeling and functional analyses showed that these variants can impair GABAergic neurotransmission through at least two mechanisms, by affecting synaptic vesicle filling and by altering synaptic short-term plasticity.
Sources: Literature
Intellectual disability v5.100 CSTF2 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Zornitza Stark (Australian Genomics), there is one family with intellectual disability, supported by functional studies. This gene should therefore be promoted to AMBER in this panel.
Intellectual disability v5.100 CSTF2 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Zornitza Stark (Australian Genomics), there is one family with intellectual disability, supported by functional studies. This gene should therefore be promoted to AMBER in this panel.
Intellectual disability v5.100 CSTF2 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Zornitza Stark (Australian Genomics), there is one family with intellectual disability, supported by functional studies. This gene should therefore be promoted to AMBER in this panel.
Intellectual disability v5.99 CSTF2 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Zornitza Stark (Australian Genomics), there is one family with intellectual disability, supported by functional studies. This gene should therefore be promoted to AMBER in this panel.
Intellectual disability v5.99 CSTF2 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Zornitza Stark (Australian Genomics), there is one family with intellectual disability, supported by functional studies. This gene should therefore be promoted to AMBER in this panel.
Intellectual disability v5.99 CSTF2 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Zornitza Stark (Australian Genomics), there is one family with intellectual disability, supported by functional studies. This gene should therefore be promoted to AMBER in this panel.
Intellectual disability v5.98 PRKAR1B Achchuthan Shanmugasundram Classified gene: PRKAR1B as Amber List (moderate evidence)
Intellectual disability v5.98 PRKAR1B Achchuthan Shanmugasundram Gene: prkar1b has been classified as Amber List (Moderate Evidence).
Intellectual disability v5.98 PRKAR1B Achchuthan Shanmugasundram Classified gene: PRKAR1B as Amber List (moderate evidence)
Intellectual disability v5.98 PRKAR1B Achchuthan Shanmugasundram Gene: prkar1b has been classified as Amber List (Moderate Evidence).
Intellectual disability v5.98 PRKAR1B Achchuthan Shanmugasundram Classified gene: PRKAR1B as Amber List (moderate evidence)
Intellectual disability v5.98 PRKAR1B Achchuthan Shanmugasundram Gene: prkar1b has been classified as Amber List (Moderate Evidence).
Intellectual disability v5.97 PRKAR1B Achchuthan Shanmugasundram Classified gene: PRKAR1B as Amber List (moderate evidence)
Intellectual disability v5.97 PRKAR1B Achchuthan Shanmugasundram Gene: prkar1b has been classified as Amber List (Moderate Evidence).
Intellectual disability v5.97 PRKAR1B Achchuthan Shanmugasundram Classified gene: PRKAR1B as Amber List (moderate evidence)
Intellectual disability v5.97 PRKAR1B Achchuthan Shanmugasundram Gene: prkar1b has been classified as Amber List (Moderate Evidence).
Intellectual disability v5.96 PRKAR1B Achchuthan Shanmugasundram Publications for gene: PRKAR1B were set to 25414040; 33833410
Intellectual disability v5.96 PRKAR1B Achchuthan Shanmugasundram Phenotypes for gene: PRKAR1B were changed from Marbach-Schaaf neurodevelopmental syndrome, OMIM:619680 to Global developmental delay; Intellectual disability; Autism; Attention deficit hyperactivity disorder; Aggressive behavior; Abnormality of movement; Upslanted palpebral fissure
Intellectual disability v5.96 PRKAR1B Achchuthan Shanmugasundram Publications for gene: PRKAR1B were set to 25414040; 33833410
Intellectual disability v5.96 PRKAR1B Achchuthan Shanmugasundram Publications for gene: PRKAR1B were set to 25414040; 33833410
Intellectual disability v5.97 PRKAR1B Achchuthan Shanmugasundram Tag Q2_23_promote_green tag was added to gene: PRKAR1B.
Intellectual disability v5.97 PRKAR1B Achchuthan Shanmugasundram Phenotypes for gene: PRKAR1B were changed from Marbach-Schaaf neurodevelopmental syndrome, OMIM:619680 to Marbach-Schaaf neurodevelopmental syndrome, OMIM:619680
Intellectual disability v5.96 PRKAR1B Achchuthan Shanmugasundram Phenotypes for gene: PRKAR1B were changed from Marbach-Schaaf neurodevelopmental syndrome, OMIM:619680 to Marbach-Schaaf neurodevelopmental syndrome, OMIM:619680
Intellectual disability v5.96 PRKAR1B Achchuthan Shanmugasundram Phenotypes for gene: PRKAR1B were changed from Global developmental delay; Intellectual disability; Autism; Attention deficit hyperactivity disorder; Aggressive behavior; Abnormality of movement; Upslanted palpebral fissure to Marbach-Schaaf neurodevelopmental syndrome, OMIM:619680
Intellectual disability v5.95 PRKAR1B Achchuthan Shanmugasundram Publications for gene: PRKAR1B were set to 25414040; 33833410
Intellectual disability v5.95 PRKAR1B Achchuthan Shanmugasundram Publications for gene: PRKAR1B were set to 25414040; 33833410
Intellectual disability v5.96 PRKAR1B Achchuthan Shanmugasundram Publications for gene: PRKAR1B were set to 25414040; 33833410
Intellectual disability v5.95 PRKAR1B Achchuthan Shanmugasundram Publications for gene: PRKAR1B were set to 25414040; 33833410
Intellectual disability v5.95 PRKAR1B Achchuthan Shanmugasundram Publications for gene: PRKAR1B were set to 25414040; 33833410
Intellectual disability v5.95 PRKAR1B Achchuthan Shanmugasundram Publications for gene: PRKAR1B were set to https://doi.org/10.1101/2020.09.10.20190314; 25414040
Intellectual disability v5.94 PRKAR1B Achchuthan Shanmugasundram Mode of inheritance for gene: PRKAR1B was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v5.94 PRKAR1B Achchuthan Shanmugasundram Mode of inheritance for gene: PRKAR1B was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v5.94 PRKAR1B Achchuthan Shanmugasundram Mode of inheritance for gene: PRKAR1B was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v5.94 PRKAR1B Achchuthan Shanmugasundram Mode of inheritance for gene: PRKAR1B was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v5.94 PRKAR1B Achchuthan Shanmugasundram Mode of inheritance for gene: PRKAR1B was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v5.93 PRKAR1B Achchuthan Shanmugasundram reviewed gene: PRKAR1B: Rating: GREEN; Mode of pathogenicity: None; Publications: 33833410; Phenotypes: Marbach-Schaaf neurodevelopmental syndrome, OMIM:619680; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v5.93 PPFIBP1 Achchuthan Shanmugasundram changed review comment from: As reviewed by Konstantinos Varvagiannis, all individuals reported in PMID:35830857 (16 individuals from 12 families) shared a core phenotype of global developmental delay/intellectual disability (GDD/ID) and epilepsy. 15 were affected by profound or severe GDD/ID (15/16). They had not acquired speech (15/16) and showed impaired motor development (15/16).

This gene has already been associated with relevant phenotypes in both OMIM (MIM #620024) and Gene2Phenotype (with 'strong' rating in the DD panel).; to: As reviewed by Konstantinos Varvagiannis, all individuals (16 individuals from 12 families) reported in PMID:35830857 shared a core phenotype of global developmental delay/intellectual disability (GDD/ID) and epilepsy. 15 were affected by profound or severe GDD/ID (15/16). They had not acquired speech (15/16) and showed impaired motor development (15/16).

This gene has already been associated with relevant phenotypes in both OMIM (MIM #620024) and Gene2Phenotype (with 'strong' rating in the DD panel).
Intellectual disability v5.93 PPFIBP1 Achchuthan Shanmugasundram changed review comment from: As reviewed by Konstantinos Varvagiannis, all individuals reported in PMID:35830857 shared a core phenotype of global developmental delay/intellectual disability (GDD/ID) and epilepsy. 15 were affected by profound or severe GDD/ID (15/16). They had not acquired speech (15/16) and showed impaired motor development (15/16).

This gene has already been associated with relevant phenotypes in both OMIM (MIM #620024) and Gene2Phenotype (with 'strong' rating in the DD panel).; to: As reviewed by Konstantinos Varvagiannis, all individuals reported in PMID:35830857 (16 individuals from 12 families) shared a core phenotype of global developmental delay/intellectual disability (GDD/ID) and epilepsy. 15 were affected by profound or severe GDD/ID (15/16). They had not acquired speech (15/16) and showed impaired motor development (15/16).

This gene has already been associated with relevant phenotypes in both OMIM (MIM #620024) and Gene2Phenotype (with 'strong' rating in the DD panel).
Intellectual disability v5.91 PPFIBP1 Achchuthan Shanmugasundram Phenotypes for gene: PPFIBP1 were changed from Global developmental delay; Intellectual disability; Microcephaly; Seizures; Abnormality of brain morphology; Abnormality of the cerebral white matter; Cerebral calcification; Abnormal cortical gyration; Hypertonia; Spastic tetraplegia; Generalized hypotonia; Small for gestational age; Growth delay; Failure to thrive; Feeding difficulties; abnormal heart morphology; Hearing abnormality; Cryptorchidism; Abnormality of vision to Neurodevelopmental disorder with seizures, microcephaly, and brain abnormalities, OMIM:620024
Intellectual disability v5.90 PPFIBP1 Achchuthan Shanmugasundram changed review comment from: As reviewed by Konstantinos Varvagiannis, all individuals reported in PMID:35830857 shared a core phenotype of global developmental delay/intellectual disability (GDD/ID) and epilepsy. 15 were affected by profound or severe GDD/ID (15/16). They had not acquired speech (15/16) and showed impaired motor development (15/16).; to: As reviewed by Konstantinos Varvagiannis, all individuals reported in PMID:35830857 shared a core phenotype of global developmental delay/intellectual disability (GDD/ID) and epilepsy. 15 were affected by profound or severe GDD/ID (15/16). They had not acquired speech (15/16) and showed impaired motor development (15/16).

This gene has already been associated with relevant phenotypes in both OMIM (MIM #620024) and Gene2Phenotype (with 'strong' rating in the DD panel).
Intellectual disability v5.85 HNRNPD Achchuthan Shanmugasundram changed review comment from: As reviewed by Zornitza Stark (Australian Genomics), several additional individuals with neurodevelopmental disorders carrying de novo HNRNPD variants identified in an international cohort have been reported in PMID:33874999. These probands displayed a high prevalence of DD/ID, speech delay, and ASD and/or other behavioural phenotypes. As this is a large cohort study and there is no complete information about DD/ID phenotypes in these probands, this gene should remain as AMBER.; to: As reviewed by Zornitza Stark (Australian Genomics), several additional individuals with neurodevelopmental disorders carrying de novo HNRNPD variants identified in an international cohort have been reported in PMID:33874999. These probands displayed a high prevalence of DD/ID, speech delay, and ASD and/or other behavioural phenotypes. As this is a large cohort study and there is no complete information about DD/ID phenotypes in these probands, this gene should remain as AMBER.

The 'watchlist' tag has been added to review this rating in light of new evidence in the future.
Intellectual disability v5.85 WIPI2 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: As reviewed by Zornitza Stark (Australian Genomics), there are three unrelated families with homozygous variants in WIPI2 gene presenting with varying degrees of intellectual disability supported by functional evidence. Hence, this gene can be promoted to GREEN at the next major review.; to: Comment on list classification: As reviewed by Zornitza Stark (Australian Genomics), there are three unrelated families with homozygous variants in WIPI2 gene presenting with varying degrees of intellectual disability (moderate to profound) and supported by functional evidence. Hence, this gene can be promoted to GREEN at the next major review.
Intellectual disability v5.81 WIPI2 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Zornitza Stark (Australian Genomics), there are three unrelated families with homozygous variants in WIPI2 gene presenting with varying degrees of intellectual disability supported by functional evidence. Hence, this gene can be promoted to GREEN at the next major review.
Intellectual disability v5.80 WIPI2 Achchuthan Shanmugasundram reviewed gene: WIPI2: Rating: GREEN; Mode of pathogenicity: None; Publications: 30968111, 34557665; Phenotypes: ?Intellectual developmental disorder with short stature and variable skeletal anomalies, OMIM:618453; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v5.80 PLXNA1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for this gene to be promoted to GREEN at the next major review. The MOI can also be set to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal" as there are more than three cases each with both monoallelic and biallelic variants.
Intellectual disability v5.79 PLXNA1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for this gene to be promoted to GREEN at the next major review. The MOI can also be set to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal" as there are more than three cases each with both monoallelic and biallelic variants.
Intellectual disability v5.72 KIF4A Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Zornitza Stark (Australian Genomics), there are at least four unrelated cases with hemizygous variants in KIF4A gene and presenting with intellectual disability. This evidence is sufficient for promoting to GREEN rating at the next major review.
Intellectual disability v5.71 KIF4A Achchuthan Shanmugasundram changed review comment from: As reviewed by Zornitza Stark (Australian Genomics), there are at least four unrelated cases with hemizygous variants in KIF4A gene and presenting with intellectual disability.

PMID:24812067 reported a family in which five males spanning three generations had intellectual disability, speech delay and global developmental delay and four of these males developed seizures in late childhood–adolescence.

PMID:34346154 reported 11 unrelated cases expanding the phenotypic spectrum to include developmental delay and intellectual disability with or without epilepsy to a congenital anomaly phenotype with hydrocephalus and various brain anomalies at the more severe end of clinical manifestations. Of eight patients with congenital anomalies, one each had severe to profound developmental delay, mild psychomotor delay and severe psychomotor delay, while the remaining five had no developmental delays. However, all three patients without congenital structural anomalies had intellectual disability (borderline intellectual functioning in one case), speech delay and global developmental delay, while motor delay and autism spectrum disorder was reported in two cases each. Isolated febrile seizure was reported in one case.

This gene has been reported in OMIM (MIM #300923) and Gene2Phenotype (with 'limited' rating) on the basis of one family from PMID:24812067.; to: PMID:24812067 reported a family in which five males spanning three generations had intellectual disability, speech delay and global developmental delay and four of these males developed seizures in late childhood–adolescence.

PMID:34346154 reported 11 unrelated cases expanding the phenotypic spectrum to include developmental delay and intellectual disability with or without epilepsy to a congenital anomaly phenotype with hydrocephalus and various brain anomalies at the more severe end of clinical manifestations. Of eight patients with congenital anomalies, one each had severe to profound developmental delay, mild psychomotor delay and severe psychomotor delay, while the remaining five had no developmental delays. However, all three patients without congenital structural anomalies had intellectual disability (borderline intellectual functioning in one case), speech delay and global developmental delay, while motor delay and autism spectrum disorder was reported in two cases each. Isolated febrile seizure was reported in one case.

This gene has been reported in OMIM (MIM #300923) and Gene2Phenotype (with 'limited' rating) on the basis of one family from PMID:24812067.
Intellectual disability v5.71 KIF4A Achchuthan Shanmugasundram changed review comment from: As reviewed by Zornitza Stark (Australian Genomics), there are at least four unrelated cases with hemizygous variants in KIF4A gene and presenting with intellectual disability.

PMID:24812067 reported a family in which five males spanning three generations had intellectual disability, speech delay and global developmental delay and four of these males developed seizures in late childhood–adolescence.

PMID:34346154 reported 11 unrelated cases expanding the phenotypic spectrum to include developmental delay and intellectual disability with or without epilepsy to a congenital anomaly phenotype with hydrocephalus and various brain anomalies at the more severe end of clinical manifestations. Of eight patients with congenital anomalies, one each had severe to profound developmental delay, mild psychomotor delay and severe psychomotor delay, while the remaining five had no developmental delays. However, all three patients without congenital structural anomalies had intellectual disability (borderline intellectual functioning in one case), speech delay and global developmental delay, while motor delay and autism spectrum disorder was reported in two cases each. Isolated febrile seizure was reported in one case.; to: As reviewed by Zornitza Stark (Australian Genomics), there are at least four unrelated cases with hemizygous variants in KIF4A gene and presenting with intellectual disability.

PMID:24812067 reported a family in which five males spanning three generations had intellectual disability, speech delay and global developmental delay and four of these males developed seizures in late childhood–adolescence.

PMID:34346154 reported 11 unrelated cases expanding the phenotypic spectrum to include developmental delay and intellectual disability with or without epilepsy to a congenital anomaly phenotype with hydrocephalus and various brain anomalies at the more severe end of clinical manifestations. Of eight patients with congenital anomalies, one each had severe to profound developmental delay, mild psychomotor delay and severe psychomotor delay, while the remaining five had no developmental delays. However, all three patients without congenital structural anomalies had intellectual disability (borderline intellectual functioning in one case), speech delay and global developmental delay, while motor delay and autism spectrum disorder was reported in two cases each. Isolated febrile seizure was reported in one case.

This gene has been reported in OMIM (MIM #300923) and Gene2Phenotype (with 'limited' rating) on the basis of one family from PMID:24812067.
Intellectual disability v5.70 INTS11 Achchuthan Shanmugasundram changed review comment from: PMID:37054711 reported ten unrelated families with biallelic variants in INTS11 gene and they present with intellectual disability, global developmental and language delay, impaired motor development, and brain atrophy.

Functional studies in Drosophila showed that dIntS11 (fly ortholog of INTS11) is essential and expressed in the central nervous systems in a subset of neurons and most glia in larval and adult stages. In addition, genes with two variants (p.Arg17Leu and p.His414Tyr) fail to rescue the lethality of null mutants in the Drosophila model, indicating that they are strong loss-of-function variants. The other five variants (p.Gly55Ser, p.Leu138Phe, p.Lys396Glu, p.Val517Met and p.Ile553Glu) rescue lethality but cause a shortened lifespan and bang sensitivity and affect locomotor activity, indicating that they are partial loss-of-function variants.
Sources: Literature; to: PMID:37054711 reported ten unrelated families with biallelic variants in INTS11 gene and they present with intellectual disability, global developmental and language delay, impaired motor development, and brain atrophy.

Functional studies in Drosophila showed that dIntS11 (fly ortholog of INTS11) is essential and expressed in the central nervous systems in a subset of neurons and most glia in larval and adult stages. In addition, genes with two variants (p.Arg17Leu and p.His414Tyr) fail to rescue the lethality of null mutants in the Drosophila model, indicating that they are strong loss-of-function variants. The other five variants (p.Gly55Ser, p.Leu138Phe, p.Lys396Glu, p.Val517Met and p.Ile553Glu) rescue lethality but cause a shortened lifespan and bang sensitivity and affect locomotor activity, indicating that they are partial loss-of-function variants.

This gene has not yet been associated with relevant phenotypes in OMIM or in Gene2Phenotype.
Sources: Literature
Intellectual disability v5.68 INTS11 Achchuthan Shanmugasundram gene: INTS11 was added
gene: INTS11 was added to Intellectual disability - microarray and sequencing. Sources: Literature
Mode of inheritance for gene: INTS11 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: INTS11 were set to 37054711
Phenotypes for gene: INTS11 were set to intellectual disability, MONDO:0001071
Review for gene: INTS11 was set to GREEN
Added comment: PMID:37054711 reported ten unrelated families with biallelic variants in INTS11 gene and they present with intellectual disability, global developmental and language delay, impaired motor development, and brain atrophy.

Functional studies in Drosophila showed that dIntS11 (fly ortholog of INTS11) is essential and expressed in the central nervous systems in a subset of neurons and most glia in larval and adult stages. In addition, genes with two variants (p.Arg17Leu and p.His414Tyr) fail to rescue the lethality of null mutants in the Drosophila model, indicating that they are strong loss-of-function variants. The other five variants (p.Gly55Ser, p.Leu138Phe, p.Lys396Glu, p.Val517Met and p.Ile553Glu) rescue lethality but cause a shortened lifespan and bang sensitivity and affect locomotor activity, indicating that they are partial loss-of-function variants.
Sources: Literature
Intellectual disability v5.67 GRIA1 Achchuthan Shanmugasundram changed review comment from: Four different heterozygous variants in GRIA1 (p.Ala636Thr, p.Gly745Asp, p.Ile627Thr & p.Arg345Gln) have been identified in six unrelated individuals and they were all reported with intellectual disability, moderate to severe cognitive impairment, delayed motor development, speech impairment and behavioural issues such as anxiety, autism spectrum disorder and attention deficit hyperactivity disorder.

Homozygous variant (p.Arg377Ter) has been identified in one individual, who presented with intellectual disability, severe cognitive impairment, delayed motor development, speech impairment (non-verbal) and self-injurious behaviour.

In vitro functional studies with major GluA1-containing AMPAR subtypes carrying the GRIA1 variant mutations showed that three of the four missense variants profoundly perturb receptor function. The homozygous stop-gain variant completely destroyed the expression of GluA1-containing AMPARs. The Xenopus gria1 models also show transient motor deficits, an intermittent seizure phenotype, and a significant impairment to working memory in mutants.; to: Four different heterozygous variants in GRIA1 (p.Ala636Thr, p.Gly745Asp, p.Ile627Thr & p.Arg345Gln) have been identified in six unrelated individuals and they were all reported with intellectual disability, moderate to severe cognitive impairment, delayed motor development, speech impairment and behavioural issues such as anxiety, autism spectrum disorder and attention deficit hyperactivity disorder.

Homozygous variant (p.Arg377Ter) has been identified in one individual, who presented with intellectual disability, severe cognitive impairment, delayed motor development, speech impairment (non-verbal) and self-injurious behaviour.

In vitro functional studies with major GluA1-containing AMPAR subtypes carrying the GRIA1 variant mutations showed that three of the four missense variants profoundly perturb receptor function. The homozygous stop-gain variant completely destroyed the expression of GluA1-containing AMPARs. The Xenopus gria1 models also show transient motor deficits, an intermittent seizure phenotype, and a significant impairment to working memory in mutants.

This gene has also been associated with relevant phenotypes in both OMIM (MIM #619927 & MIM #619931) and Gene2Phenotype (with 'moderate' rating).
Intellectual disability v5.61 C2orf69 Arina Puzriakova gene: C2orf69 was added
gene: C2orf69 was added to Intellectual disability - microarray and sequencing. Sources: Expert Review Amber,Literature
Q2_23_promote_green tags were added to gene: C2orf69.
Mode of inheritance for gene: C2orf69 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: C2orf69 were set to 34038740; 33945503
Phenotypes for gene: C2orf69 were set to Combined oxidative phosphorylation deficiency 53, OMIM:619423
Intellectual disability v5.57 TAF2 Achchuthan Shanmugasundram reviewed gene: TAF2: Rating: GREEN; Mode of pathogenicity: None; Publications: 21937992, 24084144, 34474177; Phenotypes: Mental retardation, autosomal recessive 40, OMIM:615599; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v5.54 SHANK1 Achchuthan Shanmugasundram changed review comment from: As reviewed by Zornitza Stark (Australian Genomics), PMID:34113010 reported six individuals who presented with neurodevelopmental disorders and identified with de novo truncating variants in SHANK1 gene. Of these six individuals, four had intellectual disability, one had severe learning difficulties and one with auditory processing disorder, difficulty with executive functioning, mathematic concepts, verbal reasoning and problem solving.; to: As reviewed by Zornitza Stark (Australian Genomics), PMID:34113010 reported six unrelated individuals who presented with neurodevelopmental disorders and identified with de novo truncating variants in SHANK1 gene. Of these six individuals, four had intellectual disability, one had severe learning difficulties and one with auditory processing disorder, difficulty with executive functioning, mathematic concepts, verbal reasoning and problem solving. Three of these patients were also reported with autism spectrum disorder.

This gene has been associated with relevant phenotypes in Gene2Phenotype (with 'strong' rating in the DD panel).
Intellectual disability v5.53 SHANK1 Achchuthan Shanmugasundram edited their review of gene: SHANK1: Added comment: As reviewed by Zornitza Stark (Australian Genomics), PMID:34113010 reported six individuals who presented with neurodevelopmental disorders and identified with de novo truncating variants in SHANK1 gene. Of these six individuals, four had intellectual disability, one had severe learning difficulties and one with auditory processing disorder, difficulty with executive functioning, mathematic concepts, verbal reasoning and problem solving.; Changed phenotypes to: nearodevelopmental disorder, MONDO:0700092, intellectual disability, MONDO:0001071
Intellectual disability v5.50 OTUD7A Achchuthan Shanmugasundram changed review comment from: PMID:31997314 reported a patient presenting with severe global developmental delay, language impairment and epileptic encephalopathy and was identified with homozygous variant in OTUD7A gene (c.697C>T)/ p.Leu233Phe).

PMID:33381903 reported a patient with profound hypotonia, severe intellectual disability, and seizures and identified with biallelic loss-of-function variants in OTUD7A: a 15q13.3 deletion including the OTUD7A locus, and a frameshift OTUD7A variant c.1125del/ p.Glu375Aspfs*11.

PMID:36180924 reported a patient (patient #4) presenting with severe neurodevelopmental diseases and dysmorphic features and identified with hemizygous OTUD7A frameshift variant allele c.2023_2066del/ p.D675Hfs*188 in trans with the recurrent 15q13.3 BP4-BP5 deletion.

OTUD7A knockout mice exhibited reduced body weight, developmental delay, abnormal electroencephalography patterns and seizures, reduced ultrasonic vocalisations, decreased grip strength, impaired motor learning/motor coordination, and reduced acoustic startle (PMID:29395075). The function evidence also suggest that OTUD7A may be the critical “driver gene” in the 15q13.3 deletion syndrome.; to: PMID:31997314 reported a patient presenting with severe global developmental delay, language impairment and epileptic encephalopathy and was identified with homozygous variant in OTUD7A gene (c.697C>T)/ p.Leu233Phe).

PMID:33381903 reported a patient with profound hypotonia, severe intellectual disability, and seizures and identified with biallelic loss-of-function variants in OTUD7A: a 15q13.3 deletion including the OTUD7A locus, and a frameshift OTUD7A variant c.1125del/ p.Glu375Aspfs*11.

PMID:36180924 reported a patient (patient #4) presenting with severe neurodevelopmental diseases and dysmorphic features and identified with hemizygous OTUD7A frameshift variant allele c.2023_2066del/ p.D675Hfs*188 in trans with the recurrent 15q13.3 BP4-BP5 deletion.

OTUD7A knockout mice exhibited reduced body weight, developmental delay, abnormal electroencephalography patterns and seizures, reduced ultrasonic vocalisations, decreased grip strength, impaired motor learning/motor coordination, and reduced acoustic startle (PMID:29395075). The function evidence also suggest that OTUD7A may be the critical “driver gene” in the 15q13.3 deletion syndrome.

This gene has been reported in the DD panel of Gene2Phenotype (with 'limited' rating), but has not yet been associated with phenotypes in OMIM.
Intellectual disability v5.50 OTUD7A Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence (three unrelated cases with biallelic variants and supportive functional evidence from mouse models) for this gene to be promoted to green at the next major review.
Intellectual disability v5.51 OTUD7A Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence (three unrelated cases with biallelic variants and supportive functional evidence from mouse models) for this gene to be promoted to green at the next major review.
Intellectual disability v5.50 OTUD7A Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence (three unrelated cases with biallelic variants and supportive functional evidence from mouse models) for this gene to be promoted to green at the next major review.
Intellectual disability v5.51 OTUD7A Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence (three unrelated cases with biallelic variants and supportive functional evidence from mouse models) for this gene to be promoted to green at the next major review.
Intellectual disability v5.51 OTUD7A Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence (three unrelated cases with biallelic variants and supportive functional evidence from mouse models) for this gene to be promoted to green at the next major review.
Intellectual disability v5.51 OTUD7A Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence (three unrelated cases with biallelic variants and supportive functional evidence from mouse models) for this gene to be promoted to green at the next major review.
Intellectual disability v5.50 OTUD7A Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence (three unrelated cases with biallelic variants and supportive functional evidence from mouse models) for this gene to be promoted to green at the next major review.
Intellectual disability v5.50 OTUD7A Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence (three unrelated cases with biallelic variants and supportive functional evidence from mouse models) for this gene to be promoted to green at the next major review.
Intellectual disability v5.50 OTUD7A Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence (three unrelated cases with biallelic variants and supportive functional evidence from mouse models) for this gene to be promoted to green at the next major review.
Intellectual disability v5.50 OTUD7A Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence (three unrelated cases with biallelic variants and supportive functional evidence from mouse models) for this gene to be promoted to green at the next major review.
Intellectual disability v5.47 CLCN4 Arina Puzriakova Phenotypes for gene: CLCN4 were changed from Mental retardation, X-linked 49-15 300114 to Raynaud-Claes syndrome, OMIM:300114
Intellectual disability v5.44 PC Arina Puzriakova Phenotypes for gene: PC were changed from Pyruvate carboxylase deficiency, 266150; PYRUVATE CARBOXYLASE DEFICIENCY (PC DEFICIENCY) to Pyruvate carboxylase deficiency, OMIM:266150
Intellectual disability v5.43 NDUFS1 Arina Puzriakova Phenotypes for gene: NDUFS1 were changed from Mitochondrial complex I deficiency, 252010; LEIGH SYNDROME (NUCLEAR DNA MUTATION) to Mitochondrial complex I deficiency, nuclear type 5, OMIM:618226
Intellectual disability v5.42 DARS2 Arina Puzriakova Phenotypes for gene: DARS2 were changed from Leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation, 611105; LEUKOENCEPHALOPATHY WITH BRAINSTEM AND SPINAL CORD INVOLVEMENT AND LACTATE ELEVATION to Leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation, OMIM:611105
Intellectual disability v5.38 NAPB Arina Puzriakova Phenotypes for gene: NAPB were changed from Early infantile epileptic encephalopathy to Developmental and epileptic encephalopathy 107, OMIM:620033
Intellectual disability v5.37 IQSEC2 Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: There is sufficient evidence (>3 female cases with monoallelic variants causing ID) to suggest that MOI should be updated to 'X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)' in the next major review.

In addition, intellectual disability (MIM #309530) has been associated in both OMIM and Gene2Phenotype with X-linked dominant inheritance.
Intellectual disability v5.37 IQSEC2 Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: There is sufficient evidence (>3 female cases with monoallelic variants causing ID) to suggest that MOI should be updated to 'X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)' in the next major review.

In addition, intellectual disability (MIM #309530) has been associated in both OMIM and Gene2Phenotype with X-linked dominant inheritance.
Intellectual disability v5.37 IQSEC2 Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: There is sufficient evidence (>3 female cases with monoallelic variants causing ID) to suggest that MOI should be updated to 'X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)' in the next major review.

In addition, intellectual disability (MIM #309530) has been associated in both OMIM and Gene2Phenotype with X-linked dominant inheritance.
Intellectual disability v5.37 IQSEC2 Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: There is sufficient evidence (>3 female cases with monoallelic variants causing ID) to suggest that MOI should be updated to 'X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)' in the next major review.

In addition, intellectual disability (MIM #309530) has been associated in both OMIM and Gene2Phenotype with X-linked dominant inheritance.
Intellectual disability v5.36 IQSEC2 Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: There is sufficient evidence (>3 female cases with monoallelic variants causing ID) to suggest that MOI should be updated to 'X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)' in the next major review.

In addition, intellectual disability (MIM #309530) has been associated in both OMIM and Gene2Phenotype with X-linked dominant inheritance.
Intellectual disability v5.36 IQSEC2 Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: There is sufficient evidence (>3 female cases with monoallelic variants causing ID) to suggest that MOI should be updated to 'X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)' in the next major review.

In addition, intellectual disability (MIM #309530) has been associated in both OMIM and Gene2Phenotype with X-linked dominant inheritance.
Intellectual disability v5.35 IQSEC2 Achchuthan Shanmugasundram changed review comment from: There are more than 20 unrelated cases identified with variants in IQSEC2 gene, as reported in publications. Moderate to severe intellectual disability was present in all affected males.

De novo, truncating variants correlate with severe disease in both female and male patients harboring an IQSEC2 alteration. Missense variants in male and female patients account for a milder disease overall, with more severe symptoms in males than females. This evidence suggests that the MOI should be 'X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)'.

Both OMIM and Gene2Phenotype have associated X-linked dominant variants in IQSEC2 with intellectual disability (MIM #309530); to: There are more than 20 unrelated cases identified with variants in IQSEC2 gene, as reported in publications. Moderate to severe intellectual disability was present in all affected males.

De novo, truncating variants correlate with severe disease in both female and male patients harboring an IQSEC2 alteration. Missense variants in male and female patients account for a milder disease overall, with more severe symptoms in males than females.
Intellectual disability v5.31 HUWE1 Achchuthan Shanmugasundram Phenotypes for gene: HUWE1 were changed from Mental retardation, X-linked syndromic, Turner type, 300706; MENTAL RETARDATION SYNDROMIC X-LINKED TURNER TYPE (MRXST) to Intellectual developmental disorder, X-linked syndromic, Turner type, OMIM:309590
Intellectual disability v5.30 TRAPPC10 Achchuthan Shanmugasundram Added comment: Comment on list classification: This gene should be rated AMBER as there are only two unrelated cases with intellectual disability and global developmental delay. Although there are functional studies available, no cognitive defects were reported in the mouse model.

The 'watchlist' tag has been added to review this gene rating regularly in light of any new evidence.
Intellectual disability v5.30 TRAPPC10 Achchuthan Shanmugasundram Added comment: Comment on list classification: This gene should be rated AMBER as there are only two unrelated cases with intellectual disability and global developmental delay. Although there are functional studies available, no cognitive defects were reported in the mouse model.

The 'watchlist' tag has been added to review this gene rating regularly in light of any new evidence.
Intellectual disability v5.30 TRAPPC10 Achchuthan Shanmugasundram Added comment: Comment on list classification: This gene should be rated AMBER as there are only two unrelated cases with intellectual disability and global developmental delay. Although there are functional studies available, no cognitive defects were reported in the mouse model.

The 'watchlist' tag has been added to review this gene rating regularly in light of any new evidence.
Intellectual disability v5.30 TRAPPC10 Achchuthan Shanmugasundram Added comment: Comment on list classification: This gene should be rated AMBER as there are only two unrelated cases with intellectual disability and global developmental delay. Although there are functional studies available, no cognitive defects were reported in the mouse model.

The 'watchlist' tag has been added to review this gene rating regularly in light of any new evidence.
Intellectual disability v5.30 TRAPPC10 Achchuthan Shanmugasundram Added comment: Comment on list classification: This gene should be rated AMBER as there are only two unrelated cases with intellectual disability and global developmental delay. Although there are functional studies available, no cognitive defects were reported in the mouse model.

The 'watchlist' tag has been added to review this gene rating regularly in light of any new evidence.
Intellectual disability v5.29 TRAPPC10 Achchuthan Shanmugasundram Added comment: Comment on list classification: This gene should be rated AMBER as there are only two unrelated cases with intellectual disability and global developmental delay. Although there are functional studies available, no cognitive defects were reported in the mouse model.

The 'watchlist' tag has been added to review this gene rating regularly in light of any new evidence.
Intellectual disability v5.29 TRAPPC10 Achchuthan Shanmugasundram Added comment: Comment on list classification: This gene should be rated AMBER as there are only two unrelated cases with intellectual disability and global developmental delay. Although there are functional studies available, no cognitive defects were reported in the mouse model.

The 'watchlist' tag has been added to review this gene rating regularly in light of any new evidence.
Intellectual disability v5.25 KDM5A Achchuthan Shanmugasundram changed review comment from: Comment on list classification: As reviewed by Tracy Lester (Genetics laboratory, Oxford UK), there is sufficient evidence for this gene to be promoted to GREEN in the next major review.

This gene can be associated with both monoallelic and biallelic inheritance as there are at least three cases each for both of them.; to: Comment on list classification:, There is sufficient evidence for this gene to be promoted to GREEN at the next major review.

This gene can be associated with both monoallelic and biallelic inheritance as there are at least three cases each for both of them.
Intellectual disability v5.25 KDM5A Achchuthan Shanmugasundram Phenotypes for gene: KDM5A were changed from AUTOSOMAL RECESSIVE MENTAL RETARDATION; autism spectrum disorder, MONDO:0005258; intellectual disability, MONDO:0001071 to AUTOSOMAL RECESSIVE MENTAL RETARDATION; autism spectrum disorder, MONDO:0005258; intellectual disability, MONDO:0001071
Intellectual disability v5.25 KDM5A Achchuthan Shanmugasundram Phenotypes for gene: KDM5A were changed from AUTOSOMAL RECESSIVE MENTAL RETARDATION; autism spectrum disorder, MONDO:0005258; intellectual disability, MONDO:0001071 to AUTOSOMAL RECESSIVE MENTAL RETARDATION; autism spectrum disorder, MONDO:0005258; intellectual disability, MONDO:0001071
Intellectual disability v5.25 KDM5A Achchuthan Shanmugasundram Phenotypes for gene: KDM5A were changed from AUTOSOMAL RECESSIVE MENTAL RETARDATION; autism spectrum disorder, MONDO:0005258; intellectual disability, MONDO:0001071 to AUTOSOMAL RECESSIVE MENTAL RETARDATION; autism spectrum disorder, MONDO:0005258; intellectual disability, MONDO:0001071
Intellectual disability v5.25 KDM5A Achchuthan Shanmugasundram Phenotypes for gene: KDM5A were changed from AUTOSOMAL RECESSIVE MENTAL RETARDATION to AUTOSOMAL RECESSIVE MENTAL RETARDATION; autism spectrum disorder, MONDO:0005258; intellectual disability, MONDO:0001071
Intellectual disability v5.24 KDM5A Achchuthan Shanmugasundram changed review comment from: PMID:21937992 reported a family with recessive missense KDM5A variant presenting with an undefined developmental disorder characterised with intellectual disability and facial dysmorphisms.

PMID:33350388 reported nine patients from seven unrelated families identified with variants in KDM5A, of which three unrelated patients harboured heterozygous variants, while six patients from four unrelated families had homozygous variants. These patients presented with autism spectrum disorder (ASD) and a spectrum of neurodevelopmental phenotypes including intellectual disability, lack of speech, developmental delay and motor impairment.

In addition, loss of KDM5A has resulted in repetitive behaviors, sociability deficits, cognitive dysfunction, and abnormal dendritic morphogenesis in mice.; to: PMID:21937992 reported a family with recessive missense KDM5A variant presenting with an undefined developmental disorder characterised with intellectual disability and facial dysmorphisms.

PMID:33350388 reported nine patients from seven unrelated families identified with variants in KDM5A, of which three unrelated patients harboured heterozygous variants, while six patients from four unrelated families had homozygous variants. These patients presented with autism spectrum disorder (ASD) and a spectrum of neurodevelopmental phenotypes including intellectual disability, lack of speech, developmental delay and motor impairment.

In addition, loss of KDM5A has resulted in repetitive behaviors, sociability deficits, cognitive dysfunction, and abnormal dendritic morphogenesis in mice.

This gene has already been associated with phenotype in Gene2Phenotype (biallelic inheritance with 'limited' rating), but not in OMIM.
Intellectual disability v5.24 KDM5A Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Tracy Lester (Genetics laboratory, Oxford UK), there is sufficient evidence for this gene to be promoted to GREEN in the next major review.

This gene can be associated with both monoallelic and biallelic inheritance as there are at least three cases each for both of them.
Intellectual disability v5.23 KDM5A Achchuthan Shanmugasundram changed review comment from: PMID:21937992 reported a family with recessive missense KDM5A variant presenting with an undefined developmental disorder characterised with intellectual disability and facial dysmorphisms.

PMID:33350388 reported nine patients from seven unrelated families identified with variants in KDM5A, of which three unrelated patients harboured heterozygous variants, while six patients from four unrelated families had homozygous variants. These patients presented with autism spectrum disorder (ASD) and a spectrum of neurodevelopmental phenotypes including intellectual disability, lack of speech, developmental delay and motor impairment.; to: PMID:21937992 reported a family with recessive missense KDM5A variant presenting with an undefined developmental disorder characterised with intellectual disability and facial dysmorphisms.

PMID:33350388 reported nine patients from seven unrelated families identified with variants in KDM5A, of which three unrelated patients harboured heterozygous variants, while six patients from four unrelated families had homozygous variants. These patients presented with autism spectrum disorder (ASD) and a spectrum of neurodevelopmental phenotypes including intellectual disability, lack of speech, developmental delay and motor impairment.

In addition, loss of KDM5A has resulted in repetitive behaviors, sociability deficits, cognitive dysfunction, and abnormal dendritic morphogenesis in mice.
Intellectual disability v5.19 KDM5A Achchuthan Shanmugasundram changed review comment from: PMID:21937992 reported a family with recessive missense KDM5A variant presenting with an undefined developmental disorder characterised with intellectual disability and facial dysmorphisms.

PMID:33350388 reported nine patients from seven unrelated families identified with variants in KDM5A, of which three unrelated patients harboured heterozygous variants, while six patients from four unrelated families had homozygous variants. These patients presented with autism spectrum disorder (ASD) and a spectrum of neurodevelopmental phenotypes including intellectual disability, lack of speech and developmental delay.; to: PMID:21937992 reported a family with recessive missense KDM5A variant presenting with an undefined developmental disorder characterised with intellectual disability and facial dysmorphisms.

PMID:33350388 reported nine patients from seven unrelated families identified with variants in KDM5A, of which three unrelated patients harboured heterozygous variants, while six patients from four unrelated families had homozygous variants. These patients presented with autism spectrum disorder (ASD) and a spectrum of neurodevelopmental phenotypes including intellectual disability, lack of speech, developmental delay and motor impairment.
Intellectual disability v5.17 SPG7 Sarah Leigh Phenotypes for gene: SPG7 were changed from Spastic paraplegia 7, autosomal recessive, 607259 to Spastic paraplegia 7, autosomal recessive, OMIM:607259; hereditary spastic paraplegia 7, MONDO:0011803
Intellectual disability v5.16 SPTAN1 Sarah Leigh Phenotypes for gene: SPTAN1 were changed from Epileptic encephalopathy, early infantile, 5, 613477; EPILEPTIC ENCEPHALOPATHY EARLY INFANTILE TYPE 5 (EIEE5) to Developmental and epileptic encephalopathy 5, OMIM:613477; developmental and epileptic encephalopathy, 5, MONDO:0013277
Intellectual disability v5.12 MED11 Sarah Leigh gene: MED11 was added
gene: MED11 was added to Intellectual disability - microarray and sequencing. Sources: Literature
Q2_23_promote_green tags were added to gene: MED11.
Mode of inheritance for gene: MED11 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MED11 were set to 36001086
Phenotypes for gene: MED11 were set to MED11-associated neurodevelopmental disorder
Review for gene: MED11 was set to GREEN
Added comment: Not associated with a phenotype in OMIM, but is associated with MED11-associated neurodevelopmental disorder in Gen2Phen. PMID: 36001086 reports a single MED11 variant (NM_001001683.4: c.325C>T, p.Arg109*), that segregates with the condition in five unrelated families, however, there is homozygosity between two of these families, idicating that they may be related. Global delay was observed in three individuals from three unrelated familes and seizures were evident in four individuals from four unrelated families. Severe microcephaly was apparent in the two unrelated familes where this parameter was recorded. Overall, the MED11-associated neurodevelopmental disorder appeared to result in profound effects and proved fatal at birth and 10 days in two of the cases reported.
Sources: Literature
Intellectual disability v5.11 UBAP2L Achchuthan Shanmugasundram changed review comment from: Comment on list classification: As reviewed by Konstantinos Varvagiannis, there are at least 8 unrelated cases that had borderline to severe intellectual disability (ID) as identified with formal intellectual evaluation and supported by functional studies from mouse models. This gene therefore has sufficient evidence for promoting to green at the next major review.

This gene has not yet been associated with phenotypes in OMIM, but has been reported in Gene2Phenotype with a 'moderate rating'.; to: Comment on list classification: As reviewed by Konstantinos Varvagiannis, there are at least 8 unrelated cases that had borderline to severe intellectual disability (ID) as identified with formal intellectual evaluation and the association is supported by functional studies from mouse models. This gene therefore has sufficient evidence for promotion to green at the next major review.

This gene has not yet been associated with phenotypes in OMIM, but has been reported in Gene2Phenotype with a 'moderate rating'.
Intellectual disability v5.11 UBAP2L Achchuthan Shanmugasundram changed review comment from: Comment on list classification: As reviewed by Konstantinos Varvagiannis, there are at least 8 unrelated cases that had borderline to severe intellectual disability (ID) as identified with formal intellectual evaluation and supported by functional studies from mouse models. This gene therefore has sufficient evidence for promoting to green at the next major review.

This gene has not yet been associated with phenotypes in OMIM, but has been reported in Gene2Phenotype with a 'moderate rating'.; to: Comment on list classification: As reviewed by Konstantinos Varvagiannis, there are at least 8 unrelated cases that had borderline to severe intellectual disability (ID) as identified with formal intellectual evaluation and supported by functional studies from mouse models. This gene therefore has sufficient evidence for promoting to green at the next major review.

This gene has not yet been associated with phenotypes in OMIM, but has been reported in Gene2Phenotype with a 'moderate rating'.
Intellectual disability v5.11 UBAP2L Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Konstantinos Varvagiannis, there are at least 8 unrelated cases that had borderline to severe intellectual disability (ID) as identified with formal intellectual evaluation and supported by functional studies from mouse models. This gene therefore has sufficient evidence for promoting to green at the next major review.

This gene has not yet been associated with phenotypes in OMIM, but has been reported in Gene2Phenotype with a 'moderate rating'.
Intellectual disability v5.10 UBAP2L Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Konstantinos Varvagiannis, there are at least 8 unrelated cases that had borderline to severe intellectual disability (ID) as identified with formal intellectual evaluation and supported by functional studies from mouse models. This gene therefore has sufficient evidence for promoting to green at the next major review.

This gene has not yet been associated with phenotypes in OMIM, but has been reported in Gene2Phenotype with a 'moderate rating'.
Intellectual disability v5.10 UBAP2L Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Konstantinos Varvagiannis, there are at least 8 unrelated cases that had borderline to severe intellectual disability (ID) as identified with formal intellectual evaluation and supported by functional studies from mouse models. This gene therefore has sufficient evidence for promoting to green at the next major review.

This gene has not yet been associated with phenotypes in OMIM, but has been reported in Gene2Phenotype with a 'moderate rating'.
Intellectual disability v5.10 UBAP2L Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Konstantinos Varvagiannis, there are at least 8 unrelated cases that had borderline to severe intellectual disability (ID) as identified with formal intellectual evaluation and supported by functional studies from mouse models. This gene therefore has sufficient evidence for promoting to green at the next major review.

This gene has not yet been associated with phenotypes in OMIM, but has been reported in Gene2Phenotype with a 'moderate rating'.
Intellectual disability v5.10 UBAP2L Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Konstantinos Varvagiannis, there are at least 8 unrelated cases that had borderline to severe intellectual disability (ID) as identified with formal intellectual evaluation and supported by functional studies from mouse models. This gene therefore has sufficient evidence for promoting to green at the next major review.

This gene has not yet been associated with phenotypes in OMIM, but has been reported in Gene2Phenotype with a 'moderate rating'.
Intellectual disability v5.10 UBAP2L Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Konstantinos Varvagiannis, there are at least 8 unrelated cases that had borderline to severe intellectual disability (ID) as identified with formal intellectual evaluation and supported by functional studies from mouse models. This gene therefore has sufficient evidence for promoting to green at the next major review.

This gene has not yet been associated with phenotypes in OMIM, but has been reported in Gene2Phenotype with a 'moderate rating'.
Intellectual disability v5.5 ARF1 Achchuthan Shanmugasundram Added comment: Comment on publications: PMID:36345169 reported a paediatric patient identified with a monoallelic de novo missense variant (c.296 G > A; p.R99H) in the ARF1 gene, associated with developmental delay, hypotonia, intellectual disability and motor stereotypies. This patient did not exhibit periventricular heterotopias previously observed in other patients with ARF1 variants (including p.R99H). Functional analysis shows that the pathogenetic mechanism of the R99H-ARF1 variant involves constitutive activation with resultant Golgi and endosomal alterations.
Intellectual disability v5.5 ARF1 Achchuthan Shanmugasundram Publications for gene: ARF1 were set to 28868155; 34353862; 36345169
Intellectual disability v5.5 ARF1 Achchuthan Shanmugasundram Added comment: Comment on publications: PMID:36345169 reported a paediatric patient identified with a monoallelic de novo missense variant (c.296 G > A; p.R99H) in the ARF1 gene, associated with developmental delay, hypotonia, intellectual disability and motor stereotypies. This patient did not exhibit periventricular heterotopias previously observed in other patients with ARF1 variants (including p.R99H). Functional analysis shows that the pathogenetic mechanism of the R99H-ARF1 variant involves constitutive activation with resultant Golgi and endosomal alterations.
Intellectual disability v5.5 ARF1 Achchuthan Shanmugasundram Publications for gene: ARF1 were set to 28868155; 34353862; 36345169
Intellectual disability v5.4 ARF1 Achchuthan Shanmugasundram Added comment: Comment on publications: PMID:36345169 reported a paediatric patient identified with a monoallelic de novo missense variant (c.296 G > A; p.R99H) in the ARF1 gene, associated with developmental delay, hypotonia, intellectual disability and motor stereotypies. This patient did not exhibit periventricular heterotopias previously observed in other patients with ARF1 variants (including p.R99H). Functional analysis shows that the pathogenetic mechanism of the R99H-ARF1 variant involves constitutive activation with resultant Golgi and endosomal alterations.
Intellectual disability v5.4 ARF1 Achchuthan Shanmugasundram Publications for gene: ARF1 were set to 28868155; 34353862; 36345169
Intellectual disability v5.4 ARF1 Achchuthan Shanmugasundram Added comment: Comment on publications: PMID:36345169 reported a paediatric patient identified with a monoallelic de novo missense variant (c.296 G > A; p.R99H) in the ARF1 gene, associated with developmental delay, hypotonia, intellectual disability and motor stereotypies. This patient did not exhibit periventricular heterotopias previously observed in other patients with ARF1 variants (including p.R99H). Functional analysis shows that the pathogenetic mechanism of the R99H-ARF1 variant involves constitutive activation with resultant Golgi and endosomal alterations.
Intellectual disability v5.4 ARF1 Achchuthan Shanmugasundram Publications for gene: ARF1 were set to 28868155; 34353862
Intellectual disability v5.2 FEM1C Achchuthan Shanmugasundram gene: FEM1C was added
gene: FEM1C was added to Intellectual disability - microarray and sequencing. Sources: Literature
Mode of inheritance for gene: FEM1C was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FEM1C were set to 36336956
Phenotypes for gene: FEM1C were set to Intellectual disability, MONDO:0001071
Review for gene: FEM1C was set to RED
Added comment: This gene should be rated RED as there is only one clear case of intellectual disability reported in literature.

PMID:36336956 reported a 9 year-old boy with severe global developmental delay, lack of speech, pyramidal signs and limb ataxia and identified with a heterozygous de novo missense variant c.376G>C (p.Asp126His) in the FEM1C gene. Cognitive assessment performed at 9 years of age showed that he has moderate intellectual disability.

De novo variant in the same residue (p.Asp126Val) has also been associated with an uncharacterised developmental disorder in PMID:28135719.

This gene has not yet been associated with relevant phenotypes in OMIM or in Gene2Phenotype.
Sources: Literature
Intellectual disability v4.126 Arina Puzriakova Panel name changed from Intellectual disability to Intellectual disability - microarray and sequencing
List of related panels changed from Coarse facial features including Coffin-Siris-like disorders; ID; Moderate; severe or profound intellectual disability; Schizophrenia plus additional features; Intellectual disability - microarray; fragile X and sequencing; R29 to Coarse facial features including Coffin-Siris-like disorders; ID; Moderate; severe or profound intellectual disability; Schizophrenia plus additional features; Intellectual disability - microarray; fragile X and sequencing; Intellectual disability; R29
Intellectual disability v4.122 TAB2 Achchuthan Shanmugasundram Added comment: Comment on list classification: This gene should be rated AMBER. Although there are four unrelated cases reported with ID, ID is part of a broad spectrum of phenotypes and the majority of cases in PMID:35971781 and other previous studies were not reported with ID as part of the phenotype.

ID has not been reported as part of the phenotype either in OMIM or in Gene2Phenotype.
Intellectual disability v4.122 TAB2 Achchuthan Shanmugasundram Added comment: Comment on list classification: This gene should be rated AMBER. Although there are four unrelated cases reported with ID, ID is part of a broad spectrum of phenotypes and the majority of cases in PMID:35971781 and other previous studies were not reported with ID as part of the phenotype.

ID has not been reported as part of the phenotype either in OMIM or in Gene2Phenotype.
Intellectual disability v4.121 TAB2 Achchuthan Shanmugasundram Added comment: Comment on list classification: This gene should be rated AMBER. Although there are four unrelated cases reported with ID, ID is part of a broad spectrum of phenotypes and the majority of cases in PMID:35971781 and other previous studies were not reported with ID as part of the phenotype.

ID has not been reported as part of the phenotype either in OMIM or in Gene2Phenotype.
Intellectual disability v4.121 TAB2 Achchuthan Shanmugasundram Added comment: Comment on list classification: This gene should be rated AMBER. Although there are four unrelated cases reported with ID, ID is part of a broad spectrum of phenotypes and the majority of cases in PMID:35971781 and other previous studies were not reported with ID as part of the phenotype.

ID has not been reported as part of the phenotype either in OMIM or in Gene2Phenotype.
Intellectual disability v4.120 TAB2 Achchuthan Shanmugasundram changed review comment from: 4 out of 14 patients identified with heterozygous variants in TAB2 gene in PMID:35971781 were reported with global developmental delay and intellectual disability (ID). Two other patients were reported with motor delay. Although developmental delay was reported in previous studies including the one reviewed by Andrea Haworth below, none of the previous studies reported cases with ID.

Although there are four unrelated cases reported with ID, ID is part of a broad spectrum of phenotypes and a majority of cases in this study and other previous studies did not report ID as part of the phenotype.

ID has not been reported as part of the phenotype either in OMIM or in Gene2Phenotype.; to: 4 out of 14 patients identified with heterozygous variants in TAB2 gene in PMID:35971781 were reported with global developmental delay and intellectual disability (ID). Two other patients were reported with motor delay. Although developmental delay was reported in previous studies including the one reviewed by Andrea Haworth below, none of the previous studies reported cases with ID.
Intellectual disability v4.110 YWHAZ Achchuthan Shanmugasundram gene: YWHAZ was added
gene: YWHAZ was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: YWHAZ was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: YWHAZ were set to 36001342
Phenotypes for gene: YWHAZ were set to Intellectual disability, MONDO:0001071
Review for gene: YWHAZ was set to RED
Added comment: PMID:36001342 reported one large three-generation family with intellectual disability and global developmental delay, where all affected members were identified with a heterozygous missense variant (c.147A>T/ p.Lys49Asn) in YWHAZ gene. Although there were 10 other rare variants located in 10 genes (ARHGAP4, AGPS, APOL3, CES3, DACT2, ECH1, FAM71E2, KREMEN1, YWHAZ, ZFYVE26) that co-segregated with the ID/GDD phenotype were identified in the family, they were either not present in all affected members or present in unaffected members.

In addition, computational modeling and knockdown/ knockin studies with Drosophila also confirmed the role of this YWHAZ variant in intellectual disability.
Sources: Literature
Intellectual disability v4.109 DEAF1 Achchuthan Shanmugasundram Phenotypes for gene: DEAF1 were changed from ?Dyskinesia, seizures, and intellectual developmental disorder, 617171; Mental retardation, autosomal dominant 24, 615828 to ?Dyskinesia, seizures, and intellectual developmental disorder, 617171; Mental retardation, autosomal dominant 24, 615828
Intellectual disability v4.110 DEAF1 Achchuthan Shanmugasundram Phenotypes for gene: DEAF1 were changed from ?Dyskinesia, seizures, and intellectual developmental disorder, 617171; Mental retardation, autosomal dominant 24, 615828 to ?Dyskinesia, seizures, and intellectual developmental disorder, 617171; Mental retardation, autosomal dominant 24, 615828
Intellectual disability v4.110 DEAF1 Achchuthan Shanmugasundram Phenotypes for gene: DEAF1 were changed from ?Dyskinesia, seizures, and intellectual developmental disorder, 617171; Mental retardation, autosomal dominant 24, 615828 to ?Dyskinesia, seizures, and intellectual developmental disorder, 617171; Mental retardation, autosomal dominant 24, 615828
Intellectual disability v4.109 DEAF1 Achchuthan Shanmugasundram Phenotypes for gene: DEAF1 were changed from ?Dyskinesia, seizures, and intellectual developmental disorder, 617171; Mental retardation, autosomal dominant 24, 615828 to ?Dyskinesia, seizures, and intellectual developmental disorder, 617171; Mental retardation, autosomal dominant 24, 615828
Intellectual disability v4.109 DEAF1 Achchuthan Shanmugasundram Phenotypes for gene: DEAF1 were changed from ?Dyskinesia, seizures, and intellectual developmental disorder, 617171; Mental retardation, autosomal dominant 24, 615828 to ?Dyskinesia, seizures, and intellectual developmental disorder, 617171; Mental retardation, autosomal dominant 24, 615828
Intellectual disability v4.109 DEAF1 Achchuthan Shanmugasundram Phenotypes for gene: DEAF1 were changed from ?Dyskinesia, seizures, and intellectual developmental disorder, 617171; Mental retardation, autosomal dominant 24, 615828 to ?Dyskinesia, seizures, and intellectual developmental disorder, 617171; Mental retardation, autosomal dominant 24, 615828
Intellectual disability v4.109 DEAF1 Achchuthan Shanmugasundram Phenotypes for gene: DEAF1 were changed from MENTAL RETARDATION, AUTOSOMAL DOMINANT 24; ?Dyskinesia, seizures, and intellectual developmental disorder, 617171; Mental retardation, autosomal dominant 24, 615828 to ?Dyskinesia, seizures, and intellectual developmental disorder, 617171; Mental retardation, autosomal dominant 24, 615828
Intellectual disability v4.106 SARS Arina Puzriakova Classified gene: SARS as Amber List (moderate evidence)
Intellectual disability v4.106 SARS Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update. At least three unrelated cases with biallelic variants in this gene - DD/ID detected in all families.
Intellectual disability v4.106 SARS Arina Puzriakova Gene: sars has been classified as Amber List (Moderate Evidence).
Intellectual disability v4.105 SARS Arina Puzriakova Phenotypes for gene: SARS were changed from ?Neurodevelopmental disorder with microcephaly, ataxia, and seizures, OMIM:617709 to Neurodevelopmental disorder with microcephaly, ataxia, and seizures, OMIM:617709
Intellectual disability v4.104 SARS Arina Puzriakova Publications for gene: SARS were set to 28236339; 34570399
Intellectual disability v4.103 SARS Arina Puzriakova Tag watchlist was removed from gene: SARS.
Tag Q1_23_promote_green tag was added to gene: SARS.
Intellectual disability v4.103 SARS Arina Puzriakova reviewed gene: SARS: Rating: GREEN; Mode of pathogenicity: None; Publications: 35790048; Phenotypes: Neurodevelopmental disorder with microcephaly, ataxia, and seizures, OMIM:617709; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v4.103 CTR9 Achchuthan Shanmugasundram Added comment: Comment on list classification: This gene should be rated GREEN as there are sufficient unrelated cases (at least 10) reported with varying degrees (mild to severe) intellectual disability.
Intellectual disability v4.102 CTR9 Achchuthan Shanmugasundram Added comment: Comment on list classification: This gene should be rated GREEN as there are sufficient unrelated cases (at least 10) reported with varying degrees (mild to severe) intellectual disability.
Intellectual disability v4.103 CTR9 Achchuthan Shanmugasundram Added comment: Comment on list classification: This gene should be rated GREEN as there are sufficient unrelated cases (at least 10) reported with varying degrees (mild to severe) intellectual disability.
Intellectual disability v4.103 CTR9 Achchuthan Shanmugasundram Added comment: Comment on list classification: This gene should be rated GREEN as there are sufficient unrelated cases (at least 10) reported with varying degrees (mild to severe) intellectual disability.
Intellectual disability v4.102 CTR9 Achchuthan Shanmugasundram Added comment: Comment on list classification: This gene should be rated GREEN as there are sufficient unrelated cases (at least 10) reported with varying degrees (mild to severe) intellectual disability.
Intellectual disability v4.102 CTR9 Achchuthan Shanmugasundram Added comment: Comment on list classification: This gene should be rated GREEN as there are sufficient unrelated cases (at least 10) reported with varying degrees (mild to severe) intellectual disability.
Intellectual disability v4.102 CTR9 Achchuthan Shanmugasundram Added comment: Comment on list classification: This gene should be rated GREEN as there are sufficient unrelated cases (at least 10) reported with varying degrees (mild to severe) intellectual disability.
Intellectual disability v4.102 CTR9 Achchuthan Shanmugasundram Phenotypes for gene: CTR9 were changed from Macrocephaly, HP:0000256; Motor delay, HP:0001270; intellectual disability, MONDO:0001071; Delayed speech and language development; Behavioral abnormality; Autistic behavior; Failure to thrive; Feeding difficulties; Abnormality of the cardiovascular system to Macrocephaly, HP:0000256; Motor delay, HP:0001270; intellectual disability, MONDO:0001071; Delayed speech and language development; Behavioral abnormality; Autistic behavior; Failure to thrive; Feeding difficulties; Abnormality of the cardiovascular system
Intellectual disability v4.103 CTR9 Achchuthan Shanmugasundram Phenotypes for gene: CTR9 were changed from Macrocephaly, HP:0000256; Motor delay, HP:0001270; intellectual disability, MONDO:0001071; Delayed speech and language development; Behavioral abnormality; Autistic behavior; Failure to thrive; Feeding difficulties; Abnormality of the cardiovascular system to Macrocephaly, HP:0000256; Motor delay, HP:0001270; intellectual disability, MONDO:0001071; Delayed speech and language development; Behavioral abnormality; Autistic behavior; Failure to thrive; Feeding difficulties; Abnormality of the cardiovascular system
Intellectual disability v4.102 CTR9 Achchuthan Shanmugasundram Phenotypes for gene: CTR9 were changed from Macrocephaly, HP:0000256; Motor delay, HP:0001270; intellectual disability, MONDO:0001071; Delayed speech and language development; Behavioral abnormality; Autistic behavior; Failure to thrive; Feeding difficulties; Abnormality of the cardiovascular system to Macrocephaly, HP:0000256; Motor delay, HP:0001270; intellectual disability, MONDO:0001071; Delayed speech and language development; Behavioral abnormality; Autistic behavior; Failure to thrive; Feeding difficulties; Abnormality of the cardiovascular system
Intellectual disability v4.102 CTR9 Achchuthan Shanmugasundram Phenotypes for gene: CTR9 were changed from Delayed speech and language development; Motor delay; Intellectual disability; Behavioral abnormality; Autistic behavior; Failure to thrive; Feeding difficulties; Abnormality of the cardiovascular system to Macrocephaly, HP:0000256; Motor delay, HP:0001270; intellectual disability, MONDO:0001071; Delayed speech and language development; Behavioral abnormality; Autistic behavior; Failure to thrive; Feeding difficulties; Abnormality of the cardiovascular system
Intellectual disability v4.98 CTR9 Achchuthan Shanmugasundram Mode of pathogenicity for gene: CTR9 was changed from Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments to None
Intellectual disability v4.96 CTR9 Achchuthan Shanmugasundram edited their review of gene: CTR9: Added comment: As noted by the reviewer, PMID: 35499524 reported 13 unrelated cases identified with heterozygous variants in CTR9 gene (11 different variants) and they presented with overlapping neurodegenerative phenotypes including intellectual disability, hypotonia, joint hyperlaxity, speech delay, coordination problems, tremor, and autism spectrum disorder. Mild dysmorphism and cardiac anomalies were less frequent. The intellect levels were determined only for 11 patients (the rest are too young) and 8 out of these 11 patients were reported with variable degree of intellectual disability, while other three had impairments in other domains or learning difficulties.

PMID:35717577 reported two additional unrelated cases with non-synonymous heterozygous CTR9 variants (p.Glu15Asp and p.Pro25Arg) and they presented with macrocephaly, motor delay, and intellectual disability. In addition, functional studies in zebrafish also showed that knockout/ over-expression of CTR9 variants caused motor defects and enlargement of telencephalon (homologous to the mammalian cerebrum).

This gene has not yet been associated with relevant phenotypes in OMIM. It has been associated with Wilms tumour in Gene2Phenotype (phenotype not relevant to this panel).; Changed rating: GREEN; Changed publications to: 35499524, 35717577
Intellectual disability v4.96 RBSN Achchuthan Shanmugasundram changed review comment from: Comment on list classification: This gene should be rated GREEN as bi-allelic variants in RBSN has been associated with a phenotype encompassing developmental delay and intellectual disability from four unrelated families.

This gene has not been associated with any phenotypes either in OMIM or in Gene2Phenotype.; to: Comment on list classification: This gene should be rated GREEN as bi-allelic variants in RBSN has been associated with a phenotype encompassing developmental delay and intellectual disability from four unrelated families.

This gene has not yet been associated with any phenotypes either in OMIM or in Gene2Phenotype.
Intellectual disability v4.96 RBSN Achchuthan Shanmugasundram Added comment: Comment on list classification: This gene should be rated GREEN as bi-allelic variants in RBSN has been associated with a phenotype encompassing developmental delay and intellectual disability from four unrelated families.

This gene has not been associated with any phenotypes either in OMIM or in Gene2Phenotype.
Intellectual disability v4.96 RBSN Achchuthan Shanmugasundram Added comment: Comment on list classification: This gene should be rated GREEN as bi-allelic variants in RBSN has been associated with a phenotype encompassing developmental delay and intellectual disability from four unrelated families.

This gene has not been associated with any phenotypes either in OMIM or in Gene2Phenotype.
Intellectual disability v4.95 RBSN Achchuthan Shanmugasundram gene: RBSN was added
gene: RBSN was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: RBSN was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RBSN were set to 25233840; 29784638; 35652444
Phenotypes for gene: RBSN were set to intellectual disability, MONDO:0001071
Review for gene: RBSN was set to GREEN
Added comment: PMID:25233840 reported a 6.5 year old female patient with a homozygous missense variant c.1273G > A (p.Gly425Arg) and her clinical presentation included intractable seizures, developmental delay, microcephaly, dysostosis, osteopenia, craniofacial dysmorphism, macrocytosis and megaloblastoid erythropoiesis.

PMID:29784638 reported three siblings with homozygous variant c.289G>C (p.Gly97Arg) in RBSN. The proband presented global developmental delay, had complete 46,XY male-to-female sex reversal and died at age 20 months after multiple infections. The other 2 affected siblings underwent unrelated-donor bone marrow or stem cell transplantation at 8 and 6.5 months of age, respectively. Both have severe intellectual disability and are nonambulatory and nonverbal.

PMID:35652444 reported two unrelated families (three siblings from a family of Iranian descent identified with homozygous variant c.547G>A (p.Gly183Arg) and four members from a family of indigenous Cree descent identified with homozygous variant c.538C>G (p.Arg180Gly)) with overlapping phenotypes including developmental delay, intellectual disability, distal motor axonal neuropathy and facial dysmorphism.
Sources: Literature
Intellectual disability v4.94 CTR9 Achchuthan Shanmugasundram changed review comment from: PMID:35717577 reported two additional unrelated cases with non-synonymous heterozygous CTR9 variants (p.Glu15Asp and p.Pro25Arg) and they presented with macrocephaly, motor delay, and intellectual disability. In addition, functional studies in also showed that knockout/ over-expression of CTR9 variants caused motor defects and enlargement of telencephalon (homologous to the mammalian cerebrum).

This gene has not yet been associated with relevant phenotypes in OMIM. It has been associated with Wilms tumour in Gene2Phenotype (phenotype not relevant to this panel).; to: PMID:35717577 reported two additional unrelated cases with non-synonymous heterozygous CTR9 variants (p.Glu15Asp and p.Pro25Arg) and they presented with macrocephaly, motor delay, and intellectual disability. In addition, functional studies in zebrafish also showed that knockout/ over-expression of CTR9 variants caused motor defects and enlargement of telencephalon (homologous to the mammalian cerebrum).

This gene has not yet been associated with relevant phenotypes in OMIM. It has been associated with Wilms tumour in Gene2Phenotype (phenotype not relevant to this panel).
Intellectual disability v4.93 DPYSL2 Achchuthan Shanmugasundram changed review comment from: This gene should be rated AMBER, as it has been associated with intellectual disability (ID) from two unrelated cases displaying monoallelic variants in DPYSL2/ CRMP2, and supported by functional studies. However, the evidence is not sufficient for green rating as there are variants reported in other (but different) genes in the two patients.

PMID:35861646 reported two cases identified with heterozygous variants (patient1: c.1693C>T (p.Arg565Cys); patient 2: c.42C>A (p.Ser14Arg). These patients had overlapping phenotypes including dysmorphic features, severe global developmental delay and hypoplasia of the corpus callosum. In addition, patient 2 was bed-ridden and could not roll out and had a history of myoclonic seizures and status epilepticus.

It should be noted that patient 1 is compound heterozygous for 2 missense variants in the EFCAB5 gene and was hemizygous for a maternally inherited missense variant in the GPKOW gene and patient 2 had 1 de novo missense variant in the COBLL1 gene and was compound heterozygous for 2 missense variants in the POTEF gene. The severity of the phenotypes between the two cases differs significantly and the additional variants may have possibly contributed to this phenotype.

Brain-specific Crmp2 knockout mice display neuronal development deficits and behavioural impairments associated with hypoplasia of the corpus callosum. In addition, functional studies performed in zebrafish and cell lines that the CRMP2 variants lead to the loss-of-function of CRMP2 protein and can cause intellectual disability.
Sources: Literature; to: This gene should be rated AMBER, as it has been associated with intellectual disability (ID) from two unrelated cases displaying monoallelic variants in DPYSL2/ CRMP2, and supported by functional studies. However, the evidence is not sufficient for green rating as there are variants reported in other (but different) genes in the two patients.

PMID:35861646 reported two cases identified with heterozygous variants (patient1: c.1693C>T (p.Arg565Cys); patient 2: c.42C>A (p.Ser14Arg). These patients had overlapping phenotypes including dysmorphic features, severe global developmental delay and hypoplasia of the corpus callosum. In addition, patient 2 was bed-ridden and could not roll out and had a history of myoclonic seizures and status epilepticus.

It should be noted that patient 1 is compound heterozygous for 2 missense variants in the EFCAB5 gene and was hemizygous for a maternally inherited missense variant in the GPKOW gene and patient 2 had 1 de novo missense variant in the COBLL1 gene and was compound heterozygous for 2 missense variants in the POTEF gene. The severity of the phenotypes between the two cases differs significantly and the additional variants may have possibly contributed to this phenotype.

Brain-specific Crmp2 knockout mice display neuronal development deficits and behavioural impairments associated with hypoplasia of the corpus callosum. In addition, functional studies performed in zebrafish and cell lines that the CRMP2 variants lead to the loss-of-function of CRMP2 protein and can cause intellectual disability.

This gene has not yet been associated with relevant phenotypes either in OMIM or in Gene2Phenotype.
Sources: Literature
Intellectual disability v4.93 DPYSL2 Achchuthan Shanmugasundram gene: DPYSL2 was added
gene: DPYSL2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: DPYSL2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: DPYSL2 were set to 27249678; 35861646
Phenotypes for gene: DPYSL2 were set to intellectual disability, MONDO:0001071; Aplasia/Hypoplasia of the corpus callosum, HP:0007370
Review for gene: DPYSL2 was set to AMBER
Added comment: This gene should be rated AMBER, as it has been associated with intellectual disability (ID) from two unrelated cases displaying monoallelic variants in DPYSL2/ CRMP2, and supported by functional studies. However, the evidence is not sufficient for green rating as there are variants reported in other (but different) genes in the two patients.

PMID:35861646 reported two cases identified with heterozygous variants (patient1: c.1693C>T (p.Arg565Cys); patient 2: c.42C>A (p.Ser14Arg). These patients had overlapping phenotypes including dysmorphic features, severe global developmental delay and hypoplasia of the corpus callosum. In addition, patient 2 was bed-ridden and could not roll out and had a history of myoclonic seizures and status epilepticus.

It should be noted that patient 1 is compound heterozygous for 2 missense variants in the EFCAB5 gene and was hemizygous for a maternally inherited missense variant in the GPKOW gene and patient 2 had 1 de novo missense variant in the COBLL1 gene and was compound heterozygous for 2 missense variants in the POTEF gene. The severity of the phenotypes between the two cases differs significantly and the additional variants may have possibly contributed to this phenotype.

Brain-specific Crmp2 knockout mice display neuronal development deficits and behavioural impairments associated with hypoplasia of the corpus callosum. In addition, functional studies performed in zebrafish and cell lines that the CRMP2 variants lead to the loss-of-function of CRMP2 protein and can cause intellectual disability.
Sources: Literature
Intellectual disability v4.92 CTR9 Achchuthan Shanmugasundram changed review comment from: PMID:35717577 reported two additional unrelated cases with non-synonymous heterozygous CTR9 variants (p.Glu15Asp and p.Pro25Arg) and they presented with macrocephaly, motor delay, and intellectual disability. In addition, functional studies in also showed that knockout/ over-expression of CTR9 variants caused motor defects and enlargement of telencephalon (homologous to the mammalian cerebrum).; to: PMID:35717577 reported two additional unrelated cases with non-synonymous heterozygous CTR9 variants (p.Glu15Asp and p.Pro25Arg) and they presented with macrocephaly, motor delay, and intellectual disability. In addition, functional studies in also showed that knockout/ over-expression of CTR9 variants caused motor defects and enlargement of telencephalon (homologous to the mammalian cerebrum).

This gene has not yet been associated with relevant phenotypes in OMIM. It has been associated with Wilms tumour in Gene2Phenotype (phenotype not relevant to this panel).
Intellectual disability v4.92 CTR9 Achchuthan Shanmugasundram edited their review of gene: CTR9: Added comment: PMID:35717577 reported two additional unrelated cases with non-synonymous heterozygous CTR9 variants (p.Glu15Asp and p.Pro25Arg) and they presented with macrocephaly, motor delay, and intellectual disability. In addition, functional studies in also showed that knockout/ over-expression of CTR9 variants caused motor defects and enlargement of telencephalon (homologous to the mammalian cerebrum).; Changed phenotypes to: Macrocephaly, HP:0000256, Motor delay, HP:0001270, intellectual disability, MONDO_0001071
Intellectual disability v4.92 NUP214 Eleanor Williams changed review comment from: Associated with {Encephalopathy, acute, infection-induced, susceptibility to, 9} 618426 in OMIM and Gene2Phenotype (probable).

PMID: 31178128 - Fichtman et al 2019 - report on two families one of Palestinian decent, the other Northern European (not Finnish descent). Each had two affected siblings in which neurological decline was seen after febrile events. The older son in family A, exhibited minor developmental delay from infancy. A homozygous missense variant was identified in NUP214 (p.Arg38Cys) in family A and segregated with the disease in available family members. In family B affected sisters were compound heterozygous for a frameshift and a missense variant in NUP214 (p.Pro387Ser and p.Pro525Leufs∗6). Functional studies with fibroblasts from one patient in family A showed a decrease in NUP214 and NUP88 levels compared to controls,

PMID: 30758658 - Shamseldin et al 2019 - describe a multiplex consanguineous family in which four affected members presented with severe neonatal hypotonia, profound global developmental delay, progressive microcephaly and early death (<2 year old). Whole exome sequencing revealed the presence of a novel homozygous missense variant in NUP214, p.D154G.

PMID: 29483668 - Egloff et al 2018 - report a 4-year-old girl presenting with developmental delay, growth retardation and facial dysmorphism. She was found to have a 9q deletion inherited from her healthy mother and a hemizygous one-base pair deletion in the NUP214 gene inherited from her father. From patient leukocytes it was found that the expression level of the NUP214 transcript was significantly decreased and close to zero in the patient compared to the controls. ; to: Associated with {Encephalopathy, acute, infection-induced, susceptibility to, 9} 618426 in OMIM and Gene2Phenotype (probable).

PMID: 31178128 - Fichtman et al 2019 - report on two families one of Palestinian decent, the other Northern European (not Finnish descent). Each had two affected family members in which neurological decline was seen after febrile events. The older son in family A, exhibited minor developmental delay from infancy. A homozygous missense variant was identified in NUP214 (p.Arg38Cys) in family A and segregated with the disease in available family members. In family B affected sisters were compound heterozygous for a frameshift and a missense variant in NUP214 (p.Pro387Ser and p.Pro525Leufs∗6). Functional studies with fibroblasts from one patient in family A showed a decrease in NUP214 and NUP88 levels compared to controls,

PMID: 30758658 - Shamseldin et al 2019 - describe a multiplex consanguineous family in which four affected members presented with severe neonatal hypotonia, profound global developmental delay, progressive microcephaly and early death (<2 year old). Whole exome sequencing revealed the presence of a novel homozygous missense variant in NUP214, p.D154G.

PMID: 29483668 - Egloff et al 2018 - report a 4-year-old girl presenting with developmental delay, growth retardation and facial dysmorphism. She was found to have a 9q deletion inherited from her healthy mother and a hemizygous one-base pair deletion in the NUP214 gene inherited from her father. From patient leukocytes it was found that the expression level of the NUP214 transcript was significantly decreased and close to zero in the patient compared to the controls.
Intellectual disability v4.91 SEMA6B Achchuthan Shanmugasundram gene: SEMA6B was added
gene: SEMA6B was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: SEMA6B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SEMA6B were set to 35604360
Phenotypes for gene: SEMA6B were set to Intellectual disability, MONDO:0001071
Review for gene: SEMA6B was set to GREEN
Added comment: Comment on gene classification: This gene should be rated GREEN in this panel as monoallelic variants in this gene has been associated with a final diagnosis of intellectual disability (ID) in 11 unrelated cases.

PMID:35604360 reports 14 heterozygous variants (11 novel and 3 previously reported variants) observed in 16 unrelated individuals referred for ID. Out of these, 11 of them had a final diagnosis of ID. Heterozygous variants in SEMA6B has previously been reported in patients with progressive myoclonic epilepsy (MIM #618876) and there were no cases of ID reported before. This study indicated that the clinical spectrum is wider and included ID without epilepsy or myoclonus.

Functional studies of selected variants and shRNA knock down studies showed mislocalisation and abnormal protein function.
Sources: Literature
Intellectual disability v4.90 EMC1 Achchuthan Shanmugasundram Phenotypes for gene: EMC1 were changed from Cerebellar atrophy, visual impairment, and psychomotor retardation, OMIM:616875 to Cerebellar atrophy, visual impairment, and psychomotor retardation, OMIM:616875
Intellectual disability v4.90 EMC1 Achchuthan Shanmugasundram Phenotypes for gene: EMC1 were changed from Cerebellar atrophy, visual impairment, and psychomotor retardation, OMIM:616875 to Cerebellar atrophy, visual impairment, and psychomotor retardation, OMIM:616875
Intellectual disability v4.90 EMC1 Achchuthan Shanmugasundram Phenotypes for gene: EMC1 were changed from Cerebellar atrophy, visual impairment, and psychomotor retardation, OMIM:616875 to Cerebellar atrophy, visual impairment, and psychomotor retardation, OMIM:616875
Intellectual disability v4.90 EMC1 Achchuthan Shanmugasundram Phenotypes for gene: EMC1 were changed from Cerebellar atrophy, visual impairment, and psychomotor retardation, OMIM:616875 to Cerebellar atrophy, visual impairment, and psychomotor retardation, OMIM:616875
Intellectual disability v4.89 EMC1 Achchuthan Shanmugasundram Phenotypes for gene: EMC1 were changed from Cerebellar atrophy, visual impairment, and psychomotor retardation, OMIM:616875 to Cerebellar atrophy, visual impairment, and psychomotor retardation, OMIM:616875
Intellectual disability v4.89 EMC1 Achchuthan Shanmugasundram Phenotypes for gene: EMC1 were changed from Cerebellar atrophy, visual impairment, and psychomotor retardation, OMIM:616875 to Cerebellar atrophy, visual impairment, and psychomotor retardation, OMIM:616875
Intellectual disability v4.89 EMC1 Achchuthan Shanmugasundram Phenotypes for gene: EMC1 were changed from Cerebellar atrophy, visual impairment, and psychomotor retardation, MIM 616875; Cerebellar atrophy, visual impairment, and psychomotor retardation, 616875 to Cerebellar atrophy, visual impairment, and psychomotor retardation, OMIM:616875
Intellectual disability v4.87 STXBP1 Sarah Leigh Added comment: Comment on mode of inheritance: Due to the report of biallelic STXBP1 variants in a family with encephalopathy, developmental delay, intellectual disability and epilepsy (PMID: 31855252), the mode of inheritance for this gene should be changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal.
Intellectual disability v4.86 STXBP1 Sarah Leigh Phenotypes for gene: STXBP1 were changed from Epileptic encephalopathy, early infantile, 4, 612164 (2); ANGELMAN/PITT HOPKINS SYNDROME-LIKE DISORDER to Developmental and epileptic encephalopathy 4, OMIM:612164; developmental and epileptic encephalopathy, 4, MONDO:0012812
Intellectual disability v4.78 FOXRED1 Sarah Leigh Phenotypes for gene: FOXRED1 were changed from MITOCHONDRIAL COMPLEX I DEFICIENCY to Mitochondrial complex I deficiency, nuclear type 19, OMIM:618241; mitochondrial complex 1 deficiency, nuclear type 19, MONDO:0032624
Intellectual disability v4.72 ROBO1 Achchuthan Shanmugasundram changed review comment from: Comment on gene classification: This gene should be rated green as this gene has been associated with intellectual disability from six unrelated cases. However, the MOI should be set as "BIALLELIC, autosomal or pseudoautosomal" as five of these cases were reported with biallelic variants and only one case was reported with monoallelic variant.

PMID:28286008 reported a boy with compound heterozygous variants that was presented with developmental delay in 13 months and had severe intellectual disability and hyperactivity at nine years of age. He was nonverbal and wheelchair dependent because of spastic diplegia and ataxia.

PMID:30692597 reported a five year old boy identified with a homozygous ROBO1 variant who had combined pituitary hormone deficiency, psychomotor developmental delay, severe intellectual disability, sensorineural hearing loss, strabismus and characteristic facial features.

PMID:35227688 reported eight patients including the boy reported in PMID:30692597. Of the other seven patients, three were presented with intellectual disability. Of these three patients, two harboured compound heterozygous and one harboured homozygous variants.

PMID:35348658 reported a patient identified with monoallelic de novo variant (p.D422G) who presented with early-onset epileptic encephalopathy and had severe developmental delay.

This gene has not yet been associated with any phenotypes in OMIM or Gene2Phenotype.; to: Comment on gene classification: This gene should be rated green as this gene has been associated with intellectual disability from six unrelated cases. However, the MOI should be set as "BIALLELIC, autosomal or pseudoautosomal" as five of these cases were reported with biallelic variants and only one case was reported with monoallelic variant.

PMID:28286008 reported a boy with compound heterozygous variants that was presented with developmental delay in 13 months and had severe intellectual disability and hyperactivity at nine years of age. He was nonverbal and wheelchair dependent because of spastic diplegia and ataxia.

PMID:30692597 reported a five year old boy identified with a homozygous ROBO1 variant who had combined pituitary hormone deficiency, psychomotor developmental delay, severe intellectual disability, sensorineural hearing loss, strabismus and characteristic facial features.

PMID:35227688 reported eight patients including the boy reported in PMID:30692597. Of the other seven patients, three were presented with intellectual disability. Of these three patients, two harboured compound heterozygous and one harboured homozygous variants.

PMID:35348658 reported a patient identified with monoallelic de novo variant (p.D422G) who presented with early-onset epileptic encephalopathy and had severe developmental delay.

This gene has not yet been associated with any phenotypes in OMIM or Gene2Phenotype.
Intellectual disability v4.65 RAB39B Achchuthan Shanmugasundram Added comment: Comment on publications: Additional cases diagnosed with intellectual disability, autism, macrocephaly and poor motor coordination reported in PMIDs 29152164, 32873259 & 34761259. There are also ample functional evidence including studies from animal models described in these and other publications.
Intellectual disability v4.63 RAB39B Achchuthan Shanmugasundram Phenotypes for gene: RAB39B were changed from Mental retardation, X-linked 72, 300271; Mental Retardation, X-linked; MENTAL RETARDATION X-LINKED TYPE 72 (MRX72) +/- PARKINSONS to Intellectual developmental disorder, X-linked 72, OMIM:300271; Waisman syndrome, OMIM:311510
Intellectual disability v4.58 THUMPD1 Eleanor Williams Phenotypes for gene: THUMPD1 were changed from THUMPD1 neurodevelopment disorder to Neurodevelopmental disorder with speech delay and variable ocular anomalies, OMIM:619989
Intellectual disability v4.56 ISCA-37420-Loss Arina Puzriakova Phenotypes for Region: ISCA-37420-Loss were changed from PMID: 18628315 developmental delay, hypotonia, facial dysmorphisms including a long face, a tubular or pear-shaped nose and a bulbous nasal tip, and a friendly/amiable behaviour, other clinically important features include epilepsy, heart defects and kidney/urologic anomalies; 610443; PMID: 25217958; Koolen-De Vries syndrome 610443 to Koolen-De Vries syndrome, OMIM:610443; Developmental delay/intellectual disability, hypotonia, distinctive facial features, congenital malformations, and behavioural feature
Intellectual disability v4.55 ISCA-37420-Loss Arina Puzriakova commented on Region: ISCA-37420-Loss: Previously in phenotypes field:

PMID: 18628315 developmental delay, hypotonia, facial dysmorphisms including a long face, a tubular or pear-shaped nose and a bulbous nasal tip, and a friendly/amiable behaviour, other clinically important features include epilepsy, heart defects and kidney/urologic anomalies; 610443; PMID: 25217958; Koolen-De Vries syndrome 610443
Intellectual disability v4.55 ISCA-37408-Loss Arina Puzriakova Phenotypes for Region: ISCA-37408-Loss were changed from PMID: 16963482 idiopathic intellectual disability including moderate to severe intellectual disability, autism/autistic features, microcephaly, structural brain anomalies including cortical dysplasia/pachygyria, renal anomalies (multicystic kidney, hydronephrosis), digital camptodactyly, visual impairment, strabismus, neuromotor deficits, communication and attention impairments, and a distinctive pattern of craniofacial features. Dysmorphic craniofacial features include progressive microcephaly, flat occiput, widened inner canthal distance, small palpebral fissures, ptosis, long and straight eyelashes, broad and high nasal root extending to a widened, prominent nasal tip with elongated, smooth philtrum, rounding of the upper vermillion border and everted lower lips. PMID: 18245392 A 32-year-old, mentally retarded male was referred to our centre for further clinical genetic analysis. He was born to non-consanguineous parents after 42 weeks gestation with a birth weight of 3500 g. He had a healthy older brother. In the neonatal period he was hypotonic and at 8 weeks of age he underwent surgery because of an inguinal hernia with removal of an atrophic right testis. His motor development was severely delayed with sitting at 3.5 years and walking at 5 years of age. Speech was poorly developed, characterised by the usage of only a few words. During infancy an optic nerve hypoplasia was diagnosed, and during childhood he frequently suffered from luxations of the patellae, which required surgery. At the age of 32 years his height is 163 cm (_3 SDS) and head circumference 52.5 cm (_2.5 SDS). He has a narrow receding forehead, widened inner canthal distance of 3.5 cm (90th centile), normal outer canthal distance of 8.5 cm (25th centile), telecanthus, short and down slanting palpebral fissures, epicanthal folds, ptosis, long, straight eyelashes, high nasal bridge, low set large ears, flat philtrum, small mouth with high, narrow palate and retrognathia. The thorax is broad with increased internipple distance and slight gynaecomastia. A recent renal ultrasound revealed multiple cysts in the left, dystrophic kidney and two uncomplicated cysts in the enlarged, right kidney. The patient has a normally sized phallus with absent right testis and small left testis. His hands show a simian crease right and tapering fingers with broad proximal interphalangeal joints. He shows sandal gaps on both flat feet with clinodactyly of the fourth and fifth toes (and more); 612513; PMID: 22579565 severe developmental delay, congenital microcephaly, intractable epilepsy, and renal anomalies, as well as a congenital choledochal cyst which has not been previously reported in other patients with this cytogenetic defect to Dysmorphic features, moderate to severe intellectual disability, microcephaly and renal anomalies
Intellectual disability v4.54 ISCA-37423-Gain Arina Puzriakova edited their review of Region: ISCA-37423-Gain: Added comment: Following Genomics England clinical review and NHS Genomic Medicine Service approval, the genomic coordinates and triplosensitivity score (from 3 to 2) of this region were updated based on ClinGen Region Curation Results (version on 05 Aug 2022). Regardless of the change in triplosensitivity score, it was deemed appropriate for this regions to remain green as evidence to support pathogenicity remains.; Changed rating: GREEN
Intellectual disability v4.53 ARHGEF9 Arina Puzriakova Tag Q3_21_MOI was removed from gene: ARHGEF9.
Intellectual disability v4.53 ARHGEF9 Arina Puzriakova commented on gene: ARHGEF9: The mode of inheritance of this gene has been updated to 'X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)' following NHS Genomic Medicine Service approval.
Intellectual disability v4.52 ARHGEF9 Arina Puzriakova Source NHS GMS was added to ARHGEF9.
Mode of inheritance for gene ARHGEF9 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 v4.51 KDM2B Mike Spiller gene: KDM2B was added
gene: KDM2B was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: KDM2B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KDM2B were set to PMID: 36322151; 35128353; 35710456
Review for gene: KDM2B was set to GREEN
Added comment: van Jaarsveld et al 2022 PMID: 36322151

Majority of variants are missense, strong evidence for hotspot in CXXC domain.(7 different de Novo missenses + 1 de Novo in frame del. Same inframe del also found de novo in NHS GMS patient. All absent from gnomAD, region highly constrained).

Also 3 LOF SNVs and 3 patients with deletions including this gene, although not all are de novo and most also have potential alternate causes.

All have developmental delay. Almost all have intellectual disability ranging from mild to moderate, speech delay common..7 with cardiac abnormalities, 4 with kidney abnormalities.

Also 2 variants published in this region in PMID: 35710456, 35904121.

KDM2B methylation episignature recorded. CXXC variants show strong clustering, highly distinct from control dataset. LOF variants (including dels) also reported to show distinct episignature from controls, and from CXXC variants. While the data supports a KDM2B LOF episignature, this is not as clear, and may not be as specific, as the CXXC signature.

Mouse model also supports importance of CXXC domain, with mice heterozygous for CXXC-deleted KDM2B showing neurological defects (PMID: 35128353).

Evidence very strong for CXXC missenses less clear for haploinsufficiency.

Overall sufficient evidence from cases and episignature evidence to include as green for ID.
Sources: Literature
Intellectual disability v4.51 ZMYM3 Sarah Leigh edited their review of gene: ZMYM3: Added comment: Not associated with a phenotype in OMIM, Gen2Phen or MONDO. Using the MatchMaker Exchange, PMID: 36586412 reports 23 ZMYM3 variants in 27 individuals (24 males, 3 females) with a neurodevelopmental delay phenotype. Of those assessed 17/20 had intellectual disability, there were other features that overlapped between the individuals including speech delay, motor delay, ASD traits, behavioral problems, facial dys-morphism, microcephaly, short stature.; Changed rating: GREEN; Changed publications to: 36586412; Changed phenotypes to: neurodevelopmental delay
Intellectual disability v4.46 BAP1 Mafalda Gomes commented on gene: BAP1: Kry et al. (2022) performed trio-WES in a cohort with a rare syndromic NDD and identified de novo missense variants in 11 unrelated individuals. All individuals had DD or ID characterised notably by speech (11/11) and motor delay (6/11). Additional common characteristics were hypotonia, (7/11), seizures (6/11), and abnormal behaviour (8/10), including ASD, ADHD, and hypersensitivity. Almost all individuals showed dysmorphic facial features (10/11), and more than half (6/11) had skeletal malformations involving the hands, feet, or spine. Functional analysis showed that most of the variants cannot rescue the consequences of BAP1 inactivation, suggesting a loss-of-function mechanism. In T cells isolated from two affected children, H2A deubiquitination was impaired. In summary, this gene should be promoted to GREEN in this panel, with autosomal dominant mode of inheritance.
Intellectual disability v4.43 TMEM147 Sarah Leigh gene: TMEM147 was added
gene: TMEM147 was added to Intellectual disability. Sources: Literature
Q1_23_promote_green tags were added to gene: TMEM147.
Mode of inheritance for gene: TMEM147 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TMEM147 were set to 36044892
Phenotypes for gene: TMEM147 were set to Neurodevelopmental disorder with facial dysmorphism, absent language, and pseudo-Pelger-Huet anomaly, OMIM:620075
Review for gene: TMEM147 was set to GREEN
Added comment: Associated with relevant phenotype in OMIM and as strong Gen2Phen gene. PMID: 36044892 reports 12 variants in at least 15 unrelated derived from GeneMatcher. Supportive functional evidence is also presented.
Sources: Literature
Intellectual disability v4.42 PAN2 Sarah Leigh edited their review of gene: PAN2: Added comment: PAN2 is not associated with a phenotype in OMIM, but has a moderate association with PAN2-related neurodevelopmental disorder with multiple congenital anomalies in Gen2Phen. PMID: 29620724 reports one homozygous variant in one case and PMID: 35304602 reports a further three homozygous variants in three unrelated cases. It would appear that the syndrome associated with PAN2 variants has multiple congenital anomalies (PMID: 35304602, table 1), including intellectual disabilty ranging from mild to global developmental delay.; Changed rating: GREEN
Intellectual disability v4.38 HIST1H4F Sarah Leigh edited their review of gene: HIST1H4F: Added comment: H4C6 is not associated with a phenotype in OMIM or Gen2Phen. PMID: 35202563 reports single H4C6 variant in a case with a neurodevelopmental syndrome, based on functional studies, the authors suggest that the variant does not have a loss of function action.; Changed rating: RED
Intellectual disability v4.38 HIST1H4I Sarah Leigh commented on gene: HIST1H4I: Associated with Tessadori-van Haaften neurodevelopmental syndrome 4, (OMIM:619951), but not with a phenotype in Gen2Phen. PMID: 35202563 reports two H4C9 variants in two patients with a neurodevelopmental syndrome, based on functional studies, the authors suggest that the variants do not have a loss of function action.
Intellectual disability v4.36 HIST1H4E Sarah Leigh edited their review of gene: HIST1H4E: Added comment: Associated with in Tessadori-van Haaften neurodevelopmental syndrome 3 (OMIM:619950), but not with a phenotype in Gen2Phen. PMID: 35202563 reports seven H4C5 variants in 17 patients with a neurodevelopmental syndrome, based on functional studies, the authors suggest that the variants do not have a loss of function action.; Changed rating: GREEN
Intellectual disability v4.34 ZNF292 Sarah Leigh edited their review of gene: ZNF292: Added comment: Associated with relevant phenotype in OMIM and as strong Gen2Phen gene. At least seven autosomal dominant or de novo ZNF292 variants have been reported in at least eleven unrelated cases of Intellectual developmental disorder, autosomal dominant 64 (OMIM: 619188)(PMID: 31723249).; Changed rating: GREEN
Intellectual disability v4.33 ZNF292 Sarah Leigh Phenotypes for gene: ZNF292 were changed from Intellectual disability; Autism; Attention deficit hyperactivity disorder; Abnormality of the face; Abnormal muscle tone; Abnormality of nervous system morphology; Growth abnormality; Feeding difficulties; Abnormality of the skeletal system; Abnormality of the cardiovascular system; Microcephaly; Seizures to Intellectual developmental disorder, autosomal dominant 64, OMIM:619188; intellectual developmental disorder, autosomal dominant 64, MONDO:0030934
Intellectual disability v4.29 GHR Arina Puzriakova Phenotypes for gene: GHR were changed from Laron dwarfism, 262500; Short stature, 604271; {Hypercholesterolemia, familial, modifier of}, 143890; Increased responsiveness to growth hormone to Laron dwarfism, OMIM:262500; Growth hormone insensitivity, partial, OMIM:604271; Increased responsiveness to growth hormone, OMIM:604271
Intellectual disability v4.26 PAFAH1B1 Arina Puzriakova Phenotypes for gene: PAFAH1B1 were changed from PAFAH1B1-Associated Lissencephaly/Subcortical Band Heterotopia; LISSENCEPHALY TYPE 1 (LIS1) to Lissencephaly 1, OMIM:607432; Subcortical laminar heterotopia, OMIM:607432
Intellectual disability v4.24 DDX3X Arina Puzriakova Phenotypes for gene: DDX3X were changed from Intellectual disability, Mental retardation, X-linked 102, 300958 to Intellectual developmental disorder, X-linked syndromic, Snijders Blok type, OMIM:300958
Intellectual disability v4.23 COX15 Arina Puzriakova Phenotypes for gene: COX15 were changed from Leigh syndrome due to cytochrome c oxidase deficiency, 256000Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 2, 615119; MITOCHONDRIAL COMPLEX IV DEFICIENCY (MT-C4D) to Mitochondrial complex IV deficiency, nuclear type 6, OMIM:615119
Intellectual disability v4.22 COX10 Arina Puzriakova Phenotypes for gene: COX10 were changed from LEIGH SYNDROME (LS) to Mitochondrial complex IV deficiency, nuclear type 3, OMIM:619046
Intellectual disability v4.18 KLHL20 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel review.
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Sleyp et al. 2022 (PMID: 36214804) reported on 14 patients with de novo missense variants who all presented with mild to severe ID, seizures, ASD, hyperactivity, and dysmorphic facial features. One variant (c.1069G>A, p.Gly357Arg) was recurrent in 11/14 cases but all variants clustered in the Kelch-type β-propeller domain (substrate binding surface) of the KLHL20 protein. No functional studies were performed but given the overlap in clinical presentation observed in patients with the same recurrent variant but also multiple different variants, its worth including as diagnostic-grade.
Intellectual disability v4.17 KCNK3 Arina Puzriakova Added comment: Comment on list classification: Given the number of unrelated cases with a comparable phenotype, all shown to have variants that cluster near the X-gate and cause increased channel activation, this gene should be promoted to Green status at the next GMS panel update.

The overall phenotype is likely most compatible with the Paediatric disorders super panel, and addition to the ID panel will ensure this genes' inclusion.
Intellectual disability v4.16 KCNK3 Arina Puzriakova gene: KCNK3 was added
gene: KCNK3 was added to Intellectual disability. Sources: Literature
Q4_22_promote_green tags were added to gene: KCNK3.
Mode of inheritance for gene: KCNK3 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: KCNK3 were set to 36195757
Phenotypes for gene: KCNK3 were set to Developmental disorder with sleep apnea
Mode of pathogenicity for gene: KCNK3 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: Heterozygous variant in the KCNK3 gene already have a well-established link with pulmonary arterial hypertension (OMIM:615344).

However, Sormann et al. 2022 (PMID: 36195757) identified nine unrelated individuals harbouring one of six de novo missense variants in KCNK3 who presented with developmental delay and sleep apnea among other variable features (musculoskeletal and limb anomalies, abnormalities of male genitalia/groin and digestive disturbance). The variants were shown to cause defective X-gating leading to overactive channels that no longer respond to inhibition by G-protein-coupled receptor pathways (i.e. GOF), distinct from the PAH mechanism which is caused by LOF variants.
Sources: Literature
Intellectual disability v4.15 RPL10 Dmitrijs Rots reviewed gene: RPL10: 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: 35876338; Phenotypes: ID, dysmorphic features, progressive postnatal microcephaly, and retinal anomalies; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability v4.14 FRMD5 Arina Puzriakova gene: FRMD5 was added
gene: FRMD5 was added to Intellectual disability. Sources: Literature
Q4_22_promote_green tags were added to gene: FRMD5.
Mode of inheritance for gene: FRMD5 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: FRMD5 were set to 36206744
Phenotypes for gene: FRMD5 were set to Neurodevelopmental disorder with eye movement abnormalities and ataxia, OMIM:620094
Review for gene: FRMD5 was set to GREEN
Added comment: Lu et al. 2022 (PMID: 36206744) report 8 unrelated individuals with de novo missense FRMD5 variants who presented with developmental delay (8/8), intellectual disability (7/7), ataxia (7/8), seizures (5/8), and abnormalities of eye movement (8/8). LOF mutant flies exhibited motor impairment, defective responses to light and heat-induced seizures. Fly phenotypes were rescued by expression of the wildtype gene but not by two of the patient missense mutants.

FRMD5 is associated with a relevant phenotype in OMIM (MIM# 620094) but is not yet listed in G2P.
Sources: Literature
Intellectual disability v4.13 BUB1 Sarah Leigh edited their review of gene: BUB1: Added comment: Not associated with a phenotype in OMIM, but has a moderate association with BUB1-related microcephaly and developmental disorder in Gen2Phen. PMID: 35044816 reports three BUB1 variants in two cases of developmental delay, including microcephaly, together with supportive functional studies.; Changed rating: GREEN
Intellectual disability v4.13 SLC35F1 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). Rating Red as only a single patient with a heterozygous missense variant has been reported to date (PMID:33821533). Limited information on the SLC35F1 gene is known in general.
Intellectual disability v4.11 TPR Achchuthan Shanmugasundram gene: TPR was added
gene: TPR was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: TPR was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TPR were set to 34494102
Phenotypes for gene: TPR were set to Intellectual disability, MONDO:0001071
Review for gene: TPR was set to RED
Added comment: Comment on classification of this gene: This gene should be added with a RED rating as the association of TPR to intellectual disability is based on biallelic variants identified from a report of two siblings.

Two siblings harbouring variants c.6625C>T/ p.Arg2209Ter (identified in heterozygous state in both siblings and father) and c.2610 + 5G > A (identified in heterozygous state in both siblings and mother) were reported with ataxia, microcephaly and severe intellectual disability.

Functional analyses in patient fibroblasts provide evidence that the variants affect TPR splicing, reduce steady-state TPR levels, abnormal nuclear pore composition and density, and altered global RNA distribution.

This gene has not yet been associated with any phenotypes either in OMIM or in Gene2Phenotype.
Sources: Literature
Intellectual disability v4.9 SUFU Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update under a MONOALLELIC inheritance pattern only, unless the NHS GMS working group disagree and feel the MOI should include both mono- and biallelic variants based on the current evidence.
Intellectual disability v4.2 KLHL20 Dmitrijs Rots gene: KLHL20 was added
gene: KLHL20 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: KLHL20 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KLHL20 were set to 36214804
Phenotypes for gene: KLHL20 were set to developmental disorder with intellectual disability, epilepsy, and autism spectrum disorder
Penetrance for gene: KLHL20 were set to unknown
Mode of pathogenicity for gene: KLHL20 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: KLHL20 was set to GREEN
Added comment: More 14 individuals with mostly recurrent missense variant reported in KLHL20
Sources: Literature
Intellectual disability v4.2 RARB Zornitza Stark reviewed gene: RARB: Rating: GREEN; Mode of pathogenicity: None; Publications: 30880327, 30281527, 24075189, 27120018, 25457163, 17506106; Phenotypes: Microphthalmia, syndromic 12, MIM# 615524, Neurodevelopmental disorder; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.1771 RARB Dmitrijs Rots reviewed gene: RARB: Rating: ; 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: 27120018; Phenotypes: Intellectual Disability with Progressive Motor Impairment; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.1771 FBXW7 Arina Puzriakova Phenotypes for gene: FBXW7 were changed from Neurodevelopmental abnormality; Global developmental delay; Intellectual disability; Macrocephaly; Microcephaly; Abnormality of brain morphology; Abnormality of the corpus callosum; Abnormality of the cerebellum; Abnormality of the cardiovascular system; Seizures; Strabismus; Abnormality of the palate to Developmental delay, hypotonia, and impaired language, OMIM:620012
Intellectual disability v3.1770 TAB2 Arina Puzriakova Phenotypes for gene: TAB2 were changed from Congenital heart defects, nonsyndromic, 2, 614980 to Congenital heart defects, nonsyndromic, 2, OMIM:614980
Intellectual disability v3.1769 JARID2 Eleanor Williams commented on gene: JARID2
Intellectual disability v3.1769 JARID2 Eleanor Williams Phenotypes for gene: JARID2 were changed from Intellectual disability; Neurodevelopmental syndrome to Intellectual disability; Neurodevelopmental syndrome; Developmental delay with variable intellectual disability and dysmorphic facies, OMIM:620098
Intellectual disability v3.1768 JARID2 Eleanor Williams Tag gene-checked was removed from gene: JARID2.
Intellectual disability v3.1766 HID1 Eleanor Williams Phenotypes for gene: HID1 were changed from Syndromic infantile encephalopathy; Hypopituitarism to Syndromic infantile encephalopathy; Hypopituitarism; Developmental and epileptic encephalopathy 105 with hypopituitarism, OMIM:619983
Intellectual disability v3.1764 ARFGEF1 Eleanor Williams commented on gene: ARFGEF1
Intellectual disability v3.1764 ARFGEF1 Eleanor Williams Tag gene-checked was removed from gene: ARFGEF1.
Intellectual disability v3.1764 ARFGEF1 Eleanor Williams Phenotypes for gene: ARFGEF1 were changed from Intellectual disability, MONDO:0001071; Epilepsy, MONDO:0005027 to Intellectual disability, MONDO:0001071; Epilepsy, MONDO:0005027; Developmental delay, impaired speech, and behavioral abnormalities, with or without seizures, OMIM:619964
Intellectual disability v3.1757 CTNNB1 Arina Puzriakova Phenotypes for gene: CTNNB1 were changed from Mental retardation, autosomal dominant 19, 615075Colorectal cancer, somatic, 114500Pilomatricoma, somatic, 132600Ovarian cancer, somatic, 167000Hepatocellular carcinoma, somatic, 114550; MENTAL RETARDATION, AUTOSOMAL DOMINANT 19 to Neurodevelopmental disorder with spastic diplegia and visual defects, OMIM:615075
Intellectual disability v3.1755 GRM1 Arina Puzriakova Phenotypes for gene: GRM1 were changed from Spinocerebellar ataxia, autosomal recessive 13, 614831; CONGENITAL CEREBELLAR ATAXIA to Spinocerebellar ataxia, autosomal recessive 13, OMIM:614831
Intellectual disability v3.1750 GATM Arina Puzriakova Phenotypes for gene: GATM were changed from Cerebral creatine deficiency syndrome 3, 612718; ARGININE:GLYCINE AMIDINOTRANSFERASE DEFICIENCY (AGAT DEFICIENCY) to Cerebral creatine deficiency syndrome 3, OMIM:612718
Intellectual disability v3.1749 ADAR Arina Puzriakova Phenotypes for gene: ADAR were changed from Dyschromatosis symmetrica hereditaria, 127400Aicardi-Goutieres syndrome 6, 615010; DYSCHROMATOSIS SYMMETRICA HEREDITARIA 1 to Aicardi-Goutieres syndrome 6, OMIM:615010; Dyschromatosis symmetrica hereditaria, OMIM:127400
Intellectual disability v3.1748 ADAR Arina Puzriakova reviewed gene: ADAR: Rating: ; Mode of pathogenicity: None; Publications: 16225627, 16817193, 19017046; Phenotypes: Aicardi-Goutieres syndrome 6, OMIM:615010, Dyschromatosis symmetrica hereditaria, OMIM:127400; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.1748 ACOX1 Arina Puzriakova Added comment: Comment on mode of inheritance: Adding 'watchlist_moi' tag to monitor for evidence supporting association of monoallelic variants in this gene with ID. To date, three unrelated cases have been reported (PMID: 32169171) with dominant variants. Two patients had impaired cognition while one remained cognitively intact. These cases should be picked up via other routes (neuropathy, hearing loss) but monitoring evidence pertaining to monoallelic variants may be of value.
Intellectual disability v3.1746 ADAR Tracy Lester reviewed gene: ADAR: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Intellectual disability, developmental delay, delayed speech and language, learning disability; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1746 BAP1 Rachel Challis gene: BAP1 was added
gene: BAP1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: BAP1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: BAP1 were set to 35051358
Phenotypes for gene: BAP1 were set to Intellectual disability; short stature; autism spectrum disorder
Review for gene: BAP1 was set to GREEN
gene: BAP1 was marked as current diagnostic
Added comment: 11 de novo BAP1 missense variants identified predominantly in UCH domain. Functional analysis showed that most of the variants cannot rescue the consequences of BAP1 inactivation, suggesting a loss-of-function mechanism. Analysis of blood from affected patients demonstrated impaired H2A deubiquitination compared to controls.
Sources: Literature
Intellectual disability v3.1746 YARS Dmitrijs Rots changed review comment from: 12 patients with homozygous p.(Arg367Trp) have distinct NDD reported in PMID: 34536092.; to: 12 patients with homozygous p.(Arg367Trp) have distinct NDD reported in PMID: 34536092.
Intellectual disability v3.1746 YARS Dmitrijs Rots reviewed gene: YARS: Rating: ; Mode of pathogenicity: None; Publications: PMID: 34536092; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.1746 GNAS Sarah Leigh Phenotypes for gene: GNAS were changed from Pseudohypoparathyroidism Ia, 103580McCune-Albright syndrome, 174800Pseudohypoparathyroidism Ic, 612462Osseous heteroplasia, progressive, 166350Pseudohypoparathyroidism Ib, 603233Prolonged bleeding time, brachydactyly and mental retardationAcromegaly, 102200Pseudopseudohypoparathyroidism, 612463Prolonged bleeding time, brachydactyly, and mental retardationACTH-independent macronodular adrenal hyperplasia, 219080; ACTH-INDEPENDENT MACRONODULAR ADRENAL HYPERPLASIA (AIMAH) to Pseudohypoparathyroidism Ia, OMIM:103580; pseudohypoparathyroidism type 1A, MONDO:0007078; Pseudohypoparathyroidism Ic, OMIM:612462; pseudohypoparathyroidism type 1C, MONDO:0012911; Pseudopseudohypoparathyroidism, OMIM:612463; pseudopseudohypoparathyroidism, MONDO:0012912
Intellectual disability v3.1745 GNAS Sarah Leigh Added comment: Comment on mode of inheritance: Disease causing variants in the GNAS locus have differing expression panels. Pseudohypothyroidism Ia & Ic are all caused by GNAS variants arising in the maternal alleles, therefore, the mode of inheritance (MOI) for GNAS in these conditions should be monoallelic maternally imprinted. Pseudopseudohypoparathyroidism, OMIM:612463 is associated with variants in the paternal alleles therefore, the mode of inheritance for GNAS in this condition should be monoallelic paternally imprinted. Because intellectual disability is seen in these phenotypes, the MOI has been set to monoallelic, imprinted status unknown.
Intellectual disability v3.1744 AP1S2 Arina Puzriakova changed review comment from: Comment on mode of inheritance: Review of literature did not reveal any confirmed affected females. Female carriers of AP1S2 variants are phenotypically normal and have mostly shown random X-inactivation. Huo et al., 2019 (PMID: 30714330) state that they identified a female patient (I-1) but this individual was not available for genetic testing and so it is unclear whether they harboured a variant on a one or both alleles.

As no confirmed female cases have been reported and the allelic requirement remains elusive, the MOI should be set to the default XL (i.e. monoallelic in females may cause disease) as this will ensure that both mono and biallelic variants are picked up in females by the pipeline.; to: Comment on mode of inheritance: Review of literature did not reveal any confirmed affected females. Female carriers of AP1S2 variants are phenotypically normal and have mostly shown random X-inactivation. Huo et al., 2019 (PMID: 30714330) state that they identified a female patient (I-1) but this individual was not available for genetic testing and so it is unclear whether they harboured a variant on a one or both alleles.

As it is not known definitively whether females require a variant on each allele of this gene in order to be affected, the MOI should be set to the default XL (i.e. monoallelic in females may cause disease).
Intellectual disability v3.1744 ROR2 Arina Puzriakova Added comment: Comment on list classification: Following a Red review by Tracy Lester (Genetics laboratory, Oxford UK) this gene was re-curated showing the neurocognitive function in patients with monoallelic and biallelic variants is typically normal. Cases are more likely to be picked up via skeletal abnormalities route. Therefore, ROR2 should be downgraded to Red on this panel at the next GMS panel update.
Intellectual disability v3.1743 ROR2 Arina Puzriakova Phenotypes for gene: ROR2 were changed from BRACHYDACTYLY, TYPE B1 to Brachydactyly, type B1, OMIM:113000 (AD); Robinow syndrome, autosomal recessive, OMIM:268310 (AR)
Intellectual disability v3.1742 TGFB1 Arina Puzriakova changed review comment from: Comment on mode of inheritance: Updated from 'monoallelic' to 'biallelic' inline with review by Zornitza Stark indicating two unrelated families with GDD/ID and biallelic variants in this gene. Added watchlist_moi tag to monitor for further cases. There was no evidence linking monoallelic variants to ID.; to: Comment on mode of inheritance: Updated from 'monoallelic' to 'biallelic' inline with review by Zornitza Stark indicating two unrelated families with GDD/ID and biallelic variants in this gene. Added watchlist_moi tag to monitor for further cases. Cognition is typically normal in Camurati-Engelmann disease (caused by monoallelic TGFB1 variants).
Intellectual disability v3.1740 TGFB1 Arina Puzriakova Added comment: Comment on mode of inheritance: Updated from 'monoallelic' to 'biallelic' inline with review by Zornitza Stark indicating two unrelated families with GDD/ID and biallelic variants in this gene. Added watchlist_moi tag to monitor for further cases. There was no evidence linking monoallelic variants to ID.
Intellectual disability v3.1739 TYR Arina Puzriakova Phenotypes for gene: TYR were changed from Albinism, oculocutaneous, type IA, 203100; Waardenburg; syndrome/albinism, digenic, 103470; Albinism, oculocutaneous, type IB, 606952; [Skin/hair/eye pigmentation 3, light/dark/freckling skin], 601800; {Melanoma, cutaneous malignant, susceptibility to, 8}, 601800; [Skin/hair/eye pigmentation 3, blue/green eyes], 601800 to Albinism, oculocutaneous, type IA, OMIM:203100; Albinism, oculocutaneous, type IB, OMIM:606952; Waardenburg syndrome/albinism, digenic, OMIM:103470
Intellectual disability v3.1738 NRXN1 Arina Puzriakova Phenotypes for gene: NRXN1 were changed from Pitt-Hopkins-like syndrome 2, 614325{Schizophrenia, susceptibility to, 17}, 614332; AUTISM to Pitt-Hopkins-like syndrome 2, OMIM:614325 (AR); Complex neurodevelopmental disorder (AD)
Intellectual disability v3.1736 DPH5 Sarah Leigh edited their review of gene: DPH5: Added comment: Not associated with a phenotype in OMIM, but as moderate Gen2Phen gene for DPH5-related neurodevelopmental disorder. PMID: 35482014 reports four DPH5 variants in fives cases from three unrelated families. Biallelic NM_001077394.2:c.521dup (p.Asn174LysfsTer10) was identified in a consanguinous family (PMID: 35482014, family 3), the index case, an affected sibling and cousin all died in infancy. Affected members families 1 & 2 (PMID: 35482014) were seen in childhood, all had profound intellectual disability and seizures were seen in both families. A supportive mouse model was described, as were in vitro functonal studies (PMID: 35482014).; Changed rating: GREEN
Intellectual disability v3.1736 DPH5 Sarah Leigh Phenotypes for gene: DPH5 were changed from Abnormality of prenatal development or birth; Neonatal hypotonia; Global developmental delay; Intellectual disability; Seizures; Abnormality of the cardiovascular system; Abnormality of the globe; Feeding difficulties; Short stature; Abnormality of head or neck to DPH5-related neurodevelopmental disorder
Intellectual disability v3.1734 MTSS1L Arina Puzriakova Added comment: Comment on list classification: Sufficient number of unrelated cases with shared phenotype and supported by functional studies to warrant a Green rating at the next GMS panel update.
Intellectual disability v3.1733 MTSS1L Arina Puzriakova gene: MTSS1L was added
gene: MTSS1L was added to Intellectual disability. Sources: Literature
new-gene-name, Q4_22_rating tags were added to gene: MTSS1L.
Mode of inheritance for gene: MTSS1L was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: MTSS1L were set to 36067766
Phenotypes for gene: MTSS1L were set to Global developmental delay; Intellectual disability; Ophthalmological anomalies; Microcephaly; Mild facial dysmorphisms
Review for gene: MTSS1L was set to GREEN
Added comment: Huang et al. 2022 (PMID: 36067766) reported five unrelated individuals with the same heterozygous de novo variant (c.2011C>T; p.Arg671Trp) in MTSS2 (formally known as MTSS1L). Linkage analysis was not performed but given the variants arose de novo and the mixed ethnicity of the affected individuals (4 European, 1 Chinese) a founder effect can be ruled out.

Subjects displayed a shared phenotype of GDD and/or ID, ophthalmological anomalies (most commonly nystagmus), microcephaly (primary in 2, relative in 3) and shared mild facial dysmorphisms. The single adult patient also presented with seizures and optic atrophy.

Functional studies showed the variant leads to a decrease in mRNA level but does not impact protein levels of MTSS2. However, a Drosophila model demonstrated that loss of the fly ortholog results in defects in locomotor and visual functions which were rescued by human MTSS2 and only partially rescued by the MTSS2 c.2011C>T variant. Overexpression of the c.2011C>T variant caused similar phenotypes as the LoF mutant indicating a possible dominant-negative effect.
Sources: Literature
Intellectual disability v3.1732 RELN Dmitrijs Rots changed review comment from: Multiple individuals with monoallelic and biallelic variants with different phenotypes are reported: 35769015. Monoallelic variants are mainly missense.; to: Multiple individuals with monoallelic and biallelic variants with different phenotypes are reported: 35769015. Monoallelic variants are mainly missense. The inheritance should be changed to both.
Intellectual disability v3.1731 DOHH Sarah Leigh gene: DOHH was added
gene: DOHH was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: DOHH was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DOHH were set to 35858628
Phenotypes for gene: DOHH were set to DOHH associated neurodevelopmental disorder
Review for gene: DOHH was set to GREEN
Added comment: Not associated with a phenotype in OMIM, Gen2Phen or MONDO. PMID: 35858628 reports six DOHH variants in three unrelated cases of a neurodevelopmental disorder. All of these cases had intellectual disability, microcephaly and hypotonia.
Sources: Literature
Intellectual disability v3.1728 HK1 Eleanor Williams Phenotypes for gene: HK1 were changed from Hemolytic anemia due to hexokinase deficiency, 235700; Neuropathy, hereditary motor and sensory, Russe type, 605285; Abnormal muscle tone; Global developmental delay; Intellectual disability; Visual impairment; Neurological speech impairment; Ataxia to Neurodevelopmental disorder with visual defects and brain anomalies, OMIM:618547; neurodevelopmental disorder with visual defects and brain anomalies, MONDO:0032807
Intellectual disability v3.1727 HK1 Eleanor Williams commented on gene: HK1: As noted by Tracy Lester, the cases reported by Okur et al. 2019 - PMID: 30778173 are have heterozygous de novo variants in HK1 and a phenotype of developmental delay, intellectual disability, structural brain abnormality, and visual impairments, therefore the mode of inheritance should be changed from biallelic to monoallelic.
Intellectual disability v3.1726 SCAMP5 Sarah Leigh edited their review of gene: SCAMP5: Added comment: PMIDs: 31439720; 33390987 report a total of six indiviuals with de novo heterozygous SCAMP5, p.Gly180Trp variants. All cases had neurodevelopmental disorders including intellectual disability and seizures.; Changed rating: GREEN
Intellectual disability v3.1726 SCAMP5 Sarah Leigh changed review comment from: Comment on list classification: Not associated with phenotype in OMIM (last edited on 10/06/2014) or in Gen2Phen. Two variants have been identified in three unrelated cases (one monoallelic, one biallelic). Supportive functional studies have been reported.
It would appear that the two variants reported so far in this gene result in differing mode of pathogenicity and phenotypic features. With heterozygous c.538G>T, p.Gly180Trp seeming to have a dominant-negative effect resulting in autistic spectrum disorder, intellectual disability and seizures. While homozygous c.271C>T, p.R91W seems to have a loss of function effect resulting in early onset epilepsy and Parkinson’s disease. This may be due to different functional domains of the mature protein being altered.
Based on this evidence, SCAMP5 is rated as Amber, with a Watchlist tag. This status may change if further cases are reported.; to: Comment on list classification: Not associated with phenotype in OMIM (last edited on 10/06/2014) or in Gen2Phen. Two variants have been identified in three unrelated cases (one monoallelic, one biallelic). Supportive functional studies have been reported.
It would appear that the two variants reported so far in this gene result in differing mode of pathogenicity and phenotypic features. With heterozygous c.538G>T, p.Gly180Trp seeming to have a dominant-negative effect resulting in autistic spectrum disorder, intellectual disability and seizures. While homozygous c.271C>T, p.R91W seems to have a loss of function effect resulting in early onset epilepsy and Parkinson’s disease. This may be due to different functional domains of the mature protein being altered.
Based on this evidence, SCAMP5 is rated as Amber, with a Watchlist tag. This status may change if further cases are reported.
Intellectual disability v3.1720 HK1 Tracy Lester reviewed gene: HK1: Rating: GREEN; Mode of pathogenicity: None; Publications: 30778173; Phenotypes: Intellectual disability, developmental delay, delayed speech and language, learning disability; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.1720 PTPA Konstantinos Varvagiannis gene: PTPA was added
gene: PTPA was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: PTPA was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PTPA were set to 36073231
Phenotypes for gene: PTPA were set to Intellectual disability; Parkinsonism
Penetrance for gene: PTPA were set to Complete
Review for gene: PTPA was set to AMBER
Added comment: Biallelic PTPA pathogenic variants lead to a form of ID with later-onset parkinsonism based on 4 individuals from 2 families in the literature. Affected individuals were homozygous for missense variants demonstrated to result to reduced mRNA and protein levels as well as PP2A complex activation. Drosophila studies support an age-dependent locomotor dysfunction. Variants in other PP2A-complex-related genes also lead to NDDs. Summary provided below.

There is currently no associated phenotype in OMIM, G2P, PanelApp Australia or SysNDD.

Consider inclusion in relevant panels (ID, Parkinsonism/movement disorders, etc) with amber rating pending further reports.

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Fevga, Tesson et al (2022 - PMID: 36073231) describe the features of 4 individuals, from 2 unrelated families, with biallelic pathogenic PTPA variants.

These presented with normal or delayed early milestones, learning disability and ID (mild to moderate) followed by progressive signs of parkinsonism (at the age of 11 yrs in 2 sibs, 15 yrs in another individual). Motor symptoms were responsive to levodopa and later to deep brain stimulation.

Linkage analysis in one consanguineous family followed by exome revealed homozygosity for a missense PTPA variant (NM_178001:c.893T>G/p.Met298Arg). Exome sequencing in affected subjects from the 2nd family revealed homozygosity for a further missense variant (c.512C>A/p.Ala171Asp). There were no other candidate variants for the phenotype following parental / segregation studies.

Role of the gene:
As the authors discuss, PTPA (or PPP2R4) is ubiquitously expressed in all tissues incl. brain and encodes a phosphotyrosyl phosphatase activator of the dimeric form of protein phosphatase-2A (PP2A). PP2A in turn, is the major Ser/Thr phosphatase in brain targeting a large number of proteins involved in diverse functions. Activation of PP2A is dependent on its methylation, which is negatively regulated by the PP2A-specific methylesterase (PME-1). By binding to PME-1, PTPA counteracts the negative influence of the former on PP2A. Pathogenic variants in genes encoding subunits/regulators of the PP2A complex (e.g. PPP2R1A or PPP2CA) are associated with neurodevelopmental disorders.

Variant studies:
Upon overexpression of wt and both variants in a HEK-293 cell line the authors demonstrated that both variants resulted in significantly reduced mRNA and protein levels (which for Ala171Asp were attributed to increased proteasomal degradation). Both variants were shown to result in impaired PP2A complex activation compared to wt.

Drosophila / animal models:
Pan-neuronal RNAi-mediated knockdown of ptpa in Drosophila resulted in an age-dependent locomotor dysfunction, reversible with L-DOPA treatment.
Previous studies in mice suggest cognitive/electrophysiological impairments upon downregulation of PP2A activity in transgenic mice.
Sources: Literature
Intellectual disability v3.1719 DCHS2 Sarah Leigh Added comment: Comment on phenotypes: This Mondo term is a general description and not specific to a conidition associated with DCHS2 variants.
Intellectual disability v3.1719 DCHS2 Sarah Leigh Phenotypes for gene: DCHS2 were changed from pituitary stalk interruption syndrome, MONDO:0019828 to pituitary stalk interruption syndrome, MONDO:0019828
Intellectual disability v3.1718 DCHS2 Sarah Leigh Phenotypes for gene: DCHS2 were changed from to pituitary stalk interruption syndrome, MONDO:0019828
Intellectual disability v3.1716 ANK3 Sarah Leigh Added comment: Comment on mode of inheritance: Due to the reports of heterozygous variants in PMIDs: 23390136; 28687526; 34218362, the MOI should be changed to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.1714 ANK3 Sarah Leigh edited their review of gene: ANK3: Added comment: Associated with Intellectual developmental disorder, autosomal recessive 37 (OMIM:615493) in OMIM, but not associated with a phenotype in Gen2Phen. At least six ANK3 variants have now been associated with an autosomal dominant neurodevelopmental condition (PMIDs: 23390136; 28687526; 34218362). These terminating variants affect the transcripts for all of the ANK3 isoforms and are de novo (where trio evidence is available).; Changed rating: GREEN; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.1713 ANK3 Sarah Leigh Phenotypes for gene: ANK3 were changed from ?Mental retardation, autosomal recessive, 37 615493 to Intellectual developmental disorder, autosomal recessive 37, OMIM:615493; intellectual disability-hypotonia-spasticity-sleep disorder syndrome, MONDO:0014210
Intellectual disability v3.1711 DOCK8 Sarah Leigh Added comment: Comment on phenotypes: Biallelic DOCK8 variants are associated with Hyper-IgE recurrent infection syndrome, autosomal recessive, OMIM:243700;combined immunodeficiency due to DOCK8 deficiency, MONDO:0009478
Intellectual disability v3.1711 DOCK8 Sarah Leigh Phenotypes for gene: DOCK8 were changed from Mental retardation, autosomal dominant 2, 614113Hyper-IgE recurrent infection syndrome, autosomal recessive, 243700; HYPERIMMUNOGLOBULIN E RECURRENT INFECTION SYNDROME AUTOSOMAL RECESSIVE (AR-HIES) to Intellectual developmental disorder, autosomal dominant 2, OMIM:614113
Intellectual disability v3.1707 CACNA1A Sarah Leigh edited their review of gene: CACNA1A: Added comment: PMIDs: 36063114; 34267336; 33445191; 27250579 all report biallelic CACNA1A variants in cases of Developmental and epileptic encephalopathy 42 (OMIM:617106), therefore the mode of inheritance should be changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal.; Changed publications to: 36063114, 34267336, 33445191, 27250579; Changed phenotypes to: Developmental and epileptic encephalopathy 42, OMIM:617106; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.1707 STUB1 Sarah Leigh Added comment: Comment on mode of inheritance: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. Numerous STUB1 variants have been reported in both Autosomal recessive spinocerebellar ataxia type 16, OMIM:615768 and Spinocerebellar ataxia 48, OMIM:618093. PMIDs 34906452; 35493319 report digenic occurrence of heterozygous STUB1 variants, with TBP_CAG expansions of 41-46. They question the validy of Spinocerebellar ataxia 48 (OMIM:618093) as a condition and whether it should be included into Spinocerebellar ataxia 17 (OMIM:607136).
Intellectual disability v3.1706 STUB1 Sarah Leigh Phenotypes for gene: STUB1 were changed from Spinocerebellar ataxia, autosomal recessive 16, 615768 to Autosomal recessive spinocerebellar ataxia type 16, OMIM:615768; autosomal recessive spinocerebellar ataxia 16, MONDO:0014339; Spinocerebellar ataxia 48, OMIM:618093; spinocerebellar ataxia 48, MONDO:0032526
Intellectual disability v3.1703 ST3GAL3 Sarah Leigh Phenotypes for gene: ST3GAL3 were changed from Mental retardation, autosomal recessive 12, 611090Epileptic encephalopathy, early infantile, 15, 615006; MENTAL RETARDATION, AUTOSOMAL RECESSIVE 12 to Developmental and epileptic encephalopathy 15, OMIM:615006; developmental and epileptic encephalopathy, 15, MONDO:0014003; Intellectual developmental disorder, autosomal recessive 12, OMIM:611090; intellectual disability, autosomal recessive 12, MONDO:0012612
Intellectual disability v3.1702 HEATR3 Sarah Leigh Added comment: Comment on list classification: The amber rating reflects that mild ID has been associated with HEATR3 variants.
Intellectual disability v3.1701 CPSF3 Sarah Leigh changed review comment from: Associated with relevant phenotype in OMIM and as moderate Gen2Phen gene for CPSF3-associated neurodevelopmental disorder with seizures and microcephaly. PMID: 35121750 reports two CPSF3 variants in cases, c.1403G>A, p.Gly468Glu (NM_016207.3) in two Icelandic families and c.1061T>C, p.Ile354Thr (NM_016207.3) in a large consanguineous Mexican family. Intellectual disabililty was evident in all 8/8 cases and seizures and microcephaly was apparent 7/8 cases (PMID: 35121750).; to: Associated with relevant phenotype in OMIM and as moderate Gen2Phen gene for CPSF3-associated neurodevelopmental disorder with seizures and microcephaly. PMID: 35121750 reports two CPSF3 variants in cases, c.1403G>A, p.Gly468Glu (NM_016207.3) in two Icelandic families and c.1061T>C, p.Ile354Thr (NM_016207.3) in a large consanguineous Mexican family. Intellectual disabililty was evident in all 8/8 cases and seizures and microcephaly was apparent 7/8 cases (PMID: 35121750).
The rating of this gene could be changed to green, if further disease associated variants are identified or supportive functional studies are reported.
Intellectual disability v3.1701 ERMARD Dmitrijs Rots reviewed gene: ERMARD: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.1701 UBAP2L Konstantinos Varvagiannis gene: UBAP2L was added
gene: UBAP2L was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: UBAP2L was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: UBAP2L were set to 35977029
Phenotypes for gene: UBAP2L were set to Delayed speech and language development; Motor delay; Intellectual disability; Autistic behavior; Seizures; Microcephaly; Abnormality of head or neck; Short stature; Abnormality of the skeletal system
Penetrance for gene: UBAP2L were set to unknown
Review for gene: UBAP2L was set to GREEN
Added comment: Based on Jia et al (2022 - PMID: 35977029) speech, motor delay as well as ID are observed in individuals harboring de novo pLoF variants in UBAP2L. The gene encodes a regulator of the stress granule (SG) assembly. Extensive evidence is provided on the effect of variants as well as the role of UBAP2L and other genes for components and/or regulation of SG in pathogenesis of NDDs. Among others a Ubap2l htz deletion mouse model (behavioral and cognitive impairment, abnormal cortical development due to impaired SG assembly, etc). Data from 26 previous studies, aggregating 40,853 probands with NDDs (mostly DD/ID, also ASD) suggest enrichment for DNMs in UBAP2L or other genes previously known and further shown to be important for SG formation (incl. G3BP1/G3BP2, CAPRIN1).

Details provided below.

Not associated with any phenotype in OMIM, G2P or SysNDD.

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Jia et al (2022 - PMID: 35977029) describe 12 affected individuals with heterozygous de novo pLoF variants in UBAP2L.

Phenotype: Features included hypotonia, speech (11/11) and motor delay (8/12), ID (8/10 with formal evaluation), variable behavioral concerns (ADHD 5/11, ASD in 4/10, etc). Seizures were reported in 7/12 with 3/10 having a formal diagnosis of epilepsy. Few had microcephaly (3/10). Facial dysmorphisms were common (9/9) and included abnormal palpebral fissures, deep prominent concha, high broad forehead, hypertelorism, thin upper lip and mild synophrys (each in 4 or less individuals). Short stature or skeletal alterations were described in some (4/10 each).

Role of the gene: UBAP2L encodes an essential regulator of stress granule assembly. Stress granules are membraneless cytoplasmic compartments in eukaryotic cells, induced upon a variety of stressors and playing a role in regulation of gene expression.

Variants identified : 9 nonsense/frameshift UBAP2L variants and 3 splicing ones were reported, in all cases as de novo events, upon trio/quad exome sequencing. All were absent from gnomAD. There were no other causative variants.

Variant effect/studies (NM_014847.4 / NP_055662.3) :
- Minigene assays revealed that the 3 splice variants all resulted in out-of-frame exon skipping.
- In patient fibroblasts one of these splice variants was demonstrated to result to reduced protein levels.
- 8 of the 9 nonsense/frameshift variants were predicted to result to NMD.
- 1 nonsense variant (c.88C>T/p.Q30*) was shown to result to decreased protein expression in patient fibroblasts, with detection of the protein using an antibody for the C terminus but not the N terminus. Protein N-terminal sequencing confirmed that the protein lacked the N terminus, with utilization of an alternative start site (11 codons downstream).
- Generation of HeLa UBAP2L KO cell lines resulted in significant reduction of SG numbers which was also the case for 4 variants studied, under stress conditions.
- The protein has a DUF domain (aa 495-526) known to mediate interaction of UBAP2L with G3BP1 (a stress granule marker) with deletions of this domain leading to shuttling of UBAP2L from the cytoplasm to the nucleus. Truncating variants upstream of the DUF domain were shown to result in nuclear localization.

Mouse model :
- The authors generated Ubap2l KO model with hmz deletion of Ubap2l resulting in a lethal phenotype (2.6% survived) and htz deletion leading to behavioral issues (low preference for social novelty, anxious-like behaviors) and cognitive impairment.
- Ubap2l haploinsufficiency resulted in abnormal cortical development and lamination with reduction of neural progenitor proliferation.
- Ubap2l deficiency was shown to impair SG assembly during cortical development both under physiological stress conditions or upon utilization of an oxidative stress inducer.

Additional evidence of UBAP2L and SG overall in pathogenesis of NDDs:
- Based on DNMs from 40,853 individuals with NDDs from 26 studies (9,228 with ASD, 31,625 with DD/ID) the authors demonstrate significant excess of DNM in 31 genes encoding SG components, regulators or both, the latter being the case for UBAP2L and 2 further genes (G3BP1 and G3BP2 - both with crucial roles in SG assembly).
- Excess dn splice-site (N=3) and missense (N=5) variants in G3BP1 were observed in the above cohort [c.95+1G>A, c.353+1G>T, c.539+1G>A / p.S208C, R320C, V366M].
- Excess dn missense (N=7) variants in G3BP2 were observed in the above cohort [p.R13W, D151N, E158K, L209P, E399D, K408E, R438C].
- Generation of G3BP1 or G3BP2 KO HeLa cell lines and immunofluorescence upon use of oxidative stress inducer revealed significant reduction of stress granules.
- Generation of HeLa cell lines for 5 G3BP1 mutants (R78C*, R132I*, S208C*, R320C*, V366M) and 7 G3BP2 mutants (p.R13W*, D151N*, E158K, L209P*, E399D, K408E, R438C) revealed that several (those in asterisk) resulted in significantly fewer SG formation under oxidative stress compared to WT while the subcellular distribution of the proteins under stress was identical to WT.
- Among the identified genes for SG enriched for DNMs, CAPRIN1 was implicated in previous publications as a NDD risk gene with 3 dn missense SNVs reported (p.I373K, p.Q446H, p.L484P). CAPRIN1 binding to G3BP1/2 has been shown to promote SG formation. Significant reduction of SG was observed in CAPRIN1 KO HeLa lines. p.I373K abolished interaction with G3BP1/2 and disrupted SG formation.
Sources: Literature
Intellectual disability v3.1699 CLPB Arina Puzriakova Phenotypes for gene: CLPB were changed from 3-methylglutaconic aciduria, type VII, with cataracts, neurologic involvement and neutropenia, OMIM:616271 to 3-methylglutaconic aciduria, type VIIB, autosomal recessive, OMIM:616271; 3-methylglutaconic aciduria, type VIIA, autosomal dominant, OMIM:619835; Neutropenia, severe congenital, 9, autosomal dominant, OMIM:619813
Intellectual disability v3.1698 NDUFA12 Arina Puzriakova Phenotypes for gene: NDUFA12 were changed from Leigh syndrome due to mitochondrial complex 1 deficiency to Mitochondrial complex I deficiency, nuclear type 23, OMIM:618244
Intellectual disability v3.1695 FBXO28 Sarah Leigh edited their review of gene: FBXO28: Added comment: Associated with relevant phenotype in OMIM and as definitive Gen2Phen gene. At least six variants have been reported in at least six cases. In one of these cases the variant was inherited from the unanaffected mother, who was mosaic (PMID: 33280099), otherwise the variants were de novo heterozygotes (PMIDs: 30160831; 33280099).; Changed rating: GREEN
Intellectual disability v3.1694 CDK9 Sarah Leigh edited their review of gene: CDK9: Added comment: Not associated with a phenotype in OMIM, Gen2Phen or MONDO. At least four variants have been reported in unrelated cases with a CHARGE-like syndrome:
NM_001261:c.280C>T, p.Arg94Cys (PMID: 29302074)
NM_001261.3:c.673C>T / p.Arg225Cys (PMID: 26633546, 30237576)
NM_001261.3:c.862G>A / p.Ala288Thr and c.907C>T /p.Arg303Cys (PMID: 33640901).
Supportive functional studies have also been reported (PMID: 33640901).; Changed rating: GREEN
Intellectual disability v3.1693 CCDC32 Sarah Leigh edited their review of gene: CCDC32: Added comment: Associated with relevant phenotype in OMIM and as strong Gen2Phen gene for CCDC32-associated neurodevelopmental syndrome. At least three variants have been reported in three unrelated cases (PMIDS: 32307552 & 35451546), together with supportive functional studies.; Changed rating: GREEN
Intellectual disability v3.1692 CCDC32 Sarah Leigh Phenotypes for gene: CCDC32 were changed from global developmental delay to Cardiofacioneurodevelopmental syndrome, OMIM:619123; cardiofacioneurodevelopmental syndrome, MONDO:0030873
Intellectual disability v3.1689 GLRA2 Sarah Leigh edited their review of gene: GLRA2: Added comment: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. PMID: 35294868 reports eight GLRA2 variants in affected females (n=8) and males (n=5). The variants in the females were de novo and c.887C>T,
p.Thr296Met (NC_000023.10, chrX: g.14627284C>T) was present in six individuals (PMID: 35294868, table 2) and was found to have a gain-of-function effect, which is in contrast to c.754C>T, p.Arg252Cys and c.407A>G, p.Asn136Ser (PMID: 2637014). All of the 13 GLRA2 variant carriers in PMID: 35294868 had developmental delay/intellectual disability and epilepsy was evident in 7/13 of the cases (PMID: 35294868, table 2). Supportive functional studies were also presented.; Changed rating: GREEN
Intellectual disability v3.1687 NRCAM Sarah Leigh edited their review of gene: NRCAM: Added comment: Associated with relevant phenotype in OMIM and as moderate Gen2Phen gene for NRCAM neurodevelopmental disorder with dysmorphic features, hypotonia and spasticity. At least 12 variants have been reported in PMID: 35108495 in 8 unrelated cases (table 1). Global developmental delay / intellectual disabilty was evident in 5/7 unrelated cases (individual 1 was not considered as they also had homozygous loss-of-function variant in CD55 (OMIM: 125240)(PMID: 35108495).; Changed rating: GREEN
Intellectual disability v3.1686 NRCAM Sarah Leigh Phenotypes for gene: NRCAM were changed from Hypotonia; Hypertonia; Spasticity; Global developmental delay; Intellectual disability; Microcephaly; Behavioral abnormality; Neuropathy; Hearing abnormality; Abnormality of the eye; Abnormality of the skeletal system; Scoliosis; Abnormality of the face to Neurodevelopmental disorder with neuromuscular and skeletal abnormalities, OMIM:619833
Intellectual disability v3.1684 TIAM1 Sarah Leigh edited their review of gene: TIAM1: Added comment: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. PMID: 35240055 reports six TIAM1 variants in four unrelated cases (5 cases in total) of Neurodevelopmental disorder with language delay and seizures, OMIM:619908. All of the cases displayed seizures and intellectual disability, where an assessment was made. The drospohila ortholog (still life) and funtional studies supported this gene disease association (PMID: 35240055).; Changed rating: GREEN
Intellectual disability v3.1682 CPSF3 Sarah Leigh changed review comment from: Associated with relevant phenotype in OMIM and as moderate Gen2Phen gene for CPSF3-associated neurodevelopmental disorder with seizures and microcephaly. PMID: 35121750 reports two CPSF3 variants in cases, c.1403G>A, (NM_016207.3) in two Icelandic families and c.1061T>C (NM_016207.3) in a large consanguineous Mexican family.; to: Associated with relevant phenotype in OMIM and as moderate Gen2Phen gene for CPSF3-associated neurodevelopmental disorder with seizures and microcephaly. PMID: 35121750 reports two CPSF3 variants in cases, c.1403G>A, p.Gly468Glu (NM_016207.3) in two Icelandic families and c.1061T>C, p.Ile354Thr (NM_016207.3) in a large consanguineous Mexican family. Intellectual disabililty was evident in all 8/8 cases and seizures and microcephaly was apparent 7/8 cases (PMID: 35121750).
Intellectual disability v3.1680 PDZD8 Sarah Leigh changed review comment from: Not associated with a phenotype in OMIM, Gen2Phen or MONDO. PMID: 35227461 reports two PDZD8 variants in two unrelated cases with a neurodevelopmental cognitive disorder. The PDZD8 variants were biallelic in the affected cases in two unrelated families, but heterozygous or absent in the unaffected family members (figure 1 PMID: 35227461). Supportive animal models were also presented in PMID: 35227461.; to: Not associated with a phenotype in OMIM (last edited: 02/21/2018), Gen2Phen or MONDO. PMID: 35227461 reports two PDZD8 variants in two unrelated cases with a neurodevelopmental cognitive disorder. The PDZD8 variants were biallelic in the affected cases in two unrelated families, but heterozygous or absent in the unaffected family members (figure 1 PMID: 35227461). Supportive animal models were also presented in PMID: 35227461.
Intellectual disability v3.1680 PDZD8 Sarah Leigh edited their review of gene: PDZD8: Added comment: Not associated with a phenotype in OMIM, Gen2Phen or MONDO. PMID: 35227461 reports two PDZD8 variants in two unrelated cases with a neurodevelopmental cognitive disorder. The PDZD8 variants were biallelic in the affected cases in two unrelated families, but heterozygous or absent in the unaffected family members (figure 1 PMID: 35227461). Supportive animal models were also presented in PMID: 35227461.; Changed rating: GREEN
Intellectual disability v3.1679 CHKA Sarah Leigh edited their review of gene: CHKA: Added comment: Not associated with a phenotype in OMIM, Gen2Phen or MONDO. PMID: 35202461 reports five CHKA variants in five unrelated cases with a neurodevelopmental disorder, which includes intellectual disability, epileptic
encephalopathy and severe microcephaly (PMID: 35202461). Suportive functional studies are also presented in this article.; Changed rating: GREEN
Intellectual disability v3.1677 ZMYND8 Konstantinos Varvagiannis gene: ZMYND8 was added
gene: ZMYND8 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: ZMYND8 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ZMYND8 were set to 35916866; 32530565
Phenotypes for gene: ZMYND8 were set to Delayed speech and language development; Motor delay; Intellectual disability; Abnormality of cardiovascular system morphology; Hearing abnormality; Abnormality of vision; Abnormality of the face; Seizures
Penetrance for gene: ZMYND8 were set to unknown
Review for gene: ZMYND8 was set to GREEN
Added comment: Dias et al (2022 - PMID: 35916866) describe the phenotype of 11 unrelated individuals with monoallelic de novo (or suspected de novo) missense (N=9) or truncating (N=2) ZMYND8 variants. One of these subjects was previously reported by Suzuki et al (2020 - PMID: 32530565).

Features included speech delay/language difficulties (9/11), motor delay (9/11), ID (in 10/11 - profound in 1, moderate in 2), CHD (7/11 - PDA, VSD, ASD, pulmonary stenosis, etc), hearing or vision impairment (7/11). Seizures were reported in few (in text 5/11, table 2/11). Variable non-familial facial features were present in (9/11).

As the authors discuss, ZMYND8 encodes a multidomain protein playing a role in transcription regulation, chromatin remodeling, regulation of super enhancers, DNA damage response/tumor suppression.

The protein is broadly expressed in brain and shows highest expression in early development.

Molecular modeling and/or a yeast two-hybrid system were suggestive of disrupted interaction of ZMYND8 with Drebrin (missense variants in PWWP domain) or GATAD2A (variants in MYND domain).

Neuronal Zmynd8 knockdown in Drosophila resulted in deficits in habituation learning.
Sources: Literature
Intellectual disability v3.1677 ZMYND15 Konstantinos Varvagiannis gene: ZMYND15 was added
gene: ZMYND15 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: ZMYND15 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ZMYND15 were set to 35916866; 32530565
Phenotypes for gene: ZMYND15 were set to Delayed speech and language development; Motor delay; Intellectual disability; Abnormality of cardiovascular system morphology; Hearing abnormality; Abnormality of vision; Abnormality of the face; Seizures
Penetrance for gene: ZMYND15 were set to unknown
Review for gene: ZMYND15 was set to GREEN
Added comment: Dias et al (2022 - PMID: 35916866) describe the phenotype of 11 unrelated individuals with monoallelic de novo (or suspected de novo) missense (N=9) or truncating (N=2) ZMYND8 variants. One of these subjects was previously reported by Suzuki et al (2020 - PMID: 32530565).

Features included speech delay/language difficulties (9/11), motor delay (9/11), ID (in 10/11 - profound in 1, moderate in 2), CHD (7/11 - PDA, VSD, ASD, pulmonary stenosis, etc), hearing or vision impairment (7/11). Seizures were reported in few (in text 5/11, table 2/11). Variable non-familial facial features were present in (9/11).

As the authors discuss, ZMYND8 encodes a multidomain protein playing a role in transcription regulation, chromatin remodeling, regulation of super enhancers, DNA damage response/tumor suppression.

The protein is broadly expressed in brain and shows highest expression in early development.

Molecular modeling and/or a yeast two-hybrid system were suggestive of disrupted interaction of ZMYND8 with Drebrin (missense variants in PWWP domain) or GATAD2A (variants in MYND domain).

Neuronal Zmynd8 knockdown in Drosophila resulted in deficits in habituation learning.
Sources: Literature
Intellectual disability v3.1677 EMC1 Eleanor Williams Added comment: Comment on mode of inheritance: 3 more cases of monoallelic variants in patients with an intellectual disability phenotype now reported so the mode of inheritance should be changed to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal'
Intellectual disability v3.1676 RAB11A Eleanor Williams changed review comment from: PMID: 33875846 - Bertoli-Avella et al 2021 - in a large study of patients with no initial diagnostic variants identified by ES/GS they identified two different heterozygous missense variants in RAB11A in two unrelated patients (NM_004663.4: c.375G>T, p. Lys125Asn and NM_004663.4: c.380A>G, p. Asp127Gly). One was de-novo. Little patient information but both had brain anomalies and intellectual disability reported. 1 had seizures.; to: PMID: 33875846 - Bertoli-Avella et al 2021 - in a large study of patients with no initial diagnostic variants identified by ES/GS, they identified two different heterozygous missense variants in RAB11A in two unrelated patients (NM_004663.4: c.375G>T, p. Lys125Asn and NM_004663.4: c.380A>G, p. Asp127Gly). One was de-novo. Little patient information but both had brain anomalies and intellectual disability reported. 1 had seizures.
Intellectual disability v3.1676 RAB11A Eleanor Williams changed review comment from: PMID: 33875846 - Bertoli-Avella et al 2021 - in a large study of patients with no initial diagnostic variants identified by ES/GS they identified two different heterozygous missense variants in RAB11A in two unrelated patients. One was de-novo. Little patient information but both had brain anomalies and intellectual disability reported. 1 had seizures.; to: PMID: 33875846 - Bertoli-Avella et al 2021 - in a large study of patients with no initial diagnostic variants identified by ES/GS they identified two different heterozygous missense variants in RAB11A in two unrelated patients (NM_004663.4: c.375G>T, p. Lys125Asn and NM_004663.4: c.380A>G, p. Asp127Gly). One was de-novo. Little patient information but both had brain anomalies and intellectual disability reported. 1 had seizures.
Intellectual disability v3.1676 RAB11A Eleanor Williams Added comment: Comment on list classification: Leaving the rating as amber just now, but with a recommendation of GREEN rating following GMS review. There are now 6 unrelated individuals with an intellectual disability phenotype reported and missense variants in this gene. Although there is little clinical data available the number of cases adds weight to this gene-disease association.
Intellectual disability v3.1672 SLC35B2 Sarah Leigh Added comment: Comment on list classification: The evidence for this gene is sufficient for an amber rating. Although supportive functional evidence is presented in PMID: 35325049, the presence of other variants in both cases reported in this article, means that further evidence is required for SLC35B2 to be rated Green.
Intellectual disability v3.1666 TAF4 Eleanor Williams Added comment: Comment on list classification: Promoting this gene from grey to amber. There are 3 cases reported but in one the phenotype is reported as autism, and in the other two there is no information as to the severity. The mouse knockout shows there is an effect of loss of TAF4 but the phenotype is perhaps not specific enough to add weight to rating of this gene for intellectual disability.
Intellectual disability v3.1662 TAF4 Eleanor Williams commented on gene: TAF4: Not associated with a phenotype in OMIM or Gene2Phenotype.

PMID: 33875846 - Bertoli-Avella et al 2021 - identified two de novo LoF variants (splicing and nonsense) in two unrelated patients with dysmorphic features and one with intellectual disability and one with delayed speech and language development with global developmental delay.

PMID: 28191890 - Kosmicki et al 2017 - report a child with autism with an indel in TAF4 leading to a frameshift. No phenotypic details provided.

PMID: 27026076 - Langer et al 2016 - Taf4a−/− (gene encoding Taf4) mouse embryos survive until E9.5, but show severe growth retardation and specific defects in anterior and ventral patterning and morphogenesis.
Intellectual disability v3.1661 RAP1GDS1 Eleanor Williams Added comment: Comment on list classification: Promoting this gene from red to amber. There are now 4 families reported with the same splice site variant and a similar phenotype but intellectual disability is not seen in all probands. 2 of the families come from the same region. The ancestry of the other 2 families is not known. There is one additional case with a different 1bp deletion variant in RAP1GDS1 is also reported with ID as part of the phenotype. The expert reviewer proposes this gene should be green, and it also green on the PanelApp Australia Intellectual disability panel. Therefore the recommendation is for GREEN rating following GMS consideration and expert review.
Intellectual disability v3.1659 TFE3 Arina Puzriakova Phenotypes for gene: TFE3 were changed from TFE3-related intellectual disability with pigmentary mosaicism to Intellectual developmental disorder, X-linked, syndromic, with pigmentary mosaicism and coarse facies, OMIM:301066
Intellectual disability v3.1658 PIGP Arina Puzriakova Phenotypes for gene: PIGP were changed from Epileptic encephalopathy, early infantile, 55, 617599; Generalized hypotonia; Global developmental delay; Seizures; Intellectual disability; Feeding difficulties; Cortical visual impairment to Developmental and epileptic encephalopathy 55, OMIM:617599
Intellectual disability v3.1657 KAT8 Arina Puzriakova Phenotypes for gene: KAT8 were changed from Global developmental delay; Intellectual disability; Seizures; Abnormality of vision; Feeding difficulties; Abnormality of the cardiovascular system; Autism to Li-Ghorgani-Weisz-Hubshman syndrome, OMIM:618974; Global developmental delay; Intellectual disability; Seizures; Abnormality of vision; Feeding difficulties; Abnormality of the cardiovascular system; Autism
Intellectual disability v3.1656 TAF8 Arina Puzriakova Added comment: Comment on list classification: New gene added by Jana Jezkova. There is sufficient evidence to promote this gene to Green at the next GMS panel update.

TAF8 is associated with a relevant phenotype in OMIM (MIM# 619972) but is not yet listed in G2P.

8 individuals from 5 families have been reported in literature (PMIDs: 29648665; 35759269). Four families from different ethnic backgrounds harboured the same c.781-1G>A homozygous variant while sequencing in a sib pair revealed different compound het splice variants (c.45+4A>G and c.489G>A) in the TAF8 gene. Patients presented with an overlapping phenotype including microcephaly (8/8), DD and ID (8/8), spasticity (7/8), and seizures (6/8). Brain MRI have shown hypoplastic corpus callosum, hypomyelination, enlarged ventricles in most subjects, and additionally generalised brain atrophy in two sibs.
Intellectual disability v3.1654 TAF8 Arina Puzriakova Phenotypes for gene: TAF8 were changed from severe developmental delay; feeding problems; microcephaly; growth retardation; spasticity; epilepsy to Neurodevelopmental disorder with severe motor impairment, absent language, cerebral hypomyelination, and brain atrophy, OMIM:619972
Intellectual disability v3.1652 MED13L Arina Puzriakova Phenotypes for gene: MED13L were changed from INTELLECTUAL DISABILITY to Impaired intellectual development and distinctive facial features with or without cardiac defects, OMIM:616789
Intellectual disability v3.1649 SLC38A3 Catherine Snow Phenotypes for gene: SLC38A3 were changed from Infantile axial hypotonia; Global developmental delay; Intellectual disability; Seizures; Spasticity; Microcephaly; Cerebral atrophy; Cerebellar atrophy; Abnormality of the corpus callosum; Dysphagia; Constipation; Increased serum lactate; Hyperammonemia to Developmental and epileptic encephalopathy 102, 619881
Intellectual disability v3.1648 CNNM2 Eleanor Williams Phenotypes for gene: CNNM2 were changed from Hypomagnesemia, seizures, and mental retardation 616418 to Hypomagnesemia, seizures, and mental retardation, OMIM:616418; Hypomagnesemia, seizures, and mental retardation, MONDO:0014631
Intellectual disability v3.1644 OGDHL Arina Puzriakova Phenotypes for gene: OGDHL were changed from Neurodevelopmental disorder featuring epilepsy, hearing loss and visual impairment to Yoon-Bellen neurodevelopmental syndrome, OMIM:619701
Intellectual disability v3.1643 OGDHL Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. There is sufficient evidence to promote to Green at the next GMS panel update.

The NSRP1 gene is not yet associated with any phenotype in OMIM but has a 'moderate' disease confidence rating in G2P for 'OGDHL-related neurodevelopmental disorder with seizures, hearing loss and gait ataxia'.

At least 10 individuals from 9 unrelated families identified with biallelic variants in this gene (PMIDs: 28017472; 34800363). Main clinical features include mild-to-severe DD/ID (9/10), seizures (5/10), gait ataxia (5/10), profound bilateral sensorineural hearing loss (4/10), spasticity (3/10).
Intellectual disability v3.1641 NSRP1 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. There is sufficient evidence to promote to Green at the next GMS panel update.

The NSRP1 gene is not yet associated with any phenotype in OMIM but has a 'strong' disease confidence rating in G2P for 'NSRP1-associated developmental delay, epilepsy and microcephaly'.

Six individuals from three families with different homozygous LoF NSRP1 variants identified by Calame et al. 2021 (PMID: 34385670). Main clinical features include ID/DD (6/6), epilepsy (6/6, drug-resistant in 3/6), hypotonia (6/6), appendicular spasticity (6/6), microcephaly (5/6, Z-scores −0.95 to −5.60). Brain abnormalities included under-opercularization (3/4), simplified gyral pattern (3/4), superior and/or inferior cerebellar vermian hypoplasia (3/4), corpus callosum dysgenesis (1/4), and thin brainstem (1/4).
Intellectual disability v3.1639 HMGB1 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update on ID and microcephaly gene panel based on >3 unrelated cases presenting with relevant phenotype due to heterozygous variant in the HMGB1 gene (PMID: 34164801)
Intellectual disability v3.1635 PRDM13 Ivone Leong edited their review of gene: PRDM13: Added comment: New publication. Publication reported eight individuals from four families of different origins with loss-of-function PRDM13 variants. Phenotypic findings included cerebellar hypoplasia and perinatal lethality associated with severe brainstem dysfunctions (e.g., feeding and respiratory difficulties, central apnea, bradycardia). Individuals were also reported to have severe global developmental delay. Therefore this gene should be rated Green.; Changed rating: GREEN; Changed publications to: 35390279
Intellectual disability v3.1635 PRDM13 Ivone Leong gene: PRDM13 was added
gene: PRDM13 was added to Intellectual disability. Sources: Expert Review Amber,Literature
Mode of inheritance for gene: PRDM13 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PRDM13 were set to 34730112
Phenotypes for gene: PRDM13 were set to congenital hypogonadotropic hypogonadism, MONDO:0015770; Cerebellar dysfunction, impaired intellectual development, and hypogonadotropic hypogonadism, OMIM:619761
Intellectual disability v3.1634 ATG7 Arina Puzriakova Entity copied from Ataxia and cerebellar anomalies - narrow panel v2.298
Intellectual disability v3.1634 ATG7 Arina Puzriakova gene: ATG7 was added
gene: ATG7 was added to Intellectual disability. Sources: Literature,Expert Review Amber
Q3_22_rating tags were added to gene: ATG7.
Mode of inheritance for gene: ATG7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ATG7 were set to 34161705
Phenotypes for gene: ATG7 were set to Spinocerebellar ataxia, autosomal recessive 31, OMIM:619422
Intellectual disability v3.1632 TAF8 Jana Jezkova changed review comment from: Eight patients reported in total. Six patients are homozygous for a recurrent NM_138572.2, c.781-1G>A variant. In two sibling patients, two novel compound heterozygous TAF8 splice site mutations, c.45+4A > G and c.489G>A were identified, which cause aberrant splicing as well as reduced expression and mislocalization of TAF8.
Sources: Literature; to: Eight patients reported in total. Six patients are homozygous for a recurrent NM_138572.2, c.781-1G>A variant. In two sibling patients, two novel compound heterozygous TAF8 splice site mutations, c.45+4A > G and c.489G>A were identified, which cause aberrant splicing as well as reduced expression and mislocalization of TAF8.
Sources: Literature
Intellectual disability v3.1632 TAF8 Jana Jezkova gene: TAF8 was added
gene: TAF8 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: TAF8 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TAF8 were set to PMID: 35759269
Phenotypes for gene: TAF8 were set to severe developmental delay; feeding problems; microcephaly; growth retardation; spasticity; epilepsy
Penetrance for gene: TAF8 were set to unknown
Review for gene: TAF8 was set to AMBER
Added comment: Eight patients reported in total. Six patients are homozygous for a recurrent NM_138572.2, c.781-1G>A variant. In two sibling patients, two novel compound heterozygous TAF8 splice site mutations, c.45+4A > G and c.489G>A were identified, which cause aberrant splicing as well as reduced expression and mislocalization of TAF8.
Sources: Literature
Intellectual disability v3.1632 STT3A Arina Puzriakova Added comment: Comment on mode of inheritance: Should be updated from 'biallelic' to 'both mono- and biallelic'. Congenital disorder of glycosylation due to monoallelic variants in STT3A has been identified in at least 16 patients from 9 families (PMID: 34653363). Phenotypes included mild-moderate ID/DD in 10/16 subjects.
Intellectual disability v3.1628 PPFIBP1 Konstantinos Varvagiannis gene: PPFIBP1 was added
gene: PPFIBP1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: PPFIBP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PPFIBP1 were set to 35830857; 30214071
Phenotypes for gene: PPFIBP1 were set to Global developmental delay; Intellectual disability; Microcephaly; Seizures; Abnormality of brain morphology; Abnormality of the cerebral white matter; Cerebral calcification; Abnormal cortical gyration; Hypertonia; Spastic tetraplegia; Generalized hypotonia; Small for gestational age; Growth delay; Failure to thrive; Feeding difficulties; abnormal heart morphology; Hearing abnormality; Cryptorchidism; Abnormality of vision
Penetrance for gene: PPFIBP1 were set to Complete
Review for gene: PPFIBP1 was set to GREEN
Added comment: Consider inclusion with green rating in the ID, epilepsy as well as other likely relevant gene panels (microcephaly, white matter disorders, corpus callosum abnormalities, intracerebral calficication disorders, malformations of cortical development, hereditary spastic paraplegia, growth failure in early childhood, etc) based on the summary below.

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Rosenhahn et al (2022 - PMID: 35830857) describe the phenotype of 16 individuals - belonging to 12 unrelated families - with biallelic PPFIBP1 pathogenic variants. Most (14/16) were born to consanguineous parents. One of these families was previously reported by Shaheen et al (2019 - PMID: 30214071) who first identified PPFIBP1 as a candidate gene for congenital microcephaly. In the current study, Rosenhahn also identified a fetus homozygous for a missense variant and similar features.

All individuals presented global DD/ID (16/16 - in 15 cases profound/severe) and epilepsy (16/16 - onset 1d-4y / median 2m - focal seizures in 11/16, epileptic spams in 7/16, generalized onset in 7/16, myoclonic in 6/16 - drug-resistant : 13/16). Almost all (15/16) had microcephaly, commonly congenital (9/16) and progressive (11/16). Other neurological findings included hypertonia (10/16), spastic tetraplegia (6/16), hypotonia (5/16), dystonic movements (3/16) or nystagmus (4/16). Brain abnormalities were identified in all investigated with MRI and included leukoencephalopathy (11/14) mostly periventricular, abnormal cortex morphology (7/14 - polymicrogyria 1, increased cortical thickness 4, pachygyria 3), cortical atrophy, corpus callosum hypoplasia (7/14). Intracranial calcifications were identified in all (9/9) investigated with CT scan. Abnormal growth was reported for several (SGA in 9/16, FTT 8/16, short stature 7/16) often associated with feeding difficulties (7/16). Other features incl. abnormal hearing (4/16), congenital heart defects (7/16), ophthalmologic findings (8/16), undescended testes (3/10). There were no overlapping facial features.

The fetus displayed similar features incl. SGA, microcephaly, intracranial calcifications.

Investigations incl. exome/genome sequencing (singleton or trio) with Sanger for confirmation/segregation of variants where necessary. Variable previous investigations incl. metabolic screening, TORCH screening, chromosomal studies (CMA) are mentioned in the supplement and were non-diagnostic. Additional candidate variants were identified in few cases although cases with plausible dual diagnoses (e.g. ind14) were not included in the overall phenotypic description.

9 pLoF variants (nonsense, frameshift, 1 splicing) predicted to lead to NMD were identified. There were no functional studies performed.
The missense variant c.2177G>T / p.Gly726Val (NM_003622.4) was predicted deleterious by in silico tools while the AA change causing severe steric problems upon modelling.

PPFIBP1 encodes PPFIA-binding protein 1 also known as liprin-β1. As the authors discuss: The liprin family of proteins comprises liprins α1 to 4 and liprin β1 and β2 in mammals. Liprin β1 is known to homodimerize and heterodimerize with α-liprins. In fibroblast cultures liprins β1 and α1 colocalize to cell membrane and periphery of focal adhesions. Members of the liprin-α fam. are scaffold proteins playing a role in synapse formation/signaling and axonal transport.

A ko model of the PPFIBP1 ortholog in C.elegans displayed abnormal locomotion behavior. In Drosophila, null-allele mutants resulted in altered axon outgrowth and synapse formation of R7 photoreceptors and reduced neuromuscular junction size (Refs provided in article).

Using a PPFIBP1/hlb-1 ko C.elegans model the authors demonstrated defects in spontaneous and light-induced behavior. Sensitivity of the worms to an acetylcholinesterase inhibitor (aldicarb) was suggestive of a presynaptic defect.

----

There is currently no PPFIBP1 - associated phenotype in OMIM / G2P.
SysNDD lists PPFIBP1 among the ID genes (limited evidence based on the 3 sibs reported by Shaheen et al, 2019 - PMID: 30214071).
In PanelApp Australia the gene is listed with green rating for ID, epilepsy, microcephaly based on the medRxiv pre-print.
Sources: Literature
Intellectual disability v3.1628 SEMA3E Sarah Leigh gene: SEMA3E was added
gene: SEMA3E was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: SEMA3E was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SEMA3E were set to 35628442
Phenotypes for gene: SEMA3E were set to Severe Intellectual Disability with Cognitive Regression
Review for gene: SEMA3E was set to AMBER
Added comment: Not associated with a phenotype in OMIM or Gen2Phen. One variant has been reported in a case of Severe Intellectual Disability with Cognitive Regression (PMID: 35628442). PMID: 35628442 also describes functional studies which show that this variant impairs protein secretion and hampers the binding to both embryonic mouse neuronal cells and tissues, furthermore, SEMA3E was revealed to be expressed during human brain development.
Sources: Literature
Intellectual disability v3.1627 SLC1A2 Sarah Leigh Phenotypes for gene: SLC1A2 were changed from Epileptic encephalopathy, early infantile, 41, 617105; Intellectual disability to Epileptic encephalopathy, early infantile, 41, OMIM:617105; developmental and epileptic encephalopathy, 41, MONDO:0014916
Intellectual disability v3.1624 MAL Julia Baptista gene: MAL was added
gene: MAL was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: MAL was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MAL were set to 35217805
Phenotypes for gene: MAL were set to developmental delay; nystagmus; progressive motor deterioration; dysmyelination
Review for gene: MAL was set to AMBER
Added comment: Single consanguineous family reported with two affected children (DD and nystagmus). New onset ataxia and cerebellar volume loss with patchy dysmyelination. Homozygous missense variant identified by exome analysis segregated with the condition. Functional data suggested that p.(Ala109Asp) severely affects protein folding of MAL, leading to mislocalization in the ER.
Sources: Literature
Intellectual disability v3.1623 MTM1 Arina Puzriakova Phenotypes for gene: MTM1 were changed from X-linked Myotubular Myopathy; MYOTUBULAR MYOPATHY, X-LINKED to Myopathy, centronuclear, X-linked, OMIM:310400
Intellectual disability v3.1619 WNK3 Arina Puzriakova Added comment: Comment on list classification: There is now enough evidence to promote this gene to Green at the next GMS review - at least 14 individuals from 6 unrelated families, all presenting with ID in association with variants in the WNK3 gene.
Intellectual disability v3.1617 CHD5 Sarah Leigh Phenotypes for gene: CHD5 were changed from OMIM:610771; Intellectual disability, MONDO:0001071; Epilepsy, MONDO:0005027 to Parenti-Mignot neurodevelopmental syndrome, OMIM:610771; Intellectual disability, MONDO:0001071; Epilepsy, MONDO:0005027
Intellectual disability v3.1615 NR4A2 Sarah Leigh Phenotypes for gene: NR4A2 were changed from Language impairment; Intellectual disability; Autism; Behavioral abnormality; No OMIM number to Intellectual developmental disorder with language impairment and early-onset DOPA-responsive dystonia-parkinsonism, OMIM:619911
Intellectual disability v3.1612 ATP6V0A1 Sarah Leigh edited their review of gene: ATP6V0A1: Added comment: Not associated with a phenotype in OMIM, but as definitive Gen2Phen gene for ATP6V0A1-related developmental disorder (monoallelic). At least four variants have been reported as de novo heterozygous variants in 14 apparently unrelated cases, with intellectual disability (11/11 cases who could be assessed), epilepsy/EEG abnormalities (11/13 who could be assessed), microcephaly (6/12 cases who could be assessed), ataxia (6/13 cases who could be assessed) and various other phenotypic features (PMID: 34909687 (table 1) & 33833240). Six additional ATP6V0A1 variants were reported as biallelic in four apparently unrelated cases, who all had intellectual disability, epilepsy/EEG abnormalities plus cerebral and cerebellar atrophy / brain atrophy (PMID: 34909687 (table 1) & 33833240).; Changed rating: GREEN; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.1612 ATP6V0A1 Sarah Leigh changed review comment from: Comment on mode of inheritance: Monallelic mode of inheritance has been selected for ATP6V0A1, although four families showed biallelic ATP6V0A1 variants. This in line Gen2Phen and the views Zornitza Stark and Mike Spiller who have reviewed this gene, and reflects the inconstitancies of the phenotypes amongst these individuals. As more data is obtained, it maybe that the mode of inheritance is changed to both mono and biallelic.; to: Comment on mode of inheritance: Monoallelic mode of inheritance has been selected for ATP6V0A1, although four families showed biallelic ATP6V0A1 variants. This in line Gen2Phen and the views Zornitza Stark and Mike Spiller who have reviewed this gene.
Intellectual disability v3.1611 ATP6V0A1 Sarah Leigh changed review comment from: Comment on mode of inheritance: Monallelic mode of inheritance has been selected for ATP6V0A1, although four families showed biallelic ATP6V0A1 variants. This in line the views Zornitza Stark and Mike Spiller who have reviewed this gene, and reflects the inconstitancies of the phenotypes amongst these individuals. As more data is obtained, it maybe that the mode of inheritance is changed to both mono and biallelic.; to: Comment on mode of inheritance: Monallelic mode of inheritance has been selected for ATP6V0A1, although four families showed biallelic ATP6V0A1 variants. This in line Gen2Phen and the views Zornitza Stark and Mike Spiller who have reviewed this gene, and reflects the inconstitancies of the phenotypes amongst these individuals. As more data is obtained, it maybe that the mode of inheritance is changed to both mono and biallelic.
Intellectual disability v3.1611 ATP6V0A1 Sarah Leigh Added comment: Comment on mode of inheritance: Monallelic mode of inheritance has been selected for ATP6V0A1, although four families showed biallelic ATP6V0A1 variants. This in line the views Zornitza Stark and Mike Spiller who have reviewed this gene, and reflects the inconstitancies of the phenotypes amongst these individuals. As more data is obtained, it maybe that the mode of inheritance is changed to both mono and biallelic.
Intellectual disability v3.1608 TMEM63C Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review, as mild intellectual disability has been diagnosed in the three families carrying TMEM63C variants reported in PMID: 35718349.
Intellectual disability v3.1607 TMEM63C Sarah Leigh gene: TMEM63C was added
gene: TMEM63C was added to Intellectual disability. Sources: Literature
Q3_22_rating tags were added to gene: TMEM63C.
Mode of inheritance for gene: TMEM63C was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TMEM63C were set to 35718349
Phenotypes for gene: TMEM63C were set to hereditary spastic paraplegia, MONDO:0019064
Review for gene: TMEM63C was set to GREEN
Added comment: Not associated with a phenotype in OMIM, Gen2Phen or MONDO. PMID:35718349 reports four TMEM63C variants in seven individuals from three unrelated families with childhood onset hereditary spastic paraplegia, with mild intellectual disability in some cases. Functional studies in PMID:35718349, reveal a role for TMEM63C in regulating both endoplasmic reticulum and mitochondrial morphologies.
Sources: Literature
Intellectual disability v3.1606 ATP6V0A1 Mike Spiller changed review comment from: Bott et al 2021 PMID: 34909687

17 individuals from 14 unrelated families

12 individuals with de novo variants in ATP6V0A1.
Associated with severe intellectual disability and refractory seizures following initial normal development.
1 stillborn; other 11 all have intellectual disability and slowing of developmental progression. 10 have epilepsy, microcephaly also common and MRI abnormalities in some.
Dysmorphic features less common.

7/12 have recurrent hotspot variant NM_001130021.3 c.2219G>A R740Q.

Biallelic inheritance also suggested - 2 separate families (apparently unrelated by IBD analysis) with affected individuals compound heterozygous for c.445delG p.(Glu149fs) and c.1483C>T p.(Arg495Trp).
Phenotype of ID, epilepsy, but with ataxia and cerebellar anomalies.

Gene involved in proton transport into organelles. Cell lines stably expressing R740Q show reduced endolysosome acidification consistent with reduced transporter function.
Supported by data showing impaired maturation of Cathepsin D (requires acidic pH).
Also refer to studies of yeast homologue showing that R735 (corresponds to human R740) is essential for proton transport function (Kawasaki-Nishi et al 2001 PMID: 11592980).

Strong evidence that pathogenic missense variants in this gene cause severe ID/epilepsy, Less certain for biallelic inheritance.
Recommend upgrade to Green for ID and epilepsy.; to: Bott et al 2021 PMID: 34909687

17 individuals from 14 unrelated families

12 individuals with de novo variants in ATP6V0A1.
Associated with severe intellectual disability and refractory seizures following initial normal development.
1 stillborn; other 11 all have intellectual disability and slowing of developmental progression. 10 have epilepsy, microcephaly also common and MRI abnormalities in some.
Dysmorphic features less common.

7/12 have recurrent hotspot variant NM_001130021.3 c.2219G>A R740Q.

Biallelic inheritance also suggested - 2 separate families (apparently unrelated by IBD analysis) with affected individuals compound heterozygous for c.445delG p.(Glu149fs) and c.1483C>T p.(Arg495Trp).
Phenotype of ID, epilepsy, but with ataxia and cerebellar anomalies.

Gene involved in proton transport into organelles. Cell lines stably expressing R740Q show reduced endolysosome acidification consistent with reduced transporter function.
Supported by data showing impaired maturation of Cathepsin D (requires acidic pH).
Also refer to studies of yeast homologue showing that R735 (corresponds to human R740) is essential for proton transport function (Kawasaki-Nishi et al 2001 PMID: 11592980).

Strong evidence that heterozygous pathogenic missense variants in this gene cause severe ID/epilepsy, Less certain for biallelic inheritance.
Recommend upgrade to Green for ID and epilepsy.
Intellectual disability v3.1604 SYNE2 Sarah Leigh gene: SYNE2 was added
gene: SYNE2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: SYNE2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SYNE2 were set to 34573277
Phenotypes for gene: SYNE2 were set to autism spectrum disorder, developmental delay and intellectual disability
Review for gene: SYNE2 was set to RED
Added comment: Biallelic SYNE2 variants are not associated with autism spectrum disorder, developmental delay and intellectual disability in OMIM or Gen2Phen. PMID: 34573277 reports compound heterozygous SYNE2 variants in a child with autism spectrum disorder, developmental delay and intellectual disability, together with supportive functional studies.
Sources: Literature
Intellectual disability v3.1601 ZMYM2 Sarah Leigh Phenotypes for gene: ZMYM2 were changed from Abnormality of the urinary system; Global developmental delay; Intellectual disability; Microcephaly; Abnormality of the cardiovascular system; Autism; Seizures; Abnormality of the head or neck; Abnormality of the nail; Small hand; Short foot; Clinodactyly to Neurodevelopmental-craniofacial syndrome with variable renal and cardiac abnormalities, OMIM:619522
Intellectual disability v3.1600 ZMYM2 Sarah Leigh edited their review of gene: ZMYM2: Added comment: Associated with relevant phenotype in OMIM and as strong Gen2Phen gene for ZMYM2-related developmental disorder (monoallelic). At least 3 variants have been reported in cases with mild to unclassified intellectual disability in PMID: 32891193. The review from Tracy Lester (Genetics laboratory, Oxford UK) mentions several additional de novo variants reported by Decipher associated with intellectual / developmental disability.; Changed rating: GREEN
Intellectual disability v3.1599 CUL3 Sarah Leigh edited their review of gene: CUL3: Added comment: Associated with relevant phenotype in OMIM and as definitive Gen2Phen gene. At least seven variants have been reported in publications (PMIDs: 32341456;25969726;31696658;33097317;30311385) in at least seven unrelated cases, together with a case reported by Julie Evans (South West Genomic Laboratory Hub) all being diagnosed with Neurodevelopmental disorder with or without autism or seizures, OMIM:619239. Severe intellectual disability (ID) was observed in two of these cases, mild in three cases and unclassified ID in another case. Seizures were also evident in three cases and a febrile seizure was reported in another case.; Changed rating: GREEN
Intellectual disability v3.1597 CUL3 Sarah Leigh Phenotypes for gene: CUL3 were changed from Global developmental delay; Intellectual disability; Autism Spectrum Disorder; Seizures; Abnormality of cardiovascular system morphology; Abnormality of the palate; Pseudohypoaldosteronism, type IIE, 614496 to Neurodevelopmental disorder with or without autism or seizures, OMIM:619239
Intellectual disability v3.1594 RYR2 Sarah Leigh changed review comment from: PMID: 30170228 reports 34/421 RYR2-associated catecholaminergic polymorphic ventricular tachycardia (CPVT1) patients had intellectual disability. It was also possible to establish that de novo variants had arisen in 13/24 of these cases. RYR2 has not been made green on this panel at present, as ID is not a common feature of CPVT1 and it would appear that penetrance is incomplete.; to: PMID: 30170228 reports 34/421 RYR2-associated catecholaminergic polymorphic ventricular tachycardia (CPVT1) patients had intellectual disability. It was also possible to establish that de novo RYR2 variants had arisen in 13/24 of these cases. RYR2 has not been made green on this panel at present, as ID is not a common feature of CPVT1 and it would appear that penetrance is incomplete.
Intellectual disability v3.1593 ZMYM2 Tracy Lester reviewed gene: ZMYM2: Rating: GREEN; Mode of pathogenicity: None; Publications: 32891193; Phenotypes: Intellectual disability, developmental delay, delayed speech and language, learning disability; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.1593 RYR2 Dmitrijs Rots gene: RYR2 was added
gene: RYR2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: RYR2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RYR2 were set to 30170228
Penetrance for gene: RYR2 were set to Incomplete
Review for gene: RYR2 was set to GREEN
Added comment: In a large cohort of RYR2-related CPVT, 8% of individuals (34 of 421) were having ID of various severity. Funcional data suggest that highly damaging RYR2 variants underlie ID.
Sources: Literature
Intellectual disability v3.1593 ALKBH8 Konstantinos Varvagiannis edited their review of gene: ALKBH8: Added comment: Please consider upgrade to green rating.

2 additional relevant families reported in literature, as summarized below. While affected individuals from 3 (of the 4 total) families with the disorder were homozygous for truncating variants in the last exon (potentially corresponding to hypomorphic / incomplete LoF rather than null alleles), a more recent publication describes 2 sibs homozygous for a missense SNV with demonstrated loss-of-function in the context of normal protein levels.

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Saad et al (2020 - PMID: 33544954) report 2 sibs, born to consanguineous parents from Egypt homozygous for an ALKBH8 frameshift variant. Both exhibited global DD and ID (proband IQ of 51 / Stanford Binet test, sib: 42 using Weschler scale). There was no history of seizures. Family based exome sequencing of both sibs and parents revealed homozygosity for NM_001301010.1:c.1684delC [p.(Arg562Alafs*56))] within a region of AOH. As the authors note this variant also occurred in the last exon of the gene, likely escaping NMD and based on previous evidence from Monnies et al, hypothesize that truncating variants in the last exon represent hypomorphic alleles encoding for a partially functional protein, while protein truncating variants in earlier exons may be null alleles.

Maddirevula et al (2021 - PMID: 34757492) describe the phenotype of 2 sibs, homozygous for a missense variant. Features included severe DD and ID, microcephaly, facial dysmorphism and epilepsy (the latter limited to the elder one). Exome with autozygome analysis identified homozygosity for a missense variant (NM_138775.2:c.1874G>A / p.Arg625His) with Sanger for confirmation / segregation studies.LC-MS/MS using tRNA isolated from LCLs from the affected individual, a carrier parent and controls revealed complete loss of ALKBH8-dependent tRNA posttranscriptional modifications, the results being suggestive of abrogation of the catalytic activities of both MT and Ox domains. The protein was detected at low levels in LCLs from control and patient samples, a finding that was also supported by immunoblot analysis suggesting that the observed loss-of-function is not mediated by loss of the protein.; Changed rating: GREEN; Changed publications to: 33544954, 34757492
Intellectual disability v3.1590 SRRM2 Sarah Leigh edited their review of gene: SRRM2: Added comment: Not associated with a phenotype in OMIM and as definitive Gen2Phen gene for SRRM2-related developmental disorder (monoallelic). At least 22 loss of function SRRM2 variants have been reported in PMID: 35567594 in unrelated cases of which 16/20 exhibit variable mild intellectual disability.; Changed rating: GREEN
Intellectual disability v3.1589 SRRM2 Sarah Leigh changed review comment from: Comment on phenotypes: SRRM2-related developmental disorder (monoallelic) is the phenotype listed by Gen2Phen (https://www.ebi.ac.uk/gene2phenotype/gfd?dbID=4427) to be associated with SRRM2 variants.; to: Comment on phenotypes: SRRM2-related developmental disorder (monoallelic) is the phenotype listed by Gen2Phen (https://www.ebi.ac.uk/gene2phenotype/gfd?dbID=4427) to have a definitive association with SRRM2 variants.
Intellectual disability v3.1589 SRRM2 Sarah Leigh Added comment: Comment on phenotypes: SRRM2-related developmental disorder (monoallelic) is the phenotype listed by Gen2Phen (https://www.ebi.ac.uk/gene2phenotype/gfd?dbID=4427) to be associated with SRRM2 variants.
Intellectual disability v3.1587 PRPF8 Sarah Leigh edited their review of gene: PRPF8: Added comment: Associated with Retinitis pigmentosa 13 (OMIM:600059) in OMIM, but not with PRPF8-related developmental disorder (monoallelic) and as a both RD and IF Gen2Phen gene for PRPF8-related developmental disorder (monoallelic). PMID: 35543142 reports 14 PRPF8 variants in unrelated cases (12/14 variants were confirmed as de novo). Intellectual disability was observed in 13/14 of these cases and seizures were evident in 4/14 cases.; Changed rating: GREEN
Intellectual disability v3.1581 SCAF4 Sarah Leigh edited their review of gene: SCAF4: Added comment: In repsonse to Ian Berry's (Leeds Genetics Laboratory) review, which also reports an additional patient with a de novo truncating variant, there is sufficient evidence for SCAF4 to be green on this panel.; Changed rating: GREEN
Intellectual disability v3.1580 SRRM2 Konstantinos Varvagiannis changed review comment from: Recent report of 22 unrelated individuals with nonsense / frameshift variants or microdeletions of SRRM2 reported. DD was a universal feature, with ID present in some (16/20 - in all cases mild). Note possible 'overlap' with the study by Kaplanis et al / DDD study cited in the previous review by Prof. Z. Stark.

The gene is not intolerant to missense variation (z-score of -6.28) and eventual contribution of missense variants is not known. While SRRM2 is known to encode a splicing factor promoting interaction between mRNA and the spliceosome catalytic machinery (discussed below) molecular and functional studies are required to characterize the pathogenesis of the disorder.

There is currently no SRRM2-related phenotype in OMIM. SRRM2 is included in the DD panel of G2P [confidence : definitive, SRRM2-related developmental disorder (monoallelic), cited : Kaplanis et al / DDD]. In PanelApp Australia SRRM2 has amber rating in the ID panel (based on the study by Kaplanis et al / DDD).

Consider inclusion with green rating (several individuals/families/variants - rather consistent phenotype) or amber rating (as for pathogenesis / also DD universal feature, ID observed in most but not all affected individuals, when present always mild).

-----

Cuinat et al. (2022 - PMID: 35567594) report on 22 individuals with LoF variants in SRRM2.

All subjects had DD (22/22) predominantly affecting language acquisition (16/19) while motor delay was less common. ID was present in 16/20 (in all cases mild) of the individuals with available neurocognitive evaluation. Some individuals displayed autistic features (9/22) although others had a friendly - in some cases excessively - sociable personality (8/22). Other features included hypotonia in some, growth abnormalities (12/22 overweight, 7/22 with obesity, 4/22 tall stature). Morphological features incl. facial (20/22 - e.g. deep-set eyes, bulbous nasal tip or smooth philtrum) or small hands and feet (6/22) were also reported. Visceral / skeletal abnormalities were uncommon.

SRRM2 encodes serine/arginine repetitive matrix protein 2 (or SRm300), a nuclear ubiquitous protein forming a complex with the protein encoded by SRRM1 (SRm160). As the authors summarize this complex is one of the main catalytic components of the spliceosome having a role in pre-mRNA maturation.

12 subjects harbored frameshift variants, 8 nonsense while 2 further ones had microdeletions (66-270kb) spanning - but not limited to - SRRM2 (other genes not predicted to be haploinsufficient). The gene has a pLI in gnomAD of 1 (o/e = 0.06) while it appears to be tolerant to missense variation (z-score of -6.28 / o/e = 1.43). With the exception of the 2 subjects harboring a microdeletion, all were investigated with singleton/trio ES with no other candidate variants.

Variants occurred de novo in 19/22. Mosaicism (in an asymptomatic parent) was suspected based on the reads in one case. One individual had inherited the variant (parent with DD). Segregation analyses was not possible in one case.

While one variant lied in ex2 (of 15) all others were in the large ex11 (encoding ~2000 of the 2752 total residues based on the schema provided / NM_016333.4), all predicted to lead to NMD.

There are no studies for pathogenesis of the disorder or the underlying effect of variants. Animal models not discussed.

The authors do a comparison with other 'spliceosomopathies', e.g. due to variants in SF3B4 or EFTUD2, where DD/ID can be a feature although these disorders have also prominent skeletal features.

Previously, as the authors note, the study by Kaplanis et al (2020 - PMID: 33057194) integrating exome sequence data from ~31,000 parent-offspring trios of individuals with developmental disorders had identified SRRM2 among 28 genes significantly enriched in LoF variants. [ The present study possibly includes individuals from the aforementioned cohort, e.g. from Radboudumc ].; to: Recent report of 22 unrelated individuals with nonsense / frameshift variants or microdeletions of SRRM2. DD was a universal feature, with ID present in some affected individuals (16/20 - in all cases mild). Note possible 'overlap' with the study by Kaplanis et al / DDD study cited in the previous review by Prof. Z. Stark.

The gene is not intolerant to missense variation (z-score of -6.28) and eventual contribution of missense variants is not known. While SRRM2 is known to encode a splicing factor promoting interaction between mRNA and the spliceosome catalytic machinery (discussed below) molecular and functional studies are required to characterize the pathogenesis of the disorder.

There is currently no SRRM2-related phenotype in OMIM. SRRM2 is included in the DD panel of G2P [confidence : definitive, SRRM2-related developmental disorder (monoallelic), cited : Kaplanis et al / DDD]. In PanelApp Australia SRRM2 has amber rating in the ID panel (based on the study by Kaplanis et al / DDD).

Consider inclusion with green rating (several individuals/families/variants - rather consistent phenotype) or amber rating (as for pathogenesis / also DD universal feature, ID observed in most but not all affected individuals, when present always mild).

-----

Cuinat et al. (2022 - PMID: 35567594) report on 22 individuals with LoF variants in SRRM2.

All subjects had DD (22/22) predominantly affecting language acquisition (16/19) while motor delay was less common. ID was present in 16/20 (in all cases mild) of the individuals with available neurocognitive evaluation. Some individuals displayed autistic features (9/22) although others had a friendly - in some cases excessively - sociable personality (8/22). Other features included hypotonia in some, growth abnormalities (12/22 overweight, 7/22 with obesity, 4/22 tall stature). Morphological features incl. facial (20/22 - e.g. deep-set eyes, bulbous nasal tip or smooth philtrum) or small hands and feet (6/22) were also reported. Visceral / skeletal abnormalities were uncommon.

SRRM2 encodes serine/arginine repetitive matrix protein 2 (or SRm300), a nuclear ubiquitous protein forming a complex with the protein encoded by SRRM1 (SRm160). As the authors summarize this complex is one of the main catalytic components of the spliceosome having a role in pre-mRNA maturation.

12 subjects harbored frameshift variants, 8 nonsense while 2 further ones had microdeletions (66-270kb) spanning - but not limited to - SRRM2 (other genes not predicted to be haploinsufficient). The gene has a pLI in gnomAD of 1 (o/e = 0.06) while it appears to be tolerant to missense variation (z-score of -6.28 / o/e = 1.43). With the exception of the 2 subjects harboring a microdeletion, all were investigated with singleton/trio ES with no other candidate variants.

Variants occurred de novo in 19/22. Mosaicism (in an asymptomatic parent) was suspected based on the reads in one case. One individual had inherited the variant (parent with DD). Segregation analyses was not possible in one case.

While one variant lied in ex2 (of 15) all others were in the large ex11 (encoding ~2000 of the 2752 total residues based on the schema provided / NM_016333.4), all predicted to lead to NMD.

There are no studies for pathogenesis of the disorder or the underlying effect of variants. Animal models not discussed.

The authors do a comparison with other 'spliceosomopathies', e.g. due to variants in SF3B4 or EFTUD2, where DD/ID can be a feature although these disorders have also prominent skeletal features.

Previously, as the authors note, the study by Kaplanis et al (2020 - PMID: 33057194) integrating exome sequence data from ~31,000 parent-offspring trios of individuals with developmental disorders had identified SRRM2 among 28 genes significantly enriched in LoF variants. [ The present study possibly includes individuals from the aforementioned cohort, e.g. from Radboudumc ].
Intellectual disability v3.1580 DROSHA Konstantinos Varvagiannis gene: DROSHA was added
gene: DROSHA was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: DROSHA was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: DROSHA were set to 35405010
Phenotypes for gene: DROSHA were set to Global developmental delay; Intellectual disability; Seizures; Cerebral white matter atrophy; Abnormality of the corpus callosum; Abnormality of movement; Stereotypic behavior; Abnormality of head or neck; Short foot
Penetrance for gene: DROSHA were set to unknown
Mode of pathogenicity for gene: DROSHA 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: DROSHA was set to AMBER
Added comment: Profound DD, ID and seizures have been reported in 2 unrelated subjects with de novo missense variants. The gene has a role in miRNA biogenesis. Both variants described have been shown to have effect on DROSHA's function in Drosophila / C. elegans (partial loss-of-function vs possibility of antimorphic effect discussed || in gnomAD several individuals with LoF alleles / Z=3.98 – pLI : 0.09).

There is currently no DROSHA-related phenotype in OMIM, G2P, SysNDD. In PanelApp Australia the gene has amber rating in genetic epilepsy and microcephaly panels (not currently included in the ID one).

Consider inclusion in the current panel with amber rating. Also consider inclusion in other possibly relevant panels (given postnatal microcephaly, abn. corpus callosum, progressive white matter atrophy, etc) [ NOT added ]

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Barish, Senturk, Schoch et al (2022 - PMID: 35405010) describe the phenotype of 2 unrelated individuals with de novo missense DROSHA variants.

Features included generalized hypotonia, postnatal microcephaly (-2,6 and -6 SD), feeding difficulties, profound DD and ID, seizures, abnormal movements (choreoathetosis / stereotypic movements), variable respiratory symptoms (in one case episodes of hyperventilation/apnea), cardiovascular or skeletal findings. Brain MRI demonstrated white matter atrophy and thin corpus callosum in both. Brachycephaly with broad face as well as short feet were also among the shared features.

Both were investigated by trio ES/GS which were otherwise non diagnostic and without other candidate variants. The 1st individual harbored a de novo htz missense DROSHA variant (c.3656A>G/p.Asp1219Gly) while the 2nd subject had another missense variant (c.4024C>T/p.Arg1342Trp) [NM_013235.4] confirmed by Sanger seq.

DROSHA (on 5p13.3) encodes a ribonuclease, subunit of the microprocessor complex, involved in miRNA biogenesis. Specifically, miRNAs are transcribed as part of pri-miRNAs (primary-miRNAs) which are cleaved to pre-miRNAs (precursor-miRNAs) in the nucleus by DROSHA (and its partner DGCR8 or Pasha) and then exported to the cytoplasm for further processing. Cleavage of pre-miRNAs by DICER1 generates mature miRNAs subsequently loaded to the RISC (RNA-induced silencing) complex which uses miRNA as template for recognition and cleavage of complementary mRNA with RNAse.

As the authors discuss, miRNA defects have a well-established role in development of model organisms e.g. (several Refs. provided):
- in C. elegans miRNA mutants causing lethality, developmental arrest and heterochronicity
- in Drosophila playing a role in the development of ovary, eye, nervous system etc.
- in mice mRNAs play a role in BMP and TGF-beta signaling while neuronal loss of miRNA processing leads to neurodegeneration/anatomical defects.

Feingold syndrome 2 is the single Mendelian disease associated to date with miRNAs, through deletion of a cluster containing 6 MIR genes.

miRNA dysregulation is also observed in Rett syndrome - and DROSHA implicated in the pathogenesis of the syndrome - as MECP2 and FOXG1 are cofactors of the microprocessor complex regulating processing of miRNA. One of the individuals here reported had a clinical diagnosis of Rett spectrum while both had overlapping features with Rett s.

Studies of DROSHA-dependent miRNAs in fibroblasts from one individual revealed significantly altered expression of mature miRNA (e.g. increased miR98, a miRNA with reduced expression in studies of somatic DROSHA variants) although this was not likely due to processing errors (given only a modest decrease of precursor miRNAs).

Previous studies have demonstrated that drosha (the Drosophila ortholog) null mutants die during post-embryonic development with 100% lethality before adulthood (3rd instar larval stage/beginning of pupariation). Mosaic flies with mutant eyes are small-eyed, while viable hypomorphic alleles display synaptic transmission defects (several Refs provided).

Here, homozygous flies for null alleles died at the end of 3rd instar larval stage/beginning of pupariation, while loss of drosha resulted in lack of imaginal disc tissue (which surrounds the larval brain) and severely reduced brain size, the latter similar to the microcephaly phenotype. [To the best of my understanding] introduction of a mutated genomic rescue construct (carrying similar substitutions as those observed in human subjects) in eye-specific drosha null (W1123X) flies was partially able to rescue eye/head size for wt or Asp1219Gly (human:Asp1084Gly) suggesting that the latter is a partial LoF allele. Arg1210Trp (corresponding to human Arg1342Trp) was able to rescue the eye phenotype and was not damaging to the function in the specific assay. Drosha expression levels were similar for genomic rescue flies either for wt or for the Asp-Gly variant suggesting that the effect was not due to expression levels (but rather function). Expression of mature miRNAs known to be regulated by Drosha were not affected when comparing wildtype larvae with genomic construct for wt or Asp1084Gly.

Upon expression of human cDNA using GAL4/UAS system in drosha mutant (null) eye clones, the reference partially rescued the eye size defect, Asp-Gly behaved as partial loss-of-function allele (~50% function compared to ref), while the Arg-Trp variant was shown to behave as a weaker loss-of-function allele.

The authors generated eye-specific drosha mutant clones to study the aging adult eye using ERG recordings. While null mutants display almost no response to light (7- and 20-day old flies), wt genomic rescue was shown to rescue ERG responses, Asp-Gly variant had significant defects (at both 7 and 20 days) and the Arg-Trp had defects approaching statistical significance only at the age of 20 days. Overall these data suggested that Arg-Trp had less severe effect compared to Asp-Gly (as above) while both variants led to progressive neuronal dysfunction.

Using CRISPR/Cas9 the authors generated C.elegans knock-ins for a variant analogous to the Asp1219Gly human one. Homozygous animals were inviable at larval stages, displayed a heterochronic phenotype (heterochronicity : development of cells or tissues at an abnormal time relative to other unaffected events in an organism / miRNAs are known to be involved in the heterochronic gene pathway) while this variant was deleterious to the Drosha's ability to process miRNAs.
Sources: Literature
Intellectual disability v3.1580 SOX11 Sarah Leigh Added comment: Comment on phenotypes: Described as MENTAL RETARDATION, AUTOSOMAL DOMINANT, 27 by Gen2Phen (https://www.ebi.ac.uk/gene2phenotype/gfd?dbID=405).
Intellectual disability v3.1580 SOX11 Sarah Leigh Phenotypes for gene: SOX11 were changed from MENTAL RETARDATION, AUTOSOMAL DOMINANT, 27 to Coffin-Siris syndrome 9, OMIM:615866
Intellectual disability v3.1578 PRODH Sarah Leigh edited their review of gene: PRODH: Added comment: Evidence for the association of PRODH variants with Hyperprolinemia, type I, OMIM; 239500 has been classified as Definitive by ClinGen Aminoacidopathy Gene Curation Expert Panel on 04/27/2021
(https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_5f28c677-a9b4-4bb3-9aed-14af97ad9896-2021-04-27T160000.000Z).; Changed rating: GREEN; Changed phenotypes to: Hyperprolinemia, type I, OMIM, 239500, hyperprolinemia type 1, MONDO:0009400
Intellectual disability v3.1576 PRPF8 Konstantinos Varvagiannis gene: PRPF8 was added
gene: PRPF8 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: PRPF8 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: PRPF8 were set to 35543142
Phenotypes for gene: PRPF8 were set to Global developmental delay; Intellectual disability; Seizures; Autism; Retinitis pigmentosa 13, MIM # 600059
Penetrance for gene: PRPF8 were set to unknown
Review for gene: PRPF8 was set to AMBER
Added comment: A recent study suggests that heterozygous PRPF8 variants are associated with a syndromic form of DD/ID, in some cases epilepsy with heterogeneous other clinical findings. However the authors acknowledge that not all variants within their cohort may be pathogenic (5 VUSs using ACMG criteria) and that conclusive evidence may necessitate functional studies.

Heterozygous variants (typically clustering in exon 42) have been reported to cause a non-syndromic form of RP with variable expressivity and incomplete penetrance (Retinitis pigmentosa 13, MIM # 600059) .

Overall consider inclusion with amber rating.

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O'Grady et al. (2022 - PMID: 35543142) describe the phenotype of 14 unrelated individuals with heterozygous, mostly de novo, missense and pLoF variants in PRPF8.

Nearly all had some degree of global developmental delay or ID (13/14). 6/14 had a diagnosis of ASD. Seizures were reported in 4 or 5 subjects. Other features included short stature (6/14), abnormal gait, cardiac anomalies and somewhat overlapping facial features (11/14). Ages ranged from 4 - 19 years (median : 9y).

PRPF8 encodes a component of the spliceosomes which in turn are involved in removal of introns from mRNA precursors. The gene is ubiquitously expressed with expression within brain being highest in cerebral cortex, basal ganglia and cerebellum (Refs. provided).

Individuals were investigated with exome sequencing (12/14) or an autism/ID panel of >2500 genes (likely application of virtual panel on exome data).

13 individuals harbored a missense SNV and 1 further had a frameshift variant. In 12 individuals the variant had occurred de novo. 1 individual had inherited the variant from a possibly mosaic parent, while for 1 further a single parental sample was available.

PRPF8 is intolerant to both missense (Z = 8.28) and pLoF variants (pLI : 1). Variants in 5 individuals were formally classified as VUS while 2 variants were present in gnomAD.

Additional findings (CNVs/SNVs) were reported, in some cases possibly of relevance.

As the authors discuss, heterozygous pathogenic missense SNVs cause (and account for ~2-3% of) non-syndromic AD retinitis pigmentosa with variable expressivity and incomplete penetrance. Variants for this phenotype are typically missense - although nonsense ones have also been reported - clustering within ex42 (of 43) encoding the MPN domain (aa 2103-2335 / NP_006436) and weakening interaction with 2 other spliceosomal proteins.

Variants in the present study occurred throughout the gene. Although not universally assessed within the cohort, only one participant had RP (in this case variant within the MPN domain).

There were no variant studies performed.

Animal models: the authors cite a study by Graziotto et al (2011 - PMID: 20811066) where knock-in mice for a missense variant in ex42 displayed defects of the retinal pigment epithelium. A zebrafish ko model also cited (Keightley et al, 2013 - PMID: 23714367) displayed widespread apoptosis in brain and spinal cord.

The authors cite a previous bioinformatic study identifying PRPF8 as a major hub connecting gene-interaction networks for NDDs (Casanova et al, 2018 - PMID: 30420816) as well as 2 studies demonstrating enrichment of variants in individuals with NDDs compared to controls (da Silva Montenegro et al, 2020 - PMID: 31696658, Karczewski et al, 2020 - PMID: 32461654).
Sources: Literature
Intellectual disability v3.1576 THUMPD1 Sarah Leigh changed review comment from: Not associated with a phenotype in OMIM or MONDO, but as moderate Gen2Phen gene for THUMPD1 neurodevelopment disorder. At least 7 variants have been reported, together with supportive functional studies (PMID: 35196516).; to: Not associated with a phenotype in OMIM or MONDO, but as moderate Gen2Phen gene for THUMPD1 neurodevelopment disorder. At least 8 variants have been reported in at least 7 unrelated cases, together with supportive functional studies (PMID: 35196516).
Intellectual disability v3.1576 THUMPD1 Sarah Leigh edited their review of gene: THUMPD1: Added comment: Not associated with a phenotype in OMIM or MONDO, but as moderate Gen2Phen gene for THUMPD1 neurodevelopment disorder. At least 7 variants have been reported, together with supportive functional studies (PMID: 35196516).; Changed rating: GREEN
Intellectual disability v3.1573 ZBTB7A Sarah Leigh edited their review of gene: ZBTB7A: Added comment: Associated with relevant phenotype in OMIM and as limited Gen2Phen gene. At least 11 variants have been reported in 10 unrelated cases.; Changed rating: GREEN
Intellectual disability v3.1571 CELF2 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - at least 11 unrelated individuals harbouring heterozygous variants (10 de novo) in this gene. DD/ID observed in all cases, and although in some this was subsequent to onset of seizures, at least 2 individuals showed no epilepsy and therefore inclusion of CELF2 on this panel would be of value.
Intellectual disability v3.1568 PHF14 Dmitrijs Rots gene: PHF14 was added
gene: PHF14 was added to Intellectual disability. Sources: Literature,Expert list
Mode of inheritance for gene: PHF14 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PHF14 were set to 35074918
Phenotypes for gene: PHF14 were set to Autism
Review for gene: PHF14 was set to GREEN
Added comment: Multiple individuals in the literature reported with NDD and de novo PHF14 variants + experimental findings (in 35074918).
Additional info from AutDB:"De novo missense variants in the PHF14 gene have been identified in an ASD proband from the SPARK cohort (Feliciano et al., 2019) and the Autism Sequencing Consortium cohort (Satterstrom et al., 2020), while additional rare de novo non-coding variation in this gene has also been observed in ASD probands (Sanders et al., 2015; Yuen et al., 2017). Zhou et al., 2022 reported that PHF14 forms a complex with MECP2 and TCF20; in the same report, the authors described two individuals with de novo variants in PHF14 who presented with neurodevelopmental phenotypes, including a patient with a de novo PHF14 missense variant that abolished the MECP2-PHF14-TCF20 interaction."
Sources: Literature, Expert list
Intellectual disability v3.1568 ROBO1 Konstantinos Varvagiannis gene: ROBO1 was added
gene: ROBO1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: ROBO1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: ROBO1 were set to 35348658; 35227688; 34193621; 31448886; 30692597; 29194579; 28592524; 28402530; 28286008
Phenotypes for gene: ROBO1 were set to ROBO1-related NDD
Penetrance for gene: ROBO1 were set to unknown
Review for gene: ROBO1 was set to AMBER
Added comment: DD/ID has been reported in some individuals with biallelic (e.g. 4 subjects in the study by Münch et al, 1 additional case reported by Calloni et al) or monoallelic ROBO1 variants (e.g. P2 in the study by Huang et al, with a diagnosis of EOEE due to a neomorphic variant).

Consider amber rating pending further review.

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Huang et al (2022 - PMID: 35348658) Monoallelic & Biallelic
Novel dominant and recessive variants in human ROBO1 cause distinct neurodevelopmental defects through different mechanisms.

Münch et al (2022 - PMID: 35227688) Biallelic
Biallelic pathogenic variants in roundabout guidance receptor 1 associate with syndromic congenital anomalies of the kidney and urinary tract

Woodring et al (2021 - PMID: 34193621) - Probably not relevant (VUS)
Uncertain, Not Unimportant: Callosal Dysgenesis and Variants of Uncertain Significance in ROBO1

Liu et al (2020 - PMID: 31448886) Monoallelic
A Novel Missense Mutation in Human Receptor Roundabout-1 (ROBO1) Gene Associated with Pituitary Stalk Interruption Syndrome.

Dateki et al (2019 - PMID: 30692597) Biallelic - This individual has been incl. in the study by Munch et al
A homozygous splice site ROBO1 mutation in a patient with a novel syndrome with combined pituitary hormone deficiency

Rasmussen et al (2018 - PMID: 29194579) Biallelic
Targeted gene sequencing and whole-exome sequencing in autopsied fetuses with prenatally diagnosed kidney anomalies

Kruszka et al (2017 - PMID: 28592524) Monoallelic
Loss of function in ROBO1 is associated with tetralogy of Fallot and septal defects

Bashamboo et al (2017 - PMID: 28402530) Monoallelic
Mutations in the Human ROBO1 Gene in Pituitary Stalk Interruption Syndrome

Calloni et al (2017 - PMID: 28286008) Biallelic
Compound Heterozygous Variants in ROBO1 Cause a Neurodevelopmental Disorder With Absence of Transverse Pontine Fibers and Thinning of the Anterior Commissure and Corpus Callosum
Sources: Literature
Intellectual disability v3.1568 CELF2 Julia Baptista gene: CELF2 was added
gene: CELF2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: CELF2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CELF2 were set to 34107259; 33131106
Phenotypes for gene: CELF2 were set to Developmental delay; epileptic encephalopathy
Mode of pathogenicity for gene: CELF2 was set to Other
Review for gene: CELF2 was set to GREEN
Added comment: De novo missense variants in six individuals (PMID:34107259). The variants cluster on the C‐terminus, a nuclear localization sign. Phenotypic findings include global developmental delay with moderate to severe impairment of speech and language capacities, infantile spasms, stereotypic movements and/or aggressive behaviors, and one individual was diagnosed with ASD.

A previous publication (PMID: 33131106) reported five unrelated individuals (four de novo). Two missense variants, one frameshift predicted to escape NMD and one splice site variant, c.272‐1G>C were identified; these variants, except the splicing, clustered on the C‐terminus.
Sources: Literature
Intellectual disability v3.1565 HIST1H4C Arina Puzriakova Mode of pathogenicity for gene: HIST1H4C 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
Intellectual disability v3.1564 ADD1 Konstantinos Varvagiannis gene: ADD1 was added
gene: ADD1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: ADD1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: ADD1 were set to 34906466
Phenotypes for gene: ADD1 were set to Global developmental delay; Intellectual disability; Seizures; Ventriculomegaly; Abnormality of the corpus callosum
Penetrance for gene: ADD1 were set to unknown
Review for gene: ADD1 was set to AMBER
Added comment: A recent study suggests an ADD1-related phenotype (3 subjects with monoallelic de novo variants/1 with biallelic variants) with DD/ID and ventriculomegaly or corpus callosum dysgenesis and possibly seizures among the features.

There is currently no associated phenotype in other databases (OMIM, G2P, SysID, PanelApp Australia).

Consider inclusion in the current panel with amber / green rating (3 subjects/variants/families, role of the gene and mouse models recapitulating ventriculomegaly/CC abnormalities, relevant expression, variant studies demonstrating abn. protein levels and/or disruption of adducin heterodimer formation || monoallelic vs bi-allelic variants).

Please consider inclusion in other possibly relevant gene panels (e.g. for corpus callosum / ventriculomegaly) [ Not added ].

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Qi et al (2022 - PMID: 34906466) describe the phenotype of 3 unrelated individuals with monoallelic de novo ADD1 pathogenic variants as well as of a fourth homozygous for a missense SNV.

Overall, the authors propose a common phenotype consisting of morphological brain abnormalities (incl. ventriculomegaly and corpus callosum dysgenesis) and neurological symptoms such as DD and/or ID and attention deficit.

All individuals were investigated with singleton/trio ES.

De novo variants - phenotype:
One individual investigated for hypotonia, DD & ID, partial ACC, well controlled seizures (on ketogenic diet) and proportional short stature harbored a de novo stopgain variant (NM_014189.3:c.1418G>A / p.Trp473*) absent from gnomAD.
Another affected subject with hypotonia, FTT/feeding difficulties, mild motor delays complete ACC, a seizure (2y11m), staring spells without EEG correlate, and fatigue (with low coenz. Q10, and complex I & IV deficiency in muscle biopsy) had a de novo fs variant (NM_001119:c.2029_2039del / p.Glu680Argfs*7 - gnomAD:0) and a VUS in a gene not associated with phenotype to date.
A 3rd subject investigated for seizures (onset:1y), speech delay, mild ID, ADHD, without MRI abnormalities harbored a de novo missense SNV (NM_001119:c.670C>T / p.His224Tyr - gnomAD:0) and with cmp htz for 2 missense SPTBN2 SNV not fitting the phenotype (no ataxia).

Biallelic variants - phenotype:
One individual with ID, and ACC, abnormal sulcation, enlarged lateral and 3rd ventricles, abnormal of white matter and hypoplastic vermis upon MRI was reported to harbor in homozygosity a missense SNV (NM_001119:c.169A>T / p.Arg57Trp). There was an additional variant in a gene without associated phenotype to date and not expressed in brain.

Role of the encoded protein:
ADD1 encodes adducin 1/alpha (similar to ADD2, ADD3 encoding other adducins). As the authors note, adducins are cytoskeleton proteins critical for osmotic rigidity and cell shape. In neurons they have been reported to form membrane associated periodic ring-like structures with actin and β-spectrin. Deletion of Add1 in mice results in increased MPS ring diameter and axonal degeneration (several refs provided).

ADD1/2/3 form heterodimers which in turn form heterotetramers. ADD1 is expressed in most tissues.

Mouse model:
Previous mouse models have demonstrated that Add1 null mice have also undetectable ADD2/3 (suggesting a role for stabilization of the latter) and exhibit growth delay, anemia and develop lethal hydrocephalus and ventriculomegaly with 50% penetrance (cited PMIDs: 27068466, 18723693). Here the authors demonstrated that surviving mice had ventriculomegaly and thinning of corpus callosum thus recapitulating the respective human phenotypes. Htz mice also presented thinner CC, though not to a statistically significant extent.

ADD1 expression and isoforms:
- Performing mRNA studies and W.Blot in (developing - GW15-17) human or mouse brain (E12.5-P40) the authors demonstrated dynamic expression of ADD1 with differentially expressed isoforms, notably alternative splicing of ex10 and ex15 with NM_176801 (extended ex10, inclusion of ex15) corresponding to a neuronal isoform and NM_001119 (shorter ex10, exclusion of ex15) corresponding to a neural progenitor cell (NPC) isoform.
- Variants here reported appear to affect both isoforms with the exception of NM_001119:c.2029_2039del / p.Glu680Argfs*7 affecting only the longer NPC one.
- PTBP1 is an RNA binding protein expressed in NPCs known to suppress neuronal exon insertion. The authors demonstrated in mouse Neuro2A cells, through shRNA targeting of Ptbp1, that the latter suppresses the neuronal Add1 isoform.

Variant studies demonstrated that effect of variants was mediated by decreased protein levels and/or disruption of adducin complex formation (ADD1-ADD2 dimer formation known to be mediated by N- and C- terminal ADD1 domains):
- Expression of Arg57Trp (found in hmz in one individual) NPC and neuronal isoforms in Neuro2a cells showed that while protein levels were not significantly affected, there were (also) truncated protein products for both isoforms suggesting that aberrant splicing or protein translation/cleavage may apply.
- The authors generated HEK293FT cells for the truncating variants demonstrating decreased protein levels (using N-/C- terminal antibodies).
- Reduced (HA-tagged)-ADD1-(V5-tagged)-ADD2 protein interaction was shown to apply for the Arg57Trp and Arg473* in HEK293FT cells. Similarly in Neuro2a cells, reduced ADD1-ADD2 interaction was shown for His224Tyr.
Sources: Literature
Intellectual disability v3.1564 SMARCA5 Eleanor Williams Tag gene-checked tag was added to gene: SMARCA5.
Intellectual disability v3.1564 ARFGEF1 Eleanor Williams Tag gene-checked tag was added to gene: ARFGEF1.
Intellectual disability v3.1564 BUB1 Konstantinos Varvagiannis gene: BUB1 was added
gene: BUB1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: BUB1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BUB1 were set to 35044816
Phenotypes for gene: BUB1 were set to Congenital microcephaly; Global developmental delay; Intellectual disability; Abnormal heart morphology; Growth delay
Penetrance for gene: BUB1 were set to Complete
Review for gene: BUB1 was set to AMBER
Added comment: A recent study provides evidence that this gene (biallelic variants) is relevant for inclusion in the DD/ID panel likely with amber / green rating (2 unrelated individuals with similar phenotype, 3 variants, role of this gene, extensive variant studies and demonstrated effects on cohesion and chromosome segregation, similarities with other disorders caused by mutations in mitosis-associated genes at the clinical and cellular level || number of affected subjects/families, different protein levels/kinase activity likely underlying few differences observed, role of monoallelic variants unclear).

This gene could probably be included in other panels e.g. for microcephaly (not added).

There is no BUB1-related phenotype in OMIM, G2P, SysID, PanelApp Australia.

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Carvalhal, Bader et al (2022 - PMID: 35044816) describe the phenotype of 2 unrelated individuals with biallelic BUB1 pathogenic variants and provide evidence for the underlying mechanism for this condition.

Common features comprised congenital microcephaly (2/2 | -2,8 and -2.9 SDs respectively / -7 and -4,9 SDs on last evaluation), DD/ID (2/2 - in one case with formal evaluation mild), some degree of growth retardation (2/2) and cardiovascular findings (2/2 - small ASD type II). Other findings limited to one subject included Pierre-Robin sequence, Axenfeld-Rieger anomaly, choanal stenosis, hypospadias, tracheal stenosis, etc.

Initial genetic testing was normal (incl. CMA in both, metabolic testing and individual genes incl. PITX2, GREM1, FOXD3, FOXC1 for one proband).

Exome sequencing revealed homozygosity for a start-lost variant (NM_004336.4:c.2T>G / p.?) in the first subject (P1). The variant lied within a 14-Mb region of homozygosity (no reported consanguinity). The second individual (P2) was compound htz for a splice-site and a frameshift variant (c.2625+1G>A and c.2197dupG) with Sanger sequencing used for confirmation and segregation studies.

BUB1 encodes BUB1 Mitotic checkpoint serine/threonine kinase (/Budding uninhibited by benzimidazoles 1, s. cerevisiae, homolog of) a multifunctional component of the segregation machinery contributing to multiple mitotic processes. The protein has a kinetochore localization domain, multiple binding motifs and a C-terminal kinase domain (aa 784-1085) this structure allowing both kinase dependent/independent activities.

cDNA sequencing revealed that the splice variant leads to skipping of ex21 and in-frame deletion of 54 residues in the kinase domain (c.2625+1G>A / p.Val822_Leu875del).

Both individuals exhibited normal BUB1 mRNA levels (fibroblasts in both, tracheal tissue in one) but severely reduced protein levels (fibroblasts). A shorter protein product corresponding to the in-frame deletion variant was also detected.

The authors performed additional experiments to confirm small amounts of full-length protein produced by the start-lost variant. This was shown in SV40-transformed fibroblasts from the corresponding individual (treatment with a proteasome inhibitor resulted also in higher levels). Upon generation RPE1 cells using CRISPR for the start-lost variant, again, small amounts of full length protein were detected, which was not the case for complete knockout HAP1 cells. No shorter versions could be detected in the patient cells or RPE1 cells, arguing against utilization of an alternative start codon. (Use of non-AUG start codons discussed based on literature).

In line with small amounts of full-length protein the authors provided evidence for residual kinase activity for the start-loss variant (through proxy of phosphorylation of its substrate and use of a BUB1 kinase inhibitor). Cells from the individual with the frameshift variant and the splice variant had no residual kinase activity.

The authors provide evidence for mitotic defects in cells from both individuals with prolonged mitosis duration and chromosome segregation defects. Some patient-specific findings were thought to be related with BUB1 protein levels (affecting BUB1-mediated kinetochore recruitment of BUBR1, important for chromosome alignment) and others due to residual kinase activity [->phosphorylation of H2A at Threonine 120-> affecting centromeric recruitment of Aurora B, SGO1 (role in protection of centromeric cohesion), TOP2A (a protein preventing DNA breakage during sister chromatid separation), these correlated with high anaphase bridges (in P2), aneuploidy observed in lymphoblasts and primary fibroblasts from P2 but not P2's lymphocytes or lymphocytes from P1) and defective sister chromatid cohesion defects (in primary fibroblasts from P2, milder effect for P1).

Overall the authors provide evidence for overlapping clinical and cellular phenotype for this condition with primary microcephalies (MCPH - mutations in genes for mitotic regulators incl. kinetochore proteins or regulators of chromosome organization), mosaic variegated aneuploidy (biallelic variants in genes for kinetochore proteins, with random aneuploidies occurring in >5% cells of different tissues) and cohesinopathies (mostly Roberts or Warsaw breakage syndromes - characterized by cohesion loss and/or spontaneous railroad chromosomes).

Mouse model: Hmz disruption in mice is lethal shortly after E3.5 (cited PMID: 19772675), while a hypomorphic mutant mouse (lacking exons 2-3, expressing <5% of wt protein levels) is viable but exhibits increased tumorigenesis with aging and aneuploidy (cited PMID: 19117986). Mutant mice that lack kinase activity though with preserved Bub1 protein abundance, did not display increased susceptibility, despite substantial segregation errors and aneuploidies (cited PMID: 23209306).

The authors note that monoallelic germline BUB1 variants have been described in small number of individuals with CRC, exhibiting reduced expression levels and variegated aneuploidy in multiple tissues (cited PMID: 23747338) although the role of BUB1 is debated (cited PMIDs: 27713038, 29448935).

Based on the discussion, complete loss of BUB1 activity is presumed to be embryonically lethal based on the mouse study (PMID: 19772675) and reduced BUB1 expression associated with spontaneous miscarriages (cited PMID: 20643875, to my understanding in this study mRNA levels remained relatively constant despite reduced Bub1 protein levels, mRNA RT-PCR followed by sequencing revealed only 2 synonymous BUB1 variants).
Sources: Literature
Intellectual disability v3.1563 WDR37 Eleanor Williams Phenotypes for gene: WDR37 were changed from Global developmental delay; Intellectual disability; Seizures; Abnormality of the eye; Abnormality of nervous system morphology; Hearing abnormality; Abnormality of the cardiovascular system; Abnormality of the skeletal system; Abnormality of the genitourinary system to Global developmental delay; Intellectual disability; Seizures; Abnormality of the eye; Abnormality of nervous system morphology; Hearing abnormality; Abnormality of the cardiovascular system; Abnormality of the skeletal system; Abnormality of the genitourinary system; Neurooculocardiogenitourinary syndrome, OMIM:618652
Intellectual disability v3.1562 PABPC1 Konstantinos Varvagiannis gene: PABPC1 was added
gene: PABPC1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: PABPC1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: PABPC1 were set to 35511136
Phenotypes for gene: PABPC1 were set to Global developmental delay; Expressive language delay; Intellectual disability; Behavioral abnormality; Seizures
Penetrance for gene: PABPC1 were set to unknown
Review for gene: PABPC1 was set to AMBER
Added comment: Wegler et al (2022 - PMID: 35511136) describe the phenotype of 4 individuals with de novo variants in the PABP domain of PABPC1.

Overlapping features included DD (4/4) with weak expressive language (4/4), learning disability/borderline intellectual functioning (in 2) to more severe ID (in 2 others), treatable/self-limiting seizures (in 3 for whom this information was available) as well as variable behavioral issues (impaired social skills, concentration/sleeping problems, ADHD, anxiety or autism). Other features involved feeding difficulties (3/4), hearing impairment (in 2/3) or variable other phenotypes. Contribution of de novo variants found in other genes was thought possible.

All 4 were investigated by trio exome sequencing following negative previous routine diagnostic work-up. WES revealed heterozygous de novo PABPC1 variants, 3 of which were missense SNVs (c.1687G>A/p.Gly563Ser, c.1691A>C/p.Glu564Gly, c.1709T>C/p.Ile570Thr using NM_002568.3) and a fourth an in-frame deletion (c.1664_1666del/p.Pro555del).

Additional de novo variants were reported in 3 cases (IGF2R missense SNV, htz KDM5B stopgain, RBBP4 - the latter not associated with any phenotype to date).

PABPC1 encodes Polyadenylate-binding protein, cytoplasmic, 1 which as the authors summarize has an important role overall in regulation of gene expression (poly(A) tail length, mRNA formation, export of processed mRNAs to cytoplasm, translation initiation promotion and termination, mRNA stability, NMD). Translation is regulated by Polyadenylate-binding protein–interacting proteins (PAIPs) which control PABP activity. PAIP2 in particular, which is highly expressed in CNS, is known to inhibit translation via binding to the PABP domain of PABPC1 and is thought to play an important role through transcriptional regulation for synaptic plasticity and memory.

To evaluate plausibility as a DD gene the authors performed analyses using publicly available data, with PABPC1 ranking high in terms of protein-protein interaction (PPI) and co-expression with known DD genes.

Variants were absent from gnomAD with in silico predictions in favour of a deleterious effect.

While PABPC1 is intolerant to both missense and LoF variants (z-score 4.49, pLI of 1), occurrence of these 4 dn variants and their clustering in the PABP domain appeared to be of statistical significance (p=0.002 and p=2.8x10-8) rather than being explained by random occurrence.

Structural modeling of variants suggested that all were in close spatial vicinity within the PABP domain, likely influencing PAIP2 binding.

In HeLa cells the variants were shown not to affect subcellular localization (to the cytoplasm) compared to wt. In addition, there were no significant differences upon stress conditions under which the protein localizes to stress granules.

In HeLa cells, co-immunoprecipitation assays using C-terminal HA tagged PABPC1, revealed that 3 variants (Gly563Ser, Glu564Gly, Ile570Thr) significantly reduced physical PABPC1-PAIP2 interaction compared with wt, which was also observed though to a not significant extent for Pro555del. (Other variants from literature also studied as discussed below).

Pabpc1 is highly expressed in all regions of the developing mouse brain with remarkable decrease after birth, suggesting a critical role in prenatal brain development. Through electroporation with Pabpc1-directed shRNA the authors provided evidence that Pabpc1 LoF results in abnormal neural progenitor cell proliferation with rescue experiments using human WT or missense variants (Gly563Ser, Glu564Gly, Ile570Thr) showing that only the WT could rescue the proliferation phenotype.

Overall a model whereby weakened PABPC1-PAIP2 interaction, leading to dysregulation to gene expression homeostasis and interference with proliferation of neural progenitors and the later to the NDD phenotype is proposed.

Given previous reports in the literature for de novo PABPC1 variants, namely Lys138Glu, Asp204Val, Arg481His, Pro456Leu the authors noted that the phenotypes reported in the respective individuals were rather explained by other variants (16p11.2 dup, ARID1A dn, TBL1XR1 dn variants). These PABPC1 variants do not lie in the PABP domain, have lower in silico pathogenicity scores (MPC/CADD), with structural modelling suggestive of no significant effect. Importantly, upon co-immunoprecipitation studies with PAIP2 which were here performed, these variants had no effect. Pathogenicity of these variants - not located within the PABP domain - through another mechanism cannot be however ruled out. (PMIDs cited, though not reviewed based on this discussion: De Rubeis et al, 2014 - PMID: 25363760, Guo et al, 2019 - PMID: 30504930, Kaplanis et al, 2020 - PMID: 33057194).

Currently there is no PABPC1-related phenotype in other databases (incl. OMIM, G2P, SysID, PanelApp Australia).

Consider inclusion in the gene panels for ID and epilepsy with amber / green rating (DD with or without ID in >= 3 individuals/families/variants – also the case for seizures, role of the gene, statistical evidence for the gene/occurrence and clustering of variants, functional studies with strong evidence for at least 3 variants || learning difficulties/borderline intellectual functioning in 2 affected individuals, phenotype in few might be "blended" due to additional de novo variants).
Sources: Literature
Intellectual disability v3.1562 CTR9 Konstantinos Varvagiannis reviewed gene: CTR9: Rating: AMBER; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: 35499524, 2815719, 25363760, 27479843, 25099282, 29292210; Phenotypes: Delayed speech and language development, Motor delay, Intellectual disability, Behavioral abnormality, Autistic behavior, Failure to thrive, Feeding difficulties, Abnormality of the cardiovascular system; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.1562 CTR9 Konstantinos Varvagiannis gene: CTR9 was added
gene: CTR9 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: CTR9 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CTR9 were set to 35499524; 2815719; 25363760; 27479843; 25099282; 29292210
Phenotypes for gene: CTR9 were set to Delayed speech and language development; Motor delay; Intellectual disability; Behavioral abnormality; Autistic behavior; Failure to thrive; Feeding difficulties; Abnormality of the cardiovascular system
Penetrance for gene: CTR9 were set to unknown
Mode of pathogenicity for gene: CTR9 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: CTR9 was set to AMBER
Added comment: Meuwissen, Verstraeten, Ranza et al (2022 - PMID: 35499524) describe the phenotype of 13 unrelated individuals harboring heterozygous - predominantly de novo - CTR9 missense variants.

Overlapping features included delayed speech and/or motor development (each in 9 cases) with the latter complicated by hypotonia or hyperlaxity in some cases. Balance or coordination problems were also reported in some. Variable degrees of ID ranging from mild to severe were observed in all individuals of relevant age except for 3 who however experienced impairment in other domains and/or learning difficulties (8/11 - 2 individuals were too young for evaluation). Few had evidence of regression. Other features included behavioral abnormalities (incl. ASD in 4), FTT/feeding problems (in 5), cardiovascular findings (in 4 - incl. infantile thoracic aortic aneurysm, VSD, pulm. valve stenosis, SVAS). The authors reported variable/nonspecific dysmorphic features.

WES revealed heterozygous CTR9 missense variants in all cases (NM_014633.5 as RefSeq). The variants occurred de novo in most (11/13) individuals with a one proband having inherited the variant from his affected parent. For one case, a single parental sample was available. Most SNVs were absent from gnomAD with the exception of c.1364A>G/p.Asn455Ser and c.2633G>A/p.Arg878Gln present once in the database (Z-score for CTR9: 4.3 / pLI : 1). The variants affected highly conserved residues with in silico predictions mostly in favor of a deleterious effect.

CTR9 encodes a subunit of the PAF1 complex (PAF1C) with the other subunits encoded by PAF1, LEO1, CDC73, RTF1 and WDR61/SKI8. The complex acts as a transcriptional regulator with CTR9 binding RNA polymerase II. The complex influences gene expression by promoting H2BK123 ubiquitylation, H3K4 and H3K36 methylation. In yeast, Paf1 and Ctr9 appear to mediate involvement of Paf1C in induction of mitophagy (several Refs provided).

In silico modeling: a group of N-terminal variants likely destabilize structure, another group possibly perturbs CTR9-PAF1 interactions and a 3rd class influences interactions with other subunits. p.Glu15Lys did not appear to influence protein stability.

Functional studies: H3K4/H3K36 methylation analysis, mitochondrial quality assessment and RNA-seq studies in fibroblasts did not provide conclusive evidence for downstream consequences of the variants (albeit a brain-specific effect - as demonstrated for other disorders – cannot be excluded).

Animal models: In zebrafish, the Paf1C complex has been shown to play a role in cardiac specification and heart morphogenesis with ctr9 mutants showing severe defects in morphogenesis of primitive heart tube (cited PMID: 21338598). This supports a role of the CTR9 variants in the cardiac abnormalities observed in 4 individuals. Although Paf1C zebrafish homologues are required for Notch-regulated transcription (cited PMID: 17721442), there was no supporting evidence from RNA-seq analyses performed by the authors. In Drosophila, Ctr9 has a key role at multiple stages of nervous system development in Drosophila (cited PMID: 27520958). In rat, Ctr9 is expressed in dopaminergic neurons, with its expression not restricted to the nucleus, regulating dopamine transporter activity (cited PMID: 26048990).

As commented, de novo CTR9 variants have been identified in indivdiduals with developmental disorders in larger cohorts, though without phenotypic details (DDD study - PMID:2815719, De Rubeis et al, 2014 - PMID: 25363760, Lelieveld et al PMID: 27479843) [ https://denovo-db.gs.washington.edu/denovo-db/QueryVariantServlet?searchBy=Gene&target=CTR9 ]

Two previous studies (Hanks et al, 2014 - PMID: 25099282, Martins et al 2018, PMID: 29292210) have identified individuals with pLoF variants [in almost all cases leading to skipping of ex9 e.g. NM_014633.4:c.958-9A>G or (RefSeq not provided) c.1194+2T>C, c.1194+3A>C, the single exception being c.106C>T/p.Q36*] in individuals and families with Wilms tumor after exclusion of other genetic causes. Analyses of tumor samples revealed in several of these cases either LOH (most commonly) or truncating variants as second hits. These individuals did not display neurodevelopmental phenotypes (despite detailed clinical information provided in the 2 studies). CTR9 is included in the gene panels for WT and Tumor predisposition - childhood onset with green rating. [In addition few individuals with hyperparathyroidism jaw tumor syndrome due to heterozygous variants in CDC73 - another subunit of the PAF1 complex - have been reported with WT].

Given these reports, commenting on the embryonic lethality of Ctr9 homozygous ko mice (MGI) and the observation of only missense variants in their cohort Meuwissen, Verstraeten, Ranza et al presume that a dominant-negative effect may apply for the variants they report.

Consider inclusion in the current panel with amber (variant effect/underlying mechanism unknown) or green rating (>3 individuals/families/variants, multiple reports, some supporting evidence from animal models).
Sources: Literature
Intellectual disability v3.1562 JARID2 Arina Puzriakova Tag gene-checked tag was added to gene: JARID2.
Intellectual disability v3.1561 DNAH14 Konstantinos Varvagiannis gene: DNAH14 was added
gene: DNAH14 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: DNAH14 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DNAH14 were set to 35438214
Penetrance for gene: DNAH14 were set to unknown
Review for gene: DNAH14 was set to RED
Added comment: Li et al (2022 - PMID: 35438214) describe 3 individuals harboring biallelic DNAH14 variants. In addition the authors perform a review of cases previously published in the literature.

The reported phenotype does not appear to be very consistent or specific (seizures with highly variable age of onset with or without DD / cognitive delay). Comparison with previously reported subjects (not further reviewed) - discussed in text and appearing mixed in table 1 - does not seem to support an overlapping phenotype.

The authors comment that DNAH14 encodes a heavy chain of axonemal dyneins. Little evidence is provided to support the role of the gene in the pathogenesis of the disorder and pathogenicity of the variants (ultra-rare and predicted in silico to be deleterious).
Sources: Literature
Intellectual disability v3.1561 DALRD3 Konstantinos Varvagiannis changed review comment from: Biallelic pathogenic DALRD3 variants cause ?Developmental and epileptic encephalopathy 86 (# 618910).

Lentini et al (2020 - PMID: 32427860) report 2 sibs born to first cousin parents, homozygous for a DALRD3 pathogenic variant.

Both exhibited hypotonia, severe global DD and epilepsy (onset of seizures at the age 6-7m, poorly controlled by AEDs in one) corresponding overall to an developmental and epileptic encephalopathy. The authors reported subtle dysmorphic features. Other findings included GI concerns (in both) with microcephaly, CHD or renal anomalies in the younger.

WES guided by autozygome analysis revealed homozygosity for a DALRD3 stopgain variant (NM_001009996.3:c.1251C>A/pTyr417*) with Sanger sequencing confirming status of the children and carrier state of the parents.

DALRD3 encodes DALR anticodon-binding domain-containing protein 3. A DALR

It's DALR anticodon-binding domain is similar to those found in arginyl-tRNA synthetases RARS1/2.

As the authors demonstrate, and (better) summarized in OMIM, its product is a tRNA-binding protein that interacts with METTL2 to facilitate 3-methylcytosine (m3C) modification - by METTL2 - at position 32 of the anticodon loop in specific arginine tRNAs, namely tRNA-Arg-UCU and tRNA-Arg-CCU. In particular, DALRD3 seems to serve as discrimination factor required for recognition of these specific tRNAs.

In addition to DALRD3, a DALR anticodon-binding domain is also found in arginyl-tRNA synthetases (the cytoplasmic RARS1, and mitochondrial RARS2).

Given the variant type observed, predicting truncation of the protein and/or NMD, in LCLs from the 2 sibs (and comparison with controls) the authors demonstrated that the levels of full-length DALRD3 were decreased in cell lysates, with severe reduction (/loss) of m3C modification of the specific arginine tRNAs, which was not observed for other tRNAs (eg. tRNA-Ser-UGA) or controls. These findings were suggestive of c.1251C>A / pTyr417* being a partial LoF allele.

As the authors discuss, defects in tRNA modification have been associated with numerous human - among others neurological and neurodevelopmental - disorders (cited PMID: 30529455, table 1 of this review summarizing these incl. ADAT3-, PUS3-, TRMT1- related NDDs, etc).

Consider inclusion in the current panel with amber rating.
Sources: Literature; to: Biallelic pathogenic DALRD3 variants cause ?Developmental and epileptic encephalopathy 86 (# 618910).

Lentini et al (2020 - PMID: 32427860) report 2 sibs born to first cousin parents, homozygous for a DALRD3 pathogenic variant.

Both exhibited hypotonia, severe global DD and epilepsy (onset of seizures at the age 6-7m, poorly controlled by AEDs in one) corresponding overall to an developmental and epileptic encephalopathy. The authors reported subtle dysmorphic features. Other findings included GI concerns (in both) with microcephaly, CHD or renal anomalies in the younger.

WES in both followed by autozygome analysis revealed homozygosity for a DALRD3 stopgain variant (NM_001009996.3:c.1251C>A/pTyr417*) with Sanger sequencing confirming status of the children and carrier state of the parents.

DALRD3 encodes DALR anticodon-binding domain-containing protein 3. A DALR

As the authors demonstrate, and (better) summarized in OMIM, its product is a tRNA-binding protein that interacts with METTL2 to facilitate 3-methylcytosine (m3C) modification - by METTL2 - at position 32 of the anticodon loop in specific arginine tRNAs, namely tRNA-Arg-UCU and tRNA-Arg-CCU. In particular, DALRD3 seems to serve as discrimination factor required for recognition of these specific tRNAs.

In addition to DALRD3, a DALR anticodon-binding domain is also found in arginyl-tRNA synthetases (the cytoplasmic RARS1, and mitochondrial RARS2).

Given the variant type observed, predicting truncation of the protein and/or NMD, in LCLs from the 2 sibs (and comparison with controls) the authors demonstrated that the levels of full-length DALRD3 were decreased in cell lysates, with severe reduction (/loss) of m3C modification of the specific arginine tRNAs, which was not observed for other tRNAs (eg. tRNA-Ser-UGA) or controls. These findings were suggestive of c.1251C>A / pTyr417* being a partial LoF allele.

As the authors discuss, defects in tRNA modification have been associated with numerous human - among others neurological and neurodevelopmental - disorders (cited PMID: 30529455, table 1 of this review summarizing these incl. ADAT3-, PUS3-, TRMT1- related NDDs, etc).

Consider inclusion in the current panel with amber rating.

Sources: Literature
Intellectual disability v3.1561 DALRD3 Konstantinos Varvagiannis gene: DALRD3 was added
gene: DALRD3 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: DALRD3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DALRD3 were set to 32427860
Phenotypes for gene: DALRD3 were set to ?Developmental and epileptic encephalopathy 86, # 618910
Penetrance for gene: DALRD3 were set to Complete
Review for gene: DALRD3 was set to AMBER
Added comment: Biallelic pathogenic DALRD3 variants cause ?Developmental and epileptic encephalopathy 86 (# 618910).

Lentini et al (2020 - PMID: 32427860) report 2 sibs born to first cousin parents, homozygous for a DALRD3 pathogenic variant.

Both exhibited hypotonia, severe global DD and epilepsy (onset of seizures at the age 6-7m, poorly controlled by AEDs in one) corresponding overall to an developmental and epileptic encephalopathy. The authors reported subtle dysmorphic features. Other findings included GI concerns (in both) with microcephaly, CHD or renal anomalies in the younger.

WES guided by autozygome analysis revealed homozygosity for a DALRD3 stopgain variant (NM_001009996.3:c.1251C>A/pTyr417*) with Sanger sequencing confirming status of the children and carrier state of the parents.

DALRD3 encodes DALR anticodon-binding domain-containing protein 3. A DALR

It's DALR anticodon-binding domain is similar to those found in arginyl-tRNA synthetases RARS1/2.

As the authors demonstrate, and (better) summarized in OMIM, its product is a tRNA-binding protein that interacts with METTL2 to facilitate 3-methylcytosine (m3C) modification - by METTL2 - at position 32 of the anticodon loop in specific arginine tRNAs, namely tRNA-Arg-UCU and tRNA-Arg-CCU. In particular, DALRD3 seems to serve as discrimination factor required for recognition of these specific tRNAs.

In addition to DALRD3, a DALR anticodon-binding domain is also found in arginyl-tRNA synthetases (the cytoplasmic RARS1, and mitochondrial RARS2).

Given the variant type observed, predicting truncation of the protein and/or NMD, in LCLs from the 2 sibs (and comparison with controls) the authors demonstrated that the levels of full-length DALRD3 were decreased in cell lysates, with severe reduction (/loss) of m3C modification of the specific arginine tRNAs, which was not observed for other tRNAs (eg. tRNA-Ser-UGA) or controls. These findings were suggestive of c.1251C>A / pTyr417* being a partial LoF allele.

As the authors discuss, defects in tRNA modification have been associated with numerous human - among others neurological and neurodevelopmental - disorders (cited PMID: 30529455, table 1 of this review summarizing these incl. ADAT3-, PUS3-, TRMT1- related NDDs, etc).

Consider inclusion in the current panel with amber rating.
Sources: Literature
Intellectual disability v3.1561 DPH5 Konstantinos Varvagiannis gene: DPH5 was added
gene: DPH5 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: DPH5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DPH5 were set to 35482014
Phenotypes for gene: DPH5 were set to Abnormality of prenatal development or birth; Neonatal hypotonia; Global developmental delay; Intellectual disability; Seizures; Abnormality of the cardiovascular system; Abnormality of the globe; Feeding difficulties; Short stature; Abnormality of head or neck
Penetrance for gene: DPH5 were set to unknown
Review for gene: DPH5 was set to AMBER
Added comment: Shankar et al (2022 - PMID: 35482014) present evidence for a diphthamide-deficiency syndrome due to biallelic DPH5 pathogenic variants.

As the authors summarize, DPH5 encodes a methyltransferase critical to the biosynthesis of diphthamide. Diphthamide is a post translationally modified histidine residue found in eukaryotic elongation factor 2 (eEF2). eEF2 is essential for mRNA translation and protein synthesis. The role of diphthamide is not clear, although it serves as a target for ADP-ribosylation, the latter resulting in inactivation of the eEF2 (inhibition of its translocation activity) and arrest of protein synthesis. Biosynthesis of diphthamide is complex involving multiple components (DPH1-DPH7) and the methylating co-factor S-adenosyl methionine, with 2 diphthamide-deficiency disorders due to biallelic DPH1 or DPH2 pathogenic variants and a NDD phenotype reported to date.

The authors describe a phenotypic spectrum associated with biallelic DPH5 variants ranging from a prenatally lethal presentation to profound neurodevelopmental disorder. Details are provided on 5 individuals from 3 unrelated families. While one subject died at the age of few days due to multisystem complications, the phenotype appeared to be relatively consistent with prenatal findings (decreased fetal movements in 2 from 2 families, polyhydramnios in 2 from 2 families), hypotonia, global DD and ID (4/4 from 2 families - profound in 3), seizures (3/5 from 2 families - abnormal EEG in 4/4), cardiovascular findings (5/5, MVP and regurgitation in 2 from Fam1 || aortic dilatation in 2 sibs from Fam2 || VSD, ASD and hypopl. PA, pericardial effusion in 5th), GI issues (5/5, poor feeding in 4), short stature (4/4). Ocular findings were reported in 3/4 (gray sclerae in 2, ocular melanocytosis in 2). The authors describe some common craniofacial findings incl. broad/prominent forehead (5/5), sparse eyebrows (4/5), downturned corners of mouth or triangular chin (each in 3/5).

WES/WGS revealed biallelic DPH5 variants in all affected individuals, namely: homozygosity for a missense variant in 2 sibs (NM_001077394.2:c.779A>G/p.His260Arg). Homozygosity for c.521dupA/p.Asn174LysTer10 for the individual deceased in the neonatal period (for this family there was significant history of spontaneous miscarriages/stillbirth/neonatal death). Two sibs born to non-consanguineous parents were compound htz for a stopgain and a missense SNV (c.619C>T/p.Arg207*, c.329A>G/p.Asn110Ser).

In silico modeling revealed that the pLoF variants, not predicted to lead to NMD, likely remove the domain for interaction with eEF2 while the missense ones also affected interaction with eEF2.

In recombinant MCF7 breast cancer cell line-derived DPH5-knockouts, transfected with recombinant expr. plasmids encoding wt or the 4 variants, the 2 truncating variants were shown to affect ADP-ribosylation of eEF2's diphthamide (total lack / minimal enzymatic activity for Arg207* and Asn174Lysfs respectively). Asn110Ser and His260Arg had residual activities which was thought to be explained by high expression levels compensating partial inactivation (given the multicopy plasmid-driven expression).

ADP-ribosylation assays in S. cerevisiae demonstrated loss of function for the 2 truncating variants. Although the 2 missense variants retained sufficient activity to produce diphthamide (assayed through toxin induced ADP-ribosylation of eEF2), more sensitive assays indicated that diphthamide synthesis was also partially compromised for both variants.

Generation of a knockin mouse model for His260Arg, appeared to recapitulate the human phenotypes with craniofacial, ophthalmologic, cardiac and visceral abnormalities and hmz mice being subviable. A single homozygous liveborn mouse had low birthweight, FTT, craniofacial dysmorphology, polydactyly, abnormal grooming behavior and early death. Few heterozygous embryos had craniofacial features, decreased body weight, reduced neuromuscular function without other abnormalities, either due to their inbred background or in the context of milder phenotype of heterozygosity in mice.

DPH5 is ubiquitously expressed in all human tissues. The gene has a pLI of 0 and LOEUF score of 0.77 (0.48-1.27) in gnomAD. The authors refer to unpublished data, noting that complete absence of DPH5 is incompatible with life with embryonic lethality of a Dph5(ko/ko) line.

The phenotype bears similarities to DPH1- and DPH2- related NDDs (both AR / green and amber respectively in ID panel) and appears to be more severe compared to the phenotype of de novo EEF2 variants (cited PMID: 33355653).

Please consider inclusion in the ID panel with amber (4 individuals from 2 families with ID) / green rating (rather consistent phenotype in 3 families probably representing a continuous spectrum, variant studies, mouse model, similarities with diphthamide-deficiency syndromes). Also consider amber rating in the epilepsy panel (3 individuals from 2 families reported). The gene may be also relevant in other gene panels e.g. for congenital heart disease, short stature, etc (not added).
Sources: Literature
Intellectual disability v3.1561 CCDC82 Konstantinos Varvagiannis gene: CCDC82 was added
gene: CCDC82 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: CCDC82 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CCDC82 were set to 27457812; 28397838; 35118659; 35373332
Phenotypes for gene: CCDC82 were set to Global developmental delay; Intellectual disability; Spastic paraparesis
Penetrance for gene: CCDC82 were set to Complete
Review for gene: CCDC82 was set to AMBER
Added comment: The phenotype of individuals with biallelic CCDC82 variants has been reported - in most cases briefly - in the following reports (each summarizing the findings of previous ones):

Riazzudin et al (2017 - PMID: 27457812) in a large consanguineous pedigree from Pakistan (PKMR206) identified 4 individuals homozygous for a fs variant [NM_024725.3:c.373delG / p.(Asp125Ilefs*6)] (V3,V4,V5,V10). There was no other variant segregating with the phenotype of ID (Delayed CMS, moderate ID and speech delay probably common to all, V3,4,5 had also mild hypotonia and motor weakness). There was one unaffected sib tested (homozygous for ref. alelle). 2 further affected males (V1, V2) with similar phenotype were not tested.

Harripaul et al (2018 - PMID: 28397838) reported 2 sibs with nonsyndromic ID belonging to a consanguineous family (AS17) from the Middle-East. Both were homozygous for NM_024725.3:c.535C>T / p.Arg179*. The variant was confirmed with Sanger sequencing and parents were heterozygous carriers. Two additional affected sibs were probably not tested.

Yahia et al (2022 - PMID: 35118659) described 2 sibs belonging to a consanguineous family from Sudan. These presented global DD (last evaluation at 4y and 9m) and spasticity. There was a common history of infantile spasms with the elder developing GTC convulsions with spontaneous resolution. Additionaly, both presented microcephaly (<-2 and <-3SD). Exome sequencing revealed homozygosity for c.535C>T / p.Arg179* (previously reported by Harripaul et al). Sanger sequencing was used for confirmation and demonstration of carrier state of parents. Two similarly affected sibs were not available for testing.

Bauer et al (2022 - PMID: 35373332) reported a 21 y.o. male born to consanguineous parents from Pakistan. Features included short stature, ID, spastic paraparesis (at the age of 3y). Gelastic seizures were suspected but not confirmed (repeated normal EEGs). WES revealed homozygosity for a fs CCDC82 variant [NM_001318736.1:c.183del / p.(Phe61Leufs*27)] with Sanger confirmation in proband and heterozygous parents. There was another hmz variant, albeit classified as VUS and not thought to fit the clinical presentation.

As proposed by Bauer et al. overlapping features include spastic paraparesis, DD and dysmorphic features. As commented, CCDC82 encodes coiled-coil domain protein 82, a protein with unknown function.

Consider inclusion probably with amber rating (>3 individuals/families/variants, role of the gene not known, variant studies not performed to date, animal models not discussed).
Sources: Literature
Intellectual disability v3.1561 FBXO28 Konstantinos Varvagiannis gene: FBXO28 was added
gene: FBXO28 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: FBXO28 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: FBXO28 were set to 30160831; 33280099
Phenotypes for gene: FBXO28 were set to Developmental and epileptic encephalopathy 100 (# 619777)
Penetrance for gene: FBXO28 were set to unknown
Review for gene: FBXO28 was set to GREEN
Added comment: Heterozygous pathogenic FBXO28 variants cause Developmental and epileptic encephalopathy 100 (# 619777).

At least 10 individuals with monoallelic missense / truncating FBXO28 variants have been reported. The subject with de novo frameshift variant initially reported by Balak et al (2018 - PMID:30160831) was included with additional clinical details in a recent report along with 9 further individuals (Schneider et al, 2021 - PMID: 33280099).

The phenotype corresponds to a developmental and epileptic encephalopathy with severe/profound ID. As discussed by Schneider et al, all individuals had DD prior to seizure onset which occurred at a median age of 22.5 months (range: 8m - 5y). The authors noted that missense variants may be associated with a milder phenotype (e.g. seizures occurred at the age of 4-5 years in 3 individuals).

Given these, FBXO28 appears to be relevant for inclusion in the current panel, with investigations prior to seizure onset.

As in the summary by Schneider et al, the gene encodes F-box only protein 28, a ubiquitin ligase promoting ubiquitination and degradation of phosphorylated proteins.

While FBXO28 has been suggested to have a critical role in 1q41q42 deletions (most spanning also WDR26) the authors note that a mechanism different than haploinsufficiency may underly FBXO28 encephalopathy.

Importantly, all 5 truncating variants reported (and 2/4 missense ones) occurred in the last exon, making these variants less susceptible to NMD. 2 other (of the 4) missense variants clustered in the F-box domain, which the authors hypothesize may correspond to a second pathogenic region.

7/9 variants arose de novo while 2 individuals had inherited a missense and a stopgain variant from mosaic unaffected parents (2.5% and 6%).

A comparison of the FBXO28-associated phenotype with the respective of 1q41q42 deletions and WDR26-related NDD is also made.

Consider inclusion in the ID panel with green (or amber) rating. Please consider inclusion in other possibly relevant panels (e.g. microcephaly (4/10), movement disorders, etc).
Sources: Literature
Intellectual disability v3.1561 CCDC32 Konstantinos Varvagiannis reviewed gene: CCDC32: Rating: AMBER; Mode of pathogenicity: None; Publications: 32307552, 35451546; Phenotypes: Cardiofacioneurodevelopmental syndrome (# 619123); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1561 CDK9 Konstantinos Varvagiannis changed review comment from: There are 4 studies reporting on the phenotype associated with biallelic CDK9 pathogenic variants. DD and ID are part of the phenotype which appears to be relatively consistent.

CDK9 encodes Cyclin-dependent kinase 9. There are 4 missense variants reported to date - one of which recurrent (NM_001261.3:c.673C>T / p.Arg225Cys) - with studies for 3 variants suggesting a LoF effect (loss of kinase activity) [Ref4].

Animal models also provide some supporting evidence [discussed Ref4].

Consider inclusion in the current panel (probably with green rating) as well as other possibly relevant ones. Details provided below.

[1]-----
Shaheen et al (2016 - PMID: 26633546) studied patients with apparently novel phenotypes with positive family history consistent with AR inheritance mode due to consanguinity.

After autozygome analysis the authors determined the shared autozygome (ROH >1 Mb / Axiom SNP Chip) in families with multiple affected individuals. This analysis was followed by whole exome/genome sequencing.

Using this approach, they managed to map the phenotype of interest to a single novel locus in some families, which was also the case in a large consanguineous family with 2 similarly affected cousins (11DG0424, 11DG1630).

Within a 20 Mb region of homozygosity, followed by WES in a single affected individual and Sanger confirmation with compatible segregation studies in parents and 10 unaffected sibs, the authors identified a homozygous CDK9 missense SNV (NM_001261.3:c.673C>T / p.Arg225Cys) responsible for this phenotype. In silico predictions were concordant in favor of a deleterious effect.

Features (detailed in the suppl.) included global DD (2/2), severe ID (1/1), cerebral and (mild) cerebellar atrophy (2/2), microcephaly (2/2), ocular anomalies (2/2, coloboma in 2/2, congenital cataract 2/2, etc), heart defects (2/2, PDA in both, ASD), variable genitourinary anomalies (2/2 incl. hydronephrosis, VUR reflux/recurrent UTIs, kidney atrophy, abn. genitalia in 1), abnormalities of the limbs (2/2, bilateral talipes equinovarus : 2/2) or the skeleton (1/2 - butterfly vertebrae). One was reported to have some degree of growth delay (<10th centile for length, <5th for weight and OFC). There was no hearing defect reported (large ears in 1/2). Overall, the authors used the term CHARGE-like phenotype.

[2]-----
Maddirevula et al (2019 - PMID: 30237576) performed autozygome and exome analysis of individuals with suspected Mendelian disorders. They reported 3 individuals (18DG0161, 18DG0162, 18DG0165) born to 3 different consanguineous families (information in fig2) from Qatar, homozygous for CDK9 p.Arg225Cys.

All presented a CHARGE-like phenotype with features ophtalmologic findings (3/3 - abnormal ERG in one, congenital cataracts the other, visual impairment in the 3rd, though NO evidence of coloboma in at least two), heart defect (2/3 had VSD), choanal atresia (3/3), retarded growth/FTT (1/3) or global DD (3/3 - in suppl. table 1), (genito)urinary anomalies (1/3 - dysplastic atrophic kidney) or ear anomalies (3/3 - preauricular tags 2/3, bilateral deafness 1/3, bilat.ossicular anomalies 1/3). Other features incl. epilepsy (2/3), brain MRI abnormalities (2/3), facial asymmetry in one, vertebral segmentation defect in 1/3.

[3]-----
Hu et al (2019 - PMID: 29302074) performed WES/WGS in 404 consanguineous families from Iran, having 2 or more offspring with ID.

In this context they reported 2 females and a male (III:1,4,3 belonging to fam. M9100018 - details in suppl. text) born to first cousin parents from Iran. Features included DD (3/3 - walking at 3y, words at 4y), moderate ID (3/3 - WAIS-IV IQ of 40-43), short stature (3/3 below 3rd %le). Vision and hearing were normal.

All three were homozygous for a missense SNV (NM_001261:c.280C>T, p.Arg94Cys) which was ultrarare in ExAC, with severa in silico tools in favor of a deleterious effect.

The authors commented that CDK9 is the catalytic core of transcription elongation factor p-TEFb essential for transcription elongation of numerous genes, Cdk9/Cyclin T1 complex may participate in neuronal differentiation, CDK9-cyclinK in maintenance of genomic integrity, with the protein encoded also interacted with AF4/FMR2.

In addition the gene was commented to have ubiquitous expression with high protein expression in glial and neuronal cells of the cortex (based on Uniprot and Human Protein Atlas).

[4]-----
Nishina et al (2021 - PMID: 33640901) described an 8 y.o. male with facial asymmetry, ear/hearing anomalies (microtia, preauricular tags, bilateral hearing loss), ocular/vision anomalies (blepharophimosis, lacrimal obstruction, eyelid dermoids, duane-like anomaly, congenital cataracts, retinal dystrophy), cleft lip and palate, abnormalities of the limbs (finger contractures with associated absence of creases, cutaneous syndactyly, etc). Other features included cardiac dysrhythmia and undescended testes. Development was delayed with associated ID (walking 3y, words 7y, at 10y: could count to 20, 4 word sentences). There was no evidence of coloboma or choanal atresia.

Trio exome sequencing revealed that the child was compound htz for 2 missense SNVs (NM_001261.3:c.862G>A / p.Ala288Thr and c.907C>T /p.Arg303Cys) with Sanger confirmation. These were ultrarare/not present in gnomAD. Both lied in the protein kinase catalytic domain of CDK9, with high conservation across different species and in silico predictions in favor of deleterious effect.

In vitro studies in HEK293 cells demonstrated that the kinase activity for both variants was significantly reduced compared to wt. Kinase activity was also reduced for the Arg225Cys variant (reported in Refs 1 & 2).

The authors briefly discuss evidence from zebrafish (regulates larval morphogenesis incl. brain, heart, eye, blood vessels) and mouse models. In the latter complete LoF is lethal while heterozygous LoF is associated with abnormal morphology of heart, skin and epididymis (PMIDs cited by the authors : 27715402, 30100824).
Sources: Literature; to: There are 4 studies reporting on the phenotype associated with biallelic CDK9 pathogenic variants. DD and ID are part of the phenotype which appears to be relatively consistent.

CDK9 encodes Cyclin-dependent kinase 9. There are 4 missense variants reported to date - one of which recurrent (NM_001261.3:c.673C>T / p.Arg225Cys) - with studies for 3 variants suggesting a LoF effect (loss of kinase activity) [Ref4].

Animal models also provide some supporting evidence [discussed Ref4].

Consider inclusion in the current panel (probably with green rating) as well as other possibly relevant ones. Details provided below.

[1]-----
Shaheen et al (2016 - PMID: 26633546) studied patients with apparently novel phenotypes with positive family history consistent with AR inheritance due to consanguinity.

Using autozygome analysis the authors determined the shared autozygome (ROH >1 Mb / Axiom SNP Chip) in families with multiple affected individuals. This analysis was followed by whole exome/genome sequencing.

Using this approach, they managed to map the phenotype of interest to a single novel locus in some families, which was also the case in a large consanguineous family with 2 similarly affected cousins (11DG0424, 11DG1630).

Within a 20 Mb region of homozygosity, followed by WES in a single affected individual and Sanger confirmation with compatible segregation studies in parents and 10 unaffected sibs, the authors identified a homozygous CDK9 missense SNV (NM_001261.3:c.673C>T / p.Arg225Cys) responsible for this phenotype. In silico predictions were concordant in favor of a deleterious effect.

Features (detailed in the suppl.) included global DD (2/2), severe ID (1/1), cerebral and (mild) cerebellar atrophy (2/2), microcephaly (2/2), ocular anomalies (2/2, coloboma in 2/2, congenital cataract 2/2, etc), heart defects (2/2, PDA in both, ASD), variable genitourinary anomalies (2/2 incl. hydronephrosis, VUR/recurrent UTIs, kidney atrophy, abn. genitalia in 1), abnormalities of the limbs (2/2, bilateral talipes equinovarus : 2/2) or the skeleton (1/2 - butterfly vertebrae). One was reported to have some degree of growth delay (<10th centile for length, <5th for weight and OFC). There was no hearing defect reported (large ears in one case). Overall, the authors used the term CHARGE-like for this phenotype.

[2]-----
Maddirevula et al (2019 - PMID: 30237576) performed autozygome and exome analysis of individuals with suspected Mendelian disorders. They reported 3 individuals (18DG0161, 18DG0162, 18DG0165) born to 3 different consanguineous families (information in fig2) from Qatar, homozygous for CDK9 p.Arg225Cys.

All presented a CHARGE-like phenotype with ophthalmologic findings (3/3 - abnormal ERG in one, congenital cataracts the other, visual impairment in the 3rd, though NO evidence of coloboma in at least two of them), heart defect (2/3 with VSD), choanal atresia (3/3), retarded growth/FTT (1/3) or global DD (3/3 - in suppl. table 1), (genito)urinary anomalies (1/3 - dysplastic atrophic kidney) or ear anomalies (3/3 - preauricular tags in 2/3, bilateral deafness 1/3, bilateral ossicular anomalies 1/3). Other features incl. epilepsy (2/3), brain MRI abnormalities (2/3), facial asymmetry in one, vertebral segmentation defect in 1/3.

[3]-----
Hu et al (2019 - PMID: 29302074) performed WES/WGS in 404 consanguineous families from Iran, having 2 or more offspring with ID.

In this context they reported 2 females and a male (III:1,4,3 belonging to fam. M9100018 | suppl. text) born to first cousin parents from Iran. Features included DD (3/3 - walking at 3y, words at 4y), moderate ID (3/3 - WAIS-IV IQ of 40-43), short stature (3/3 below 3rd %le). Vision and hearing were normal.

All three were homozygous for a missense SNV (NM_001261:c.280C>T, p.Arg94Cys) which was ultrarare in ExAC, with several in silico tools in favor of a deleterious effect.

The authors commented that CDK9 is the catalytic core of transcription elongation factor p-TEFb essential for transcription elongation of numerous genes, Cdk9/Cyclin T1 complex may participate in neuronal differentiation, CDK9-cyclinK in maintenance of genomic integrity, with the protein encoded also interacting with AF4/FMR2.

In addition the gene was commented to have ubiquitous expression with high protein expression in glial and neuronal cells of the cortex (based on Uniprot and Human Protein Atlas).

[4]-----
Nishina et al (2021 - PMID: 33640901) described an 8 y.o. male with facial asymmetry, ear/hearing anomalies (microtia, preauricular tags, bilateral hearing loss), ocular/vision anomalies (blepharophimosis, lacrimal obstruction, eyelid dermoids, duane-like anomaly, congenital cataracts, retinal dystrophy), cleft lip and palate, abnormalities of the limbs (finger contractures with associated absence of creases, cutaneous syndactyly, etc). Other features included cardiac dysrhythmia and undescended testes. Development was delayed with ID (walking 3y, words 7y, at 10y: could count to 20, 4 word sentences). There was no evidence of coloboma or choanal atresia.

Trio exome revealed that the child was compound htz for 2 missense SNVs (NM_001261.3:c.862G>A / p.Ala288Thr and c.907C>T /p.Arg303Cys) with Sanger confirmation. These were ultrarare/not present in gnomAD. Both lied in the protein kinase catalytic domain of CDK9, with high conservation across different species and in silico predictions in favor of deleterious effect.

In vitro studies in HEK293 cells demonstrated that the kinase activity for both variants was significantly reduced compared to wt. Kinase activity was also reduced for the Arg225Cys variant (reported in Refs 1 & 2).

The authors briefly discuss evidence from zebrafish (regulates larval morphogenesis incl. brain, heart, eye, blood vessels) and mouse models. In the latter complete LoF is lethal while heterozygous LoF is associated with abnormal morphology of heart, skin and epididymis (PMIDs cited : 27715402, 30100824).
Sources: Literature
Intellectual disability v3.1561 CDK9 Konstantinos Varvagiannis gene: CDK9 was added
gene: CDK9 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: CDK9 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CDK9 were set to 26633546; 30237576; 29302074; 33640901
Phenotypes for gene: CDK9 were set to Global developmental delay; Intellectual disability; Abnormality of vision; Congenital cataract; Iris coloboma; Abnormal heart morphology; Choanal atresia; Abnormality of the ear; Preauricular skin tag; Hearing impairment; Abnormality of the genitourinary system; Abnormality of limbs; Abnormality of the vertebrae; Abnormality of nervous system morphology; Seizures
Penetrance for gene: CDK9 were set to Complete
Review for gene: CDK9 was set to GREEN
Added comment: There are 4 studies reporting on the phenotype associated with biallelic CDK9 pathogenic variants. DD and ID are part of the phenotype which appears to be relatively consistent.

CDK9 encodes Cyclin-dependent kinase 9. There are 4 missense variants reported to date - one of which recurrent (NM_001261.3:c.673C>T / p.Arg225Cys) - with studies for 3 variants suggesting a LoF effect (loss of kinase activity) [Ref4].

Animal models also provide some supporting evidence [discussed Ref4].

Consider inclusion in the current panel (probably with green rating) as well as other possibly relevant ones. Details provided below.

[1]-----
Shaheen et al (2016 - PMID: 26633546) studied patients with apparently novel phenotypes with positive family history consistent with AR inheritance mode due to consanguinity.

After autozygome analysis the authors determined the shared autozygome (ROH >1 Mb / Axiom SNP Chip) in families with multiple affected individuals. This analysis was followed by whole exome/genome sequencing.

Using this approach, they managed to map the phenotype of interest to a single novel locus in some families, which was also the case in a large consanguineous family with 2 similarly affected cousins (11DG0424, 11DG1630).

Within a 20 Mb region of homozygosity, followed by WES in a single affected individual and Sanger confirmation with compatible segregation studies in parents and 10 unaffected sibs, the authors identified a homozygous CDK9 missense SNV (NM_001261.3:c.673C>T / p.Arg225Cys) responsible for this phenotype. In silico predictions were concordant in favor of a deleterious effect.

Features (detailed in the suppl.) included global DD (2/2), severe ID (1/1), cerebral and (mild) cerebellar atrophy (2/2), microcephaly (2/2), ocular anomalies (2/2, coloboma in 2/2, congenital cataract 2/2, etc), heart defects (2/2, PDA in both, ASD), variable genitourinary anomalies (2/2 incl. hydronephrosis, VUR reflux/recurrent UTIs, kidney atrophy, abn. genitalia in 1), abnormalities of the limbs (2/2, bilateral talipes equinovarus : 2/2) or the skeleton (1/2 - butterfly vertebrae). One was reported to have some degree of growth delay (<10th centile for length, <5th for weight and OFC). There was no hearing defect reported (large ears in 1/2). Overall, the authors used the term CHARGE-like phenotype.

[2]-----
Maddirevula et al (2019 - PMID: 30237576) performed autozygome and exome analysis of individuals with suspected Mendelian disorders. They reported 3 individuals (18DG0161, 18DG0162, 18DG0165) born to 3 different consanguineous families (information in fig2) from Qatar, homozygous for CDK9 p.Arg225Cys.

All presented a CHARGE-like phenotype with features ophtalmologic findings (3/3 - abnormal ERG in one, congenital cataracts the other, visual impairment in the 3rd, though NO evidence of coloboma in at least two), heart defect (2/3 had VSD), choanal atresia (3/3), retarded growth/FTT (1/3) or global DD (3/3 - in suppl. table 1), (genito)urinary anomalies (1/3 - dysplastic atrophic kidney) or ear anomalies (3/3 - preauricular tags 2/3, bilateral deafness 1/3, bilat.ossicular anomalies 1/3). Other features incl. epilepsy (2/3), brain MRI abnormalities (2/3), facial asymmetry in one, vertebral segmentation defect in 1/3.

[3]-----
Hu et al (2019 - PMID: 29302074) performed WES/WGS in 404 consanguineous families from Iran, having 2 or more offspring with ID.

In this context they reported 2 females and a male (III:1,4,3 belonging to fam. M9100018 - details in suppl. text) born to first cousin parents from Iran. Features included DD (3/3 - walking at 3y, words at 4y), moderate ID (3/3 - WAIS-IV IQ of 40-43), short stature (3/3 below 3rd %le). Vision and hearing were normal.

All three were homozygous for a missense SNV (NM_001261:c.280C>T, p.Arg94Cys) which was ultrarare in ExAC, with severa in silico tools in favor of a deleterious effect.

The authors commented that CDK9 is the catalytic core of transcription elongation factor p-TEFb essential for transcription elongation of numerous genes, Cdk9/Cyclin T1 complex may participate in neuronal differentiation, CDK9-cyclinK in maintenance of genomic integrity, with the protein encoded also interacted with AF4/FMR2.

In addition the gene was commented to have ubiquitous expression with high protein expression in glial and neuronal cells of the cortex (based on Uniprot and Human Protein Atlas).

[4]-----
Nishina et al (2021 - PMID: 33640901) described an 8 y.o. male with facial asymmetry, ear/hearing anomalies (microtia, preauricular tags, bilateral hearing loss), ocular/vision anomalies (blepharophimosis, lacrimal obstruction, eyelid dermoids, duane-like anomaly, congenital cataracts, retinal dystrophy), cleft lip and palate, abnormalities of the limbs (finger contractures with associated absence of creases, cutaneous syndactyly, etc). Other features included cardiac dysrhythmia and undescended testes. Development was delayed with associated ID (walking 3y, words 7y, at 10y: could count to 20, 4 word sentences). There was no evidence of coloboma or choanal atresia.

Trio exome sequencing revealed that the child was compound htz for 2 missense SNVs (NM_001261.3:c.862G>A / p.Ala288Thr and c.907C>T /p.Arg303Cys) with Sanger confirmation. These were ultrarare/not present in gnomAD. Both lied in the protein kinase catalytic domain of CDK9, with high conservation across different species and in silico predictions in favor of deleterious effect.

In vitro studies in HEK293 cells demonstrated that the kinase activity for both variants was significantly reduced compared to wt. Kinase activity was also reduced for the Arg225Cys variant (reported in Refs 1 & 2).

The authors briefly discuss evidence from zebrafish (regulates larval morphogenesis incl. brain, heart, eye, blood vessels) and mouse models. In the latter complete LoF is lethal while heterozygous LoF is associated with abnormal morphology of heart, skin and epididymis (PMIDs cited by the authors : 27715402, 30100824).
Sources: Literature
Intellectual disability v3.1561 HESX1 Arina Puzriakova Phenotypes for gene: HESX1 were changed from Septooptic dysplasia, 182230Pituitary hormone deficiency, combined, 5, 182230Growth hormone deficiency with pituitary anomalies, 182230; HESX1-RELATED COMBINED PITUITARY HORMONE DEFICIENCY to Growth hormone deficiency with pituitary anomalies, OMIM:182230; Pituitary hormone deficiency, combined, 5, OMIM:182230; Septooptic dysplasia, OMIM:182230
Intellectual disability v3.1560 FH Arina Puzriakova Phenotypes for gene: FH were changed from Fumarase deficiency, 606812Leiomyomatosis and renal cell cancer, 150800; FUMARASE DEFICIENCY to Fumarase deficiency, OMIM:606812
Intellectual disability v3.1559 AFG3L2 Arina Puzriakova Phenotypes for gene: AFG3L2 were changed from Spastic ataxia 5, autosomal recessive OMIM:614487; spastic ataxia 5 MONDO:0013776; Spinocerebellar ataxia 28 OMIM:610246; spinocerebellar ataxia type 28 MONDO:0012450 to Optic atrophy 12, OMIM:618977; Spinocerebellar ataxia 28, OMIM:610246; Spastic ataxia 5, autosomal recessive, OMIM:614487
Intellectual disability v3.1558 SLC35B2 Konstantinos Varvagiannis gene: SLC35B2 was added
gene: SLC35B2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: SLC35B2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC35B2 were set to 35325049
Phenotypes for gene: SLC35B2 were set to Abnormality of the skeletal system; Short long bone; Short stature; Abnormality of epiphysis morphology; Scoliosis; Multiple joint dislocation; Global develpmental delay; Intellectual disability; CNS hypomyelination; Abnormality of the corpus callosum; Cerebral atrophy; Abnormality of the amniotic fluid
Penetrance for gene: SLC35B2 were set to Complete
Review for gene: SLC35B2 was set to AMBER
Added comment: 2 unrelated individuals with biallelic SLC35B2 variants have been reported. DD and ID were part of the phenotype.

There is currently no associated phenotype in OMIM/G2P/SysID. The gene has amber rating in the leukodystrophies panel of PanelApp Australia.

Consider inclusion in the current panel (or other possibly relevant ones eg. for skeletal disorders, short stature, white matter disorders, corpus callosum, etc) with amber rating.

---

Guasto et al (2022 - PMID:35325049) report 2 unrelated individuals with biallelic SLC35B2 variants.

SLC35B2 encodes solute carrier family 35 (3'-phosphoadenosine 5'-phosphosulfate (PAPS) transporter), member B2.

The protein is located in the Golgi membrane and serves as transporter of the activated nucleotide sulfate PAPS from the cytosol, where it is synthesized to the Golgi lumen. Another PAPS transporter is encoded by SLC35B3. In the Golgi apparatus PAPS serves as substrate of sulfotransferases for the addition sulfate to the covalently attached GAG chains of proteoglycans (PGs).

The phenotype corresponded to a chondrodysplasia manifesting as severe pre- and postnatal growth retardation (height <-4 SD and -8 SD), early scoliosis, multiple joint dislocations (in one). There was severe DD affecting motor and expressive language development with associated ID. Brain imaging was suggestive of hypomyelinating leukodystrophy with thin corpus callosum and cerebral atrophy. One individual had a cleft palate in the context of Pierre Robin sequence.

Both individuals were investigated with exome sequencing.

The first individual - born to consanguineous parents - was homozygous for an in-frame del (NM_178148.3:c.1218_1220del, p.Leu407del) with Sanger sequencing confirming the variants, and heterozygosity in parents and 2 unaffected sibs. There was an initially identified hmz CUL7 variant (for 3M syndrome), which was not felt sufficient to explain the severity of the phenotype and notably ID.

The 2nd proband was homozygous for a fs variant (c.1224_1225delAG / p.Arg408SerfsTer18 - leading to loss of the last 8 amino acids) occurring in the context of uniparental isodisomy [iUPD(6)] spanning the complete chr6 based on the exome data.

Among the evidence presented for SLC35B2 and the variants :
- SLC35B2 has high mRNA expression in fetal and adult mouse brain and other tissues.
- Upon qPCR analysis of mRNA expression in human brain samples, the gene had expression across the brain (frontal lobe grey matter, subcortical frontal white matter/cerebellum).
- High expression was shown upon analysis of mouse brain single cell RNA data (EMBL) in oligodendrocytes and microglial cells.
- RT-PCR on mRNA from skin fibroblasts (both individuals) revealed significant decrease of SCL35B2 mRNA levels compared to controls.
- Transfection of C-terminal c-myc tagged wt or mutant proteins in HEK293F cells, followed by western blotting did not reveal significant difference at the protein level. Wt SLC35B2 localized at the Golgi apparatus as suggested by colocalization with GM130 marker. The 2 variants however displayed only partial colocalization (/loss of localization specificity) with diffuse signal in the cell.
- Chondroitin sulfate disaccharide sulfation was decreased upon HPLC disaccharide analysis in patient fibroblasts and bikunin (a circulating proteoglycan in blood) electrophoretic pattern in patient sera.
- Disorders due to variants in genes implicated in proteoglycan biogenesis (e.g. XYLT1, B3GALT6, CHSY1) are associated with skeletal/connective tissue manifestations with DD/ID.
- C-elegans model lacking pst-1 (SLC35B2 ortholog) provides support that the protein is required for migration, axonal guidance, and presynaptic development in a subset of neurons.
- dsm-1 - the rat ortholog - is expressed in rat brain in D-serine and NMDA receptor rich regions. When expressed in Xenopus oocytes it accelerated the efflux of D-serine (a co-agonist for NMDA receptor).
- Variants in other members of SLC superfamily (e.g. SLC17A5, SLC35A3, SLC29A3, SLC35A2) have been associated with brain-bone phenotypes.
Sources: Literature
Intellectual disability v3.1556 FBXW7 Konstantinos Varvagiannis gene: FBXW7 was added
gene: FBXW7 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: FBXW7 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: FBXW7 were set to 33057194; 35395208; 30885698; 26482194; 19963109; 20332316
Phenotypes for gene: FBXW7 were set to Neurodevelopmental abnormality; Global developmental delay; Intellectual disability; Macrocephaly; Microcephaly; Abnormality of brain morphology; Abnormality of the corpus callosum; Abnormality of the cerebellum; Abnormality of the cardiovascular system; Seizures; Strabismus; Abnormality of the palate
Penetrance for gene: FBXW7 were set to unknown
Review for gene: FBXW7 was set to AMBER
Added comment: While Kaplanis et al (2020 - Ref1), identified FBXW7 among 285 genes significantly associated with developmental disorders, a recent study by Stephenson et al (2022 - Ref2) describes the neurodevelopmental phenotype of 35 individuals making this gene relevant to the current panel. There are previous reports of dn/inh germline variants in individuals (likely 7) with tumor predisposition although a neurodevelopmental phenotype was not reported in most cases.

There is currently no FBXW7-related phenotype in OMIM.

The gene is included in the DD panel of G2P [associated with: FBXW7-related developmental disorder (monoallelic), confidence: definitive, citing the study by Kaplanis et al]. SysID lists FBXW7 among the candidate ID genes (same Ref.). The gene has a green rating for ID in PanelApp Australia (VCGS participating in the recent publication).

Consider inclusion with amber/green rating. Also consider inclusion in other panels that may be relevant(macro/microcephaly, seizures, CHD, corpus callosum / cerebellar abnormalities, cleft palate, WT, etc).

[1]------------
Kaplanis et al (2020 - PMID: 33057194), by combining exome data from 31,058 parent offspring trios from the DDD study, Radboudumc and GeneDx, identified 285 genes significantly associated with developmental disorders, 28 of which (incl. FBXW7) not previously robustly associated with these disorders.

[2]------------
Stephenson et al (2022 - PMID: 35395208) provide clinical information on 35 individuals harboring germline monoallelic FBXW7 variants or chromosomal deletions spanning this gene.

The phenotype corresponded to a phenotypically variable NDD characterized by hypotonia (in about 2/3), neurodevelopmental abnormality (34/35 - as discussed later), seizures (8/35), abnormal brain morphology (13/17 - in 7/17 abnormal CC, in 5/17 abn. cerebellum, etc), head circumference (macrocephaly in 10/35, microcephaly in 2/35). Additional features included abnormal palate or uvula morphology (10/35 - cleft palate in 3 from 2 families while 1 individual from a 3rd family had bifid uvula) or abnormal heart morphology (11/35), ophthalmologic features (e.g. strabismus in 5/35) or hearing impairment (2/35). There was no recognizable gestalt (deeply set eyes with upper eyelid fullness in 9/35).

As for the DD/ID this ranged from borderline to severe, characterized as mild-moderate in 27/35, severe in 3/35. One individual did not present neurodevelopmental abnormality 1/35.

FBXW7 encodes F-box and WD40 domain protein 7 which is part of the SCF E3 ligase complex (SKP1/CUL1/F-box protein) exerting a role of recognition and binding of target proteins for degradation by the ubiquitin proteasome system. In this way FBWX7 participates in regulating a network of proteins involved in cell division, growth, differentiation (as summarized by Roversi et al - Ref2).

Most individuals were investigated by trio-WES/WGS (few with singleton WES or CMA only). 28 germline FBXW7 variants were identified incl. missense (N=21), pLoF (predicted or not to undergo NMD) and 2 deletions encompassing but not limited to FBXW7.

Additional SNVs/CNVs (e.g. an inh intragenic DPP6 dup in one individual (#9) with deletion, other de novo 4q CNVs (#10), an inh 22q spanning partially an ISCA TS region, a CACNA1A and KMT2D SNV, etc) were reported in few individuals.

Most variants arose dn (N=30) with two individuals displaying mosaicism (2/30) and three individuals having inherited the variant from their affected parent. CNVs had occurred dn.

3 missense SNVs were recurrent in unrelated individuals.

All variants identified affected all FBXW7 isoforms.

As the authors comment missense variants clustered at the C-terminal half of the protein with most (16/21) occurring within the WD40 domain. [The N-terminal part commented in the literature to affect localization].

The crystal structure of FBXW7 and SKP1 complex has been determined with CYCLIN E1/DISC1 as substrates, and in silico modeling revealed that all missense variants aligned with residues required for this interaction, or adjacent ones.

All were absent from gnomAD, while missense variants from gnomAD (N=78) were not predicted have significant effect on the binding affinity.

Variant studies revealed that most missense variants (6/7 tested - Arg689Gln being the exception) are unlikely to cause protein instability or degradation in vivo.

Co-expression of these missense variants with CYCLIN E1 / E2, known FBXW7 substrates revealed that variants were less efficient at degrading the substrate with variants in the WD40 domain having greater impact (in some cases E1 / E2 - specific).

Elav-Gal4 mediated neuronal knockdown of the Drosophila ortholog archipelago (ago) using 2 RNAi-s with different efficiency was shown to affect learning or compromise neuronal function (also related to the level of knockdown).

The authors summarize results from animal models for the role of this gene in development and the nervous system.

KO mice die in utero at E10.5 manifesting abn. of hematopoietic or vascular development and heart-chamber maturation(*). Some htz knock-in for human cancer variants, display perinatal lethality, abn lung, cleft palate (30%)(*),etc. Conditional gut specific deletion results in impaired differentiation of intestinal goblet cells (*)(constipation in 16/35 in cohort). KO limited to CNS and PNS results in defective sucking and morphological brain abnormalities. Haploinsufficiency in the nervous system was associated with impaired differentiation of neural stem cells (possibly through a Notch-mediated mechanism). KO in Schwann cells of the peripheral nervous system resulted in enhanced myelination.

Excessive oligodendrocyte cells and hypermyelination (as a result of elevated Notch & mTOR signaling) are observed in homozygous mutant zebrafish or after morpholino-mediated fbxw7 knockdown.

Overall, the authors propose haploinsufficiency or loss-of-function as the underlying mechanism.

Finally, as the authors comment, FBXW7 is a tumor suppressor among the most commonly mutated genes in human cancer (3.5%). Germline variants have been previously reported in individuals with cancer (Wilms tumor, rhabdoid, etc - most summarized below). However, none of the 35 individuals in this cohort (oldest 44 y.o.) had any history of cancer.

Reports of individuals with germline variants causing (monoallelic) disruption of FBXW7 - cases without DD/ID:

[3]------------
Mahamdallie et al (2019 - PMID: 30885698) investigated with WES a cohort of 890 individuals with Wilms tumor (799 non-familial disease, 91 from WT pedigrees). In this context they identified 4 individuals having developed WT (ages: 28-76m) with FBXW7 dn or inherited LoF variants (710G>A / p.Trp237* dn - 1972C>T / p.Arg658* - inh:NA, 1017_1021del5, 670C>T - paternal / p.Arg224* inh:NA - RefSeq not provided). One additional individual with a missense variant (1753A>T / p.Ser585Cys - dn) had developed rhabdoid tumor. While the authors mentioned additional features for other subjects in their cohort, among the 5 individuals with FBXW7 variants, only one had hypotonia (ID_0592) and another (ID_7520) had two febrile convulsions.

[4]------------
Roversi et al (2015 - PMID: 26482194) described the phenotype of a 34 y.o. female with syndromic presentation (macrocephaly, nephrotic syndrome due to FSGS, Hodgkin's lymphoma, Wilms tumor, ovarian cystadenoma, breast carcinoma) harboring a 157 kb deletion of 4q31.3.

Eventual DD/ID was not reported despite detailed clinical description.

The deletion spanned almost the entire FBXW7 gene and a pseudogene (hg19 - chr4:153205202-153362047). The authors provided evidence that the del affected the maternal allele as dn event (maternal mosaicism excluded). Expression of FBXW7 in patient-derived EBV lymphoblastoid cell line revealed decreased levels of expression compared to controls. At somatic level, the authors looked for eventual 2nd hit in tumor tissue (which was not the case) while they demonstrated decreased FBXW7 expression in a WT sample compared to normal renal tissue. Previously, variants in other genes candidate for the phenotype were ruled out (Sanger & MLPA for TP53, BRCA1/2, PALB2, WT1, 11p15 MS-MLPA, std karyotype).

[5]------------
Kuiper et al (2015 - PMID: 19963109), in a 58 y.o. patient with recurrence of RCC, identified a constitutional translocation [t(3;4)(q21;q31)]. Using long-range PCR they defined the breakpoints at 3q21.3 (128379059 - hg18) between the PLXNA1 and C3orf56 genes while the chr4 breakpoint was located within the second intron of FBXW7 (pos. 153500813 - hg18). There were no additional phenotypes reported.

[6]------------
Williams et al (2010 - PMID: 20332316) reported a patient with WT harboring germline variants in WT1 and FBXW7. While the phenotype was sufficiently explained by a germline stopgain WT1 variant with a frameshift WT1 variant (as 2nd hit) confined to the tumor, the authors identified a germline in-frame FBXW7 insertion in the same individual (c.45_46insCCT / p.Thr15_Gly16insPro - RefS : NA) [if correct corresponding to: https://gnomad.broadinstitute.org/variant/4-153332910-C-CAGG - 345/281696 alleles in gnomAD].
Sources: Literature
Intellectual disability v3.1555 DTYMK Sarah Leigh Phenotypes for gene: DTYMK were changed from 31271740; 34918187; 35346037 to Global developmental delay; Intellectual disability; Microcephaly; Seizures; Global brain atrophy; Cardiorespiratory arrest
Intellectual disability v3.1554 DTYMK Sarah Leigh Publications for gene: DTYMK were set to Global developmental delay; Intellectual disability; Microcephaly; Seizures; Global brain atrophy; Cardiorespiratory arrest
Intellectual disability v3.1551 HSPD1 Arina Puzriakova Phenotypes for gene: HSPD1 were changed from Spastic paraplegia 13, autosomal dominant, 605280Leukodystrophy, hypomyelinating, 4, 612233; SPASTIC PARAPLEGIA AUTOSOMAL DOMINANT TYPE 13 to Leukodystrophy, hypomyelinating, 4, OMIM:612233
Intellectual disability v3.1549 HSPD1 Arina Puzriakova Added comment: Comment on mode of inheritance: Should be updated from 'both mono- and biallelic' to 'biallelic' only at the next GMS panel update. Biallelic variants cause a paediatric-onset leukodystrophy (MIM# 612233) which can feature severe DD/ID in some cases (PMID: 18571143, 27405012), whereas monoallelic variants are associated with a pure adult-onset HSP (SPG13, MIM# 605280) which is not pertinent to this panel.
Intellectual disability v3.1548 PLEC Arina Puzriakova Phenotypes for gene: PLEC were changed from Muscular dystrophy with epidermolysis bullosa simplex, 226670; Epidermolysis bullosa simplex, Ogna type, 131950; Epidermolysis bullosa simplex with pyloric atresia, 612138; Muscular dystrophy, limb-girdle, type 2Q, 613723 to Epidermolysis bullosa simplex 5D, generalized intermediate, autosomal recessive, OMIM:616487; Epidermolysis bullosa simplex 5A, Ogna type, OMIM:131950; Epidermolysis bullosa simplex 5B, with muscular dystrophy, OMIM:226670; Epidermolysis bullosa simplex 5C, with pyloric atresia, OMIM:612138; Muscular dystrophy, limb-girdle, autosomal recessive 17, OMIM:613723
Intellectual disability v3.1547 PARN Arina Puzriakova Phenotypes for gene: PARN were changed from Dyskeratosis congenita, autosomal recessive 6, 616353 to Dyskeratosis congenita, autosomal recessive 6, OMIM:616353
Intellectual disability v3.1544 DTYMK Konstantinos Varvagiannis gene: DTYMK was added
gene: DTYMK was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: DTYMK was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DTYMK were set to Global developmental delay; Intellectual disability; Microcephaly; Seizures; Global brain atrophy; Cardiorespiratory arrest
Phenotypes for gene: DTYMK were set to 31271740; 34918187; 35346037
Penetrance for gene: DTYMK were set to Complete
Review for gene: DTYMK was set to GREEN
Added comment: 4 individuals (from 3 families) harboring biallelic DTYMK pathogenic variants have been reported.

Consider inclusion in the current panel with green rating given consistent and relevant phenotype and evidence provided to date [effect of variants (LoF), pathogenesis, similar phenotypes in zebrafish model, etc].

Relevant studies are summarized below.
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Lam et al (2019 - PMID: 31271740) described two siblings aged 25m and 7y, harboring biallelic DTYMK variants.

The phenotype consisted of hypotonia, congenital microcephaly, DD, severe ID. Other shared features included raised serum lactate, pyruvate and alanine. The phenotype was more pronounced in the younger one (epilepticus during febrile illness, epilepsy on multiple anti-convulsants, evidence of regression, etc). Brain MRI revealed marked cerebral atrophy among the findings while a lactate peak was present in spectroscopy. The elder brother developed an episode of sudden onset coma with respiratory failure at the age of 7y.

Quartet WES identified compound heterozygosity for a fs and a missense DTYMK variant (NM_012145.3:c.287_320del / p.Asp96Valfs*8 - c.295G>A / p.Ala99Thr). There were no additional findings. Previous genetic panel analysis for epilepsy was unremarkable for the 1st sib.

There are two pathways for synthesis of dNTPs, the de novo pathway operating in the cytosol only and the salvage operating in both cytosol and mitochondria. DTYMK encodes (deoxy)thymidylate kinase which catalyzes conversion (phosphorylation) of dTMP to dTDP - a step right after convergence of both pathways - in the dTTP synthesis pathway.

Mutations in TK2, an enzyme phosphorylating thymidine in mitochondria to dTMP have been associated with mitochondrial DNA depletion syndrome (MDDS).

Given this and as the 2 sibs had raised serum lactate and pyruvate, the authors performed in silico analyses to calculate mtDNA/nDNA ratio dividing the respective read depths for mitochondrial and nuclear DNA obtained from WGS data of the two sibs (blood).

This ratio was shown to be reduced in the more severely affected sib (65.5% of control) although this was not the case for the mildly affected brother (114.6%). As a control a non-MDDS mitochondrial cytopathy sample (corresponding to m.8993T>G) was used. The respective ratio which was calculated for a known POLG-related MDDS case was 15.6%.
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Vanoevelen et al (2022 - PMID: 34918187) describe two unrelated children with hypotonia, absence of developmental progress, microcephaly, seizures (recurrent febrile seizures/myoclonic jerks). Severe cerebral atrophy (with unaffected cerebellum) was observed upon brain imaging. Other findings included puffy body/extremities. Both had complications following respiratory illness leading to demise. CNS pathology in the 1st individual revealed massive neuronal dropout, with sparing of dentate nucleus and brainstem.

CMA in both cases was normal. This was also the case for extensive metabolic investigations (which provided no evidence of eventual mitochondrial dysfunction).

WES revealed compound heterozygosity for 2 missense variants in the first individual (NM_012145.3:c.382G>A - p.Asp128Asn and c.242C>T - p.Pro81Leu). The second individual, born to consanguineous parents, was homozygous for c.242C>T / p.Pro81Leu.

In silico predictions varied although each variant were (mostly) suggestive of a deleterious effect.

Variants were both ultrarare without homozygotes in ExAC,.

The authors generated a dtymk ko zebrafish model (hmz for a frameshift variant). Zebrafish exhibited markedly smaller eyes and pericardiac edema (3dpf-), twitching movements somewhat reminiscent of epilepsy (at 3dpf), prominent edema of brain and intestine. Head size was significantly smaller at a timepoint prior to brain edema (also after correction for length). Histology provided evidence of empty spaces in brain, suggestive of neurodegeneration, with high amounts of apoptotic cells.

dTMPK activity was measured in zebrafish (at 5dpf) as well as in fibroblasts from one individual and in both cases, it was barely detectable and significantly lower compared to wt/htz zebrafish or to the activity in fibroblasts from the parents of the individual tested.

In fibroblasts from the same individual with comparison to his parents, the authors demonstrated that DNA replication was impaired (using pulse-EdU staining to quantify cells in S-phase).

Assessment of cell proliferation in the brain of dtymk ko zebrafish using phospo-Ser10-Histone H3 (pH3) staining was suggestive of severe proliferation defects in forebrain.

Impaired biosynthesis of nucleotides for DNA synthesis/repair would be predicted to result in nucleotide pool imbalance, leading to incorporation of ribonucleotides in genomic DNA with - in turn - impairment of DNA replication and genomic instability (sensitivity to strand breakage).

In line with this, genomic DNA of ko zebrafish following alkaline hydrolysis and alkaline gel electrophoresis was shown to migrate at lower position and to be more fragmented indicating increased sensitivity (due to incorporation of ribonucleotides).

Visualization of DNA breakage by γH2AX staining, following UV-irradiation of zebrafish embryos revealed persistence of elevated γH2AX levels and DNA damage response signaling, interpreted as increase in unrepaired DNA breaks.

mtDNA copy numbers in fibroblasts from the affected individual was somewhat but not significantly lower compared to his parents. Importantly, the copy numbers were similar to controls (N=5) which overall does not support mtDNA depletion as a consequence of DTYMK deficiency.

Integrity of mtDNA did not appear to be compromised , with the mitochondrial genome migrating at the expected length of 16,5 kb with no indications of mtDNA deletions for both affected individual and his parents.

Activity of the mitochondrial respiratory complexes I-V in fibroblasts from the affected individual was comparable to that of his parents.

Overall, there was no evidence for mtDNA depletion (although not studied in muscle biopsy) while functional studies failed to demonstrate mitochondrial dysfunction.

The authors discuss other disorders of impaired dTTP metabolism due to mutations in TYMP, RRM2B or CAD.
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In a recent study using zebrafish model, Hu Frisk et al (2022 - PMID: 35346037) further demonstrate that Dtymk is essential for neurodevelopment providing evidence for expression of a compensatory thymidylate kinase-like enzyme at later stages of development (explaining survival of ko dtymk zebrafish despite the central role of this enzyme in dTTP generation). [Not further reviewed]
Sources: Literature
Intellectual disability v3.1544 KDM5B Arina Puzriakova Phenotypes for gene: KDM5B were changed from neurodevelopment delay and autism spectrum disorder; Mental retardation, autosomal recessive 65, 618109 to Intellectual developmental disorder, autosomal recessive 65, OMIM:618109
Intellectual disability v3.1542 HEPACAM Arina Puzriakova Phenotypes for gene: HEPACAM were changed from Megalencephalic leukoencephalopathy with subcortical cysts 2B, remitting, with or without mental retardation (AD), 613926; Megalencephalic leukoencephalopathy with subcortical cysts 2A (AR), 613925 to Megalencephalic leukoencephalopathy with subcortical cysts 2A, OMIM:613925; Megalencephalic leukoencephalopathy with subcortical cysts 2B, remitting, with or without mental retardation, OMIM:613926
Intellectual disability v3.1541 NAPB Arina Puzriakova gene: NAPB was added
gene: NAPB was added to Intellectual disability. Sources: Expert Review Amber,NHS GMS
Q2_22_rating, Q2_22_NHS_review tags were added to gene: NAPB.
Mode of inheritance for gene: NAPB was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NAPB were set to 28097321; 33189936; 26235277; 21040848
Phenotypes for gene: NAPB were set to Early infantile epileptic encephalopathy
Penetrance for gene: NAPB were set to unknown
Intellectual disability v3.1540 SLC5A6 Arina Puzriakova Phenotypes for gene: SLC5A6 were changed from Feeding difficulties; Failure to thrive; Global developmental delay; Developmental regression; Intellectual disability; Seizures; Microcephaly; Cerebral atrophy; Abnormality of the corpus callosum; Vomiting; Chronic diarrhea; Gastrointestinal hemorrhage; Abnormal immunoglobulin level; Osteopenia; Abnormality of metabolism/homeostasis to Neurodegeneration, infantile-onset, biotin-responsive, OMIM:618973
Intellectual disability v3.1537 GDAP1 Arina Puzriakova Phenotypes for gene: GDAP1 were changed from Charcot-Marie-Tooth disease, type 4A, 214400; Charcot-Marie-Tooth; disease, axonal, with vocal cord paresis, 607706; Charcot-Marie-Tooth disease, axonal, type 2K, 607831; Charcot-Marie-Tooth disease, recessive; intermediate, A, 608340 to Charcot-Marie-Tooth disease, axonal, type 2K, OMIM:607831; Charcot-Marie-Tooth disease, axonal, with vocal cord paresis, OMIM:607706; Charcot-Marie-Tooth disease, recessive intermediate, A, OMIM:608340; Charcot-Marie-Tooth disease, type 4A, OMIM:214400
Intellectual disability v3.1534 ZBTB7A Konstantinos Varvagiannis gene: ZBTB7A was added
gene: ZBTB7A was added to Intellectual disability. Sources: Literature,Other
Mode of inheritance for gene: ZBTB7A was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ZBTB7A were set to 31645653; 34515416
Phenotypes for gene: ZBTB7A were set to Global developmental delay; Intellectual disability; Macrocephaly; Abnormality of the lymphatic system; Sleep apnea; Increased body weight; Autism; Persistence of hemoglobin F; Abnormal leukocyte count; Recurrent infections; Umbilical hernia
Penetrance for gene: ZBTB7A were set to unknown
Review for gene: ZBTB7A was set to AMBER
Added comment: Monoallelic pathogenic ZBTB7A variants cause Macrocephaly, neurodevelopmental delay, lymphoid hyperplasia, and persistent fetal hemoglobin (#619769).
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Ohishi et al (2020 - PMID: 31645653) described the phenotype of a 6y5m-old male harboring a heterozygous, de novo ZBTB7A missense variant. Features included macrocephaly, mild intellectual disability (tIQ 65) and sleep apnea. Available hemoglobin levels (in the 1st month) supported high Hb and HbF levels. Other features included PDA and an umbilical hernia.

Initial investigations incl. karyotype and CMA were normal.

The ZBTB7A variant (NM_015898.3:c.1152C>G / p.Cys384Tyr) was identified following trio WES with a list of additional findings (in suppl.) not explaining the phenotype. This SNV, confirmed by Sanger sequencing, was absent from public db with several in silico predictions in favor of a deleterious effect.

ZBTB7A on 19p encodes zinc finger- and BTB domain-containing protein 7 (or Pokemon).

The authors performed a review of 19p13.3 microdeletion cases supporting a minimum region of overlap spanning PIAS4, ZBTB7A and MAP2K2 and common features of DD and ID, macrocephaly with prominent forehead, sleep apnea. The authors argue that loss of ZBTB7A explains part of - but probably not all - features of 19p13.3 microdeletions.

ZBTB7A is known to repress expression of HBG1 and HBG2 (γ-globin), with the few available HbF patient measurements in line with this role.

Based on the structure of the protein, Cys384 (along with 3 other residues) forms a coordinate bond with the Zn+2 ion, this bond predicted to be disrupted by Tyr. Further they favor a dominant negative effect given that ZBTB7A protein is known to form dimer via interaction at the BTB domain [hetero (variant+wt) and homodimers (variant+variant) having compromised function]. To support this notion, 3 previously reported somatic variants within the zinc-finger domain have been shown to exert a dominant-negative effect (PMID cited: 26455326).
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In a collaborative study, von der Lippe et al (2022 - PMID: 34515416) identified 12 additional individuals (from 10 families) harboring monoallelic ZBTB7A missense/pLoF variants most commonly as de novo events.

The authors describe a consistent phenotype with motor (9/11) and speech delay (9/12), cognitive impairment/ID (12/12 - commonly mild, ranged from specific learning difficulties to severe ID), macrocephaly (>90%le in 11/12, >97% in 7/12), lymphoid hypertrophy of pharyngeal tissue/adenoid overgrowth (12/12), sleep apnea (9/12). Autistic features were observed in 7/12. Other phenotypes included frequent upper airway infections (10/11), weight above 97th percentile (7/11). HbF levels were elevated in 4/5 individuals with available measurements (range: 2.2% to 11.2% - ref. for subjects above 6m of age : <2% ). Other hematological issues were observed in few individuals (abn. monocyte/neutrophil counts in 3-4). Cardiovascular issues were reported in 4 (2 fam). 3 subjects had umbilical hernia. There was no common dysmorphic feature.

Various initial investigations were normal or did not appear to explain the NDD phenotype and incl. standard karyotype, CMA, targeted testing for genes/disorders previously considered (PTEN, FMR1, NSD1, BWS and PWS methylation studies, CFTR, etc). One male had a maternally inherited chrX dup not thought to explain his complex phenotype, while another had a concurrent diagnosis of thalassemia.

Individuals were investigated with singleton (or trio) WES. Of note some individuals were DDD study participants.

8 had de novo ZBTB7A variants, incl. one who harbored 2 de novo missense SNVs several residues apart. 2 sibs had inherited a fs variant from their affected parent. For the latter as well as for another subject parental samples were unavailable.

There were no other variants of interest upon exome analysis.

5 different missense, 2 nonsense and 3 fs variants were identified with pLoF all predicted to lead to NMD.

All variants were absent from gnomAD (pLI of 0.96, LOEUF 0.33 and missense Z-score of 4.04) which lists one individual with htz LoF, likely not an artifact.

Given this individual (and the familial case) the authors discuss on the mild phenotype and/or eventual reduced penetrance or underdiagnosis of the disorder.

There was no difference in severity between those with missense/truncating variants.

ZBTB7A transcription factor (or pokemon or lymphoma/leukemia-related factor) is widely expressed. It is involved in several activities being among others required to block Notch signaling which in turn drives T-cell at the expense of B-cell development. Notch pathway activation has been demonstrated in Zbtba7 ko mouse models. Finally, the authors discuss the role of notch signaling in thymus and the nervous system, as well as that ZBTB7A up/down-regulation known to repress/increase respectively HbF expression (several refs in text).
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MGI (1335091) for Zbtb7a : "Mice homozygous for a knock-out allele die around E16.5 due to anemia and exhibit a cell autonomous defect in early B cell development". (Phenotypes from nervous system not commented on).
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Apart from OMIM (#619769), ZBTB7A is included in the DD panel of G2P (ZBTB7A-associated developmental disorder / monoallelic_autosomal / absent gene product / confidence limited) as well as among the primary ID genes in SysID. In PanelApp Australia the gene is incl. with green rating in the ID and Macrocephaly gene panels.
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Consider inclusion with amber or green rating (several individuals/families/variants, highly consistent phenotype, overlap with 19p microdeletions || variant effect not studied, animal models supporting contribution of the gene to the phenotype though no data on associated NDD ones).

Please also consider inclusion in other relevant panels (macrocephaly, lymphatic disorders, ASD, etc).
Sources: Literature, Other
Intellectual disability v3.1534 ATP2B1 Konstantinos Varvagiannis gene: ATP2B1 was added
gene: ATP2B1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: ATP2B1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ATP2B1 were set to 35358416; 35358416
Phenotypes for gene: ATP2B1 were set to Global developmental delay; Intellectual disability; Autism; Behavioral abnormality; Seizures; Abnormality of head or neck
Penetrance for gene: ATP2B1 were set to unknown
Review for gene: ATP2B1 was set to GREEN
Added comment: Monoallelic missense/pLoF ATP2B1 variants have been reported in 12 unrelated individuals with DD/ID making this gene relevant to the current panel.

Currently there is no associated phenotype in OMIM, G2P, SysID, PanelApp Australia.

Based also on the evidence discussed below, please consider inclusion with green (rather than amber) rating.
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Rahimi et al (2022 - PMID: 35358416) describe 12 unrelated individuals with monoallelic ATP2B1 variants.

Phenotype consisted of DD (12/12), ID [9/12 - mild or less commonly moderate, with 3 additional subjects "unclassified" likely due to their age (#6: 3y nonverbal/nonambulatory, could sit and roll / #8: 3y, sitting at 1y, 1st words:26m / #12: at 5y nonambulatory/nonverbal)]. Behavioral issues were observed in 8/11 (ASD in 5/11). Seizures were reported in 5/12 (one further had abnormal EEG). Minor features - albeit not consistent/without recognizable gestalt - were reported in 6. Anomalies of digits and marfanoid habitus were reported in 4 and 2.

All subjects were investigated by singleton/trio exome sequencing.

Previous investigations incl. karyotype, CMA, analysis of individual genes (e.g. FMR1, ZEB2) or metabolic workup were normal for several individuals with one having a concurrent diagnosis of mosaic (20%) XXY and another harboring an additional hmz variant for a liver disorder.

9 different missense and 3 nonsense ATP2B1 variants were identified, shown to have occurred de novo in all cases where parental samples were available (9/12).

ATPase plasma membrane Ca+2 transporting 1, the protein encoded by ATP2B1, is an ATP-driven calmodulin-dependent Ca+2 pump which removes intracellular calcium from the cytosol. As the authors comment calcium pumps are thought to have a crucial role on neuronal function.

All variants identified were absent from gnomAD with the exception of c.2365C>T / p.Arg789Cys (de novo) which is present once in the database. ATP2B1 has a pLI of 1 and a missense Z-score of 5.29.

The variants affected several ATP2B1 isoforms. Variants were reported using NM_001001323.2, corresponding to ATP2B1a isoform which is mainly detected in brain (as also in GTEx).

In silico predictions were in favor of a deleterious effect and structural modeling supported the role of the affected residues.

The nonsense variants occurred in positions predicted to lead to NMD (not studied).

Transfection of an ATP2B1-yellow fluorescent protein (YFP) expression plasmid for wt or variants in HEK293 cells, revealed membranous fluorescence for wt, significantly altered localization for 3 variants (Asp239Gly, Thr264Ile, Arg991Gln), shift to cytoplasmic localization for 4 others (Thr425Lys, Arg763Pro, Glu824Lys, Gln857Arg) with statistically non-significant effect for 2 others (His459Arg and Arg789Cys).

Fluorometric [Ca+2]i analysis in HEK293 cells expressing wt or variant ATP2B1 revealed that all missense variants affected Ca+2 transport. This was not the case for wt ATP2B1 or for another missense variant used as control (drawn from gnomAD).

Of note, a further (13th) affected individual with another missense variant (c.1793T>C / p.Ile598Thr) was excluded from the phenotypic analysis. The membrane localization and Ca+2 transport did not appear to be affected by this variant which was classified as VUS although it a different impact from those studied.

Overall loss-of-function is thought to be the underlying mechanism based on the above (and supported by few reported cases with gross deletions spanning also ATP2B1). A dominant negative effect for missense variants (affecting heteromeric complex formation with neuroplastin or basigin) could not be completely excluded, but not supported either by the localization of the identified variants.

In the supplement the authors include 3 DDD study participants previously reported to harbor de novo pLoF/missense variants though with few available clinical information (PMID: 33057194 - DDD13k.05076 : c.2883del / DDD13k.04028 : c2512A>C - p.Ile838Val / DDD13k.08944 : c.2129A>C - p.Asp710Ala).

The authors discuss on the role of ATP2B1 on Ca+2 homeostasis in the CNS and neurodevelopment overall (also based on isoform expression in rat brain).
Sources: Literature
Intellectual disability v3.1533 PEX6 Sarah Leigh Added comment: Comment on mode of inheritance: The Q1_22_MOI tag has been added to this gene. The mode of inheritance for PEX6 should be set to: BOTH monoallelic and biallelic, autosomal or pseudoautosomal, in order to detect the dominant Peroxisome biogenesis disorder 4B (OMIM:614863). Incomplete penetrance has been noted, in order to highlight that unaffected parents may also carry rs61753230.
Intellectual disability v3.1530 MAN2C1 Konstantinos Varvagiannis gene: MAN2C1 was added
gene: MAN2C1 was added to Intellectual disability. Sources: Literature,Other
Mode of inheritance for gene: MAN2C1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MAN2C1 were set to 35045343
Phenotypes for gene: MAN2C1 were set to Global developmental delay; Intellectual disability; Abnormality of nervous system morphology; Abnormality of the corpus callosum; Ventriculomegaly; Polymicrogyria; Abnormality of the face; Macrocephaly
Penetrance for gene: MAN2C1 were set to unknown
Review for gene: MAN2C1 was set to GREEN
Added comment: Biallelic pathogenic MAN2C1 variants cause Congenital disorder of deglycosylation 2 (# 619775). Mild to moderate impairment of intellectual development is a feature in most patients as in the OMIM's clinical synopsis for this disorder.
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Specifically, Maia et al (2022 - PMID: 35045343) report the clinical features based of 6 relevant individuals (4/6 aged 4-18years and 2/6 fetuses) from 4 families. These individuals had non-specific dysmorphic features (micro/retrognathia being the most common in 5/6), different congenital anomalies, variable degrees of ID (3/4), as well as brain MRI abnormalities (PMG in 3/6 from 3 fam, ventriculomegaly in 3/6 from 2 fam, callosal anomalies in 4/6 from 3 fam, cerebellar hypoplasia 2/6 - 2 fam, vermis hypoplasia 4/6 - 3 fam etc). Macrocephaly was reported for 2/6 individuals (2 fam).

While ID was observed in 3/4 individuals of relevant age (mild in 1/4, moderate in 1/4, unk in 1/4), delayed motor and language development was reported for all (4/4).

All individuals harbored biallelic MAN2C1 variants following exome sequencing (previous investigations not reported), and Sanger sequencing was used for validation and segregation (parents/sibs).

There were no putative pathogenic variants in known disease genes.

MAN2C1 encodes mannosidase, alpha, class 2c, member 1, an enzyme playing a role in deglycosylation of free oligosaccharides (fOSs). The latter are generated and released in the cytoplasm or the ER lumen during N-glycosylation of proteins. fOSs are generated from two different pathways (ERAD and LLO) with a defect in an enzyme of the NGLY1 already described to cause a NDD due to defect of deglycosylation. In a later step oligossaccharides are trimmed by the action of ENGase to form fOS containing one GlcNAc (N-Acetylglucosamine) residue (fOSGn1) at the reducing end. Processing of these fOSs by the cytosolic α-mannosidase (MAN2C1) converts Man7-9Gn1 to Man5Gn1 subsequently transported to lysosomes for degradation.

Variants incl. 3 missense SNVs incl. c.2612G>C/p.Cys871Ser, c.2303G>A/p.Arg768Gln, c.607G>A/p.Gly203Arg, one splice variant (c.601-2A>G/p.Gly201Profs*10) and one indel (c.2733_2734del/p.His911Glnfs*67). [RefSeq NM_006715.3]

Most were present in gnomAD with low AF ranging from 0.013% to 0.11% while c.2303G>A/p.Arg768 has an AF of 0.33% with 5 homozygotes(*) in the database. Conservation and in silico predictions supported their effect.

For the variant affecting the splicing acceptor site (c.601-2A>G) studies in patient fibroblasts confirmed skipping of ex6. Fibroblasts from 2 sibs cmp htz for Arg768Gln and c.601-2A>G (Gly201Profs*10) were studied for protein levels, demonstrating 90% reduction in the amount of MAN2C1. There was no truncated protein observed upon immunoblot. Protein abundance was not affected in fibroblasts from the individual who was homozygous for Gly203Arg.

Mannosidase activities were studied upon overexpression in a HEK293 model, with Gly203Arg presenting similar activity to WT and Arg768Gln exhibiting only a tiny residual activity. Cys871Ser showed increased activity compared to WT.

Using fibroblasts from controls and the same individuals as above, the authors showed that pathogenic MAN2C1 variants caused defects in fOS processing (delayed processing of high oligomannose species, reduced production of M5Gn1 with M8 and M9Gn1/2 species remaining at high levels) supporting a total/partial loss of mannosidase activity for Arg768Gln and Gly203Arg.

In MAN2C1-KO HAP1 cell lines, M7-M9Gn1 species accumulated while M5Gn1 - the product of MAN2C1 - were absent. Complementation of KO HAP1 cells with Gly203Arg, Arg768Gln and Cys871Ser suggested impaired fOS processing for Gly203Arg and Arg768Gln (with significant amounts of M7-M9Gn1 species). Cells complemented with Cys871Ser did not exhibit fOS processing defects.

The authors speculate that Cys871Ser could affect a non-mannosidase function of the enzyme relevant to brain development or that it might lead to abnormal inter-subunit interactions or tetramer formation.

Finally, Maia et al summarize findings in previously described Man2c1-KO mice (cited PMID: 24550399). These appeared normal, did not exhibit differences in growth or lifespan and did not present behavioral alterations. Man2c1-KO mice had CNS involvement with histological analyses in favor of neuronal and glial degeneration with multiple vacuoles in deep neocortical layers and telencephalic white matter tracts. Vacuolization was not observed upon brain histology for the 2 fetuses studied which Maia et al speculate may occur at a later stage. In KO mice there was considerable accumulation of Man8–9GlcNAc oligosaccharides.
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G2P includes MAN2C1 in it's DD panel (confidence: strong, MAN2C1-associated neurodevelopmental disorder with cerebral malformations). In PanelApp Australia, this gene is rated green in the ID, polymicrogyria, cerebellar hypoplasia and fetal anomalies gene panels.

Consider inclusion in the current panel with green (3 individuals/families/variants, role of the gene, NDD phenotype also reported for NGLY1-related disorder of deglycosylation, variant studies) or amber rating (ID not a universal feature, still DD observed in all affected individuals).

Please consider adding this gene in other relevant panels (as in PanelApp Australia, also for corpus callosum abnormalities, metabolic disorders, etc).
Sources: Literature, Other
Intellectual disability v3.1529 SLC38A3 Konstantinos Varvagiannis gene: SLC38A3 was added
gene: SLC38A3 was added to Intellectual disability. Sources: Literature,Other
Mode of inheritance for gene: SLC38A3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC38A3 were set to 34605855
Phenotypes for gene: SLC38A3 were set to Infantile axial hypotonia; Global developmental delay; Intellectual disability; Seizures; Spasticity; Microcephaly; Cerebral atrophy; Cerebellar atrophy; Abnormality of the corpus callosum; Dysphagia; Constipation; Increased serum lactate; Hyperammonemia
Penetrance for gene: SLC38A3 were set to Complete
Review for gene: SLC38A3 was set to GREEN
Added comment: Marafi et al (2021 - PMID: 34605855) describe the phenotype of 10 individuals, belonging to 7 families (6/7 consanguineous), harboring biallelic deleterious SLC38A3 variants. One subject (from fam3) was previously reported in the context of a larger cohort of consanguineous families investigated with exome sequencing (2017, PMID: 31130284).

The phenotype overall corresponded to a DEE and features included axial hypotonia (10/10), severe global DD or ID (10/10), seizures (8/10, onset : 1w-15m, NOT observed in 2/10 aged 1y3m and 4y | s. types: tonic-clonic in 3/8, tonic 2/8, focal 2/8 with secondary generalization, myoclonic 1/8, gelastic 1/8 | EEG burst-suppression, hypsarrhythmia in few). Microcephaly was observed in (8/10) and was more commonly postnatal and/or progressive. Variable abnormalities were observed upon brain imaging incl. cerebral (5/10) or cerebellar atrophy (2/10) and abnormal CC (6/10), abnormal myelination for age (6/10). Other phenotypes included visual impairment (9/10), peripheral hypertonia (8/9) constipation (8/9) and dysphagia (7/9), FTT (4/8), movement disorder (3/10). Metabolic studies indicated (transient) elevation of lactate (7/8 - also pyruvate in 2) and elevated plasma ammonia (4/7).

Individuals from the 1st family were investigated with ES, and the SLC38A3 splice site variant (NM_006841.6:c.855+1G>T) was the most likely candidate, additional SNVs not contributing to the NDD phenotype. Other affected subjects were ascertained through GeneMatcher/collaborations.

In total, 3 different missense and 4 pLoF (1 fs, 2 nonsense, 1 splicing) variants were identified with individuals from 2 families being hmz or cmd htz for missense variants. Variants were absent/ultrarare with no homozygotes in public/in-house databases with several in silico predictions in favor of a deleterious effect. Regions of AOH (around SLC38A3/total) are provided for some individuals/families.

Sanger sequencing was used for confirmation and segregation studies (apart from carrier parents in 7/7 fam, 11 unaffected sibs tested in 6/7 fam).

The solute carrier (SLC) superfamily of transmembrane transporters - highly expressed in mammalian brain - is involved in exchange of amino-acids (AAs), nutrients, ions, neurotransmitters and metabolites etc across biological membranes with >100 SLC-encoding genes associated with NDDs.

SLC38A3 specifically encodes SNAT3, a sodium-coupled neutral amino-acid transporter, principal transporter of Asn, His, Gln (precursor for GABA and glutamate), expressed in brain, liver, kidney, retina and pancreas. In the brain, it localizes to peri-synaptic astrocytes playing an important role in glutamate/GABA-glutamine cycle.

While the pLoF variants are predicted to undergo NMD or result in non-functional protein, protein modelling suggested that missense ones affect protein activity or stability.

Biochemical and metabolic screening was carried out for several individuals with plasma AAs reported normal (10/10), urinary OAs normal in 9/9, CSF AAs (incl. GABA/glutamine) normal in 2 sibs, CSF lactate normal in 1 indiv. studied. As discussed above plasma ammonia was elevated in 4/7 (2 fam), and 7/10 had elevated lactate and/or pyruvate (2/7).

Untargeted metabolomic profiles performed in biofluids (plasma from 3 subjects, CSF:1, urine:1) were suggestive of altered AA and nitrogen metabolism. In particular, alterations in levels of AA known to be transported by SNAT3 were found. 676 molecules overall showed deviation in plasma samples, 630 in urine and 241 in CSF (albeit with no consistent pattern). Perturbations in several biochemical pathways were shown to occur (incl. Gln-,Asn- and His- pathways).

Slc38a3-/- mice have reductions in brain glutamate and GABA neurotransmitters in homogenized brain tissue (GABA analytes being normal in plasma samples or the single CSF sample available from affected subjects). Snat3-deficient mice had elevation of plasma urea and normal ammonia levels (urea was low in all human samples and ranged from -2 to -3.5 SD in plasma, ammonia was elevated in 4/7). Slc38a3-/- mice have impaired growth, lethargy and ataxic gait, altered plasma AAs, normal glutamine in plasma with abundance in brain and exhibit early lethality. Plasma AAs were normal in 4 affected individuals, impaired growth observed in 4 and gait impairment was observed in 9/10. Hypoglycemia, previously reported in Slc38a3-/- mice, was not observed in any of the patients although this is presumably explained by diet/feeding intervals with abnormalities in pentose phosphate pathway in one individual hypothesized to be reflective of abn. glucose metabolism. The human phenotypes of microcephaly and seizures were not observed in mice. For mouse studies PMIDs cited by the authors : 27362266, 26490457.

There is currently no SLC38A3-related phenotype reported in OMIM. In G2P this gene is incl. in the DD panel (biallelic, confidence: strong, SLC38A3-associated epileptic encephalopathy). SLC38A3 is listed among the primary ID genes in SysID. In PanelApp Australia, SLC38A3 is included with green rating in the epilepsy, ID and microcephaly panels.

Consider inclusion with green rating (10 individuals, 7 families, 7 variants, role of SLCs and SLC38A3, alterations in AA/nitrogen metabolism etc) or amber rating (if discordances with mouse model considered).

Please consider inclusion in other panels e.g. for microcephaly, CC abnormalities, metabolic disorders, etc.
Sources: Literature, Other
Intellectual disability v3.1528 ADAT3 Arina Puzriakova Phenotypes for gene: ADAT3 were changed from Mental retardation, autosomal recessive 36, 615286; MRT36 to Neurodevelopmental disorder with brain abnormalities, poor growth, and dysmorphic facies, OMIM:615286
Intellectual disability v3.1526 SPTBN2 Arina Puzriakova Phenotypes for gene: SPTBN2 were changed from Spinocerebellar ataxia, autosomal recessive 14; MIM:615386; Developmental delay to Spinocerebellar ataxia, autosomal recessive 14, OMIM:615386
Intellectual disability v3.1525 CACNA2D1 Konstantinos Varvagiannis gene: CACNA2D1 was added
gene: CACNA2D1 was added to Intellectual disability. Sources: Literature,Other
Mode of inheritance for gene: CACNA2D1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CACNA2D1 were set to 35293990; 28097321
Phenotypes for gene: CACNA2D1 were set to Abnormal muscle tone; Feeding difficulties; Global developmental delay; Intellectual disability; Seizures; Microcephaly; Abnormality of the corpus callosum; Cerebral atrophy; Abnormality of movement; Cortical visual impairment; Pain insensitivity
Penetrance for gene: CACNA2D1 were set to Complete
Review for gene: CACNA2D1 was set to GREEN
Added comment: Consider inclusion in the current panel with green rating.

Recent report of 2 unrelated individuals with DEE due to biallelic CACNA2D1 variants. Both referred to neurology/genetics for hypotonia/severe DD prior to onset of seizures.

One further individual with hypotonia and severe ID (seizures not discussed, age unknown).

Gene with established role, encoding α2δ-1 subunit of Cav channels. Studies for the variants support loss-of-function as the underlying effect.

Eventual contribution of monoallelic variants to NDD-phenotypes discussed (and put in question) in Ref [1] below.

There is currently no phenotype for CACNA2D1 in OMIM/G2P. In SysID this gene is listed among the candidates for ID, based on a previous report. CACNA2D1 is not currently included in the ID/epilepsy panels in PanelApp Australia.

See also relevant review in epilepsy panel (Dr. H. Lord).

Please consider also inclusion in other panels (e.g. microcephaly, corpus callosum, movement disorders, etc).

[1] ----
Dahimene et al (2022 - PMID: 35293990) describe the phenotype of 2 unrelated individuals with biallelic CACNA2D1 variants.

Overall, the phenotype corresponded to an early-onset DEE, characterized by abnormal muscle tone (axial hypotonia 2/2 with spasticity in extremities in 2/2), feeding difficulties (2/2), profound DD and ID (2/2), microcephaly (2/2 - approx. -2 SD in both), seizures (2/2 - 1st : onset 9m with absences and later generalized seizures, 2nd : onset 11m with hemi-clonic seizures and atypical absences). Other features included cortical visual impairment (2/2) and movement disorder (incl. choreiform movements 2/2, orofacial dyskinesia 2/2 and dystonic episodes 1/2). Brain MRI revealed corpus callosum anomalies (2/2) and cerebral atrophy (2/2). Both had echocardiography (abnormal in 1/2 - tiny PFO) and electrocardiography which was normal. Both exhibited insensibility to pain.

Presentation is relevant to the current panel as first symptoms in the first 3 months with severe hypotonia and poor head control (2/2) with evaluation in neurology/genetics preceding onset of seizures in both.

Trio ES was performed for both individuals and their (healthy) parents and revealed homozygosity for a fs variant in the first [NM_000722.3:c.818_822dup / p.(Ser275Asnfs*13)] and compound htz for a fs and a missense variant [c.13_23dup / p.(Leu9Alafs*5) and c.626G>A / p.(Gly209Asp)] in the second affected individual, respectively.

Eventual additional variants were not discussed.

Previous investigations are only provided for the 2nd and were all normal (karyotype, CMA, 15q methylation, epilepsy/neurometabolic gene panels).

Voltage-gated calcium channels are heteromultimers comprising different subunits incl. an alpha-1 (α1), α2δ (alpha-2/delta), beta (β) and gamma (γ). CACNA2D1 is one of the 4 genes (CACNA2D1-4) encoding the alpha-2/delta subunit. Its product is post-translationally processed into 2 peptides, an alpha-2 and a delta subunit, held by a disulfide bond.

Biallelic variants in CACNA2D2 - also encoding an alpha-2/delta subunit - cause cerebellar atrophy with seizures and variable developmental delay (# 618501).

Variant studies support loss-of-function effect for the studied variants, notably by NMD for the fs one, and severe impairment of the Cav2 channel function for the missense one :
- CACNA2D1 mRNA was reduced to 6-9% compared with control in fibroblasts from the 1st individual. mRNA levels for the 2nd subject were similar to control.
- Quantification of the protein in whole-cell lysates from fibroblasts revealed lower α2δ levels compared to control (10-12% and 31-38% applying to the 1st and 2nd individual).
- CACNA2D3 mRNA levels in fibroblasts from the 2nd patient were 2-7x higher compared to the 1st or controls suggesting a possible compensatory effect. CACNA2D2/4 mRNA levels were too low for quantification.
- Gly209 lies within the gabapentin and amino-acid binding pocket and this residue is invariable in CACNA2D1/CACNA2D2 in all vertebrates and paralogs.
- Transfection of tsA-201 cells with either WT or G209D HA-tagged α2δ revealed reduced cell surface expression for this missense variant (~80, for biotinylated form ~86%).
- In tsA-201 cells transfected with HA-tagged Cav2.2/β1b and either α2δ-1-WT, no α2δ-1 or α2δ-1-G209D, WT resulted in increased 13x currents with no increase applying to G209D (or in absence of α2δ). Plasma membrane expression of double (GFP/HA) tagged Cav2.2 was increased upon co-expression with WT α2δ-1 which was not the case for α2δ-1-G209D.
- In hippocampal neurons, double (GFP/HA)-tagged Cav2.2 could not be detected at the cell surface in the presence of α2δ-1-G209D (or no α2δ) in contrast with strong expression in presence of α2δ-1-WT. α2δ-1-G209D did not promote trafficking of Cav2.2 into hippocampal neurites, as indicated by reduced signals for both HA and GFP (for cell surface and total Cav2.2 respectively).
- Co-expression of double (GFP/HA) tagged Cav2.2 with β1b and either HA-α2δ-1-WT or HA-α2δ-1-G209D in tsA-201 cells, revealed reduced complex formation of G209D with Cav2.2 Co-immunoprecipitated HA-α2δ-1-G209D had higher molecular weight compared to HA-α2δ-1-WT which suggests that α2δ-1-G209D remains as the uncleaved immature form (probably in the ER).

Mouse model (several Refs in text):
Mild cardiac phenotype and reduced ventricular myocyte Ca current density was observed in hmz ko mice. Similarly to the insensibility to pain human phenotype, mice had delayed neuropathic pain-related responses. Overexpression of a2δ-1 resulted in epileptiform EEG and behavioral arrest, overall supporting a critical role of α2δ-1 for mouse brain.

The authors underscore that the parents of both patients (htz carriers) were healthy and review previous literature for association of monoallelic variants with epilepsy, ID and arrhythmogenic disorders (in suppl.) [Refs not here reviewed].

As for the NDD phenotype, CACNA2D1 is within a previously defined small region of overlap for 7q21.11 microdeletions associated with ID+/-epilepsy. The same study did not reveal de novo SNVs in any of the 3 contained genes within this SRO (HGF, CACNA2D1, PCLO) in 4293 patients with NDD [cited PMID: 28240412]. A frameshift variant (c.2625del) was identified in a 13-yo girl with infantile spasms and normal intelligence [cited PMID: 25877686]. A 1-bp insertion (c.659-2_659-1insT / not studied at the mRNA level) was identified in another 14-yo female with ID and epilepsy [cited PMID: 34356170]. The authors state that the phenotype (/differences) of these individuals as well as presence of pLoF CACNA2D1 variants in gnomAD [still pLI of 1] put in question pathogenicity of monoallelic variants for these phenotypes.

The role of heterozygous missense variants described in relation to arrhythmogenic disorders is also discussed extensively (some downgraded to LB/VUS, others having a relatively high MAF and presence of 1-2 homozygotes in gnomAD).

[2] ----
In an article cited by SysID for CACNA2D1 (2017 - PMID: 28097321), Reuter et al studied with WES and autozygosity mapping individuals with NDD belonging to consanguineous families.

As in eTables1/3, a male - single affected individual born to consanguineous parents from Turkey (MR150) - was investigated by singleton ES.

This individual was homozygous for a missense CACNA2D1 SNV [NM_000722.2:c.1514C>T;p.(Thr505Ile)].

Prior investigations are unavailable (although individuals with previously known P/LP CNVs were excluded).

The phenotype - briefly reported - included hypotonia, severe ID, stereotypic behaviors, inguinal hernia and omphalocele. Presence of seizures was not commented on. The age of this individual was not reported.
Sources: Literature, Other
Intellectual disability v3.1524 ACER3 Arina Puzriakova Entity copied from White matter disorders and cerebral calcification - narrow panel v1.227
Intellectual disability v3.1524 ACER3 Arina Puzriakova gene: ACER3 was added
gene: ACER3 was added to Intellectual disability. Sources: Expert Review Amber,Literature
Q1_22_rating tags were added to gene: ACER3.
Mode of inheritance for gene: ACER3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ACER3 were set to 26792856; 32816236; 34281620
Phenotypes for gene: ACER3 were set to Leukodystrophy, progressive, early childhood-onset, OMIM:617762
Intellectual disability v3.1520 PAN2 Konstantinos Varvagiannis gene: PAN2 was added
gene: PAN2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: PAN2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PAN2 were set to 29620724; https://doi.org/10.1038/s41431-022-01077-y
Phenotypes for gene: PAN2 were set to Global developmental delay; Intellectual disability; Sensorineural hearing impairment; Abnormality of the genitourinary system; Abnormality of the cardiovascular system; Abnormality of blood and blood-forming tissues; EEG abnormality; Seizures; Anorectal anomaly; Abnormality of the skeletal system; Abnormality of the eye; Abnormality of head or neck
Penetrance for gene: PAN2 were set to Complete
Review for gene: PAN2 was set to AMBER
Added comment: 1.
Maddirevula et al (2018 - PMID: 29620724) first reported on the phenotype associated with biallelic pathogenic variants in PAN2.

This concerned a male (15DG2222) born to consanguineous parents and exhibiting MCA, dysmorphic features and global DD (age of 34 m). Features incl. imperforate anus, metopic craniosynostosis, scoliosis, CHD (PFO, PDA, VSD), renal anomalies (duplicated collecting system) and abnormalities of the eye (posterior embryotoxon, maculopathy).

As the other 411 individuals from the cohort, the child had 1st-tier testing genetic testing using a dysmorphology/skeletal dysplasia panel of 296 genes.

Subsequent autozygome analysis (Axiom genotyping platform) was used to identify ROH (authors state "segregating within the family", in pedigree the proband was the single affected person and single child).

WES revealed a PAN2 indel. [NM_001166279.1:c.3162delC / p.(Ser1055Profs*4)].

There were no additional studies.

Role of PAN2 and animal models discussed as below.
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2.
Reuter et al. (2022 - https://doi.org/10.1038/s41431-022-01077-y) describe the phenotype of 5 additional individuals - from 3 unrelated families (2 consanguineous) - harboring biallelic PAN2 variants. The authors review the phenotype of the previously described case.

Features included DD (6/6), ID (4/5 with relevant age in the mild-moderate range, 1/5 had borderline IF), sensorineural hearing loss (5/6) and incompletely penetrant congenital anomalies of the heart (4/6 - TOF, septal defects, Ao root dilat), urinary malformations (4/6 - hypoplasia/agenesis, anovesical fistula), ophthalmological anomalies (2/6 - Rieger, posterior embryotoxon, etc). EEG anomalies or seizures were noted in 4/6. Craniofacial feat. in >=2/6 included cleft palate/bifid uvula, ptosis, hypertelorism, abn. of the nose, low-set ears, short neck. There was no comprehensive evaluation for skeletal dysplasia despite short stature/skeletal anomalies in multiple individuals. Hematological anomalies were reported in 2, possibly explained by another concurrent diagnosis (of GSD) in one individual.

WGS was performed for 1 individual, and WES for 4 members of the 2nd family and the proband in the 3rd. ROH identified in all 3 families (1 non-consanguineous but from the same region of Italy) are mentioned in the suppl. Sanger sequencing for parents and affected/unaffected sibs was mentioned for the 2 families with solo WGS/WES. One individual had a dual - previously established - diagnosis (of SLC37A4-related GSD) not related to his NDD. There were no other candidate variants except for VUS or variants in 'genes of uncertain significance'.

The majority of mammalian mature mRNAs have polyA tails, added during RNA processing. PAN2 encodes a subunit of the Pan2-Pan3 deadenylation complex which shortens mRNA 3' polyA tails, regulating mRNA stability/translation efficiency.

Specifically Pan2 is the catalytic subunit, while the interaction with Pan3 mediates efficient mRNA binding. Deadenylation in cytoplasm is mostly carried out by the Pan2-Pan3 or Ccr4-Not compexes. While perturbations of mRNA metabolism/decay are established causes of NDD and ID. In particular, monoallelic variants in genes of Ccr4-Not complex (inc. CNOT1/2/3) already causative of NDDs.

All affected individuals were homozygous for pLoF PAN2 variants, namely (NM_001166279.2): c.2335G>T / p.(Glu779*) [Fam1], c.3408dupT / p.(Glu1137*) [Fam2], c.574-2A>G / p.? [Fam3].

Variants were absent from gnomAD (where PAN2 has a pLI:0.94, o/e:0.19).

There were no variant studies performed. The splicing variant is predicted in silico to abolish the splice-acceptor site, with in-frame skippling of ex5 which codes a repeat within the WD40 domain. Previous studies in yeast have shown that this domain is important for sensing the length of the polyA tail, with absence of this domain resulting in impaired deadenylation of 90A tails (similarly to complete Pan2 del) [cited PMID: 31104843].

Overall PAN2 loss-of-function is thought to be the underlying disease mechanism.

Partial functional redundancy of Pan2/Pan3 (initiation of deadenylation) and Ccr4-Not complexes (further shortening of polyA) is speculated to mitigate consequences of PAN2 LoF in humans.

In yeast Pan2Δ, Ccr4Δ and Pan2Δ/Ccr4Δ have been studied with more severe phenotypes in double mutants where ability to shorten mRNA polyA tails was abolished [cited PMID:11239395]. In yeast extracts lacking Pan2p and Pan3p, transcripts were polyadenylated to >90-200 adenosines [cited PMID: 9774670]

Mouse mutants (MGI:1918984) had increased heart weight, increased eosinophil cell number while homozygosity for a stopgain allele (by ENU mutagenesis) was shown to result in embyonic lethality.

Finally, given the presence of thrombocytopenia and anemia in 3 individuals (2 families) as well as the link between mRNA deadenylation and telomere disease, telomere length analyses from WGS data were performed (TelSeq/Expansion Hunter dn), but there was no evidence for telomeric shortening.
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Currently, there is no PAN2-related phenotype in OMIM/G2P/SysID/PanelApp Australia.
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Consider inclusion in the ID panel with amber rating [>3 individuals/families/variants, though variant studies not performed (NMD/splicing) and authors of 2nd study recognize possibility of additional/concurrent diagnoses in individuals from consanguineous families, possibility of missed dn variants due to singleton WGS/WES in 2 fam. Also the presumed deadenylation defect not studied to date].

Please consider adding this gene to other panels - eg. for sens. hearing loss (5/6 - 3 fam), urinary tract anomalies (4/6 - 4 fam), congenital (4/6 - 3fam), anorectal malformations (2/6 - 2 families, incl. fistula or imperforate anus), clefting (2/6 - 1 fam), hematological disorders, etc.

For the time being, not added in epilepsy panel as some individuals had only EEG anomalies, few had also clinical seizures not necessarily requiring treatment.
Sources: Literature
Intellectual disability v3.1520 HIST1H4C Konstantinos Varvagiannis reviewed gene: HIST1H4C: 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: 28920961, 35202563; Phenotypes: Tessadori-van Haaften neurodevelopmental syndrome 1, #619758; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.1520 HIST1H4J Konstantinos Varvagiannis reviewed gene: HIST1H4J: Rating: AMBER; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: 31804630, 35202563; Phenotypes: ?Tessadori-van Haaften neurodevelopmental syndrome 2, #619759; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.1520 HIST1H4D Konstantinos Varvagiannis gene: HIST1H4D was added
gene: HIST1H4D was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: HIST1H4D was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: HIST1H4D were set to 35202563
Phenotypes for gene: HIST1H4D were set to Global developmental delay; Intellectual disability; Microcephaly; Growth abnormality; Abnormality of the face
Penetrance for gene: HIST1H4D were set to Complete
Mode of pathogenicity for gene: HIST1H4D 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: HIST1H4D was set to AMBER
Added comment: Histone H4 is a core component of the nucleosome, the basic repeating unit of eukaryotic chromatin. Each nucleosome consists of ~150 bp of DNA wrapped around a histone octamer. Each histone octamer is composed of 2 copies of each of the histones H2A, H2B, H3, H4. This organization is important for DNA replication, transcription and repair.

There are 14 canonical histone H4 genes in the human genome, which despite being different at the nucleotide level encode an identical protein. These cluster in 3 genomic loci. Their transcription is independently regulated with differing expression during brain development and in human tissues.

Histone H4 forms a dimer with H3 (which however has variant isoforms linked to specific cellular processes).

Pathogenic variants in genes encoding H4 have been reported in several individuals. Irrrespective of the gene for H4 involved, all patients presented with highly overlapping features, DD and ID being universal. Available reports to date concern :
- H4C3/HIST1H4C (9 subjects - PMID: 28920961, 35202563),
- H4C11/HIST1H4J (1 subject - PMID: 31804630, 35202563),
- H4C4/HIST1H4D (1 subject - PMID:35202563),
- H4C5/HIST1H4E (17 subjects - PMID: 35202563),
- H4C6/HIST1H4F (1 subject - PMID: 35202563),
- H4C9/HIST1H4I (3 subjects - PMID: 35202563).

Variants in all cases were missense SNVs, occurring (in almost all cases) as dn variants and affecting the same residue in the same and/or different H4 genes (details for clusters below). Eg. Arg45Cys was a recurrent variant for H4C5 (>=7 subjects), while variants affecting Arg40 have been reported in H4C4, H4C5, H4C9, H4C11 (7 subjects overall).

Zebrafish studies for all genes reported have included most - if not all - patient variants and recapitulate features observed in affected individuals (head size/structure and growth).

Additional studies specificaly for H4C3/HIST1H4C have been performed in patient fibroblasts (demonstrating among others transcriptional dysregulation) and zebrafish (accumulation of DSBs, increased apoptosis in head/tail, abn. cell cycle progression).

Note that the nomenclature for variants - at the protein level - used in literature commonly takes into consideration cleavage of Met1, thus the numbering may not correspond to the HGVS one.

Relevant entries exist in OMIM, G2P and SysID only for H4C3/HIST1H4C (Tessadori-van Haaften neurodevelopmental syndrome 1, #619758) and H4C11/HIST1H4J (?Tessadori-van Haaften neurodevelopmental syndrome 2, #619759) but not for other genes.

Rating in PanelApp Australia - ID Panel : HIST1H4C Green, H4J Amber, H4D Amber, H4E Green, H4F Amber, H4I Green.

Please consider inclusion in other possibly relevant panels (microcephaly, short stature/FTT, etc).

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Initial work from Tessadori et al (incl. DDD study, 2017 - PMID:28920961) identified monoallelic missense SNVs affecting the same residue of H4C3 (HIST1H4C), in 3 individuals from 2 families. [c.274A>C/ HGVS p.(Lys92Gln) dn in 1 subject and c.275A>C/ HGVS p.(Lys92Arg) inherited from unaffected mosaic parent].

Individuals from both families having relevant age had intellectual disability (2/2 - 2 families). Other features incl. growth delay (3/3) and microcephaly (3/3).

Expression of the variants in zebrafish severely affected structural development recapitulating the patient phenotypes (microcephaly and short stature).

RNA sequencing in fibroblasts from 2 unrelated patients and a control, revealed that expression of H4C3 variants was similar to wt. The authors estimated that ~8% of H4 cDNA molecules contained the variant. LC-MS/MS analysis suggested that the mutant protein was present in nucleosomes at a level of 1-2% while RNA-seq identified 115 differential expressed genes, with enrichment for relevant procedures (chr. organization, histone binding, DNA packaging, nucleosomal organization, cell cycle).

Post-translational modifications of Lys92 (H4K91) are highly conserved and have been previously associated with processes from chromatin assembly , DNA damage sensitivity, etc. Post-translational marks on Lys92 (K91) were absent in patient derived cells as a result of each variant.

Zebrafish models for both variants were suggestive for accumulation of double strand breaks (DSBs) more visible in heads and tails of larvae. Embryos expressing mutants displayed increased apoptosis in head and tail. Additional studies in larvae were suggestive of abnormal cell cycle progression (rel. increase in cellls in S/G2/M phase, increased occurrence of activated CHK2 with p53 stabilization) applying to both variants studied.

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In a subsequent publication, Tessadori et al. (2020 - PMID: 31804630) described the phenotype of a 14 y.o. boy harboring a dn heterozygous missense H4C11 (HIST1H4J) variant following trio-ES [c.274A>G / HGVS p.(Lys92Glu)]. Features incl. profound ID, microcephaly, short stature with some dysmorphic features (uplsanting p-f, hypertelorism, etc). Previous work-up was normal/non-diagnostic and incl. FMR1, MECP2 and a CMA showing an inherited 207 kb CNV involving KCNV1. Upon mRNA microinjection in zebrafish embryos - either for wt or for Lys92Glu HIST1H4J - effect for wt was very mild. Lys92Glu expression led to defective development of head structures (brain, eyes), faulty body axis growth and dysmorphic tail reproducing the microcephaly and short stature phenotype. This was similar to previous zebrafish studies for HIS1H4C variants (above).

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Tessadori et al. (2022 - PMID: 35202563) describe 29 *additional individuals with de novo missense variants in genes encoding H4, namely:
- H4C3 (HIST1H4C/N=6 subjects),
- H4C11 (HIST1H4J/N=1),
- H4C4 (HIST1H4D/N=1),
- H4C5 (HIST1H4E/N=17),
- H4C6 (HIST1H4F/N=1),
- H4C9 (HIST1H4I/N=3).

All individuals, exhibited DD and ID (29/29). Other features incl. hypotonia (10/29), seizures (5/29), autism (5/29), ataxia (4/29). Abnormal growth incl. progressive microcephaly (2/19 prenatal, 20/29 postnatal onset), short stature/FTT (each 11/29). Few had skeletal features (craniosynostosis 2/29, abn. digits 4/29, vertebral 4/29). Some had visual (17/28) or hearing impairment (7/29). Facial features incl. hypertelorism (5/29), upslanting p-f (3/29), broad nasal tip (11/29), thin upper lip (4/29) and teeth anomalies (6/29 - notably gap between central incisors).

The authors state that the cohort was collected with trio WES but also after data sharing via Genematcher / DECIPHER.

Identified variants were in all cases missense and de novo, the latter either by trio WES or Sanger sequencing of parents.

Previous work-up or presence of additional variants are not discussed.

At the protein level 10 aa were affected, 6 of which recurrently within the same gene (Arg45, His75, Lys91, Tyr98) as well among several genes for H4 (Pro32, Arg40). Variants lied within two clusters, one corresponding to the α-helix of H4 (reported variants affected Lys31 - Arg45) important for DNA contacts, interactions with H3 and histone chaperones. The other within the core of nucleosome (reported patient variants : His75-Tyr98) with important strucural contact between H3-H4 dimer and histone chaperones.

There were no detectable genotype-phenotype patterns separating individual H4 genes or protein regions. Of note, variability was observed even among 7 individuals with the same dn H4C5 variant (Arg45Cys).

All variants were absent from control databases incl. gnomAD and affected residues conserved through to S. cerevisiae. Substitutions affecting Arg45 and Gly94 and His75 have been studied previously with effect in growth/fitness/chromatin remodeling/DNA damage repair depending on variant (5 studies cited).

Zebrafish embryos at the 1 cell stage were injected with mRNA encoding either wt or identified variants, the latter inducing significant developmental defects with the exception of Pro32Ala (H4C3) and Arg40Cys (H4C5, H4C11).

For Pro32Ala and Arg40Cys however, the strong recurrence in this cohort supports pathogenicity. A dosage dependent effect was observed for 2 variants.

H4 genes appear to be tolerant to both missense and loss-of-function variation (the latter even in homozygous form) suggesting a dominant effect of the variants.

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[RefSeqs : H4C3/HIST1H4C - NM_0035242.4 | H4C4/HIST1H4D - NM_003539.4 | H4C5/HIST1H4E - NM_003545.3 | H4C6/HIST1H4F - NM_003540.4 | H4C9/HIST1H4I - NM_003495.2 | H4C11/HIST1H4J - NM_021968.4 // Variants at the protein level above are according to the HGVS nomenclature. However as the N-terminal methionine is cleaved, numbering relative to the mature peptide has also been used in publications eg. p.Pro33Ala HGVS corresponding to Pro32Ala]
Sources: Literature
Intellectual disability v3.1520 HIST1H4E Konstantinos Varvagiannis gene: HIST1H4E was added
gene: HIST1H4E was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: HIST1H4E was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: HIST1H4E were set to 35202563
Phenotypes for gene: HIST1H4E were set to Global developmental delay; Intellectual disability; Microcephaly; Growth abnormality; Abnormality of the face
Penetrance for gene: HIST1H4E were set to unknown
Mode of pathogenicity for gene: HIST1H4E 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: HIST1H4E was set to GREEN
Added comment: Histone H4 is a core component of the nucleosome, the basic repeating unit of eukaryotic chromatin. Each nucleosome consists of ~150 bp of DNA wrapped around a histone octamer. Each histone octamer is composed of 2 copies of each of the histones H2A, H2B, H3, H4. This organization is important for DNA replication, transcription and repair.

There are 14 canonical histone H4 genes in the human genome, which despite being different at the nucleotide level encode an identical protein. These cluster in 3 genomic loci. Their transcription is independently regulated with differing expression during brain development and in human tissues.

Histone H4 forms a dimer with H3 (which however has variant isoforms linked to specific cellular processes).

Pathogenic variants in genes encoding H4 have been reported in several individuals. Irrrespective of the gene for H4 involved, all patients presented with highly overlapping features, DD and ID being universal. Available reports to date concern :
- H4C3/HIST1H4C (9 subjects - PMID: 28920961, 35202563),
- H4C11/HIST1H4J (1 subject - PMID: 31804630, 35202563),
- H4C4/HIST1H4D (1 subject - PMID:35202563),
- H4C5/HIST1H4E (17 subjects - PMID: 35202563),
- H4C6/HIST1H4F (1 subject - PMID: 35202563),
- H4C9/HIST1H4I (3 subjects - PMID: 35202563).

Variants in all cases were missense SNVs, occurring (in almost all cases) as dn variants and affecting the same residue in the same and/or different H4 genes (details for clusters below). Eg. Arg45Cys was a recurrent variant for H4C5 (>=7 subjects), while variants affecting Arg40 have been reported in H4C4, H4C5, H4C9, H4C11 (7 subjects overall).

Zebrafish studies for all genes reported have included most - if not all - patient variants and recapitulate features observed in affected individuals (head size/structure and growth).

Additional studies specificaly for H4C3/HIST1H4C have been performed in patient fibroblasts (demonstrating among others transcriptional dysregulation) and zebrafish (accumulation of DSBs, increased apoptosis in head/tail, abn. cell cycle progression).

Note that the nomenclature for variants - at the protein level - used in literature commonly takes into consideration cleavage of Met1, thus the numbering may not correspond to the HGVS one.

Relevant entries exist in OMIM, G2P and SysID only for H4C3/HIST1H4C (Tessadori-van Haaften neurodevelopmental syndrome 1, #619758) and H4C11/HIST1H4J (?Tessadori-van Haaften neurodevelopmental syndrome 2, #619759) but not for other genes.

Rating in PanelApp Australia - ID Panel : HIST1H4C Green, H4J Amber, H4D Amber, H4E Green, H4F Amber, H4I Green.

Please consider inclusion in other possibly relevant panels (microcephaly, short stature/FTT, etc).

------
Initial work from Tessadori et al (incl. DDD study, 2017 - PMID:28920961) identified monoallelic missense SNVs affecting the same residue of H4C3 (HIST1H4C), in 3 individuals from 2 families. [c.274A>C/ HGVS p.(Lys92Gln) dn in 1 subject and c.275A>C/ HGVS p.(Lys92Arg) inherited from unaffected mosaic parent].

Individuals from both families having relevant age had intellectual disability (2/2 - 2 families). Other features incl. growth delay (3/3) and microcephaly (3/3).

Expression of the variants in zebrafish severely affected structural development recapitulating the patient phenotypes (microcephaly and short stature).

RNA sequencing in fibroblasts from 2 unrelated patients and a control, revealed that expression of H4C3 variants was similar to wt. The authors estimated that ~8% of H4 cDNA molecules contained the variant. LC-MS/MS analysis suggested that the mutant protein was present in nucleosomes at a level of 1-2% while RNA-seq identified 115 differential expressed genes, with enrichment for relevant procedures (chr. organization, histone binding, DNA packaging, nucleosomal organization, cell cycle).

Post-translational modifications of Lys92 (H4K91) are highly conserved and have been previously associated with processes from chromatin assembly , DNA damage sensitivity, etc. Post-translational marks on Lys92 (K91) were absent in patient derived cells as a result of each variant.

Zebrafish models for both variants were suggestive for accumulation of double strand breaks (DSBs) more visible in heads and tails of larvae. Embryos expressing mutants displayed increased apoptosis in head and tail. Additional studies in larvae were suggestive of abnormal cell cycle progression (rel. increase in cellls in S/G2/M phase, increased occurrence of activated CHK2 with p53 stabilization) applying to both variants studied.

------
In a subsequent publication, Tessadori et al. (2020 - PMID: 31804630) described the phenotype of a 14 y.o. boy harboring a dn heterozygous missense H4C11 (HIST1H4J) variant following trio-ES [c.274A>G / HGVS p.(Lys92Glu)]. Features incl. profound ID, microcephaly, short stature with some dysmorphic features (uplsanting p-f, hypertelorism, etc). Previous work-up was normal/non-diagnostic and incl. FMR1, MECP2 and a CMA showing an inherited 207 kb CNV involving KCNV1. Upon mRNA microinjection in zebrafish embryos - either for wt or for Lys92Glu HIST1H4J - effect for wt was very mild. Lys92Glu expression led to defective development of head structures (brain, eyes), faulty body axis growth and dysmorphic tail reproducing the microcephaly and short stature phenotype. This was similar to previous zebrafish studies for HIS1H4C variants (above).

------
Tessadori et al. (2022 - PMID: 35202563) describe 29 *additional individuals with de novo missense variants in genes encoding H4, namely:
- H4C3 (HIST1H4C/N=6 subjects),
- H4C11 (HIST1H4J/N=1),
- H4C4 (HIST1H4D/N=1),
- H4C5 (HIST1H4E/N=17),
- H4C6 (HIST1H4F/N=1),
- H4C9 (HIST1H4I/N=3).

All individuals, exhibited DD and ID (29/29). Other features incl. hypotonia (10/29), seizures (5/29), autism (5/29), ataxia (4/29). Abnormal growth incl. progressive microcephaly (2/19 prenatal, 20/29 postnatal onset), short stature/FTT (each 11/29). Few had skeletal features (craniosynostosis 2/29, abn. digits 4/29, vertebral 4/29). Some had visual (17/28) or hearing impairment (7/29). Facial features incl. hypertelorism (5/29), upslanting p-f (3/29), broad nasal tip (11/29), thin upper lip (4/29) and teeth anomalies (6/29 - notably gap between central incisors).

The authors state that the cohort was collected with trio WES but also after data sharing via Genematcher / DECIPHER.

Identified variants were in all cases missense and de novo, the latter either by trio WES or Sanger sequencing of parents.

Previous work-up or presence of additional variants are not discussed.

At the protein level 10 aa were affected, 6 of which recurrently within the same gene (Arg45, His75, Lys91, Tyr98) as well among several genes for H4 (Pro32, Arg40). Variants lied within two clusters, one corresponding to the α-helix of H4 (reported variants affected Lys31 - Arg45) important for DNA contacts, interactions with H3 and histone chaperones. The other within the core of nucleosome (reported patient variants : His75-Tyr98) with important strucural contact between H3-H4 dimer and histone chaperones.

There were no detectable genotype-phenotype patterns separating individual H4 genes or protein regions. Of note, variability was observed even among 7 individuals with the same dn H4C5 variant (Arg45Cys).

All variants were absent from control databases incl. gnomAD and affected residues conserved through to S. cerevisiae. Substitutions affecting Arg45 and Gly94 and His75 have been studied previously with effect in growth/fitness/chromatin remodeling/DNA damage repair depending on variant (5 studies cited).

Zebrafish embryos at the 1 cell stage were injected with mRNA encoding either wt or identified variants, the latter inducing significant developmental defects with the exception of Pro32Ala (H4C3) and Arg40Cys (H4C5, H4C11).

For Pro32Ala and Arg40Cys however, the strong recurrence in this cohort supports pathogenicity. A dosage dependent effect was observed for 2 variants.

H4 genes appear to be tolerant to both missense and loss-of-function variation (the latter even in homozygous form) suggesting a dominant effect of the variants.

------
[RefSeqs : H4C3/HIST1H4C - NM_0035242.4 | H4C4/HIST1H4D - NM_003539.4 | H4C5/HIST1H4E - NM_003545.3 | H4C6/HIST1H4F - NM_003540.4 | H4C9/HIST1H4I - NM_003495.2 | H4C11/HIST1H4J - NM_021968.4 // Variants at the protein level above are according to the HGVS nomenclature. However as the N-terminal methionine is cleaved, numbering relative to the mature peptide has also been used in publications eg. p.Pro33Ala HGVS corresponding to Pro32Ala]
Sources: Literature
Intellectual disability v3.1520 HIST1H4F Konstantinos Varvagiannis gene: HIST1H4F was added
gene: HIST1H4F was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: HIST1H4F was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: HIST1H4F were set to 35202563
Phenotypes for gene: HIST1H4F were set to Global developmental delay; Intellectual disability; Microcephaly; Growth abnormality; Abnormality of the face
Penetrance for gene: HIST1H4F were set to unknown
Mode of pathogenicity for gene: HIST1H4F 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: HIST1H4F was set to AMBER
Added comment: Histone H4 is a core component of the nucleosome, the basic repeating unit of eukaryotic chromatin. Each nucleosome consists of ~150 bp of DNA wrapped around a histone octamer. Each histone octamer is composed of 2 copies of each of the histones H2A, H2B, H3, H4. This organization is important for DNA replication, transcription and repair.

There are 14 canonical histone H4 genes in the human genome, which despite being different at the nucleotide level encode an identical protein. These cluster in 3 genomic loci. Their transcription is independently regulated with differing expression during brain development and in human tissues.

Histone H4 forms a dimer with H3 (which however has variant isoforms linked to specific cellular processes).

Pathogenic variants in genes encoding H4 have been reported in several individuals. Irrrespective of the gene for H4 involved, all patients presented with highly overlapping features, DD and ID being universal. Available reports to date concern :
- H4C3/HIST1H4C (9 subjects - PMID: 28920961, 35202563),
- H4C11/HIST1H4J (1 subject - PMID: 31804630, 35202563),
- H4C4/HIST1H4D (1 subject - PMID:35202563),
- H4C5/HIST1H4E (17 subjects - PMID: 35202563),
- H4C6/HIST1H4F (1 subject - PMID: 35202563),
- H4C9/HIST1H4I (3 subjects - PMID: 35202563).

Variants in all cases were missense SNVs, occurring (in almost all cases) as dn variants and affecting the same residue in the same and/or different H4 genes (details for clusters below). Eg. Arg45Cys was a recurrent variant for H4C5 (>=7 subjects), while variants affecting Arg40 have been reported in H4C4, H4C5, H4C9, H4C11 (7 subjects overall).

Zebrafish studies for all genes reported have included most - if not all - patient variants and recapitulate features observed in affected individuals (head size/structure and growth).

Additional studies specificaly for H4C3/HIST1H4C have been performed in patient fibroblasts (demonstrating among others transcriptional dysregulation) and zebrafish (accumulation of DSBs, increased apoptosis in head/tail, abn. cell cycle progression).

Note that the nomenclature for variants - at the protein level - used in literature commonly takes into consideration cleavage of Met1, thus the numbering may not correspond to the HGVS one.

Relevant entries exist in OMIM, G2P and SysID only for H4C3/HIST1H4C (Tessadori-van Haaften neurodevelopmental syndrome 1, #619758) and H4C11/HIST1H4J (?Tessadori-van Haaften neurodevelopmental syndrome 2, #619759) but not for other genes.

Rating in PanelApp Australia - ID Panel : HIST1H4C Green, H4J Amber, H4D Amber, H4E Green, H4F Amber, H4I Green.

Please consider inclusion in other possibly relevant panels (microcephaly, short stature/FTT, etc).

------
Initial work from Tessadori et al (incl. DDD study, 2017 - PMID:28920961) identified monoallelic missense SNVs affecting the same residue of H4C3 (HIST1H4C), in 3 individuals from 2 families. [c.274A>C/ HGVS p.(Lys92Gln) dn in 1 subject and c.275A>C/ HGVS p.(Lys92Arg) inherited from unaffected mosaic parent].

Individuals from both families having relevant age had intellectual disability (2/2 - 2 families). Other features incl. growth delay (3/3) and microcephaly (3/3).

Expression of the variants in zebrafish severely affected structural development recapitulating the patient phenotypes (microcephaly and short stature).

RNA sequencing in fibroblasts from 2 unrelated patients and a control, revealed that expression of H4C3 variants was similar to wt. The authors estimated that ~8% of H4 cDNA molecules contained the variant. LC-MS/MS analysis suggested that the mutant protein was present in nucleosomes at a level of 1-2% while RNA-seq identified 115 differential expressed genes, with enrichment for relevant procedures (chr. organization, histone binding, DNA packaging, nucleosomal organization, cell cycle).

Post-translational modifications of Lys92 (H4K91) are highly conserved and have been previously associated with processes from chromatin assembly , DNA damage sensitivity, etc. Post-translational marks on Lys92 (K91) were absent in patient derived cells as a result of each variant.

Zebrafish models for both variants were suggestive for accumulation of double strand breaks (DSBs) more visible in heads and tails of larvae. Embryos expressing mutants displayed increased apoptosis in head and tail. Additional studies in larvae were suggestive of abnormal cell cycle progression (rel. increase in cellls in S/G2/M phase, increased occurrence of activated CHK2 with p53 stabilization) applying to both variants studied.

------
In a subsequent publication, Tessadori et al. (2020 - PMID: 31804630) described the phenotype of a 14 y.o. boy harboring a dn heterozygous missense H4C11 (HIST1H4J) variant following trio-ES [c.274A>G / HGVS p.(Lys92Glu)]. Features incl. profound ID, microcephaly, short stature with some dysmorphic features (uplsanting p-f, hypertelorism, etc). Previous work-up was normal/non-diagnostic and incl. FMR1, MECP2 and a CMA showing an inherited 207 kb CNV involving KCNV1. Upon mRNA microinjection in zebrafish embryos - either for wt or for Lys92Glu HIST1H4J - effect for wt was very mild. Lys92Glu expression led to defective development of head structures (brain, eyes), faulty body axis growth and dysmorphic tail reproducing the microcephaly and short stature phenotype. This was similar to previous zebrafish studies for HIS1H4C variants (above).

------
Tessadori et al. (2022 - PMID: 35202563) describe 29 *additional individuals with de novo missense variants in genes encoding H4, namely:
- H4C3 (HIST1H4C/N=6 subjects),
- H4C11 (HIST1H4J/N=1),
- H4C4 (HIST1H4D/N=1),
- H4C5 (HIST1H4E/N=17),
- H4C6 (HIST1H4F/N=1),
- H4C9 (HIST1H4I/N=3).

All individuals, exhibited DD and ID (29/29). Other features incl. hypotonia (10/29), seizures (5/29), autism (5/29), ataxia (4/29). Abnormal growth incl. progressive microcephaly (2/19 prenatal, 20/29 postnatal onset), short stature/FTT (each 11/29). Few had skeletal features (craniosynostosis 2/29, abn. digits 4/29, vertebral 4/29). Some had visual (17/28) or hearing impairment (7/29). Facial features incl. hypertelorism (5/29), upslanting p-f (3/29), broad nasal tip (11/29), thin upper lip (4/29) and teeth anomalies (6/29 - notably gap between central incisors).

The authors state that the cohort was collected with trio WES but also after data sharing via Genematcher / DECIPHER.

Identified variants were in all cases missense and de novo, the latter either by trio WES or Sanger sequencing of parents.

Previous work-up or presence of additional variants are not discussed.

At the protein level 10 aa were affected, 6 of which recurrently within the same gene (Arg45, His75, Lys91, Tyr98) as well among several genes for H4 (Pro32, Arg40). Variants lied within two clusters, one corresponding to the α-helix of H4 (reported variants affected Lys31 - Arg45) important for DNA contacts, interactions with H3 and histone chaperones. The other within the core of nucleosome (reported patient variants : His75-Tyr98) with important strucural contact between H3-H4 dimer and histone chaperones.

There were no detectable genotype-phenotype patterns separating individual H4 genes or protein regions. Of note, variability was observed even among 7 individuals with the same dn H4C5 variant (Arg45Cys).

All variants were absent from control databases incl. gnomAD and affected residues conserved through to S. cerevisiae. Substitutions affecting Arg45 and Gly94 and His75 have been studied previously with effect in growth/fitness/chromatin remodeling/DNA damage repair depending on variant (5 studies cited).

Zebrafish embryos at the 1 cell stage were injected with mRNA encoding either wt or identified variants, the latter inducing significant developmental defects with the exception of Pro32Ala (H4C3) and Arg40Cys (H4C5, H4C11).

For Pro32Ala and Arg40Cys however, the strong recurrence in this cohort supports pathogenicity. A dosage dependent effect was observed for 2 variants.

H4 genes appear to be tolerant to both missense and loss-of-function variation (the latter even in homozygous form) suggesting a dominant effect of the variants.

------
[RefSeqs : H4C3/HIST1H4C - NM_0035242.4 | H4C4/HIST1H4D - NM_003539.4 | H4C5/HIST1H4E - NM_003545.3 | H4C6/HIST1H4F - NM_003540.4 | H4C9/HIST1H4I - NM_003495.2 | H4C11/HIST1H4J - NM_021968.4 // Variants at the protein level above are according to the HGVS nomenclature. However as the N-terminal methionine is cleaved, numbering relative to the mature peptide has also been used in publications eg. p.Pro33Ala HGVS corresponding to Pro32Ala]
Sources: Literature
Intellectual disability v3.1520 HIST1H4I Konstantinos Varvagiannis gene: HIST1H4I was added
gene: HIST1H4I was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: HIST1H4I was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: HIST1H4I were set to 35202563
Phenotypes for gene: HIST1H4I were set to Global developmental delay; Intellectual disability; Microcephaly; Growth abnormality; Abnormality of the face
Penetrance for gene: HIST1H4I were set to unknown
Mode of pathogenicity for gene: HIST1H4I 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: HIST1H4I was set to GREEN
Added comment: Histone H4 is a core component of the nucleosome, the basic repeating unit of eukaryotic chromatin. Each nucleosome consists of ~150 bp of DNA wrapped around a histone octamer. Each histone octamer is composed of 2 copies of each of the histones H2A, H2B, H3, H4. This organization is important for DNA replication, transcription and repair.

There are 14 canonical histone H4 genes in the human genome, which despite being different at the nucleotide level encode an identical protein. These cluster in 3 genomic loci. Their transcription is independently regulated with differing expression during brain development and in human tissues.

Histone H4 forms a dimer with H3 (which however has variant isoforms linked to specific cellular processes).

Pathogenic variants in genes encoding H4 have been reported in several individuals. Irrrespective of the gene for H4 involved, all patients presented with highly overlapping features, DD and ID being universal. Available reports to date concern :
- H4C3/HIST1H4C (9 subjects - PMID: 28920961, 35202563),
- H4C11/HIST1H4J (1 subject - PMID: 31804630, 35202563),
- H4C4/HIST1H4D (1 subject - PMID:35202563),
- H4C5/HIST1H4E (17 subjects - PMID: 35202563),
- H4C6/HIST1H4F (1 subject - PMID: 35202563),
- H4C9/HIST1H4I (3 subjects - PMID: 35202563).

Variants in all cases were missense SNVs, occurring (in almost all cases) as dn variants and affecting the same residue in the same and/or different H4 genes (details for clusters below). Eg. Arg45Cys was a recurrent variant for H4C5 (>=7 subjects), while variants affecting Arg40 have been reported in H4C4, H4C5, H4C9, H4C11 (7 subjects overall).

Zebrafish studies for all genes reported have included most - if not all - patient variants and recapitulate features observed in affected individuals (head size/structure and growth).

Additional studies specificaly for H4C3/HIST1H4C have been performed in patient fibroblasts (demonstrating among others transcriptional dysregulation) and zebrafish (accumulation of DSBs, increased apoptosis in head/tail, abn. cell cycle progression).

Note that the nomenclature for variants - at the protein level - used in literature commonly takes into consideration cleavage of Met1, thus the numbering may not correspond to the HGVS one.

Relevant entries exist in OMIM, G2P and SysID only for H4C3/HIST1H4C (Tessadori-van Haaften neurodevelopmental syndrome 1, #619758) and H4C11/HIST1H4J (?Tessadori-van Haaften neurodevelopmental syndrome 2, #619759) but not for other genes.

Rating in PanelApp Australia - ID Panel : HIST1H4C Green, H4J Amber, H4D Amber, H4E Green, H4F Amber, H4I Green.

Please consider inclusion in other possibly relevant panels (microcephaly, short stature/FTT, etc).

------
Initial work from Tessadori et al (incl. DDD study, 2017 - PMID:28920961) identified monoallelic missense SNVs affecting the same residue of H4C3 (HIST1H4C), in 3 individuals from 2 families. [c.274A>C/ HGVS p.(Lys92Gln) dn in 1 subject and c.275A>C/ HGVS p.(Lys92Arg) inherited from unaffected mosaic parent].

Individuals from both families having relevant age had intellectual disability (2/2 - 2 families). Other features incl. growth delay (3/3) and microcephaly (3/3).

Expression of the variants in zebrafish severely affected structural development recapitulating the patient phenotypes (microcephaly and short stature).

RNA sequencing in fibroblasts from 2 unrelated patients and a control, revealed that expression of H4C3 variants was similar to wt. The authors estimated that ~8% of H4 cDNA molecules contained the variant. LC-MS/MS analysis suggested that the mutant protein was present in nucleosomes at a level of 1-2% while RNA-seq identified 115 differential expressed genes, with enrichment for relevant procedures (chr. organization, histone binding, DNA packaging, nucleosomal organization, cell cycle).

Post-translational modifications of Lys92 (H4K91) are highly conserved and have been previously associated with processes from chromatin assembly , DNA damage sensitivity, etc. Post-translational marks on Lys92 (K91) were absent in patient derived cells as a result of each variant.

Zebrafish models for both variants were suggestive for accumulation of double strand breaks (DSBs) more visible in heads and tails of larvae. Embryos expressing mutants displayed increased apoptosis in head and tail. Additional studies in larvae were suggestive of abnormal cell cycle progression (rel. increase in cellls in S/G2/M phase, increased occurrence of activated CHK2 with p53 stabilization) applying to both variants studied.

------
In a subsequent publication, Tessadori et al. (2020 - PMID: 31804630) described the phenotype of a 14 y.o. boy harboring a dn heterozygous missense H4C11 (HIST1H4J) variant following trio-ES [c.274A>G / HGVS p.(Lys92Glu)]. Features incl. profound ID, microcephaly, short stature with some dysmorphic features (uplsanting p-f, hypertelorism, etc). Previous work-up was normal/non-diagnostic and incl. FMR1, MECP2 and a CMA showing an inherited 207 kb CNV involving KCNV1. Upon mRNA microinjection in zebrafish embryos - either for wt or for Lys92Glu HIST1H4J - effect for wt was very mild. Lys92Glu expression led to defective development of head structures (brain, eyes), faulty body axis growth and dysmorphic tail reproducing the microcephaly and short stature phenotype. This was similar to previous zebrafish studies for HIS1H4C variants (above).

------
Tessadori et al. (2022 - PMID: 35202563) describe 29 *additional individuals with de novo missense variants in genes encoding H4, namely:
- H4C3 (HIST1H4C/N=6 subjects),
- H4C11 (HIST1H4J/N=1),
- H4C4 (HIST1H4D/N=1),
- H4C5 (HIST1H4E/N=17),
- H4C6 (HIST1H4F/N=1),
- H4C9 (HIST1H4I/N=3).

All individuals, exhibited DD and ID (29/29). Other features incl. hypotonia (10/29), seizures (5/29), autism (5/29), ataxia (4/29). Abnormal growth incl. progressive microcephaly (2/19 prenatal, 20/29 postnatal onset), short stature/FTT (each 11/29). Few had skeletal features (craniosynostosis 2/29, abn. digits 4/29, vertebral 4/29). Some had visual (17/28) or hearing impairment (7/29). Facial features incl. hypertelorism (5/29), upslanting p-f (3/29), broad nasal tip (11/29), thin upper lip (4/29) and teeth anomalies (6/29 - notably gap between central incisors).

The authors state that the cohort was collected with trio WES but also after data sharing via Genematcher / DECIPHER.

Identified variants were in all cases missense and de novo, the latter either by trio WES or Sanger sequencing of parents.

Previous work-up or presence of additional variants are not discussed.

At the protein level 10 aa were affected, 6 of which recurrently within the same gene (Arg45, His75, Lys91, Tyr98) as well among several genes for H4 (Pro32, Arg40). Variants lied within two clusters, one corresponding to the α-helix of H4 (reported variants affected Lys31 - Arg45) important for DNA contacts, interactions with H3 and histone chaperones. The other within the core of nucleosome (reported patient variants : His75-Tyr98) with important strucural contact between H3-H4 dimer and histone chaperones.

There were no detectable genotype-phenotype patterns separating individual H4 genes or protein regions. Of note, variability was observed even among 7 individuals with the same dn H4C5 variant (Arg45Cys).

All variants were absent from control databases incl. gnomAD and affected residues conserved through to S. cerevisiae. Substitutions affecting Arg45 and Gly94 and His75 have been studied previously with effect in growth/fitness/chromatin remodeling/DNA damage repair depending on variant (5 studies cited).

Zebrafish embryos at the 1 cell stage were injected with mRNA encoding either wt or identified variants, the latter inducing significant developmental defects with the exception of Pro32Ala (H4C3) and Arg40Cys (H4C5, H4C11).

For Pro32Ala and Arg40Cys however, the strong recurrence in this cohort supports pathogenicity. A dosage dependent effect was observed for 2 variants.

H4 genes appear to be tolerant to both missense and loss-of-function variation (the latter even in homozygous form) suggesting a dominant effect of the variants.

------
[RefSeqs : H4C3/HIST1H4C - NM_0035242.4 | H4C4/HIST1H4D - NM_003539.4 | H4C5/HIST1H4E - NM_003545.3 | H4C6/HIST1H4F - NM_003540.4 | H4C9/HIST1H4I - NM_003495.2 | H4C11/HIST1H4J - NM_021968.4 // Variants at the protein level above are according to the HGVS nomenclature. However as the N-terminal methionine is cleaved, numbering relative to the mature peptide has also been used in publications eg. p.Pro33Ala HGVS corresponding to Pro32Ala]
Sources: Literature
Intellectual disability v3.1519 FAR1 Sarah Leigh reviewed gene: FAR1: Rating: GREEN; Mode of pathogenicity: None; Publications: 25439727, 30561787; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Intellectual disability v3.1519 FAR1 Sarah Leigh Tag to_be_confirmed_NHSE tag was added to gene: FAR1.
Intellectual disability v3.1519 SMARCA5 Ivone Leong Tag Q2_21_rating was removed from gene: SMARCA5.
Tag Q2_21_NHS_review was removed from gene: SMARCA5.
Intellectual disability v3.1519 FARSA Ivone Leong Tag Q4_21_rating was removed from gene: FARSA.
Intellectual disability v3.1519 ARFGEF1 Ivone Leong Tag Q4_21_rating was removed from gene: ARFGEF1.
Intellectual disability v3.1519 ARF1 Ivone Leong Tag Q3_21_rating was removed from gene: ARF1.
Intellectual disability v3.1519 SMARCA5 Sarah Leigh commented on gene: SMARCA5
Intellectual disability v3.1519 FARSA Sarah Leigh commented on gene: FARSA
Intellectual disability v3.1519 ARFGEF1 Sarah Leigh commented on gene: ARFGEF1
Intellectual disability v3.1519 ARF1 Sarah Leigh commented on gene: ARF1
Intellectual disability v3.1519 SMARCA5 Ivone Leong Source Expert Review Green was added to SMARCA5.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 FARSA Ivone Leong Source Expert Review Green was added to FARSA.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 ARFGEF1 Ivone Leong Source Expert Review Green was added to ARFGEF1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 ARF1 Ivone Leong Source Expert Review Green was added to ARF1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1518 CPSF3 Konstantinos Varvagiannis gene: CPSF3 was added
gene: CPSF3 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: CPSF3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CPSF3 were set to 35121750
Phenotypes for gene: CPSF3 were set to Failure to thrive; Abnormal muscle tone; Global developmental delay; Intellectual disability; Microcephaly; Seizures
Penetrance for gene: CPSF3 were set to Complete
Review for gene: CPSF3 was set to AMBER
Added comment: Arnadottir (2022 - PMID: 35121750) describe the phenotype associated with biallelic CPSF3 pathogenic variants.

Based on WGS of 56,969 Icelanders and imputing the genotype of another 153,054 chip-genotyped Icelanders, the authors identified missense variants with a deficit of homozygous carriers to what would be expected based on AF. (For variants with MAF>0.4%, for which >=3 hmz carriers would be expected by H-W equilibrium, no identified hmz carriers within this cohort/dataset). A total of 114 such missense variants was identified.

5 of these SNVs, among which a CPSF3 one (NM_016207.3:c.1403G>A / p.Gly468Glu), were however observed in a series of 764 individuals investigated with clinical WGS at the National University Hospital.

The CPSF3 variant with a MAF of 0.41% (3 hmz expected but none observed in the population set) was found in homozygosity in 2 closely related individuals, both investigated for FTT, severe DD, ID, microcephaly, seizures but remaining unresolved following WGS with no other candidate variants.

Using genealogical information from the db of deCODE genetics, the authors identified 3 couples from the 153k genotyped Icelanders where both partners were htz carriers for this SNV. These 3 couples had 10 offspring, 4 of whom deceased but with the same phenotypic features as above (hypotonia 4/4, ID 4/4, seizures 3/4, microcephaly 2/4). Paraffin embedded samples of 2 of these children and WG & Sanger sequencing confirmed hmz for Gly468Glu in 2 sibs, without other candidate variants. Samples of the 2 other individuals were N/A.

Through GeneMatcher 2 additional first-cousin patients from Mexico were identified, being hmz for another CPSF3 variant (c.1061T>C/p.Ile354Thr) and having overlapping phenotype of abnormal muscle tone, ID, seizures and microcephaly. There were no other variants in WES analysis.

mRNA studies in WBCs from Gly468Glu htz carriers did not reveal reduced levels and W.Blot of lymphocytes from a hmz individual confirmed expression, overall suggesting that the variant does not affect the protein levels but presumably the function.

CPSF3 encodes cleavage and polyadenylation specificity factor 3, a 684 aa protein, subunit of the cleavage and polyadenylation specificity factor compex. As discussed, cleavage and polyadenylation of the 3' of pre-mRNAs is necessary before transport out of the nucleus with CPSF playing a crucial role in the process of cleavage.

CPSF3 ko mice exhibit embryonic lethality, while in yeast mutations in key residues of the CPSF3 homolog are lethal.

In gnomAD, CPSF3 has a pLI of 0, z-score of 3.61 with no homozygotes for pLoF variants in 141k individuals (or ~57k WGS Icelanders).

The 2 missense variants concerned highly conserved residues (GERP ~5.8). Both are hypothesized to affect the ability of the protein to bind other factors involved in pre-mRNA cleavage.

Overall the authors speculate that not only complete loss of CPSF3 would result in drastic phenotypic effects - as in the murine model - but also variants altering its enzymatic function.

There is currently no CPSF3-related phenotype in OMIM, G2P, SysID, The gene is included with green rating in the ID, epilepsy and microcephaly panels in PanelApp Australia.

Consider inclusion probably with amber rating (Highly consistent phenotype, biological function, evidence from animal models. 2 identified variants, authors state that follow-up functional studies are needed). Also consider inclusion in other possibly relevant panels.
Sources: Literature
Intellectual disability v3.1518 NRCAM Konstantinos Varvagiannis gene: NRCAM was added
gene: NRCAM was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: NRCAM was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NRCAM were set to 35108495
Phenotypes for gene: NRCAM were set to Hypotonia; Hypertonia; Spasticity; Global developmental delay; Intellectual disability; Microcephaly; Behavioral abnormality; Neuropathy; Hearing abnormality; Abnormality of the eye; Abnormality of the skeletal system; Scoliosis; Abnormality of the face
Penetrance for gene: NRCAM were set to Complete
Review for gene: NRCAM was set to GREEN
Added comment: Kurolap et al (2022 - PMID: 35108495) describe the phenotype of 10 individuals (from 8 families) with biallelic variants in NRCAM.

Features included tone abnormalities (hypotonia in 4/10, hypertonia/spasticity in 4/10), DD (8/10 - 7 families) and cognitive impairment (in 7/10 - 6 fam), neuropathy (4/10 - incl. 2 sibs without DD/ID). Other phenotypes incl. FTT (2/8), microcephaly (3/6), variable behavioral issues (3/5), abnormalities from the eyes/vision (6/8 - cataract in 2), abnormal hearing (3/7) or skeletal findings (8/9 - incl. scoliosis in 5). Nonspecific facial features were reported in 5/8.

Previous metabolic, genetic (incl. karyotype or CMA, FMR1, testing for Steinert disease or SMA) or other work-up (e.g. muscle biopsy) is reported for several subjects but was normal/non-diagnostic.

All were investigated by WES/WGS which revealed biallelic NRCAM variants. Sanger sequencing was used for confirmation and segregation analyses, with compatible results in several affected/unaffected sibs tested. There were no alternative explanations for the NDD phenotype with the exception of one subject with a mosaic functionally characterized LP KRAS variant suspected to contribute to his phenotype.

NRCAM encodes neuronal cell adhesion molecule (CAM). CAMs are membrane bound proteins with important role in tissue morphogenesis and maintenance. They mediate interactions between neighboring cells or cells and the extracellular matrix. The L1 subgroup of immunoglobulin CAMS - consisting of L1CAM, neurofascin, NRCAM, CHL1 - is the most abundant in the CNS with several critical functions in CNS development, among others in neural cell differentiation, axonal growth and guidance, myelination, synapse formation. Pathogenic L1CAM (XL) and NFASC variants (AR) are associated with NDD.

Different missense (N=7), stopgain/frameshift (N=3), a splice variant (NM_001037132.2:c.2647-2A>G) as well as a deep intronic one (c.230+824G>C / rs575851831). Variants occurred in different domains with a cluster (42%) in the fibronectin III domain.

Missense SNVs were ultrarare or not present in gnomAD, occurred in conserved residues, with several in silico predictions in favor of a deleterious effect. Structural modelling suggested that all substitutions occurred at residues exposed to solvent and possible abrogated interaction with other proteins.

There were no expression studies performed at the mRNA/protein level. The splice variant is predicted to cause ex22 skipping leading to frameshift. The deep intronic variant is predicted to disrupt a site for spl. regulator SC35 and may cause activation of a cryptic acceptor site with inclusion of a cryptic exon.

The zebrafish nrcama gene is the sole ortholog of human NRCAM, with another gene proposed as possible ortholog (nrcamb) mapping upon BLAST analysis to cntn1a. The authors performed CRISPR-Cas9 mutagenesis in zebrafish introducing a partial deletion of ex18 and 19. Mutant zebrafish were viable, displayed altered axonal projections and abnormal swimming behavior (increased movement in darkness).

Currently, there is no NRCAM-associated phenotype in OMIM/G2P/SysID. PanelApp Australia includes NRCAM in its ID panel with green rating.

Consider inclusion probably with green (>3 individuals/families/variants, segregation, gene in the L1-Ig CAM family causing NDD, zebrafish model) or amber rating (ID not a universal feature, variant effect not studied).
Sources: Literature
Intellectual disability v3.1518 TIAM1 Konstantinos Varvagiannis gene: TIAM1 was added
gene: TIAM1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: TIAM1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TIAM1 were set to 35240055; 33328293
Phenotypes for gene: TIAM1 were set to Delayed speech and language development; Global developmental delay; Intellectual disability; Seizures; Behavioral abnormality; Abnormality of the endocrine system; Hypothyroidism; Abnormality of nervous system morphology
Penetrance for gene: TIAM1 were set to Complete
Review for gene: TIAM1 was set to AMBER
Added comment: Lu et al (2022 - PMID: 35240055) describe 5 individuals (from 4 families) with biallelic TIAM1 missense variants.

The phenotype overall corresponded to a neurodevelopmental disorder with DD (5/5), ID (4/4 individuals of relevant age - 3 families), speech delay (5/5), seizures (5/5 - onset: 2m-13y) and behavioral abnormalities (2/2, sibs with autism and ADHD). Several subjects had endocrine symptoms, namely hypothyroidism (N=3 - 2 families), Addison's disease (1) or hypomagnesemia (1). Non-consistent abnormalities were reported in (3/3) subjects who had a brain MRI.

Previous investigations were mentioned for 3 individuals (incl. 2 sibs) and included normal CMA and/or metabolic workup.

Singleton or trio exome sequencing (in one family) revealed biallelic missense TIAM1 variants.

6 different missense variants were reported, all ultra-rare or not present in gnomAD (also o/e:0.2, pLI:0.96), with CADD scores in favor of deleterious effect (NM_001353694.2): c.67C>T/p.Arg23Cys*, c.2584C>T/p.Leu862Phe*, c.983G>T/p.Gly328Val*, c.4640C>A/p.Ala1547Glu, c.1144G>C/p.Gly382Arg, c.4016C>T/p.Ala1339Val.

TIAM1 encodes a RAC1-specific guanine exchange factor (GEF), regulating RAC1 signaling pathways that in turn affect cell shape, migration, adhesion, growth, survival, and polarity, and influence actin cytoskeletal organization, endocytosis, and membrane trafficking. RAC1 signaling plays important role in control of neuronal morphogenesis and neurite outgrowth (based on the summary by Entrez and authors).

TIAM1 is highly expressed in human brain (GTEx).

The authors provide evidence that sif, the Drosophila ortholog, is expressed primarily in neurons of the fly CNS (but not in glia). Using different sif LoF mutant flies they demonstrate that loss of sif impairs viability. Surviving flies exhibited climbing defects and seizure-like behaviors, both significantly rescued upon UAS-sif expression. Neuronal specific sif knockdown resulted in similar phenotypes to ubiquitous knockdown, while glial knockdown did not result in climbing defects.

The semi-lethal phenotype could be fully rescued by expression of the fly sif cDNA, but only partially by human TIAM1 cDNA reference. Upon expression, 3 patient-variants (R23C, L862F, G328V) had variable rescue abilities similar to or lower (R23C) than TIAM1 Ref. TIAM1 Ref and variants could not rescue the neurological phenotypes though. Higher/ectopic expression of sif or TIAM1 Ref was toxic, which was also observed to a lesser extent for variants.

Overall, the evidence provided suggests that the 3 variants tested induce partial LoF.

In a recent study cited (PMID: 33328293), Tiam1 KO mice had simplified dendritic arbors, reduced spine density and diminished excitatory transmission in dentate gyrus. The authors comment that this mouse model presented only subtle behavioral abnormalities which they speculate may be secondary to GEF redundancy (eg. Tiam2).

There is no TIAM1-associated phenotype in OMIM/G2P/SysID. TIAM1 is included in PanelApp Australia in the ID and epilepsy panels with green rating.

Consider inclusion in the current panel with amber rating [As authors discuss: some phenotypic features differed in their small cohort and the contribution of other recessive conditions in 2 consanguineous families cannot be excluded. Also: in fig S1 only status of parents but not of affected/unaffected sibs is specified with the exception of Fam1].
Sources: Literature
Intellectual disability v3.1518 THUMPD1 Konstantinos Varvagiannis reviewed gene: THUMPD1: Rating: GREEN; Mode of pathogenicity: None; Publications: 30237576, 35196516; Phenotypes: Global developmental delay, Intellectual disability, Microcephaly, Hearing abnormality, Abnormality of the eye, Febrile seizures, Behavioral abnormality, Abnormality of brain morphology, Abnormality of the face; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability v3.1518 HEATR3 Konstantinos Varvagiannis gene: HEATR3 was added
gene: HEATR3 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: HEATR3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HEATR3 were set to 35213692
Phenotypes for gene: HEATR3 were set to Anemia; Thrombocytopenia; Growth delay; Short stature; Abnormality of the skeletal system; Abnormality of finger; Abnormality of the thumb; Intellectual disability; Obesity; Abnormality of the face
Penetrance for gene: HEATR3 were set to Complete
Review for gene: HEATR3 was set to AMBER
Added comment: O'Donohue et al (2022 - PMID: 35213692) describe the clinical features of 6 individuals (from 4 unrelated families) with biallelic pathogenic HEATR3 variants.

These included bone marrow failure (anemia/anemia and thrombocytopenia at presentation), short stature/growth retardation (4/6), facial features (5/6 - in some: straight eyebrows, d-s palpebral fissures, synophrys) and skeletal findings incl. disproportionately short fingers/thumb anomaly. ID was reported in 4/6 individuals from 3 families (all: mild ID | 2/6 without ID). The phenotype corresponded overall to a variant form Diamond-Blackfan anemia (DBA, disorder caused by variants in genes encoding for ribosomal proteins) with additional features.

The 1st family (2 affected sibs and parents) underwent WES, not diagnostic for DBA. Analysis suggested variants in HEATR3 (prioritized due to its potential role in ribosome biogenesis) and 4 additional genes as candidates. Collaboration in the European DBA consortium and national DBA consortia led to identification of additional families.

HEATR3 encodes Heat-repeat-containing protein 3 or symportin, a protein that co-imports uL5 (encoded by RPL11) and uL18 (RPL5) in the nucleus where they assemble with 5S rRNA to form 5S RNP. The 5S RNP complex incorporates with maturing large ribosomal subunits to form the central protuberance. When 5S RNP is not incorporated, it accumulates and associates with Hdm2 ubiquitin ligase, the later normally targeting p53 proteasomal degradation.

The following missense and splice variants were identified (NM_182922):
- c.1751G>Α/p.(Gly584Glu) hmz
- c.1337G>A/p.(Cys446Tyr) hmz
- c.399+1G>T in trans with c.719C>T/p.(Pro240Leu)
- c.400T>C/p.(Cys134Arg) hmz

Variants were confirmed with Sanger sequencing. They were dispersed across HEATR3 without clustering although they affect residues either in the ARM (38-320) or HEAT (415-675) repeat domains, at positions evolutionary conserved, with in silico predictions in favor of a deleterious effect. With the exception of Cys134Arg (AF:4.11x10-6/no hmz), all were absent from gnomAD.

Studies in yeast suggested that deletions in symportin gene (syo1) lead to a mild growth defect and accumulation of 40S subunits. Similarly, two yeast strains engineered to test for the effect of the p.Gly584Glu (yeast p.Gly522Glu/Ala) exhibited growth defect and ribosomal subunit imbalance, both restored by wt Syo1.

HA-tagged HEATR3 in HeLa cells suggested that the co-translational capture mechanism to chaperone uL18 (RPL5) is conserved in human cells but was not observed upon expression of the p.Cys446Tyr variant.

While HEATR3 transcription was not affected in LCLs from individuals hmz for Gly584Glu or Cys446Tyr, protein levels were barely detectable, suggesting destabilization of the protein.

While uL18 accumulates in cytoplasm and nucleus with expected enrichment in nucleolus, upon siRNA knockdown of HEATR3 in HeLa cells this enrichment was lost. Studies in fibroblasts (Gly584Glu) demonstrated reduced uL18 nuclear staining. Overall, HEATR3 was suggested to be important for nuclear import of uL18 (though not for uL5).

LCL studies demonstrated pre-rRNA processing defects in patient cells with accumulation of 32S and 12S pre-rRNAs, the former being reminiscent of accumulations observed in individuals with RPL5- and RPL11-related DBA. Expression of wt HEATR3 restored processing defects.

LCLs from affected individuals revealed loss of free 60S subunits (as in yeast) with expression of wt cDNA restoring Nl levels.

Western blots of LCLs demonstrated that the levels of uL5, uL18 and p53 were not affected (the latter also observed in RPL5-related DBA)

Studies of bone marrow smears from 2 affected individuals allowed to conclude in a strong defect in erythroid cell proliferation.

Currently, there is no HEATR3-associated phenotype in OMIM, PanelApp Australia, G2P or the SysID database.

Consider inclusion in the ID panel with amber (mild ID in >3 individuals/families/variants although not universal feature) or green rating. Also consider inclusion in other possibly relevant panels eg. for cytopenias/congenital anemias, short stature, etc.
Sources: Literature
Intellectual disability v3.1513 JARID2 Arina Puzriakova Tag for-review was removed from gene: JARID2.
Intellectual disability v3.1513 NARS Arina Puzriakova Tag for-review was removed from gene: NARS.
Intellectual disability v3.1513 LARS Arina Puzriakova Tag for-review was removed from gene: LARS.
Intellectual disability v3.1513 NUS1 Arina Puzriakova Phenotypes for gene: NUS1 were changed from #617082 - ?Congenital disorder of glycosylation, type 1aa; #617831 - Mental retardation, autosomal dominant 55, with seizures; Abnormality of extrapyramidal motor function to Mental retardation, autosomal dominant 55, with seizures, OMIM:617831; Congenital disorder of glycosylation, type 1aa, OMIM:617082
Intellectual disability v3.1511 RARS Arina Puzriakova Tag for-review was removed from gene: RARS.
Intellectual disability v3.1511 VARS2 Arina Puzriakova Tag for-review was removed from gene: VARS2.
Intellectual disability v3.1511 SARS2 Arina Puzriakova Tag for-review was removed from gene: SARS2.
Intellectual disability v3.1511 EARS2 Arina Puzriakova Tag for-review was removed from gene: EARS2.
Intellectual disability v3.1511 ADARB1 Arina Puzriakova Tag for-review was removed from gene: ADARB1.
Intellectual disability v3.1510 SCN8A Sarah Leigh commented on gene: SCN8A: Just 2 families reported with possible AR inheritance: v rare - all het parents seem to have features so prob ok to keep as monoallelic only (source NHS Genomic Medicine Service).
Intellectual disability v3.1510 AGO2 Sarah Leigh commented on gene: AGO2: Green rating is for monoallelic MOI only, many cases reported with speech delay and variable ID (source NHS Genomic Medicine Service).
Intellectual disability v3.1510 JARID2 Sarah Leigh commented on gene: JARID2
Intellectual disability v3.1510 NARS Sarah Leigh commented on gene: NARS
Intellectual disability v3.1510 LARS Sarah Leigh commented on gene: LARS
Intellectual disability v3.1510 RARS Sarah Leigh commented on gene: RARS: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Intellectual disability v3.1510 VARS2 Sarah Leigh commented on gene: VARS2
Intellectual disability v3.1510 SARS2 Sarah Leigh commented on gene: SARS2: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Intellectual disability v3.1510 EARS2 Sarah Leigh commented on gene: EARS2: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Intellectual disability v3.1510 ADARB1 Sarah Leigh commented on gene: ADARB1: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Intellectual disability v3.1509 JARID2 Arina Puzriakova Source Expert Review Green was added to JARID2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 NARS Arina Puzriakova Source Expert Review Green was added to NARS.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 LARS Arina Puzriakova Source Expert Review Green was added to LARS.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 RARS Arina Puzriakova Source Expert Review Green was added to RARS.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 VARS2 Arina Puzriakova Source Expert Review Green was added to VARS2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 SARS2 Arina Puzriakova Source Expert Review Green was added to SARS2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 EARS2 Arina Puzriakova Source Expert Review Green was added to EARS2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 ADARB1 Arina Puzriakova Source Expert Review Green was added to ADARB1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1506 PDZD8 Konstantinos Varvagiannis changed review comment from: Al-Amri et al (2022 - PMID: 35227461) describe 4 affected individuals, belonging to 2 independent consanguineous families, harboring biallelic pLoF PDZD8 variants. The phenotype corresponded to a syndromic form of ID with autistic features. Animal models provide additional evidence for a role of the gene.

Details are provided concerning 3 affected sibs born to consanguineous parents (Fam-A) and a male proband born to first cousin parents (Fam-B) from different countries of the Arabian Peninsula.

Features included DD (4/4), ID (4/4 - moderate to severe), autistic features[*](4/4), other behavioral problems (3/4 - 2 families). Variable facial features were observed (4/4 - incl. hypertelorism 4/4, myopathic face, open mouth, low-set ears, ptosis). 3 sibs presented with myopathy[*](3/4 overall - 1 fam - see below), and marfanoid habitus was observed in 2 (2/4 - 1 fam). 2 sibs had epilepsy (2/4 - from 1 family). 1 individual had congenital heart defect. [* -also to consider for MOI]Autistic features were however observed in a parent and a htz sib. Mild myopathy/reduced facial expression was also observed in both parents. Contribution of another variant - also within the region of shared homozygosity - to the phenotype of myopathy was deemed to be possible within this family.

Previous genetic testing was not reported.

Homozygosity mapping in the 1st family identified 3 homozygous regions (2.57 - 28 Mb) shared by all affected sibs. Singleton WES revealed 2 candidate variants within these regions, a PDZD8 frameshift variant [NM_173791.5:c.2197_2200del;p.(S733*)] lying in the last exon and an ANKRD2 missense one (discussed above).

The proband in Fam-B was hmz for a nonsense variant in ex2 (of 5), namely c.894C>G/p.(Y298*) considered to be the most likely cause of his phenotype following singleton WES.

Sanger sequencing was used for validation and segregation studies confirming carrier status of the parents and compatible results in unaffected sibs (tested : 2 in Fam-A, 3 in Fam-B).

Both variants were absent from gnomAD (the first also from a pool of 50 control individuals of the same origin) where PDZD8 has a pLI of 1 (5 different pLoF variants, none hmz).

Expression was not studied for the 2 variants. As a result, it is not known whether they escape NMD (as could be expected for the variant in the last exon).

PDZD8 encodes an endoplasmatic reticulum (ER) transmembrane protein (TM). As the authors discuss, it has been previously shown that depletion of PDZD8 in neurons impairs endosomal homeostasis, decreases proximity of ER-mitochondria and decreases Ca+2 uptake mitochondria following synaptic transmission-induced release from the ER (sev. refs. provided).

The gene is highly expressed in the human brain (incl. subclasses of GABAergic / glutamatergic neurons in adult primary motor cortex). The authors analyzed RNA-seq data from the BrainSpan project, demonstrating stable expression in human brain from 8 wks after conception to adulthood. The gene is not expressed in blood.

The authors performed in vivo functional studies. Knockdown of the orthologous gene (CG10362) in Drosophila via RNA interference was shown to result in impairment of long-term memory. Mice homozygous for a variant introducing a premature termination codon exhibited restricted growth, brain structural alterations (incl. relative reduction of the CC, as in one subject), spontaneous stereotypies, decreased anxiety-like behavior with deficits in spatial memory and impaired hippocampal neurophysiology.

Currently, there is no associated phenotype in OMIM, Gene2Phenotype, SysID or PanelApp Australia.

Overall, this gene can be considered for inclusion in the ID panel probably with amber rating pending further reports.
Sources: Literature; to: Al-Amri et al (2022 - PMID: 35227461) describe 4 affected individuals, belonging to 2 independent consanguineous families, harboring biallelic pLoF PDZD8 variants. The phenotype corresponded to a syndromic form of ID with autistic features. Animal models provide additional evidence for a role of the gene.

Details are provided concerning 3 affected sibs born to consanguineous parents (Fam-A) and a male proband born to first cousin parents (Fam-B) from different countries of the Arabian Peninsula.

Features included DD (4/4), ID (4/4 - moderate to severe), autistic features[*](4/4), other behavioral problems (3/4 - 2 families). Variable facial features were observed (4/4 - incl. hypertelorism 4/4, myopathic face, open mouth, low-set ears, ptosis). 3 sibs presented with myopathy[*](3/4 overall - 1 fam - see below), and marfanoid habitus was observed in 2 (2/4 - 1 fam). 2 sibs had epilepsy (2/4 - from 1 family). 1 individual had congenital heart defect. [*] (also to consider for MOI) : Autistic features were however observed in a parent and a htz sib. Mild myopathy/reduced facial expression was also observed in both parents. Contribution of another variant - also within the region of shared homozygosity - to the phenotype of myopathy was deemed to be possible within this family.

Previous genetic testing was not reported.

Homozygosity mapping in the 1st family identified 3 homozygous regions (2.57 - 28 Mb) shared by all affected sibs. Singleton WES revealed 2 candidate variants within these regions, a PDZD8 frameshift variant [NM_173791.5:c.2197_2200del;p.(S733*)] lying in the last exon and an ANKRD2 missense one (discussed above).

The proband in Fam-B was hmz for a nonsense variant in ex2 (of 5), namely c.894C>G/p.(Y298*) considered to be the most likely cause of his phenotype following singleton WES.

Sanger sequencing was used for validation and segregation studies confirming carrier status of the parents and compatible results in unaffected sibs (tested : 2 in Fam-A, 3 in Fam-B).

Both variants were absent from gnomAD (the first also from a pool of 50 control individuals of the same origin) where PDZD8 has a pLI of 1 (5 different pLoF variants, none hmz).

Expression was not studied for the 2 variants. As a result, it is not known whether they escape NMD (as could be expected for the variant in the last exon).

PDZD8 encodes an endoplasmatic reticulum (ER) transmembrane protein (TM). As the authors discuss, it has been previously shown that depletion of PDZD8 in neurons impairs endosomal homeostasis, decreases proximity of ER-mitochondria and decreases Ca+2 uptake mitochondria following synaptic transmission-induced release from the ER (sev. refs. provided).

The gene is highly expressed in the human brain (incl. subclasses of GABAergic / glutamatergic neurons in adult primary motor cortex). The authors analyzed RNA-seq data from the BrainSpan project, demonstrating stable expression in human brain from 8 wks after conception to adulthood. The gene is not expressed in blood.

The authors performed in vivo functional studies. Knockdown of the orthologous gene (CG10362) in Drosophila via RNA interference was shown to result in impairment of long-term memory. Mice homozygous for a variant introducing a premature termination codon exhibited restricted growth, brain structural alterations (incl. relative reduction of the CC, as in one subject), spontaneous stereotypies, decreased anxiety-like behavior with deficits in spatial memory and impaired hippocampal neurophysiology.

Currently, there is no associated phenotype in OMIM, Gene2Phenotype, SysID or PanelApp Australia.

Overall, this gene can be considered for inclusion in the ID panel probably with amber rating pending further reports.
Sources: Literature
Intellectual disability v3.1506 PDZD8 Konstantinos Varvagiannis gene: PDZD8 was added
gene: PDZD8 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: PDZD8 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PDZD8 were set to 35227461
Phenotypes for gene: PDZD8 were set to Global developmental delay; Intellectual disability; Autistic behavior; Behavioral abnormality; Myopathy; Abnormality of the face; Hypertelorism; Seizures; Disproportionate tall stature
Penetrance for gene: PDZD8 were set to Complete
Review for gene: PDZD8 was set to AMBER
Added comment: Al-Amri et al (2022 - PMID: 35227461) describe 4 affected individuals, belonging to 2 independent consanguineous families, harboring biallelic pLoF PDZD8 variants. The phenotype corresponded to a syndromic form of ID with autistic features. Animal models provide additional evidence for a role of the gene.

Details are provided concerning 3 affected sibs born to consanguineous parents (Fam-A) and a male proband born to first cousin parents (Fam-B) from different countries of the Arabian Peninsula.

Features included DD (4/4), ID (4/4 - moderate to severe), autistic features[*](4/4), other behavioral problems (3/4 - 2 families). Variable facial features were observed (4/4 - incl. hypertelorism 4/4, myopathic face, open mouth, low-set ears, ptosis). 3 sibs presented with myopathy[*](3/4 overall - 1 fam - see below), and marfanoid habitus was observed in 2 (2/4 - 1 fam). 2 sibs had epilepsy (2/4 - from 1 family). 1 individual had congenital heart defect. [* -also to consider for MOI]Autistic features were however observed in a parent and a htz sib. Mild myopathy/reduced facial expression was also observed in both parents. Contribution of another variant - also within the region of shared homozygosity - to the phenotype of myopathy was deemed to be possible within this family.

Previous genetic testing was not reported.

Homozygosity mapping in the 1st family identified 3 homozygous regions (2.57 - 28 Mb) shared by all affected sibs. Singleton WES revealed 2 candidate variants within these regions, a PDZD8 frameshift variant [NM_173791.5:c.2197_2200del;p.(S733*)] lying in the last exon and an ANKRD2 missense one (discussed above).

The proband in Fam-B was hmz for a nonsense variant in ex2 (of 5), namely c.894C>G/p.(Y298*) considered to be the most likely cause of his phenotype following singleton WES.

Sanger sequencing was used for validation and segregation studies confirming carrier status of the parents and compatible results in unaffected sibs (tested : 2 in Fam-A, 3 in Fam-B).

Both variants were absent from gnomAD (the first also from a pool of 50 control individuals of the same origin) where PDZD8 has a pLI of 1 (5 different pLoF variants, none hmz).

Expression was not studied for the 2 variants. As a result, it is not known whether they escape NMD (as could be expected for the variant in the last exon).

PDZD8 encodes an endoplasmatic reticulum (ER) transmembrane protein (TM). As the authors discuss, it has been previously shown that depletion of PDZD8 in neurons impairs endosomal homeostasis, decreases proximity of ER-mitochondria and decreases Ca+2 uptake mitochondria following synaptic transmission-induced release from the ER (sev. refs. provided).

The gene is highly expressed in the human brain (incl. subclasses of GABAergic / glutamatergic neurons in adult primary motor cortex). The authors analyzed RNA-seq data from the BrainSpan project, demonstrating stable expression in human brain from 8 wks after conception to adulthood. The gene is not expressed in blood.

The authors performed in vivo functional studies. Knockdown of the orthologous gene (CG10362) in Drosophila via RNA interference was shown to result in impairment of long-term memory. Mice homozygous for a variant introducing a premature termination codon exhibited restricted growth, brain structural alterations (incl. relative reduction of the CC, as in one subject), spontaneous stereotypies, decreased anxiety-like behavior with deficits in spatial memory and impaired hippocampal neurophysiology.

Currently, there is no associated phenotype in OMIM, Gene2Phenotype, SysID or PanelApp Australia.

Overall, this gene can be considered for inclusion in the ID panel probably with amber rating pending further reports.
Sources: Literature
Intellectual disability v3.1506 POU1F1 Arina Puzriakova Phenotypes for gene: POU1F1 were changed from Gene2Phenotype confirmed gene with ID HPO to Pituitary hormone deficiency, combined or isolated, 1, OMIM:613038
Intellectual disability v3.1502 HSF4 Arina Puzriakova Phenotypes for gene: HSF4 were changed from Cataract 5, multiple types, 116800 to Cataract 5, multiple types, OMIM:116800
Intellectual disability v3.1501 NALCN Arina Puzriakova Phenotypes for gene: NALCN were changed from ?Neuroaxonal neurodegeneration, infantile, with facial dysmophism, 615419; CONGENITAL CONTRACTURES OF THE LIMBS AND FACE, HYPOTONIA, AND DEVELOPMENTAL DELAY to Congenital contractures of the limbs and face, hypotonia, and developmental delay, OMIM:616266; Hypotonia, infantile, with psychomotor retardation and characteristic facies 1, OMIM:615419
Intellectual disability v3.1500 CHKA Konstantinos Varvagiannis gene: CHKA was added
gene: CHKA was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: CHKA was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CHKA were set to 35202461
Phenotypes for gene: CHKA were set to Abnormal muscle tone; Global developmental delay; Intellectual disability; Seizures; Microcephaly; Abnormality of movement; Abnormality of nervous system morphology; Short stature
Penetrance for gene: CHKA were set to Complete
Review for gene: CHKA was set to GREEN
Added comment: Klöckner (2022 - PMID: 35202461) describe the phenotype of 6 individuals (from 5 unrelated families) harboring biallelic CHKA variants.

Shared features incl. abnormal muscle tone(6/6 - hypertonia or hypotonia, 3/6 each), DD/ID (6/6,severe in 4, severe/profound in 2), epilepsy (6/6 - onset: infancy - 3y2m | epileptic spasms or GS at onset), microcephaly (6/6), movement disorders (3/6 - incl. dyskinesia, rigidity, choreoatetotic movements). 2/5 individuals exhibited MRI abnormalities, notably hypomyelination. Short stature was observed in 4/6.

Eventual previous genetic testing was not discussed.

Exome sequencing (quattro ES for 2 sibs, trio ES for 1 individual, singleton for 3 probands) revealed biallelic CHKA variants in all affected individuals. Sanger sequencing was performed for confirmation and segregation studies.

Other variants (in suppl.) were not deemed to be causative for the neurodevelopmental phenotype.

3 different missense, 1 start-loss and 1 truncating variant were identified, namely (NM_0012772.2):
- c.421C>T/p.(Arg141Trp) [3 hmz subjects from 2 consanguineous families],
- c.580C>T/p.Pro194Ser [1 hmz individual born to consanguineous parents],
- c.2T>C/p.(Met1?) [1 hmz individual born to related parents],
- c.14dup/p.(Cys6Leufs*19) in trans with c.1021T>C/p.(Phe341Leu) in 1 individual.

CHKA encodes choline kinase alpha, an enzyme catalyzing the first step of phospholipid synthesis in the Kennedy pathway. The pathway is involved in de novo synthesis of glycerophospholipids, phosphatidylcholine and phosphatidylethanolamine being the most abundant in eukaryotic membranes.

CHKA with its paralog (CHKB) phosphorylates either choline or ethanolamine to phosphocholine or phosphoethanolamine respectively with conversion of ATP to ADP.

As the authors comment, biallelic pathogenic variants in CHKB cause a NDD with muscular dystrophy, hypotonia, ID, microcephaly and structural mitochondrial anomalies (MIM 602541). [Prominent mitochondrial patterning was observed in a single muscle biopsy available from an individual with biallelic CHKA variants].

Other disorders of the Kennedy pathway (due to biallelic PCYT2, SELENOI, PCYT1A variants) present with overlapping features incl. variable DD/ID (no-severe), microcephaly, seizures, visual impairment etc.

CHKA variants were either absent or observed once in gnomAD, affected highly conserved AAs with multiple in silico predictions in favor of a deleterious effect.

In silico modeling suggests structural effects for several of the missense variants (Arg141Trp, Pro194Ser presumably affect ADP binding, Phe341 lying close to the binding site of phosphocholine).

Each of the missense variants was expressed in yeast cells and W. Blot suggested expression at the expected molecular weight at comparative levels. The 3 aforementioned variants exhibited reduced catalytic activity (20%, 15%, 50% respectively).

NMD is thought to underly the deleterious effect of the frameshift one (not studied).

The start-loss variant is expected to result in significantly impaired expression and protein function as eventual utilization of the next possible start codon - occurring at position 123 - would remove 26% of the protein.

Chka(-/-) is embryonically lethal in mice, suggesting that complete loss is not compatible with life. Reduction of choline kinase activity by 30% in heterozygous mice did not appear to result in behavioral abnormalities although this was not studied in detail (PMID cited: 18029352). Finally, screening of 1566 mouse lines identified 198 genes whose disruption yields neuroanatomical phenotypes, Chka(+/-) mice being among these (PMID cited: 31371714).

There is no associated phenotype in OMIM, Gene2Phenotype or SysID.

Overall this gene can be considered for inclusion in the ID and epilepsy panes with green or amber rating (>3 individuals, >3 variants, variant studies, overlapping phenotype of disorders belonging to the same pathway, etc). Consider also inclusion in the microcephaly panel (where available this seemed to be of postnatal onset).
Sources: Literature
Intellectual disability v3.1497 GJC2 Arina Puzriakova Phenotypes for gene: GJC2 were changed from Leukodystrophy, hypomyelinating, 2, 608804Spastic paraplegia 44, autosomal recessive, 613206Lymphedema, hereditary, IC, 613480; LYMPHEDEMA, HEREDITARY, IC to Leukodystrophy, hypomyelinating, 2, OMIM:608804
Intellectual disability v3.1496 PRKAR1B Zornitza Stark reviewed gene: PRKAR1B: Rating: GREEN; Mode of pathogenicity: None; Publications: 33833410; Phenotypes: Marbach-Schaaf neurodevelopmental syndrome MIM#619680; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.1496 SPRED2 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in Gene2Phenotype (Strong) but not in OMIM. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Intellectual disability v3.1496 SPRED2 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in Gene2Phenotype (Strong) but not in OMIM. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Intellectual disability v3.1491 SPATA5L1 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in OMIM and Gene2Phenotype (limited). There is enough evidence to support a gene-disease association, this gene should be rated Green.
Intellectual disability v3.1490 SPATA5L1 Ivone Leong Phenotypes for gene: SPATA5L1 were changed from Neurodevelopmental disorder with hearing loss and spasticity, MIM# 619616 to Neurodevelopmental disorder with hearing loss and spasticity, OMIM:619616
Intellectual disability v3.1485 MYO5B Arina Puzriakova Phenotypes for gene: MYO5B were changed from Microvillus inclusion disease, 251850 to Diarrhea 2, with microvillus atrophy, OMIM:251850
Intellectual disability v3.1481 KCND2 Eleanor Williams Added comment: Comment on list classification: Promoting from red to amber but with a recommendation for green rating following GMS review. 3 cases reported with missense variants in this gene with no seizures, plus further cases with seizures.
Intellectual disability v3.1480 KCND2 Eleanor Williams gene: KCND2 was added
gene: KCND2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: KCND2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: KCND2 were set to 34245260; 16934482; 24501278
Phenotypes for gene: KCND2 were set to global developmental delay, HP:0001263
Mode of pathogenicity for gene: KCND2 was set to Other
Added comment: 6 new unrelated cases with developmental delay reported in PMID: 34245260 (Zhang et al 2021), 3 of whom had seizures. All had heterozygous missense variants of KCND2 in sites known to be critical for channel gating (E323K, P403A, two individuals, V404L, two individuals and V404M). Functional studies suggest that these missense changes cause both a partial loss-of-function (LOF) and gain-of-function (GOF). The V404 change appears to increase epileptic seizure susceptibility with the 3 patients with a V404 change showing this phenotype.

PMID:16934482 - Singh et al, 2006 - reports a patient with cognitive impairment who also went on to have seizures starting from age 13 with a 5 bp deletion in KCND2 leading to premature stop codon. The proband's asymptomatic father also shared this variant.

Also:
PMID:24501278 - Lee et al, 2014 - reports pair of monozygotic twin boys with infantile onset severe refractory epilepsy and autism. A de novo heterozygous missense variant was identified by WES - V404M.
Sources: Literature
Intellectual disability v3.1479 GNB5 Arina Puzriakova Phenotypes for gene: GNB5 were changed from Language delay and ADHD/cognitive impairment with or without cardiac arrhythmia, 617182; Intellectual developmental disorder with cardiac arrhythmia, 617173 to Intellectual developmental disorder with cardiac arrhythmia, OMIM:617173; Language delay and ADHD/cognitive impairment with or without cardiac arrhythmia, OMIM:617182
Intellectual disability v3.1478 NSRP1 Zornitza Stark gene: NSRP1 was added
gene: NSRP1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: NSRP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NSRP1 were set to 34385670
Phenotypes for gene: NSRP1 were set to Epilepsy; Cerebral palsy; microcephaly; Intellectual disability
Review for gene: NSRP1 was set to GREEN
gene: NSRP1 was marked as current diagnostic
Added comment: Novel gene regulating splicing. Biallelic LoF pathogenic variants reported in 6 individuals from 3 unrelated families associated with a phenotype characterized by developmental delay, epilepsy, microcephaly, and spastic cerebral palsy.
Sources: Literature
Intellectual disability v3.1478 SPRED2 Zornitza Stark gene: SPRED2 was added
gene: SPRED2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: SPRED2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SPRED2 were set to 34626534
Phenotypes for gene: SPRED2 were set to developmental delay; intellectual disability; cardiac defects; short stature; skeletal anomalies; a typical facial gestalt
Review for gene: SPRED2 was set to GREEN
gene: SPRED2 was marked as current diagnostic
Added comment: PMID: 34626534
Homozygosity for three different variants c.187C>T (p.Arg63∗), c.299T>C (p.Leu100Pro), and c.1142_1143delTT (p.Leu381Hisfs∗95) were identified in four subjects from three families. All variants severely affected protein stability, causing accelerated degradation, and variably perturbed SPRED2 functional behaviour. The clinical phenotype of the four affected individuals included developmental delay, intellectual disability, cardiac defects, short stature, skeletal anomalies, and a typical facial gestalt as major features, without the occurrence of the distinctive skin signs characterizing Legius syndrome.
Sources: Literature
Intellectual disability v3.1478 SPATA5L1 Zornitza Stark gene: SPATA5L1 was added
gene: SPATA5L1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: SPATA5L1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SPATA5L1 were set to 34626583
Phenotypes for gene: SPATA5L1 were set to Neurodevelopmental disorder with hearing loss and spasticity, MIM# 619616
Review for gene: SPATA5L1 was set to GREEN
gene: SPATA5L1 was marked as current diagnostic
Added comment: 47 individuals from 26 unrelated families from various ethnicities with biallelic variants reported. Phenotypes include ID, hearing impairment, movement disorder, abnormal MRI, hypotonia, visual impairment, epilepsy, and microcephaly.

~53% of patients had ID.
Sources: Literature
Intellectual disability v3.1478 OGDHL Zornitza Stark gene: OGDHL was added
gene: OGDHL was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: OGDHL was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: OGDHL were set to 34800363
Phenotypes for gene: OGDHL were set to Neurodevelopmental disorder featuring epilepsy, hearing loss and visual impairment
Review for gene: OGDHL was set to GREEN
Added comment: Nine individuals from eight unrelated families carrying bi-allelic variants in OGDHL with a range of neurological and neurodevelopmental phenotypes including epilepsy, hearing
loss, visual impairment, gait ataxia, microcephaly, and hypoplastic corpus callosum.

Homozygous and compound heterozygous variants reported. Variant types reported include missense, PTCs and a synonymous variant that was shown to affect splicing.

Functional studies with a CRISPR-Cas9-mediated tissue knockout with cDNA rescue system showed that the missense variants result in loss-of-function.
Sources: Literature
Intellectual disability v3.1478 FOXR1 Zornitza Stark gene: FOXR1 was added
gene: FOXR1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: FOXR1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FOXR1 were set to 34723967
Phenotypes for gene: FOXR1 were set to Postnatal microcephaly, progressive brain atrophy and global developmental delay
Review for gene: FOXR1 was set to AMBER
Added comment: 1 patient described with a de novo missense variant. Phenotypes include: postnatal microcephaly, progressive brain atrophy, skeletal abnormalities, brain abnormalities, ophthalmic abnormalities, neuromuscular abnormalities, and dysmorphic features. A variant in ATP1A3 was considered to have contributed to the final phenotype.

In vitro functional evidence is supportive of pathogenicity (variant causes protein instability and abnormal nuclear aggregation).

A mouse knockout has comparable phenotypes, and a severe survival deficit.

Rated amber (1 patient, functional evidence, mouse model).
Sources: Literature
Intellectual disability v3.1478 RNPC3 Ivone Leong changed review comment from: PMID:33650182 a third case reported with growth failure and ID. This is the second case where a patient with a variant in RNPC3 has ID. Therefore the Amber rating.; to: PMID:33650182 a third case reported with growth failure. This is the second case where a patient with a variant in RNPC3 has ID. Therefore the Amber rating.
Intellectual disability v3.1478 RNPC3 Ivone Leong changed review comment from: PMID:33650182 a third case reported with growth failure and ID.; to: PMID:33650182 a third case reported with growth failure and ID. This is the second case where a patient with a variant in RNPC3 has ID. Therefore the Amber rating.
Intellectual disability v3.1477 RNPC3 Ivone Leong Phenotypes for gene: RNPC3 were changed from isolated growth hormone deficiency; ?Growth hormone deficiency, isolated, type V, 618160; developmental delay/intellectual deficiency and delayed puberty to Pituitary hormone deficiency, combined or isolated, 7, OMIM:618160
Intellectual disability v3.1473 RNASEH2B Arina Puzriakova Phenotypes for gene: RNASEH2B were changed from Aicardi-Goutieres syndrome 2, 610181; AICARDI-GOUTIERES SYNDROME 2 to Aicardi-Goutieres syndrome 2, OMIM:610181
Intellectual disability v3.1472 RAB3GAP2 Arina Puzriakova Phenotypes for gene: RAB3GAP2 were changed from Martsolf syndrome, 212720Warburg micro syndrome 2, 614225; MARTSOLF SYNDROME (MARTS) to Martsolf syndrome 1, OMIM:212720; Warburg micro syndrome 2, OMIM:614225
Intellectual disability v3.1471 MAPK8IP3 Arina Puzriakova Phenotypes for gene: MAPK8IP3 were changed from Abnormal muscle tone; Global developmental delay; Intellectual disability; Abnormality of nervous system morphology; Neurodevelopmental disorder with or without variable brain abnormalities, 618443 to Neurodevelopmental disorder with or without variable brain abnormalities, OMIM:618443
Intellectual disability v3.1470 IFIH1 Arina Puzriakova Phenotypes for gene: IFIH1 were changed from AICARDI-GOUTIERES SYNDROME 7 to Aicardi-Goutieres syndrome 7, OMIM:615846
Intellectual disability v3.1468 GPT2 Arina Puzriakova Phenotypes for gene: GPT2 were changed from Microcephaly; Mental retardation, autosomal recessive 49, 138210; Intellectual disability; Progressive spasticity to Neurodevelopmental disorder with microcephaly and spastic paraplegia, OMIM:616281
Intellectual disability v3.1466 EXOSC3 Arina Puzriakova Phenotypes for gene: EXOSC3 were changed from PONTOCEREBELLAR HYPOPLASIA TYPE 1 to Pontocerebellar hypoplasia, type 1B, OMIM:614678
Intellectual disability v3.1465 ATP9A Sarah Leigh edited their review of gene: ATP9A: Added comment: Not associated with a phenotype in OMIM, Gen2Phen or MONDO. At least four variants reported in four unrelated families with a neurodevelopmental disorder (PMIDs: 34379057, 34764295). Model Atp9a−/− mice had neurobehavioural disabilities reminiscent to the behavioral patterns in the publications quoted here (PMID: 27626380).; Changed rating: GREEN; Changed publications to: 27626380
Intellectual disability v3.1463 AP5Z1 Arina Puzriakova Phenotypes for gene: AP5Z1 were changed from Spastic paraplegia 48, autosomal recessive 613647 to Spastic paraplegia 48, autosomal recessive, OMIM:613647
Intellectual disability v3.1461 KIDINS220 Arina Puzriakova Phenotypes for gene: KIDINS220 were changed from Spastic paraplegia, intellectual disability, nystagmus, and obesity, 617296 to Spastic paraplegia, intellectual disability, nystagmus, and obesity OMIM:617296
Intellectual disability v3.1459 CARS Arina Puzriakova Phenotypes for gene: CARS were changed from Brittle hair; Fragile nails; Microcephaly; Neurodevelopmental delay; Microcephaly, developmental delay, and brittle hair syndrome MIM#618891 to Microcephaly, developmental delay, and brittle hair syndrome, OMIM:618891
Intellectual disability v3.1458 GABRD Arina Puzriakova Added comment: Comment on list classification: There are sufficient unrelated cases to rate this gene as Green at the next GMS panel update. Although all patients presented epilepsy, it is not clear from the case reports whether cognitive impairment was secondary or independent of seizures. For this reason I think its worth including GABRD on this panel as it is plausible that DD may be evident prior to seizure onset (ranging from 4 months to 4 years in report)
Intellectual disability v3.1457 GABRD Arina Puzriakova gene: GABRD was added
gene: GABRD was added to Intellectual disability. Sources: Literature
Q4_21_rating tags were added to gene: GABRD.
Mode of inheritance for gene: GABRD was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: GABRD were set to 34633442
Phenotypes for gene: GABRD were set to {Epilepsy, idiopathic generalized, 10}, OMIM:613060; {Epilepsy, juvenile myoclonic, susceptibility to}, OMIM:613060
Mode of pathogenicity for gene: GABRD 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: GABRD was set to GREEN
Added comment: Ahring et al., 2021 (PMID: 34633442) reports on at least 3 unrelated individuals with de novo variants and one family with 3 affected individuals harbouring an inherited variant in the GABRD gene. All variants exerted a gain-of-function effect and all carriers displayed a homogenous phenotype of generalised epilepsy (median age of onset 10.5 months, medically refractory in 5/6) and various degrees of learning difficulties or ID (learning difficulties in 1, mild ID in 2, mild to moderate ID in 1, and severe to profound ID in 2).

NB. A further three individuals were excluded from phenotypic analysis as their variants (p.M87L and p.V442I) did not show any detectable functional changes. There was also another patient with a loss-of-function variant but they displayed ASD, normal intelligence and no seizure history.
Sources: Literature
Intellectual disability v3.1455 CLPB Arina Puzriakova Added comment: Comment on mode of inheritance: MOI should be updated from 'Biallelic' to 'Both mono- and biallelic' at the next GMS update.

Association between biallelic variants and disease is well established, with more than 35 affected individuals reported. Recently, Wortmann et al. 2021 (PMID: 34140661) published six unrelated individuals with one of four different de novo monoallelic missense variants in CLPB. The phenotype strongly overlapped with that observed in the recessive disease, including mild to severe DD/ID in all cases. Some functional studies of heterozygous variants were performed.
Intellectual disability v3.1454 AR Arina Puzriakova Phenotypes for gene: AR were changed from Spinal and bulbar muscular atrophy of Kennedy, OMIM:313200 to Androgen insensitivity, OMIM:300068; Androgen insensitivity, partial, with or without breast cancer, OMIM:312300; Hypospadias 1, X-linked, OMIM:300633; Spinal and bulbar muscular atrophy of Kennedy, OMIM:313200
Intellectual disability v3.1451 GLS Arina Puzriakova Phenotypes for gene: GLS were changed from Global developmental delay, progressive ataxia, and elevated glutamine, OMIM:618412; Global developmental delay, progressive ataxia, and elevated glutamine, MONDO:0032733; ?Infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development, OMIM:618339; Infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development, MONDO:0032685 to Global developmental delay, progressive ataxia, and elevated glutamine, OMIM:618412; Developmental and epileptic encephalopathy 71, OMIM:618328; ?Infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development, OMIM:618339
Intellectual disability v3.1449 NOP56 Arina Puzriakova Phenotypes for gene: NOP56 were changed from Spinocerebellar ataxia 36, 614153 to Spinocerebellar ataxia 36, OMIM:614153
Intellectual disability v3.1448 PPP2R2B Arina Puzriakova Mode of pathogenicity for gene: PPP2R2B was changed from to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Intellectual disability v3.1446 PPP2R2B Arina Puzriakova Phenotypes for gene: PPP2R2B were changed from Spinocerebellar ataxia 12, 604326 to Spinocerebellar ataxia 12, OMIM:604326
Intellectual disability v3.1445 PPP2R2B_CAG Arina Puzriakova Phenotypes for STR: PPP2R2B_CAG were changed from Spinocerebellar ataxia 12 604326 to Spinocerebellar ataxia 12, OMIM:604326
Intellectual disability v3.1443 TBP Arina Puzriakova Mode of pathogenicity for gene: TBP was changed from to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Intellectual disability v3.1442 TBP Arina Puzriakova Phenotypes for gene: TBP were changed from Spinocerebellar ataxia 17, 607136; {Parkinson disease, susceptibility to}, 168600 to Spinocerebellar ataxia 17, OMIM:607136
Intellectual disability v3.1440 HTT Arina Puzriakova Phenotypes for gene: HTT were changed from Lopes-Maciel-Rodan syndrome, 617435; LOMARS; Intellectual disability to Lopes-Maciel-Rodan syndrome, OMIM:617435; LOMARS
Intellectual disability v3.1438 FMR1 Arina Puzriakova Phenotypes for gene: FMR1 were changed from Fragile X syndrome, 300624Fragile X tremor/ataxia syndrome, 300623Premature ovarian failure 1, 311360; PREMATURE OVARIAN FAILURE SYNDROME TYPE 1 (POF1) to Fragile X syndrome, OMIM:300624; Fragile X tremor/ataxia syndrome, OMIM:300623
Intellectual disability v3.1437 ATXN1 Arina Puzriakova Phenotypes for gene: ATXN1 were changed from Spinocerebellar ataxia 1 164400 to Spinocerebellar ataxia 1, OMIM:164400
Intellectual disability v3.1435 ATXN1_CAG Arina Puzriakova Phenotypes for STR: ATXN1_CAG were changed from Spinocerebellar ataxia 1 164400 to Spinocerebellar ataxia 1, OMIM:164400
Intellectual disability v3.1434 JPH3 Arina Puzriakova Phenotypes for gene: JPH3 were changed from Intellectual disability; dystonia to Neurodevelopmental disorder, MONDO:0700092; Paroxysmal dystonia, MONDO:0016058
Intellectual disability v3.1428 FARSA Ivone Leong Tag Q4_21_rating tag was added to gene: FARSA.
Intellectual disability v3.1428 FARSA Ivone Leong Classified gene: FARSA as Amber List (moderate evidence)
Intellectual disability v3.1428 FARSA Ivone Leong Gene: farsa has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1427 CACNA1A Arina Puzriakova Phenotypes for gene: CACNA1A were changed from Epileptic encephalopathy, early infantile, 42 617106; Episodic ataxia, type 2 108500; Migraine, familial hemiplegic, 1 141500; Migraine, familial hemiplegic, 1, with progressive cerebellar ataxia 141500; Spinocerebellar ataxia 6 183086 to Developemental and epileptic encephalopathy 42, OMIM:617106
Intellectual disability v3.1425 C9orf72 Arina Puzriakova Mode of pathogenicity for gene: C9orf72 was changed from to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Intellectual disability v3.1422 ATXN7_CAG Arina Puzriakova Phenotypes for STR: ATXN7_CAG were changed from Spinocerebellar ataxia 7 164500 to Spinocerebellar ataxia 7, OMIM:164500
Intellectual disability v3.1421 ATXN7 Arina Puzriakova Phenotypes for gene: ATXN7 were changed from Spinocerebellar ataxia 7 164500 to Spinocerebellar ataxia 7, OMIM:164500
Intellectual disability v3.1418 ATXN3 Arina Puzriakova Mode of pathogenicity for gene: ATXN3 was changed from to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Intellectual disability v3.1415 ATXN2_CAG Arina Puzriakova Phenotypes for STR: ATXN2_CAG were changed from Spinocerebellar ataxia 2 183090 to Spinocerebellar ataxia 2, OMIM:183090; {Amyotrophic lateral sclerosis, susceptibility to, 13}, OMIM:183090; {Parkinson disease, late-onset, susceptibility to}, OMIM:168600
Intellectual disability v3.1414 ATXN2 Arina Puzriakova Mode of pathogenicity for gene: ATXN2 was changed from to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Intellectual disability v3.1412 ATXN2 Arina Puzriakova Phenotypes for gene: ATXN2 were changed from Spinocerebellar ataxia 2 183090; {Amyotrophic lateral sclerosis, susceptibility to, 13} 183090 to Spinocerebellar ataxia 2, OMIM:183090; {Amyotrophic lateral sclerosis, susceptibility to, 13}, OMIM:183090; {Parkinson disease, late-onset, susceptibility to}, OMIM:168600
Intellectual disability v3.1411 ATXN10_ATTCT Arina Puzriakova Phenotypes for STR: ATXN10_ATTCT were changed from Spinocerebellar ataxia 10 603516 to Spinocerebellar ataxia 10, OMIM:603516
Intellectual disability v3.1409 ATXN10 Arina Puzriakova Phenotypes for gene: ATXN10 were changed from Spinocerebellar ataxia 10 603516 to Spinocerebellar ataxia 10, OMIM:603516
Intellectual disability v3.1407 ATN1 Arina Puzriakova Phenotypes for gene: ATN1 were changed from Generalized hypotonia; Global developmental delay; Intellectual disability; Seizures; Feeding difficulties; Abnormality of the cardiovascular system; Cleft palate; Abnormality of the kidney to Congenital hypotonia, epilepsy, developmental delay, and digital anomalies, OMIM:618494
Intellectual disability v3.1405 NUP85 Eleanor Williams changed review comment from: PMID: 34170319 - Ravindran et al 2021 report two pedigrees with an MCPH-SCKS phenotype spectrum without SRNS. In the first family, a 9 yo female, with consanguineous parents, is reported to have a missense variant in NUP85 (c.932G > A; p.R311Q). Intrauterine growth restriction was noticed. At birth microcephaly was observed (OFC < 3rd centile, < −3.6 SD) as well as hypotrophy [weight −2.8 SD), length 45 cm (−2.7 SD), both <3rd centile], facial dysmorphism, syndactyly, long and thin fingers, and bilateral pes adductus. She has severe developmental delay with strongly delayed motor milestones and absent speech. Drug-resistant, genetic epilepsy with focal-onset seizures started in the first year of life. She had no clinical, laboratory or radiological findings indicative of kidney dysfunction

In the second family, compound heterozygous missense variants in NUP85 were detected
(c.1109A > G, c.1589 T > C;p.N370S, p.M530T ) in a fetus. MRI of the fetal brain at 24 + 2 GW indicated complete agenesis of the corpus callosum, abnormal sulcation in the left frontal lobe, nodularity of the frontal horn and trigone with focal puckering of the left lateral ventricle.

PMID: 30179222 - Braun et al 2018 - 2 individuals from the 1 of the families reported with steroid-resistant nephrotic syndrome were also reported to have intellectual disability but showed no structural brain defects. The degree of intellectual disability is not stated. They were found to have 2 compound heterozygous alleles (c.405+1G>A and c.1741G>C, p.Ala581Pro), which segregated from the maternal and the paternal side.
Sources: Literature; to: PMID: 34170319 - Ravindran et al 2021 report two pedigrees with an MCPH-SCKS phenotype spectrum without SRNS. In the first family, a 9 yo female, with consanguineous parents, is reported to have a missense variant in NUP85 (c.932G > A; p.R311Q). Intrauterine growth restriction was noticed. At birth microcephaly was observed (OFC < 3rd centile, < −3.6 SD) as well as hypotrophy [weight −2.8 SD), length 45 cm (−2.7 SD), both <3rd centile], facial dysmorphism, syndactyly, long and thin fingers, and bilateral pes adductus. She has severe developmental delay with strongly delayed motor milestones and absent speech. Drug-resistant, genetic epilepsy with focal-onset seizures started in the first year of life. She had no clinical, laboratory or radiological findings indicative of kidney dysfunction.

In the second family, compound heterozygous missense variants in NUP85 were detected
(c.1109A > G, c.1589 T > C;p.N370S, p.M530T ) in a fetus. MRI of the fetal brain at 24 + 2 GW indicated complete agenesis of the corpus callosum, abnormal sulcation in the left frontal lobe, nodularity of the frontal horn and trigone with focal puckering of the left lateral ventricle.

PMID: 30179222 - Braun et al 2018 - 2 individuals from 1 of the families reported with steroid-resistant nephrotic syndrome were also reported to have intellectual disability but showed no structural brain defects. The degree of intellectual disability is not stated. They were found to have 2 compound heterozygous alleles (c.405+1G>A and c.1741G>C, p.Ala581Pro) in NUP85.
Sources: Literature
Intellectual disability v3.1405 NUP85 Eleanor Williams gene: NUP85 was added
gene: NUP85 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: NUP85 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NUP85 were set to 34170319
Phenotypes for gene: NUP85 were set to Primary autosomal recessive microcephaly and Seckel syndrome spectrum disorders (MCPH-SCKS)
Review for gene: NUP85 was set to AMBER
Added comment: PMID: 34170319 - Ravindran et al 2021 report two pedigrees with an MCPH-SCKS phenotype spectrum without SRNS. In the first family, a 9 yo female, with consanguineous parents, is reported to have a missense variant in NUP85 (c.932G > A; p.R311Q). Intrauterine growth restriction was noticed. At birth microcephaly was observed (OFC < 3rd centile, < −3.6 SD) as well as hypotrophy [weight −2.8 SD), length 45 cm (−2.7 SD), both <3rd centile], facial dysmorphism, syndactyly, long and thin fingers, and bilateral pes adductus. She has severe developmental delay with strongly delayed motor milestones and absent speech. Drug-resistant, genetic epilepsy with focal-onset seizures started in the first year of life. She had no clinical, laboratory or radiological findings indicative of kidney dysfunction

In the second family, compound heterozygous missense variants in NUP85 were detected
(c.1109A > G, c.1589 T > C;p.N370S, p.M530T ) in a fetus. MRI of the fetal brain at 24 + 2 GW indicated complete agenesis of the corpus callosum, abnormal sulcation in the left frontal lobe, nodularity of the frontal horn and trigone with focal puckering of the left lateral ventricle.

PMID: 30179222 - Braun et al 2018 - 2 individuals from the 1 of the families reported with steroid-resistant nephrotic syndrome were also reported to have intellectual disability but showed no structural brain defects. The degree of intellectual disability is not stated. They were found to have 2 compound heterozygous alleles (c.405+1G>A and c.1741G>C, p.Ala581Pro), which segregated from the maternal and the paternal side.
Sources: Literature
Intellectual disability v3.1403 CLPB Ivone Leong Phenotypes for gene: CLPB were changed from 3-METHYLGLUTACONIC ACIDURIA, TYPE VII, WITH CATARACTS, NEUROLOGIC INVOLVEMENT AND NEUTROPENIA to 3-methylglutaconic aciduria, type VII, with cataracts, neurologic involvement and neutropenia, OMIM:616271
Intellectual disability v3.1402 LMNB2 Arina Puzriakova Phenotypes for gene: LMNB2 were changed from Congenital microcephaly; Global developmental delay; Intellectual disability to Microcephaly 27, primary, autosomal dominant, OMIM:619180
Intellectual disability v3.1401 LMNB1 Arina Puzriakova Phenotypes for gene: LMNB1 were changed from Global developmental delay; Intellectual disability; Microcephaly; Short stature; Seizures; Abnormality of the corpus callosum; Cortical gyral simplification; Feeding difficulties; Scoliosis; LMNB1-associated developmental disorder to Microcephaly 26, primary, autosomal dominant, OMIM:619179
Intellectual disability v3.1398 CDK8 Arina Puzriakova Phenotypes for gene: CDK8 were changed from Generalized hypotonia; Feeding difficulties; Global developmental delay; Intellectual disability; Behavioral abnormality; Abnormality of cardiovascular system morphology; Hearing impairment; Abnormality of vision; Anorectal anomaly; Seizures; Intellectual developmental disorder with hypotonia and behavioral abnormalities #618748 to Intellectual developmental disorder with hypotonia and behavioral abnormalities, OMIM:618748
Intellectual disability v3.1397 ERCC6 Ivone Leong Added comment: Comment on phenotypes: Previous phenotype entry:
Cockayne syndrome, type B, 133540Cerebrooculofacioskeletal syndrome 1, 214150De Sanctis-Cacchione syndrome, 278800{Macular degeneration, age-related, susceptibility to 5}, 613761UV-sensitive syndrome 1, 600630{Lung cancer, susceptibility to}, 211980;DE SANCTIS-CACCHIONE SYNDROME (DSC)
Intellectual disability v3.1397 ERCC6 Ivone Leong Phenotypes for gene: ERCC6 were changed from Cockayne syndrome, type B, 133540Cerebrooculofacioskeletal syndrome 1, 214150De Sanctis-Cacchione syndrome, 278800{Macular degeneration, age-related, susceptibility to 5}, 613761UV-sensitive syndrome 1, 600630{Lung cancer, susceptibility to}, 211980; DE SANCTIS-CACCHIONE SYNDROME (DSC) to De Sanctis-Cacchione syndrome, OMIM:278800
Intellectual disability v3.1396 RAP1GDS1 Dmitrijs Rots changed review comment from: Additional cases (three with same splice variant, which segregates in one family) and one frameshift variant reported in PMID: 33875846; to: Additional cases (three with same splice variant, which segregates in one family) and one frameshift variant reported in PMID: 33875846. Cases seem to overlap those reported in PMID: 32431071.
Intellectual disability v3.1396 PLK1 Dmitrijs Rots gene: PLK1 was added
gene: PLK1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: PLK1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PLK1 were set to PMID: 33875846
Phenotypes for gene: PLK1 were set to Epilepsy; microcephaly; intellectual disability
Review for gene: PLK1 was set to GREEN
Added comment: >5 cases with epileptic encephalopathy with homozygous variants in PMID: 33875846
Sources: Literature
Intellectual disability v3.1396 SNIP1 Sarah Leigh commented on gene: SNIP1: Q4_21_expert_review tag has been added to this gene. Helen Brittain (Genomics England Clinical Fellow) has suggested that the rating of this gene should be considered by TEWG oversight committee, to decide whether this gene could be green, as the disease association has only been associated with a the founder variant.
Intellectual disability v3.1395 DHDDS Arina Puzriakova Added comment: Comment on mode of inheritance: MOI should be updated from 'Both mono- and biallelic' to 'Monoallelic' at the next GMS panel update. Monoallelic variants are associated with a neurodevelopmental disorder comprising DD/ID, epilepsy and a variable movement disorder phenotype - >3 unrelated individuals reported in literature. To date, only one individual with biallelic variants and ID has been reported (PMID: 27343064). This patient presented with glycosylation defects but no corroborating cases have been reported since.
As only one patient has been described with biallelic inheritance and this phenotype, MOI should be set to 'Monoallelic' until evidence of additional cases emerges - biallelic variants would still be picked up by the Genomics England pipeline under this MOI.
Intellectual disability v3.1393 CRYBB3 Arina Puzriakova Phenotypes for gene: CRYBB3 were changed from Cataract 22, autosomal recessive, 609741 to Cataract 22, OMIM:609741
Intellectual disability v3.1386 COL6A3 Arina Puzriakova Phenotypes for gene: COL6A3 were changed from Gene2Phenotype confirmed gene with ID HPO to Bethlem myopathy, OMIM:158810; Ullrich congenital muscular dystrophy, OMIM:254090
Intellectual disability v3.1385 COL6A1 Arina Puzriakova Phenotypes for gene: COL6A1 were changed from Bethlem myopathy, 158810; Ullrich congenital muscular dystrophy, 254090 to Bethlem myopathy 1, OMIM:158810; Ullrich congenital muscular dystrophy 1, OMIM:254090
Intellectual disability v3.1381 CLPB Dmitrijs Rots reviewed gene: CLPB: Rating: ; 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: 34140661; Phenotypes: Neutropenia, intellectual disability; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.1381 CDH15 Arina Puzriakova Added comment: Comment on list classification: Gene should be demoted to Red as there is limited evidence supporting this gene-disease association. The only cases reported to date with SNVs were discovered by targeted sequencing of CDH15. Clinical information was limited, describing only mild ID in some cases. There are also multiple benign LOF variants in population databases. Asymptomatic carriers lead authors to suggest incomplete penetrance but all identified variants are in gnomAD so are unlikely to be causal.
Intellectual disability v3.1379 CDH15 Arina Puzriakova Phenotypes for gene: CDH15 were changed from Mental retardation, autosomal dominant 3, 612580; MENTAL RETARDATION AUTOSOMAL DOMINANT TYPE 3 (MRD3) to Mental retardation, autosomal dominant 3, OMIM:612580
Intellectual disability v3.1376 ARFGEF1 Ivone Leong Phenotypes for gene: ARFGEF1 were changed from Intellectual disability; Epilepsy to Intellectual disability, MONDO:0001071; Epilepsy, MONDO:0005027
Intellectual disability v3.1375 ARFGEF1 Ivone Leong Classified gene: ARFGEF1 as Amber List (moderate evidence)
Intellectual disability v3.1375 ARFGEF1 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in Gene2Phenotype (probable) but not in OMIM. There are >3 unrelated cases. ID in patients ranged from mild to moderate, which does not satisfy the criteria for this panel (moderate to severe); however, as this is one of the presenting features this gene has will be recommended to be Green at the next review.
Intellectual disability v3.1375 ARFGEF1 Ivone Leong Gene: arfgef1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1374 ARFGEF1 Ivone Leong Tag Q4_21_rating tag was added to gene: ARFGEF1.
Intellectual disability v3.1373 PRDM12 Sarah Leigh Phenotypes for gene: PRDM12 were changed from NA to Neuropathy, hereditary sensory and autonomic, type VIII OMIM:616488; congenital insensitivity to pain-hypohidrosis syndrome MONDO:0014662
Intellectual disability v3.1371 ZC4H2 Ivone Leong Phenotypes for gene: ZC4H2 were changed from ARTHROGRYPOSIS MULTIPLEX CONGENITA AND INTELLECTUAL DISABILITY to Wieacker-Wolff syndrome, OMIM:314580; Wieacker-Wolff syndrome, female-restricted, OMIM:301041
Intellectual disability v3.1369 AP1S2 Arina Puzriakova Added comment: Comment on mode of inheritance: Review of literature did not reveal any confirmed affected females. Female carriers of AP1S2 variants are phenotypically normal and have mostly shown random X-inactivation. Huo et al., 2019 (PMID: 30714330) state that they identified a female patient (I-1) but this individual was not available for genetic testing and so it is unclear whether they harboured a variant on a one or both alleles.

As no confirmed female cases have been reported and the allelic requirement remains elusive, the MOI should be set to the default XL (i.e. monoallelic in females may cause disease) as this will ensure that both mono and biallelic variants are picked up in females by the pipeline.
Intellectual disability v3.1368 AP1S2 Arina Puzriakova Phenotypes for gene: AP1S2 were changed from Mental retardation, X-linked syndromic, Fried type, 300630; MENTAL RETARDATION X-LINKED TYPE 59 (MRX59) to Pettigrew syndrome, OMIM:304340
Intellectual disability v3.1367 BLOC1S1 Dmitrijs Rots gene: BLOC1S1 was added
gene: BLOC1S1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: BLOC1S1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BLOC1S1 were set to PMID: 33875846
Phenotypes for gene: BLOC1S1 were set to severe intellectual disability; severe global developmental delay; epilepsy
Penetrance for gene: BLOC1S1 were set to unknown
Review for gene: BLOC1S1 was set to GREEN
Added comment: 4 cases with similar phenotype and inheritance reported
Sources: Literature
Intellectual disability v3.1367 CLCN2 Arina Puzriakova Added comment: Comment on mode of inheritance: MOI has been changed from 'Both mono- and biallelic' to 'Biallelic' only. Mild cognitive impairment has been reported in some patients with CLCN2-related Leukoencephalopathy (MIM# 615651) which is caused by biallelic variants. Autosomal dominant pathogenic variants are also associated with hyperaldosteronism (MIM# 605635) and susceptibility to idiopathic epilepsy (MIM# 607628) but neither of these phenotypes include ID. There is also controversy regarding any link between CLCN2 and epilepsy.
Intellectual disability v3.1364 ZDHHC15 Ivone Leong Added comment: Comment on phenotypes: Previously associated with ?Mental retardation, X-linked 91, OMIM:300577; however, OMIM has removed this
Intellectual disability v3.1364 ZDHHC15 Ivone Leong Phenotypes for gene: ZDHHC15 were changed from ?Mental retardation, X-linked 91, 300577 to cerebral palsy; intellectual disability; autism spectrum disorder; epilepsy
Intellectual disability v3.1362 RAD51 Arina Puzriakova Added comment: Comment on list classification: Intellectual disability has been reported in 2/3 individuals with RAD51-associated FA (third patient with mild early DD). However, a syndromic presentation prior to this is expected. Potential for VUSs in pure ID cohort, although there is an allied chromosome breakage test. Upgrading from Red to Amber - which also reflects the rating of other FA genes associated with ID.
Intellectual disability v3.1359 ABHD16A Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not associated with a phenotype in OMIM or Gene2Phenotype. There are >3 unrelated cases, therefore there is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Intellectual disability v3.1356 SARS Ivone Leong Classified gene: SARS as Amber List (moderate evidence)
Intellectual disability v3.1356 SARS Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in OMIM and Gene2Phenotype. As there are only 2 cases there is not enough evidence to support a gene-disease association. This gene has been given an Amber rating.
Intellectual disability v3.1356 SARS Ivone Leong Gene: sars has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1355 SARS Ivone Leong Tag watchlist tag was added to gene: SARS.
Intellectual disability v3.1355 SARS Ivone Leong commented on gene: SARS
Intellectual disability v3.1355 SARS Ivone Leong Tag new-gene-name tag was added to gene: SARS.
Intellectual disability v3.1355 SARS Ivone Leong Phenotypes for gene: SARS were changed from Intellectual disability to ?Neurodevelopmental disorder with microcephaly, ataxia, and seizures, OMIM:617709
Intellectual disability v3.1354 ATP6V0C Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not associated with a phenotype in OMIM or Gene2Phenotype. There is currently not enough evidence to support a gene-disease association. This gene has been given an Amber rating.
Intellectual disability v3.1353 ATP11A Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not associated with a phenotype in OMIM or Gene2Phenotype. There is currently only 1 case and a mouse model which showed neurological deficit phenotypes (including tremors, abnormal gait, hind limb clasping and reduction in brain size. The patient was a 26 yo male born to healthy non-consanguineous Japanese parents. At birth his length was -3.3. SD and OFC was -1.3 SD. Developed epilepsy at 2 weeks followed by global developmental delay and mild hypothyroidism and cataracts.He suffered gradual lost of developmental milestones. At 18 yo, height was -4.6 SD and OFC was -4.0 SD.

As there is currently not enough evidence to support a gene-disease association, this gene has been given an Amber rating.
Intellectual disability v3.1352 SNIP1 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as possible Gen2Phen gene. A single (founder) variant NM_024700.4:c.1097A>G, p.(Glu366Gly) has been reported in over 30 cases of Psychomotor retardation, epilepsy, and craniofacial dysmorphism OMIM:614501 in the Amish community (PMIDs: 22279524; 34570759). Cases are homozygous for this variant and unaffected members of the families are heterozygous or wt. Overexpression of the equivalent mouse variant in mouse inner medullary collecting duct cells, resulted in a more aggregated appearance in the nucleus compared to wildtype. The variant protein maybe unstable as Western blots showed reduced levels of the variant protein (PMID: 22279524). Whole transcriptomic analysis of patient blood was performed in PMID: 34570759. This revealed 11 upregulated and 32 downregulated genes, of which 24 had previously been associated with neurological disease.
Intellectual disability v3.1350 SNIP1 Sarah Leigh Phenotypes for gene: SNIP1 were changed from Psychomotor retardation, epilepsy, and craniofacial dysmorphism, 614501; severe developmental delay to Psychomotor retardation, epilepsy, and craniofacial dysmorphism OMIM:614501; psychomotor retardation, epilepsy, and craniofacial dysmorphism MONDO:0013787
Intellectual disability v3.1345 WDR11 Ivone Leong Added comment: Comment on mode of inheritance: Changed MOI from "MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown" to "BIALLELIC, autosomal or pseudoautosomal" as biallelic variants in this gene is associated with ID.
Intellectual disability v3.1342 GRIK2 Ivone Leong Phenotypes for gene: GRIK2 were changed from Mental retardation, autosomal recessive, 6, OMIM:611092; on-syndromic neurodevelopmental disorder (NDD), autosomal dominant to Mental retardation, autosomal recessive, 6, OMIM:611092; non-syndromic neurodevelopmental disorder (NDD), autosomal dominant
Intellectual disability v3.1340 GRIK2 Ivone Leong Phenotypes for gene: GRIK2 were changed from Mental retardation, autosomal recessive, 6, 611092; MENTAL RETARDATION AUTOSOMAL RECESSIVE TYPE 6 (MRT6) to Mental retardation, autosomal recessive, 6, OMIM:611092; on-syndromic neurodevelopmental disorder (NDD), autosomal dominant
Intellectual disability v3.1339 CACNA1I Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not associated with a phenotype in OMIM or Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Intellectual disability v3.1338 PLXNA1 Zornitza Stark gene: PLXNA1 was added
gene: PLXNA1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: PLXNA1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: PLXNA1 were set to 34054129
Phenotypes for gene: PLXNA1 were set to Neurodevelopmental disorder with cerebral and eye anomalies
Review for gene: PLXNA1 was set to GREEN
Added comment: Dworschak et al. (2021) via WES reported 10 patients from 7 families with biallelic (n=7) or de novo (n=3) PLXNA1 variants. Shared phenotypic features include global developmental delay (9/10), brain anomalies (6/10), and eye anomalies (7/10). Seizures were predominantly reported in patients with monoallelic variants. Zebrafish studies showed an embryonic role of plxna1a in the development of the central nervous system and the eye. Biallelic variants in the extracellular Plexin-A1 domains lead to impaired dimerization or lack of receptor molecules, whereas monoallelic variants in the intracellular Plexin-A1 domains might impair downstream signaling through a dominant-negative effect.
Sources: Literature
Intellectual disability v3.1338 CHRM1 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not associated with a phenotype in OMIM or Gene2Phenotype. As there is currently not enough evidence to support a gene-disease association this gene has been given an Amber rating.
Intellectual disability v3.1338 CHRM1 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not associated with a phenotype in OMIM or Gene2Phenotype. As there is currently not enough evidence to support a gene-disease association this gene has been given an Amber rating.
Intellectual disability v3.1336 SARS Zornitza Stark gene: SARS was added
gene: SARS was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: SARS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SARS were set to 28236339; 34570399
Phenotypes for gene: SARS were set to Intellectual disability
Review for gene: SARS was set to AMBER
Added comment: Summary - 2 unrelated families with overlapping ID phenotype, and supporting in vitro and patient cell assays.

PMID: 28236339 - an Iranian family (distantly related) segregating a homozygous missense (c.514G>A, p.Asp172Asn) with moderate ID, microcephaly, ataxia, speech impairment, and aggressive behaviour. Also, supporting in vitro functional assays demonstrating altered protein function.
PMID: 34570399 - a consanguineous Turkish family segregating a homozygous missense (c.638G>T, p.(Arg213Leu)) with developmental delay, central deafness, cardiomyopathy, and metabolic decompensation during fever leading to death. Also, reduced protein level and enzymatic activity in patient cells.
Sources: Literature
Intellectual disability v3.1336 ZNF699 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in OMIM but not Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Intellectual disability v3.1335 ZDHHC15 Zornitza Stark reviewed gene: ZDHHC15: Rating: RED; Mode of pathogenicity: None; Publications: 34345675; Phenotypes: Mental retardation, X-linked 91, 300577, cerebral palsy, intellectual disability, autism spectrum disorder, epilepsy; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability v3.1335 ATP11A Zornitza Stark gene: ATP11A was added
gene: ATP11A was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: ATP11A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ATP11A were set to 34403372
Phenotypes for gene: ATP11A were set to Neurodevelopmental disorder
Review for gene: ATP11A was set to AMBER
Added comment: PMID: 34403372:
- Single de novo missense variant reported in a patient with developmental delay and neurological deterioration.
- Patient MRI showed severe cerebral atrophy, ventriculomegaly, hypomyelination leukodystrophy, thinned corpus callosum. Axonal neuropathy suggested.
- K/I heterozygous mice died perinatally.
- Functional studies on missense variant show plasma membrane lipid content impairment, reduced ATPase activity etc.

gnomAD: some NMD PTCs present, good quality variants found with 4-5 hets.
Sources: Literature
Intellectual disability v3.1334 ABHD16A Zornitza Stark gene: ABHD16A was added
gene: ABHD16A was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: ABHD16A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ABHD16A were set to 34587489
Phenotypes for gene: ABHD16A were set to Spastic paraplegia; Intellectual disability
Review for gene: ABHD16A was set to GREEN
gene: ABHD16A was marked as current diagnostic
Added comment: 11 individuals from 6 families with a complicated form of hereditary spastic paraplegia who carry bi-allelic deleterious variants in ABHD16A. Affected individuals present with a similar phenotype consisting of global developmental delay/intellectual disability, progressive spasticity affecting the upper and lower limbs, and corpus callosum and white matter anomalies. Immunoblot analysis on extracts from fibroblasts from four affected individuals demonstrated little to no ABHD16A protein levels compared to controls.
In 5 of the families the affected members were homozygous, 3 of these families were consanguineous. 2 families have the same variant- both families are French-Canadian.
4 missense variants, 1 frameshift, 1 nonsense.
Sources: Literature
Intellectual disability v3.1334 JAKMIP1 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not associated with a phenotype in OMIM or Gene2Phenotype. Currently there are only 2 cases; however, there is very little information about the two cases in the papers. Therefore, this gene has been given an Amber rating until more evidence is available.
Intellectual disability v3.1332 ARFGEF1 Zornitza Stark gene: ARFGEF1 was added
gene: ARFGEF1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: ARFGEF1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ARFGEF1 were set to 34113008
Phenotypes for gene: ARFGEF1 were set to Intellectual disability; Epilepsy
Review for gene: ARFGEF1 was set to GREEN
Added comment: 13 individuals reported with variants in this gene and a neurodevelopmental disorder characterised by variable ID, seizures present in around half. Variants were inherited from mildly affected parents in 40% of families.
Sources: Literature
Intellectual disability v3.1332 KIF4A Zornitza Stark reviewed gene: KIF4A: Rating: GREEN; Mode of pathogenicity: None; Publications: 24812067, 34346154; Phenotypes: Mental retardation, X-linked 100, MIM# 300923; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability v3.1332 TAF2 Zornitza Stark reviewed gene: TAF2: Rating: GREEN; Mode of pathogenicity: None; Publications: 34474177, 21937992, 22633631, 26350204; Phenotypes: Mental retardation, autosomal recessive 40, OMIM # 615599; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1332 DDX23 Zornitza Stark edited their review of gene: DDX23: Added comment: PMID 34050707: 9 unrelated individuals (gathered through GeneMatcher) with de novo missense alterations in DDX23. Clinical features include: tone abnormalities, global developmental delay, facial dysmorphism, autism spectrum disorder, and seizures. Additionally, there were a variety of other findings in the skeletal, renal, ocular, and cardiac systems. The missense alterations all occurred within a highly conserved RecA-like domain of the protein, and are located within or proximal to the DEAD box sequence. The gene is ubiquitously expressed and functions in RNA splicing, maintenance of genome stability, and the sensing of double-stranded RNA.; Changed rating: GREEN; Changed publications to: 33057194, 34050707
Intellectual disability v3.1332 HMGB1 Zornitza Stark gene: HMGB1 was added
gene: HMGB1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: HMGB1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: HMGB1 were set to 34164801
Phenotypes for gene: HMGB1 were set to Developmental delay and microcephaly
Review for gene: HMGB1 was set to GREEN
gene: HMGB1 was marked as current diagnostic
Added comment: 13q12.3 microdeletion syndrome is a rare cause of syndromic ID. Previous studies identified four genes within the ~300 Kb minimal critical region including two candidate protein coding genes: KATNAL1 and HMGB1.

Uguen et al. (2021) report 6 patients with LOF variants involving HMGB1 with features similar to 13q12.3 microdeletion syndrome (i.e. developmental delay, language delay, microcephaly, obesity and dysmorphic features). In silico analyses suggest that HMGB1 is likely to be intolerant to LOF, and previous in vitro data are in line with the role of HMGB1 in neurodevelopment. They suggest that haploinsufficiency of the HMGB1 gene may play a critical role in the pathogenesis of the 13q12.3 microdeletion syndrome.
Sources: Literature
Intellectual disability v3.1332 WIPI2 Zornitza Stark edited their review of gene: WIPI2: Added comment: PMID: 34557665 (2021)
- two novel homozygous variants were identified in four individuals of two consanguineous families.
- one family presented with microcephaly, profound global developmental delay/intellectual disability, refractory infantile/childhood-onset epilepsy, progressive tetraplegia with joint contractures and dyskinesia.
- second family (similar to initial publication) presented with a milder phenotype, encompassing moderate intellectual disability, speech and visual impairment, autistic features, and an ataxic gait.
- functional studies showed dysregulation of the early steps of the autophagy pathway.; Changed rating: GREEN; Changed publications to: 30968111, 34557665; Set current diagnostic: yes
Intellectual disability v3.1332 ZNF668 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). There is currently no phenotypes associated with this gene in OMIM or Gene2Phenotype. As there are only 2 cases there is currently not enough evidence to support a gene-disease association. Therefore, this gene has been given an Amber rating.
Intellectual disability v3.1331 UBE2U Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not associated with a disease in Gene2Phenotype (there is currently no entry for this gene in OMIM). As there is currently only 1 case this gene has been given a Red rating.
Intellectual disability v3.1330 UBE2U Ivone Leong Phenotypes for gene: UBE2U were changed from Retinoschisis; cataracts; learning disabilities; developmental delay to Retinoschisis, MONDO:0004579; cataracts; learning disability, MONDO:0004681; developmental delay
Intellectual disability v3.1329 RNF220 Ivone Leong Phenotypes for gene: RNF220 were changed from Leukodystrophy; CNS hypomyelination; Ataxia; Intellectual disability; Sensorineural hearing impairment; Elevated hepatic transaminases; Hepatic fibrosis; Dilated cardiomyopathy; Spastic paraplegia; Dysarthria; Abnormality of the corpus callosum to Intellectual disability, MONDO:0001071
Intellectual disability v3.1328 RNF220 Ivone Leong Added comment: Comment on list classification: New gene added by Konstantinos Varvagiannis. This gene is currently not associated with a phenotype in OMIM or Gene2Phenotype. There are >3 cases for this gene; however, 3 of the cases described in PMID:33964137 are of Roma descent and haplotype analysis has shown that the variant found in these families are due to a founder effect (c.1094G>A, p.Arg365Gly). A separate Roma family also has the same variant (c.1094G>A, p.Arg365Gly). An Italian family with similar phenotypes has a different variant (c.1088G>A, p.Arg363Gly). The authors also report on in vitro and in vivo studies.

There is enough evidence to support a gene-disease association; however, the ID severity in these patients do not meet the criteria (moderate to severe) for this panel (patients show mild (mostly) to moderate severity). Therefore, this gene has been given an Amber rating.
Intellectual disability v3.1325 PLXNA2 Ivone Leong Added comment: Comment on list classification: New gene added by Konstantinos Varvagiannis (Other). This gene is not associated with a phenotype in OMIM or Gene2Phenotype. As there are currently only 2 cases there is not enough evidence to support a gene-disease association. Therefore, this gene has been given an Amber rating.
Intellectual disability v3.1324 PLXNA2 Ivone Leong Phenotypes for gene: PLXNA2 were changed from Intellectual disability; Abnormality of the face; Failure to thrive; Abnormal heart morphology to Intellectual disability, MONDO:0001071; Abnormality of the face; Failure to thrive; Abnormal heart morphology
Intellectual disability v3.1322 VPS50 Ivone Leong changed review comment from: Comment on list classification: New gene added by Konstantinos Varvagiannis (Other). This gene is not associated with a phenotype in OMIM or Gene2Phenotype.

PMID: 34037727. Both patients have severe microcephaly (-7.65 to -10.35 z-score), height at 2 years (-2.65 to -3.84 z-score), seizures, hypoplastic coprus callosum, neonatal cholestasis and feeding difficulties.

Based on the available evidence there is currently not enough evidence to support a gene-disease association. This gene has been given an Amber rating.; to: Comment on list classification: New gene added by Konstantinos Varvagiannis (Other). This gene is not associated with a phenotype in OMIM or Gene2Phenotype.

PMID: 34037727. Both patients have severe microcephaly (-7.65 to -10.35 z-score), height at 2 years (-2.65 to -3.84 z-score), seizures, hypoplastic corpus callosum, neonatal cholestasis and feeding difficulties.

Based on the available evidence there is currently not enough evidence to support a gene-disease association. This gene has been given an Amber rating.
Intellectual disability v3.1322 VPS50 Ivone Leong Added comment: Comment on list classification: New gene added by Konstantinos Varvagiannis (Other). This gene is not associated with a phenotype in OMIM or Gene2Phenotype.

PMID: 34037727. Both patients have severe microcephaly (-7.65 to -10.35 z-score), height at 2 years (-2.65 to -3.84 z-score), seizures, hypoplastic coprus callosum, neonatal cholestasis and feeding difficulties.

Based on the available evidence there is currently not enough evidence to support a gene-disease association. This gene has been given an Amber rating.
Intellectual disability v3.1321 ARF3 Ivone Leong Tag watchlist tag was added to gene: ARF3.
Intellectual disability v3.1321 ARF3 Ivone Leong Classified gene: ARF3 as Amber List (moderate evidence)
Intellectual disability v3.1321 ARF3 Ivone Leong Added comment: Comment on list classification: New gene added by Konstantinos Varvagiannis (Other). This gene is not associated with a phenotype in OMIM or Gene2Phenotype.

PMID:34346499, individual 1 also has severe microcephaly (-3.3SD), spasticity, cerebellum atrophy and brainstem atrophy. Individual 2 does not have microcephaly, but has cerebellar hypoplasia.

Based on the available evidence, there is currently not enough evidence to support a gene-disease association, therefore this gene has been given an Amber rating.
Intellectual disability v3.1321 ARF3 Ivone Leong Gene: arf3 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1320 ARF3 Ivone Leong Phenotypes for gene: ARF3 were changed from Global developmental delay; Intellectual disability; Seizures; Morphological abnormality of the central nervous system to Global developmental delay; Intellectual disability, MONDO:0001071; Seizures; Morphological abnormality of the central nervous system; microcephaly, MONDO:0001149
Intellectual disability v3.1318 GTF2E2 Arina Puzriakova changed review comment from: Comment on list classification: Two distinct homozygous variants identified in 5 individuals from 4 families who all presented with DD/ID. Despite indication that one of these represents a founder variants, discovery of a distinct homozygous variant in a patient with an overlapping phenotype corroborates pertinence of GTF2E2. Furthermore, there are some supportive functional studies.

Overall this is sufficient evidence to promote this gene to Green at the next GMS panel update.; to: Comment on list classification: Two distinct homozygous variants identified in 5 individuals from 4 families who all presented with DD/ID among other features. Despite indication that one of these represents a founder variant, discovery of a distinct homozygous variant in a patient with an overlapping phenotype corroborates pertinence of GTF2E2. Furthermore, there are some supportive in vitro studies that demonstrate functional impairment.

Overall this is sufficient evidence to promote this gene to Green at the next GMS panel update.
Intellectual disability v3.1318 GTF2E2 Arina Puzriakova Added comment: Comment on list classification: Two distinct homozygous variants identified in 5 individuals from 4 families who all presented with DD/ID. Despite indication that one of these represents a founder variants, discovery of a distinct homozygous variant in a patient with an overlapping phenotype corroborates pertinence of GTF2E2. Furthermore, there are some supportive functional studies.

Overall this is sufficient evidence to promote this gene to Green at the next GMS panel update.
Intellectual disability v3.1315 MED12 Eleanor Williams changed review comment from: Comment on mode of inheritance: Leaving the mode of inheritance as XL hemizigous in males, biallelic in females for now, but there are several (10+ female cases reported now with de novo variants in MED12 and an intellectual disability phenotype) so consideration should be given to changing the mode of inheritance to monoallelic in females.; to: Comment on mode of inheritance: Leaving the mode of inheritance as XL hemizigous in males, biallelic in females for now, but there are several (10+) female cases reported now with de novo variants in MED12 and an intellectual disability phenotype so consideration should be given to changing the mode of inheritance to monoallelic in females.
Intellectual disability v3.1315 MED12 Eleanor Williams Added comment: Comment on mode of inheritance: Leaving the mode of inheritance as XL hemizigous in males, biallelic in females for now, but there are several (10+ female cases reported now with de novo variants in MED12 and an intellectual disability phenotype) so consideration should be given to changing the mode of inheritance to monoallelic in females.
Intellectual disability v3.1313 CDH15 Zornitza Stark reviewed gene: CDH15: Rating: RED; Mode of pathogenicity: None; Publications: 19012874, 12052883, 28422132, 26506440; Phenotypes: Mental retardation, autosomal dominant 3, MIM#612580; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.1311 EIF2AK2 Arina Puzriakova edited their review of gene: EIF2AK2: Added comment: A further 5 families reported (PMID: 33236446) harbouring 3 different variants in this gene (including the first homozygous case). Clinical presentation was prominent in all cases for dystonia with onset in infancy or childhood, with subsequent generalisation. 3 unrelated individuals additionally developed mild ID, spasticity, and brain MRI alterations; while 6 individuals from the remaining 2 families had only isolated dystonia.; Changed publications to: 32197074, 33236446
Intellectual disability v3.1309 CPE Arina Puzriakova Added comment: Comment on list classification: There are now sufficient unrelated families (5) reported in literature presenting a relevant phenotype associated with variants in this gene to rate as Green at the next GMS panel update.
Intellectual disability v3.1308 CPE Arina Puzriakova edited their review of gene: CPE: Added comment: Bosch et al. 2021 (PMID: 34383079) reported on 4 individuals from 3 additional families harbouring 2 different homozygous truncating variants in this gene. Clinical presentation was prominent for obesity and intellectual disability. Hypogonadotropic hypogonadism was confirmed in one individual and was suspected but not tested for in another two subjects.; Changed rating: GREEN; Changed publications to: 26120850, 32936766, 34383079; Changed phenotypes to: Intellectual developmental disorder and hypogonadotropic hypogonadism, OMIM:619326; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1306 PITRM1 Ivone Leong Phenotypes for gene: PITRM1 were changed from Ataxia; Intellectual disability to Spinocerebellar ataxia, autosomal recessive 30, OMIM:619405
Intellectual disability v3.1305 TNPO2 Arina Puzriakova Added comment: Comment on list classification: Upgraded from Red to Amber but there are now sufficient unrelated cases with a relevant phenotype associated with various variants in this gene to rate as Green at the next GMS panel update.
Intellectual disability v3.1301 LINGO4 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. There a sufficient unrelated cases with a relevant phenotype to rate as Green at the next GMS panel update.
-----
PMID: 33098801 - 4 individuals from 3 unrelated families harbouring private biallelic variants in this gene which co-segregated with disease. 4/4 cases presented with GDD and ID.
Intellectual disability v3.1300 IMPDH2 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. This gene is not yet associated with a relevant phenotype in OMIM or G2P, but sufficient unrelated cases with relevant phenotype to rate Green at the next GMS review. Neurodevelopmental delay is an early feature that may be evident prior to other manifestations (plausible that other cases may develop dystonic signs later in life) and so inclusion on this panel is warranted.
Intellectual disability v3.1299 CLCN3 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. There is enough evidence to promote this gene to Green at the next GMS panel update. Sufficient number of unrelated cases with relevant phenotype to add to the ID and epilepsy panels. Functional studies and animal model support pathogenicity. CLCN3 is also associated with a relevant phenotype in OMIM (MIM# 619512 and 619517)
Intellectual disability v3.1296 ANK2 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. There is sufficient evidence to promote this gene to Green at the next GMS panel review - sufficient unrelated cases with relevant phenotype and de novo PTVs in this gene. Definitive gene-disease association is supported by the ClinGen ID and Autism Expert Panel.
Intellectual disability v3.1295 TP73 Arina Puzriakova Added comment: Comment on list classification: There is now sufficient evidence to promote this gene to Green at the next GMS panel review - at least 7 unrelated families with distinct variants and relevant phenotypes. Supported by some functional data.

TP73 is also now associated with a relevant phenotype in OMIM (MIM# 619466) but is not yet listed in G2P.
Intellectual disability v3.1294 TP73 Arina Puzriakova edited their review of gene: TP73: Changed rating: GREEN; Changed publications to: 31130284, 34077761; Changed phenotypes to: Ciliary dyskinesia, primary, 47, and lissencephaly, OMIM:619466
Intellectual disability v3.1294 TP73 Arina Puzriakova commented on gene: TP73: PMID: 34077761 (2021) - Further 7 individuals from 5 families identified with different homozygous variants in this gene. All affected individuals exhibited cortical malformations characterised by lissencephaly, central muscular hypotonia and moderate to severe cognitive dysfunction.
Intellectual disability v3.1294 TP73 Arina Puzriakova Phenotypes for gene: TP73 were changed from Intellectual disability; lissencephaly to Ciliary dyskinesia, primary, 47, and lissencephaly, OMIM:619466
Intellectual disability v3.1292 AP1G1 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. Usmani et al., 2021 (PMID: 34102099) identified 9 families with heterozygous and 2 families with homozygous variants in this gene. All individuals (12) had GDD and ID of various severity (mild to severe), except one patient who died at 22 days. Other features include hypotonia (9/10), seizures (6/10) and spasticity (4/10). Some supportive functional data included.

There is sufficient evidence to promote this gene to Green at the next GMS panel update, with 'monoallelic' MOI. Biallelic cases would still be picked up by the Genomics England pipeline - but this may be reviewed if additional cases are discovered.
Intellectual disability v3.1289 CAMK4 Arina Puzriakova Added comment: Comment on list classification: New gene added by Konstantinos Varvagiannis. There are sufficient unrelated cases (3) presenting with a relevant phenotype in association with different variants in the CAMK4 gene.
Intellectual disability v3.1288 CAMK4 Arina Puzriakova Mode of pathogenicity for gene: CAMK4 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
Intellectual disability v3.1285 SYNCRIP Arina Puzriakova Added comment: Comment on list classification: Upgraded from Red to Amber but there are sufficient unrelated cases to rate as Green at the next GMS review. All individuals reported to date have presented with ID of various severity as the predominant feature.
Intellectual disability v3.1282 ATP1A3 Arina Puzriakova commented on gene: ATP1A3: Gene was reassessed following a further Green review by Zornitza Stark (8 Jul 2021). Vetro et al. (PMID: 33880529) identified several individuals with variants in this gene who presented with DD/ID as the predominant feature. Therefore, ATP1A3 will be flagged for GMS expert review as inclusion on this panel may be of value in some patients but previous comments regarding association with several phenotypes should be considered.
Intellectual disability v3.1280 RFX7 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). 14 unrelated individuals were identified with different variants in the RFX7 gene (13 de novo, 1 unknown). Presenting phenotypes were predominantly of ID/GDD (13/14) and dysmorphism (12/14).

There are sufficient unrelated cases with a relevant phenotype associated with variants in this gene to rate as Green at the next GMS panel update.
Intellectual disability v3.1279 RFX4 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). 6 individuals from 4 unrelated families were identified with different variants in the RFX4 gene (3 de novo, 1 inherited). Presenting phenotypes include ID/GDD (6/6) and ASD (5/6).

There are sufficient unrelated cases with a relevant phenotype associated with variants in this gene to rate as Green at the next GMS panel update.
Intellectual disability v3.1278 RFX3 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). 18 individuals from 15 unrelated families were identified with different heterozygous variants in the RFX3 gene (14 de novo, 1 inherited). Presenting phenotypes include ID/GDD (14/18), ASD (13/18) and ADHD (10/18).

There are sufficient unrelated cases with a relevant phenotype associated with variants in this gene to rate as Green at the next GMS panel update.
Intellectual disability v3.1277 EIF2AK2 Dmitrijs Rots reviewed gene: EIF2AK2: 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: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.1276 COPB2 Eleanor Williams changed review comment from: PMID: 34450031 - Marom et al 2021 describes 6 individuals from 5 families. In 4 families loss of function heterozygous variants in COPB2 were found. In the 5th family, two affected siblings were found to have a homozygous variant in COPB2. Osteopenia was noted in 4/5 families (5th unknown) and fractures in 2/5. Developmental delay was observed in all 6 individuals with variable severity. Severe intellectual disability, seizures and microcephaly was noted in the siblings with the homozygous variants. Copb2þ +/-mice exhibit low bone mass
Sources: Literature; to: PMID: 34450031 - Marom et al 2021 describes 6 individuals from 5 families. In 4 families loss of function heterozygous variants in COPB2 were found. In the 5th family, two affected siblings were found to have a homozygous variant in COPB2. Osteopenia was noted in 4/5 families (5th unknown) and fractures in 2/5. Developmental delay was observed in all 6 individuals with variable severity. Severe intellectual disability, seizures and microcephaly was noted in the siblings with the homozygous variants. Copb2þ +/-mice exhibit low bone mass

PMID: 29036432 - original report of microcephaly in the two siblings with the COPB2 homozygous variant.
Intellectual disability v3.1276 COPB2 Eleanor Williams Added comment: Comment on mode of inheritance: 4 families with heterozygous variants and 1 with biallelic (more severe phenotype)
Intellectual disability v3.1275 COPB2 Eleanor Williams gene: COPB2 was added
gene: COPB2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: COPB2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: COPB2 were set to 34450031
Phenotypes for gene: COPB2 were set to osteoporosis; developmental delay
Review for gene: COPB2 was set to GREEN
Added comment: PMID: 34450031 - Marom et al 2021 describes 6 individuals from 5 families. In 4 families loss of function heterozygous variants in COPB2 were found. In the 5th family, two affected siblings were found to have a homozygous variant in COPB2. Osteopenia was noted in 4/5 families (5th unknown) and fractures in 2/5. Developmental delay was observed in all 6 individuals with variable severity. Severe intellectual disability, seizures and microcephaly was noted in the siblings with the homozygous variants. Copb2þ +/-mice exhibit low bone mass
Sources: Literature
Intellectual disability v3.1273 HID1 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. There is enough evidence to promote this gene to Green at the next GMS panel update.
Intellectual disability v3.1272 GNB1 Sarah Leigh Added comment: Comment on mode of pathogenicity: Gen2Phen entry for GNB1 (https://www.ebi.ac.uk/gene2phenotype/gfd?dbID=2121) lists the mutation consequence summary as Activating
Intellectual disability v3.1271 GRIN1 Sarah Leigh Phenotypes for gene: GRIN1 were changed from Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal recessive, 617820; NDHMSR; Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal dominant, 614254; NDHMSD; Mental retardation, autosomal dominant 8, 614254; EPILEPTIC ENCEPHALOPATHY to Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal dominant OMIM:614254; intellectual disability, autosomal dominant 8 MONDO:0013655; Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal recessive OMIM:617820; neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal recessive MONDO:0060629
Intellectual disability v3.1269 GNB1 Sarah Leigh Phenotypes for gene: GNB1 were changed from Mental retardation, autosomal dominant 42 OMIM:616973; intellectual disability, autosomal dominant 42 MONDO:0014855 to Mental retardation, autosomal dominant 42 OMIM:616973; intellectual disability, autosomal dominant 42 MONDO:0014855
Intellectual disability v3.1269 GNB1 Sarah Leigh Phenotypes for gene: GNB1 were changed from Mental retardation, autosomal dominant 42, OMIM:616973 to Mental retardation, autosomal dominant 42 OMIM:616973; intellectual disability, autosomal dominant 42 MONDO:0014855
Intellectual disability v3.1263 PARP6 Arina Puzriakova Classified gene: PARP6 as Amber List (moderate evidence)
Intellectual disability v3.1263 PARP6 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. At least 3 individuals with heterozygous PARP6 variants and a relevant phenotype have been reported (PMID: 34067418) - however, segregation analysis has only been complete for one of these cases. Furthermore, identification of two sibs with biallelic variants and unaffected parents who were heterozygous carriers arises possibility of incomplete penetrance or role of variants in other genes.

Overall there is not enough evidence to add this gene as diagnostic grade, so rating Amber with watchlist tag.
Intellectual disability v3.1263 PARP6 Arina Puzriakova Gene: parp6 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1262 PARP6 Arina Puzriakova Tag watchlist tag was added to gene: PARP6.
Intellectual disability v3.1262 PARP6 Arina Puzriakova reviewed gene: PARP6: Rating: ; Mode of pathogenicity: None; Publications: 34067418; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.1262 ZNF668 Zornitza Stark gene: ZNF668 was added
gene: ZNF668 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: ZNF668 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZNF668 were set to 34313816; 26633546
Phenotypes for gene: ZNF668 were set to DNA damage repair defect; microcephaly; growth deficiency; severe global developmental delay; brain malformation; facial dysmorphism
Review for gene: ZNF668 was set to AMBER
Added comment: 2 consanguineous families reported with different biallelic truncating (not NMD) variants in ZNF668. Phenotypes included microcephaly, growth deficiency, severe global developmental delay, brain malformation, and distinct facial dysmorphism.

Immunofluorescence indicated ZNF668 deficiency. An increased DNA damage phenotype was demonstrated in patient fibroblasts.
Sources: Literature
Intellectual disability v3.1262 UBE2U Zornitza Stark gene: UBE2U was added
gene: UBE2U was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: UBE2U was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: UBE2U were set to 33776059
Phenotypes for gene: UBE2U were set to Retinoschisis; cataracts; learning disabilities; developmental delay
Review for gene: UBE2U was set to RED
Added comment: Single family with 5 individuals reported.
Sources: Literature
Intellectual disability v3.1262 CACNA1I Zornitza Stark gene: CACNA1I was added
gene: CACNA1I was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: CACNA1I was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CACNA1I were set to 33704440
Phenotypes for gene: CACNA1I were set to Neurodevelopmental disorder
Mode of pathogenicity for gene: CACNA1I was set to Other
Review for gene: CACNA1I was set to GREEN
gene: CACNA1I was marked as current diagnostic
Added comment: 4 different missense variants identified and shown to result in a gain of function.

2 individuals with de novo variants (a 3rd also suspected de novo but their father was unavailable for testing) - these patients all had severe neurodevelopmental disorders, involving severe global developmental delay, absence of speech, gross motor delay, muscular hypotonia, early-onset seizures, cortical visual impairment, and feeding difficulties. Variable clinical features include various brain malformations, startle response or seizures, postnatal growth retardation, gastroesophageal reflux, and gastrostomy.

1 family had three affected individuals - variable cognitive impairment in all, involving borderline intellectual functioning or mild or moderate intellectual disability as main clinical feature, with late-onset seizures in the mother and speech retardation in one of the children. This variant had a milder functional effect than the variants in sporadic cases.
Sources: Literature
Intellectual disability v3.1262 GRIK2 Zornitza Stark reviewed gene: GRIK2: Rating: GREEN; Mode of pathogenicity: None; Publications: 34375587, 17847003, 25039795; Phenotypes: Mental retardation, autosomal recessive, 6 MIM# 611092, Non-syndromic neurodevelopmental disorder (NDD), autosomal dominant; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.1262 CHRM1 Zornitza Stark gene: CHRM1 was added
gene: CHRM1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: CHRM1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CHRM1 were set to 34212451; 31981491; 12483218
Phenotypes for gene: CHRM1 were set to Neurodevelopmental delay; intellectual disability; autism
Review for gene: CHRM1 was set to AMBER
Added comment: PMID: 34212451 - 2 unrelated cases with de novo missense variants (p.Pro380Leu and p.Phe425Ser), one case with early-onset refractory epilepsy, severe disability, and progressive cerebral and cerebellar atrophy, and the second case with mild dysmorphism, global developmental delay, and moderate intellectual disability. In vitro biochemical analyses of p.Pro380Leu demonstrated a reduction in protein levels, impaired cellular trafficking, and defective activation of intracellular signaling pathways.
PMID: 31981491 - an autism spectrum disorder (no other information on phenotype, except ascertained to have severe neurodevelopmental delay) case with a de novo missense variant p.(Arg210Leu)
PMID: 12483218 - null mouse model assessing memory demonstrated selective cognitive dysfunction.
Sources: Literature
Intellectual disability v3.1262 ZNF699 Zornitza Stark gene: ZNF699 was added
gene: ZNF699 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: ZNF699 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZNF699 were set to 33875846
Phenotypes for gene: ZNF699 were set to DEGCAGS syndrome, MIM# 619488
Review for gene: ZNF699 was set to GREEN
Added comment: DEGCAGS syndrome is a neurodevelopmental disorder characterized by global developmental delay, coarse and dysmorphic facial features, and poor growth and feeding apparent from infancy. Affected individuals have variable systemic manifestations often with significant structural defects of the cardiovascular, genitourinary, gastrointestinal, and/or skeletal systems. Additional features may include sensorineural hearing loss, hypotonia, anaemia or pancytopaenia, and immunodeficiency with recurrent infections.

12 unrelated families reported, 5 different homozygous frameshift variants.
Sources: Literature
Intellectual disability v3.1262 JAKMIP1 Zornitza Stark gene: JAKMIP1 was added
gene: JAKMIP1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: JAKMIP1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: JAKMIP1 were set to 29158550; 26627310; 27799067
Phenotypes for gene: JAKMIP1 were set to Intellectual disability; seizures
Review for gene: JAKMIP1 was set to AMBER
Added comment: Identified in two independent patients in the literature with a mouse model. Patient 1 (27799067) with developmental delay, speech delay, and cognitive impairment; self-injurious and aggressive behaviour, seizures, dysmorphic features. De-novo missense JAKMIP1 (p.D586H). Patient 2 (29158550) with feeding difficulties, hypotonia, epilepsy, severe ID, no active speech, kyphoscoliosis, constipation, autism, short stature. Splice variant c.1432-2A>G, no segregation or RNA data available. KO mouse model (27799067) displays social deficits, stereotyped activity, abnormal postnatal vocalizations, and other autistic-like behaviors.
Sources: Literature
Intellectual disability v3.1261 DEPDC5 Arina Puzriakova Phenotypes for gene: DEPDC5 were changed from FAMILIAL FOCAL EPILEPSY WITH VARIABLE FOCI (FFEVF) to Epilepsy, familial focal, with variable foci 1, OMIM:604364
Intellectual disability v3.1260 DCHS1 Arina Puzriakova Phenotypes for gene: DCHS1 were changed from PERIVENTRICULAR NEURONAL HETEROTOPIA; Van Maldergem syndrome 1, 601390 to Van Maldergem syndrome 1, OMIM:601390
Intellectual disability v3.1257 PIDD1 Arina Puzriakova Added comment: Comment on list classification: New gene added by Konstantinos Varvagiannis. Overall there are sufficient unrelated cases (>3) with a relevant phenotype and biallelic variants in this gene to rate as Green at the next GMS panel update.
Intellectual disability v3.1256 CRADD Arina Puzriakova Phenotypes for gene: CRADD were changed from Mental retardation, autosomal recessive 34, with variant lissencephaly 614499 to Mental retardation, autosomal recessive 34, with variant lissencephaly, OMIM:614499
Intellectual disability v3.1254 JAG1 Arina Puzriakova Phenotypes for gene: JAG1 were changed from Alagille syndrome, 118450; Tetralogy of Fallot, 187500; Deafness, congenital heart defects, and posterior embryotoxon to Alagille syndrome 1, OMIM:118450
Intellectual disability v3.1252 ARF1 Arina Puzriakova edited their review of gene: ARF1: Added comment: Added to ID panel as developmental delay (especially in speech) is a reported feature in all cases (except for one individuals for which only limited clinical information was available). Although only one patient has been reported with a moderate ID diagnosis, developmental delay is likely to be noticed earlier in the course of disease than cortical malformations and may prompt genetic investigation. Inclusion on this panel could increase the likelihood of detecting cases and therefore a Green rating is warranted.; Changed rating: GREEN; Changed publications to: 28868155, 34353862; Changed phenotypes to: Periventricular nodular heterotopia 8, OMIM:618185; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.1252 ARF1 Arina Puzriakova gene: ARF1 was added
gene: ARF1 was added to Intellectual disability. Sources: Expert list,Expert Review Amber
Q3_21_rating tags were added to gene: ARF1.
Mode of inheritance for gene: ARF1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ARF1 were set to 28868155; 34353862
Phenotypes for gene: ARF1 were set to Periventricular nodular heterotopia 8, OMIM:618185
Intellectual disability v3.1251 GMPPB Sarah Leigh Phenotypes for gene: GMPPB were changed from Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 14 615350; Muscular dystrophy-dystroglycanopathy (congenital with mental retardation), type B, 14 615351; Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 14 615352 to Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 14 OMIM:615350; muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A14 MONDO:0014140; Muscular dystrophy-dystroglycanopathy (congenital with mental retardation), type B, 14 OMIM:615351; muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B14 MONDO:0014141; Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 14 OMIM:615352; autosomal recessive limb-girdle muscular dystrophy type 2T MONDO:0014142
Intellectual disability v3.1249 MAP1B Arina Puzriakova edited their review of gene: MAP1B: Added comment: MAP1B was flagged by a GLH following identification of some potential cases relating to variants in this gene and predominantly ID phenotypes within 100K data. Although these are pending confirmations (will request update once cases are validated), upon reassessment of MAP1B it was highlighted that inclusion on this panels may still be warranted to increase the likelihood of detecting cases, particularly given that DD/ID is more likely to be observed earlier in the course of disease albeit at varying severities.

For this reason, MAP1B should be promoted to Green status at the next GMS panel review (tagged Q3_21_rating); Changed rating: GREEN
Intellectual disability v3.1249 PI4KA Ivone Leong Entity copied from Ataxia and cerebellar anomalies - narrow panel v2.233
Intellectual disability v3.1249 PI4KA Ivone Leong gene: PI4KA was added
gene: PI4KA was added to Intellectual disability. Sources: Expert Review Amber
Q3_21_rating tags were added to gene: PI4KA.
Mode of inheritance for gene: PI4KA was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PI4KA were set to 25855803; 34415322; 34415310
Phenotypes for gene: PI4KA were set to Polymicrogyria, perisylvian, with cerebellar hypoplasia and arthrogryposis, OMIM:616531
Intellectual disability v3.1244 ALDH3A2 Arina Puzriakova Phenotypes for gene: ALDH3A2 were changed from Sjogren-Larsson syndrome, 270200; SJOEGREN-LARSSON SYNDROME (SLS) to Sjogren-Larsson syndrome, OMIM:270200
Intellectual disability v3.1242 L1CAM Arina Puzriakova Phenotypes for gene: L1CAM were changed from Hydrocephalus due to aqueductal stenosis, 307000MASA syndrome, 303350CRASH syndrome, 303350Hydrocephalus with Hirschsprung disease, 307000Hydrocephalus with congenital idiopathic intestinal pseudoobstruction, 307000Corpus callosum, partial agenesis of, 304100; MENTAL RETARDATION-APHASIA-SHUFFLING GAIT-ADDUCTED THUMBS SYNDROME (MASA) to Corpus callosum, partial agenesis of, OMIM:304100; CRASH syndrome, OMIM:303350; MASA syndrome, OMIM:303350; Hydrocephalus due to aqueductal stenosis, OMIM:307000; Hydrocephalus with congential idiopathic intestinal pseudoobstruction, OMIM:307000; Hydrocephalus with Hirschsprung disease, OMIM:307000
Intellectual disability v3.1241 C12orf65 Arina Puzriakova Phenotypes for gene: C12orf65 were changed from COMBINED OXIDATIVE PHOSPHORYLATION DEFICIENCY 7 to Combined oxidative phosphorylation deficiency 7, OMIM:613559; Spastic paraplegia 55, autosomal recessive, OMIM:615035
Intellectual disability v3.1240 WDR45B Arina Puzriakova Phenotypes for gene: WDR45B were changed from AUTOSOMAL RECESSIVE MENTAL RETARDATION; Neurodevelopmental disorder with spastic quadriplegia and brain abnormalities with or without seizures, 617977 to Neurodevelopmental disorder with spastic quadriplegia and brain abnormalities with or without seizures, OMIM:617977
Intellectual disability v3.1239 TFG Arina Puzriakova Phenotypes for gene: TFG were changed from Hereditary motor and sensory neuropathy, proximal type, 604484; ?Spastic paraplegia 57, autosomal recessive, 615658 to Spastic paraplegia 57, autosomal recessive, OMIM:615658
Intellectual disability v3.1238 SPART Arina Puzriakova Phenotypes for gene: SPART were changed from Troyer syndrome; MIM:275900; developmental delay to Troyer syndrome, OMIM:275900
Intellectual disability v3.1233 KDM5C Arina Puzriakova Added comment: Comment on mode of inheritance: MOI should be updated from 'X-linked.. biallelic in females' to 'X-linked.. monoallelic in females may cause disease' at the next GMS panel update.

A subset of female carriers have been shown to have impaired intellectual development and/or developmental delay (PMIDs: 10982473; 16538222; 18697827; 19826449; 21575681; 32279304)

This also reflects the current MOI on all other relevant panels.
Intellectual disability v3.1232 KDM5C Arina Puzriakova Phenotypes for gene: KDM5C were changed from Mental retardation, X-linked, syndromic, Claes-Jensen type, 300534 -3; MENTAL RETARDATION SYNDROMIC X-LINKED JARID1C-RELATED (MRXSJ) to Mental retardation, X-linked, syndromic, Claes-Jensen type, OMIM:300534
Intellectual disability v3.1230 FIG4 Sarah Leigh Phenotypes for gene: FIG4 were changed from CHARCOT-MARIE-TOOTH DISEASE, TYPE 4J to Charcot-Marie-Tooth disease, type 4J, OMIM:611228; Charcot-Marie-Tooth disease type 4J MONDO:0012640; Yunis Varon syndrome OMIM:216340; Yunis-Varon syndrome MONDO:0008995
Intellectual disability v3.1228 HNMT Ivone Leong Phenotypes for gene: HNMT were changed from Mental retardation, autosomal recessive 51, MIM#616739 to Mental retardation, autosomal recessive 51, OMIM:616739
Intellectual disability v3.1226 ENTPD1 Arina Puzriakova Added comment: Comment on list classification: Upgraded from Red to Amber as there is some evidence of cognitive impairment associated with SPG64, but perhaps too mild in most cases to warrant inclusion on this panel. Cases are expected to be picked up via the HSP route which presents a more prominent feature of this disorder.
Intellectual disability v3.1224 ENTPD1 Arina Puzriakova Phenotypes for gene: ENTPD1 were changed from AUTOSOMAL RECESSIVE MENTAL RETARDATION to Spastic paraplegia 64, autosomal recessive, OMIM:615683
Intellectual disability v3.1223 ENTPD1 Arina Puzriakova reviewed gene: ENTPD1: Rating: AMBER; Mode of pathogenicity: None; Publications: 24482476, 29691679, 30652007; Phenotypes: Spastic paraplegia 64, autosomal recessive, OMIM:615683; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1223 ARG1 Arina Puzriakova Phenotypes for gene: ARG1 were changed from Argininemia, 207800; ARGININEMIA (ARGIN) to Argininemia, OMIM:207800
Intellectual disability v3.1222 RNF220 Konstantinos Varvagiannis gene: RNF220 was added
gene: RNF220 was added to Intellectual disability. Sources: Literature,Other
Mode of inheritance for gene: RNF220 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RNF220 were set to 33964137; 10881263
Phenotypes for gene: RNF220 were set to Leukodystrophy; CNS hypomyelination; Ataxia; Intellectual disability; Sensorineural hearing impairment; Elevated hepatic transaminases; Hepatic fibrosis; Dilated cardiomyopathy; Spastic paraplegia; Dysarthria; Abnormality of the corpus callosum
Penetrance for gene: RNF220 were set to Complete
Review for gene: RNF220 was set to GREEN
Added comment: Sferra et al (2021 - PMID: 33964137) provide extensive evidence that biallelic RNF220 mutations cause a disorder characterized by hypomyelinating leukodystrophy, ataxia (9/9 - onset 1-5y), borderline intellectual functioning (3/9) / intellectual disability (5/9 - in most cases mild), sensorineural deafness (9/9) with complete hearing loss in the first decade of life, hepatopathy (9/9) with associated periportal fibrosis, and dilated cardiomyopathy (9/9) which was fatal.

Other neurologic manifestations apart from ataxia incl. hyperreflexia (8/8), spastic paraplegia (9/9), dysarthria (9/9), peripheral neuropathy (4/9), seizures in one case (1/9). Upon brain MRI there was thin corpus callosum (9/9) or cerebellar atrophy in some (2/9).

The authors identified homozygosity for 2 recurrent missense RNF220 variants in affected members belonging to these 5 broad consanguineous pedigrees (7 families), namely NM_018150.4:c.1094G>A / p.Arg365Gly in 4 Roma families in the context of a shared haplotype (/founder effect) as well as c.1088G>A / p.Arg363Gly in a large pedigree from southern Italy initially reported by Leuzzi et al (2000 - PMID: 10881263).

Extensive segregation analyses were carried out including several affected and unaffected members.

RNF220 encodes ring finger protein 220, which functions as an E3 ubiquitin ligase. Previous studies have shown among others a role in modulation of Sonic hedgehog/GLI signaling and cerebellar development

Evidence for the role of RNF220 included relevant expression, localization within the cell, interaction partners (lamin B1, 20S proteasome), similarities with other laminopathies in terms of phenotype, etc :
*RNF220 has a relevant expression pattern in CNS (based on qRT-PCR analyses in human brain, cerebellum, cerebral cortex / mRNA levels in human fetal CNS with higher expression in cerebellum, spinal cord and cortex / previous GTEx data / protein levels in mouse CNS)
*The protein displays nuclear localization based on iPSC cells differentiated to motor neurons (also supported by data from the Human Protein Atlas). Transfection of COS-1 cells demonstrated localization primarily to the nucleus (as also previously demonstrated in HEK293T cells) in vesicle like structures with ASF2/SF2 colocalization suggesting enrichment in nuclear speckles. There was also partial co-distribution with the 20S proteasome. R363Q and R365Q additionally coalesced in the cytoplasm forming protein aggregates/inclusions.
*Immunofluorescence studies in patient fibroblasts also confirmed abnormal increase of the protein in the cytoplasm and increased fluorescence with the 20S proteasome.
*Proteomic identification of RNF220-interacting proteins in transfected HEK293T cells demonstrated enrichment for all members of the lamin protein family (incl . lamin B1, AC, B2).
*RNAi-mediated downregulation of RNF222 in Drosophila suggested altered subcellular localization and accumulation of the fly orthologue for human lamin B1.
*Immunoprecipitation of lamin B1 from the nuclear matrix of cerebellar cells suggested significant interaction of endogenous lamin B1 with RNF220, while transfection studies in HEK293T cells for wt/mt suggested reduced binding to endogenous lamin B1 for RNF220 mt compared to wt (more prominent for R365Q). RNF220 mutants also reduced ubiquitination of nuclear lamin B1 compared to wt.
*Patient fibroblasts immunostained with different nuclear envelope markers displayed abnormal nuclear shapes with multiple invaginations and lobulations, findings also observed in laminopathies.

There is currently no associated phenotype in OMIM or G2P. SysID includes RNF220 among the current primary ID genes.

Consider inclusion in panels for leukodystrophies, childhood onset ataxia, sensorineural hearing loss, corpus callosum anomalies, cardiomyopathies, hepatopathies, etc in all cases with green rating.
Sources: Literature, Other
Intellectual disability v3.1222 ALS2 Arina Puzriakova Phenotypes for gene: ALS2 were changed from ALS2-RELATED DISORDERS; Amyotrophic lateral sclerosis 2, juvenile, 205100 to Amyotrophic lateral sclerosis 2, juvenile, OMIM:205100; Primary lateral sclerosis, juvenile, OMIM:606353; Spastic paralysis, infantile onset ascending, OMIM:607225
Intellectual disability v3.1220 ARF3 Konstantinos Varvagiannis gene: ARF3 was added
gene: ARF3 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: ARF3 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ARF3 were set to 34346499
Phenotypes for gene: ARF3 were set to Global developmental delay; Intellectual disability; Seizures; Morphological abnormality of the central nervous system
Penetrance for gene: ARF3 were set to unknown
Review for gene: ARF3 was set to AMBER
Added comment: Sakamoto et al (2021 - PMID: 34346499) provide some evidence that monoallelic ARF3 pathogenic variants may be associated with a NDD with brain abnormality.

Using trio exome sequencing, the authors identified 2 individuals with NDD harboring de novo ARF3 variants, namely: NM_001659.2:c.200A>T / p.Asp67Val and c.296G>T / p.Arg99Leu.

Individual 1 (with Asp67Val / age : 4y10m), appeared to be more severelely affected with prenatal onset progressive microcephaly, severe global DD, epilepsy. Upon MRI there was cerebellar and brainstem atrophy. Individual 2 (Arg99Leu / 14y) had severe DD and ID (IQ of 23), epilepsy and upon MRI cerebellar hypoplasia. This subject did not exhibit microcephaly. Common facial features incl. broad nose, full cheeks, small philtrum, strabismus, thin upper lips and abnormal jaw. There was no evidence of systemic involvement in both.

ARF3 encodes ADP-ribosylation factor 3. Adenosine diphosphate ribosylation factors (ARFs) are key proteins for regulation of cargo sorting at the Golgi network, with ARF3 mainly working at the trans-Golgi network. ARFs belong to the small GTP-binding protein (G protein) superfamily. ARF3 switches between an active GTP-bound form and an inactive GDP-bound form, regulated by guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs) respectively.

Members of the ARF superfamily regulate various aspects of membrane traffic, among others in neurons.

There are 5 homologs of ARF families, divided in 3 classes. ARF3 and ARF1 belong to class I. Monoallelic ARF1 mutations are associated with Periventricular nodular heterotopia 8 (MIM 618185).

In vivo, in vitro and in silico studies for the 2 variants suggest that both impair the Golgi transport system although each variant most likely exerts a different effect (gain-of-function for Arg99Leu vs loss-of-function/dominant-negative for Asp67Val).

This was also reflected in somewhat different phenotype of the subjects with the respective variants. Common features included severe DD, epilepsy and brain abnormalities although Asp67Val was associated with diffuse brain atrophy as well as congenital microcephaly and Arg99Leu with cerebellar hypoplasia.

Evidence to support the effect of each variant include:

Arg99Leu:
Had identical Golgi localization to that of wt
Had increased binding activity with GGA1, a protein recruited by the GTP-bound active form of ARF3 to the TGN membrane (supporting GoF)
In silico structural analysis suggested it may fail to stabilize the conformation of Asp26, resulting in impaired GTP hydrolysis (GoF).
In transgenic fruit flies, evaluation of the ARF3 variant toxicity using the rough eye phenotype this variant was associated with increased severity of the r-e phenotype similar to a previously studied GoF variant (Gln71Leu)

Asp67Val:
Did not show a Golgi-like pattern of localization (similar to Thr31Asn a previously studied dominant-negative variant)
Displayed decreased protein stability
In silico structural analysis suggested that Asp67Val may lead to compromised binding of GTP or GDP (suggestive of LoF)
In transgenic Drosophila eye-specific expression of Asp67Val (similar to Thr31Asn, a known dominant-negative variant) was lethal possibly due to high toxicity in very small amounts in tissues outside the eye.

There is no associated phenotype in OMIM, G2P or SysID.
Sources: Literature
Intellectual disability v3.1220 PLXNA2 Konstantinos Varvagiannis changed review comment from: Altuame et al (2021 - PMID: 34327814) describe 3 individuals from 2 consanguineous Arab families with biallelic PLXNA2 variants.

The index patient from the 1st family presented with CHD (hypoplastic right ventricle, ASD), DD and moderate ID (IQ of 40), failure to thrive as well as some dysmorphic features (obtuse mandibular angle, mild overbite, synophrys with downslanting p-f, strabismus, etc). There were additional features (eg. postaxial polydactyly) which were found in other affected and unaffected family members.

Exome sequencing with autozygome analysis revealed homozygosity for a PLXNA2 stopgain variant (NM_025179:c.3603C>A / p.(Cys1201*)).

Sanger confirmation was carried out and segregation analyses confirmed carrier status of the unaffected parents and a sib as well as a brother homozygous for the same variant. Clinical evaluation of the latter, following this finding revealed borderline intellectual functioning, ADHD, failure to thrive. There was no mandibular anomaly or overbite and no clinical evidence of CHD (no echo performed).

The index patient from the 2nd consanguineous family was evaluated for ID (IQ of 63), with previous borderline motor development, ADHD and some dysmorphic features (obtuse mandibular angle and overbite). There was no clinical evidence of CHD (no echo performed).

Exome sequencing with autozygosity mapping revealed a homozygous missense PLXNA2 variant (c.3073G>A / p.(Asp1025Asn), present only once in gnomAD (htz), with rather non-concordant in silico predictions SIFT 0.22, PolyPhen 0.682 and CADD 23.5. The aa was however highly conserved.

Segregation analysis confirmed carrier state of the parents and 2 unaffected sibs, with a 3rd sib homozygous for the wt allele.

As the authors discuss:
*PLXNA2 belongs to the plexin family of genes, encoding transmbembrane proteins functioning as semaphorin receptors. It has predominant expression in neural tissue. The protein is thought to bind semaphorin-3A, -3C or -5 followed by plexin A2 dimerization, activation of its GTPase-activating protein domain, negative regulation of Rap1B GTPase and initiation of a signal transduction cascade mediating axonal repulsion/guidance, dendritic guidance, neuronal migration.
*Murine Plxna2 knockout models display structural brain defects. In addition they display congenital heart defects incl. persistent truncus arteriosus and interrupted aortic arch.
*Rare CNVs in adult humans with tetralogy of Fallot have suggested a potential role of PLXNA2 in cardiac development and CHD.
*Expression and the role of PLXNA2 in human chondrocytes as well as a GWAS in 240 japanese patients with mandibular prognathism where PLXNA2 was suggested as a susceptibility locus.

Overall, the authors recognize some common features (as for cognitive functioning, some dysmorphic features incl. obtuse mandibular angle and overbite in 2 unrelated subjects, failure to thrive 3/3) and provide plausible explanations for the variability / discordance of others eg:
- Cyanotic heart disease explaining discordance in cognitive outcome among sibs
- Incomplete penetrance for CHD (and/or ID or mandibular anomaly) as for few AR disorders and/or
- Additional pathogenic variants explaining the CHD in the first subject.

There is no associated phenotype in OMIM or G2P. SysID includes PLXNA2 among the candidate ID genes.
Sources: Literature, Other; to: Altuame et al (2021 - PMID: 34327814) describe 3 individuals from 2 consanguineous Arab families with biallelic PLXNA2 variants.

The index patient from the 1st family presented with CHD (hypoplastic right ventricle, ASD), DD and moderate ID (IQ of 40), failure to thrive as well as some dysmorphic features (obtuse mandibular angle, mild overbite, synophrys with downslanting p-f, strabismus, etc). There were additional features (eg. postaxial polydactyly) which were found in other affected and unaffected family members.

Exome sequencing with autozygome analysis revealed homozygosity for a PLXNA2 stopgain variant (NM_025179:c.3603C>A / p.(Cys1201*)).

Sanger confirmation was carried out and segregation analyses confirmed carrier status of the unaffected parents and a sib as well as a brother homozygous for the same variant. Clinical evaluation of the latter, following this finding revealed borderline intellectual functioning, ADHD, failure to thrive. There was no mandibular anomaly or overbite and no clinical evidence of CHD (no echo performed).

The index patient from the 2nd consanguineous family was evaluated for ID (IQ of 63), with previous borderline motor development, ADHD and some dysmorphic features (obtuse mandibular angle and overbite). There was no clinical evidence of CHD (no echo performed).

Exome sequencing with autozygosity mapping revealed a homozygous missense PLXNA2 variant (c.3073G>A / p.(Asp1025Asn), present only once in gnomAD (htz), with rather non-concordant in silico predictions SIFT 0.22, PolyPhen 0.682 and CADD 23.5. The aa was however highly conserved.

Segregation analysis confirmed carrier state of the parents and 2 unaffected sibs, with a 3rd sib homozygous for the wt allele.

As the authors discuss:
*PLXNA2 belongs to the plexin family of genes, encoding transmbembrane proteins functioning as semaphorin receptors. It has predominant expression in neural tissue. The protein is thought to bind semaphorin-3A, -3C or -5 followed by plexin A2 dimerization, activation of its GTPase-activating protein domain, negative regulation of Rap1B GTPase and initiation of a signal transduction cascade mediating axonal repulsion/guidance, dendritic guidance, neuronal migration.
*Murine Plxna2 knockout models display structural brain defects. In addition they display congenital heart defects incl. persistent truncus arteriosus and interrupted aortic arch.
*Rare CNVs in adult humans with tetralogy of Fallot have suggested a potential role of PLXNA2 in cardiac development and CHD.
*Expression and the role of PLXNA2 in human chondrocytes as well as a GWAS in 240 japanese patients with mandibular prognathism where PLXNA2 was suggested as a susceptibility locus.

Overall, the authors recognize some common features (as for cognitive functioning, some dysmorphic features incl. obtuse mandibular angle and overbite in 2 unrelated subjects, failure to thrive 3/3) and provide plausible explanations for the variability / discordance of others eg:
- Cyanotic heart disease explaining discordance in cognitive outcome among sibs
- Incomplete penetrance for CHD (and/or ID or mandibular anomaly) as for few AR disorders and/or
- Additional pathogenic variants possibly explaining the CHD in the first subject.

There is no associated phenotype in OMIM or G2P. SysID includes PLXNA2 among the candidate ID genes.
Sources: Literature, Other
Intellectual disability v3.1220 PLXNA2 Konstantinos Varvagiannis gene: PLXNA2 was added
gene: PLXNA2 was added to Intellectual disability. Sources: Literature,Other
Mode of inheritance for gene: PLXNA2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PLXNA2 were set to 34327814
Phenotypes for gene: PLXNA2 were set to Intellectual disability; Abnormality of the face; Failure to thrive; Abnormal heart morphology
Penetrance for gene: PLXNA2 were set to Incomplete
Review for gene: PLXNA2 was set to AMBER
Added comment: Altuame et al (2021 - PMID: 34327814) describe 3 individuals from 2 consanguineous Arab families with biallelic PLXNA2 variants.

The index patient from the 1st family presented with CHD (hypoplastic right ventricle, ASD), DD and moderate ID (IQ of 40), failure to thrive as well as some dysmorphic features (obtuse mandibular angle, mild overbite, synophrys with downslanting p-f, strabismus, etc). There were additional features (eg. postaxial polydactyly) which were found in other affected and unaffected family members.

Exome sequencing with autozygome analysis revealed homozygosity for a PLXNA2 stopgain variant (NM_025179:c.3603C>A / p.(Cys1201*)).

Sanger confirmation was carried out and segregation analyses confirmed carrier status of the unaffected parents and a sib as well as a brother homozygous for the same variant. Clinical evaluation of the latter, following this finding revealed borderline intellectual functioning, ADHD, failure to thrive. There was no mandibular anomaly or overbite and no clinical evidence of CHD (no echo performed).

The index patient from the 2nd consanguineous family was evaluated for ID (IQ of 63), with previous borderline motor development, ADHD and some dysmorphic features (obtuse mandibular angle and overbite). There was no clinical evidence of CHD (no echo performed).

Exome sequencing with autozygosity mapping revealed a homozygous missense PLXNA2 variant (c.3073G>A / p.(Asp1025Asn), present only once in gnomAD (htz), with rather non-concordant in silico predictions SIFT 0.22, PolyPhen 0.682 and CADD 23.5. The aa was however highly conserved.

Segregation analysis confirmed carrier state of the parents and 2 unaffected sibs, with a 3rd sib homozygous for the wt allele.

As the authors discuss:
*PLXNA2 belongs to the plexin family of genes, encoding transmbembrane proteins functioning as semaphorin receptors. It has predominant expression in neural tissue. The protein is thought to bind semaphorin-3A, -3C or -5 followed by plexin A2 dimerization, activation of its GTPase-activating protein domain, negative regulation of Rap1B GTPase and initiation of a signal transduction cascade mediating axonal repulsion/guidance, dendritic guidance, neuronal migration.
*Murine Plxna2 knockout models display structural brain defects. In addition they display congenital heart defects incl. persistent truncus arteriosus and interrupted aortic arch.
*Rare CNVs in adult humans with tetralogy of Fallot have suggested a potential role of PLXNA2 in cardiac development and CHD.
*Expression and the role of PLXNA2 in human chondrocytes as well as a GWAS in 240 japanese patients with mandibular prognathism where PLXNA2 was suggested as a susceptibility locus.

Overall, the authors recognize some common features (as for cognitive functioning, some dysmorphic features incl. obtuse mandibular angle and overbite in 2 unrelated subjects, failure to thrive 3/3) and provide plausible explanations for the variability / discordance of others eg:
- Cyanotic heart disease explaining discordance in cognitive outcome among sibs
- Incomplete penetrance for CHD (and/or ID or mandibular anomaly) as for few AR disorders and/or
- Additional pathogenic variants explaining the CHD in the first subject.

There is no associated phenotype in OMIM or G2P. SysID includes PLXNA2 among the candidate ID genes.
Sources: Literature, Other
Intellectual disability v3.1220 VPS50 Konstantinos Varvagiannis gene: VPS50 was added
gene: VPS50 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: VPS50 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: VPS50 were set to 34037727
Phenotypes for gene: VPS50 were set to Neonatal cholestatic liver disease; Failure to thrive; Profound global developmental delay; Postnatal microcephaly; Seizures; Abnormality of the corpus callosum
Penetrance for gene: VPS50 were set to Complete
Review for gene: VPS50 was set to AMBER
Added comment: Schneeberger et al (2021 - PMID: 34037727) describe the phenotype of 2 unrelated individuals with biallelic VPS50 variants.

Common features included transient neonatal cholestasis, failure to thrive, severe DD with failure to achieve milestones (last examination at 2y and 2y2m respectively), postnatal microcephaly, seizures (onset at 6m and 25m) and irritability. There was corpus callosum hypoplasia on brain imaging.

Both individuals were homozygous for variants private to each family (no/not known consanguinity applying to each case). The first individual was homozygous for a splicing variant (NM_017667.4:c.1978-1G>T) and had a similarly unaffected sister deceased with no available DNA for testing. The other individual was homozygous for an in-frame deletion (c.1823_1825delCAA / p.(Thr608del)).

VPS50 encodes a critical component of the endosome-associated recycling protein (EARP) complex, which functions in recycling endocytic vesicles back to the plasma membrane [OMIM based on Schindler et al]. The complex contains VPS50, VPS51, VPS52, VPS53, the three latter also being components of GARP (Golgi-associated-retrograde protein) complex. GARP contains VPS54 instead of VPS50 and is required for trafficking of proteins to the trans-golgi network. Thus VPS50 (also named syndetin) and VPS54 function in the EARP and GARP complexes, to define directional movement of their endocytic vesicles [OMIM based on Schindler et al]. The VPS50 subunit is required for recycling of the transferrin receptor.

As discussed by Schneeberger et al (refs provided in text):
- VPS50 has a high expression in mouse and human brain as well as throughout mouse brain development.
- Mice deficient for Vps50 have not been reported. vps50 knockdown in zebrafish results in severe developmental defects of the body axis. Knockout mice for other proteins of the EARP/GARP complex (e.g. Vps52, 53 and 54) display embryonic lethality.

Studies performed by Schneeberger et al included:
- Transcript analysis for the 1st variant demonstrated skipping of ex21 (in patient derived fabriblasts) leading to an in frame deletion of 81 bp (r.1978_2058del) with predicted loss of 27 residues (p.Leu660_Leu686del).
- Similar VPS50 mRNA levels but significant reduction of protein levels (~5% and ~8% of controls) were observed in fibroblasts from patients 1 and 2. Additionally, significant reductions in the amounts of VPS52 and VPS53 protein levels were observed despite mRNA levels similar to controls. Overall, this suggested drastic reduction of functional EARP complex levels.
- Lysosomes appeared to have similar morphology, cellular distribution and likely unaffected function in patient fibroblasts.
- Transferrin receptor recycling was shown to be delayed in patient fibroblasts suggestive of compromise of endocytic-recycling function.

As the authors comment, the phenotype of both individuals with biallelic VPS50 variants overlaps with the corresponding phenotype reported in 15 subjects with biallelic VPS53 or VPS51 mutations notably, severe DD/ID, microcephaly and early onset epilepsy, CC anomalies. Overall, for this group, they propose the term "GARP and/or EARP deficiency disorders".

There is no VPS50-associated phenotype in OMIM or G2P. SysID includes VPS50 among the ID candidate genes.

Consider inclusion in other relevant gene panels (e.g. for neonatal cholestasis, epilepsy, microcephaly, growth failure in early infancy, corpus callosum anomalies, etc) with amber rating pending further reports.
Sources: Literature
Intellectual disability v3.1219 CTC1 Arina Puzriakova Added comment: Comment on list classification: This gene should be demoted from Green to Amber, as per the recent review by Zornitza Stark. The disorder is primarily characterised by intracranial calcifications to which cognitive decline is secondary. Some individuals have normal cognition.
Intellectual disability v3.1218 PGM2L1 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. There is sufficient evidence to promote this gene to Green at the next GMS panel update (tagged).

Morava et al. 2021 (PMID: 33979636) identified 4 unrelated individuals with different biallelic protein-truncating variants in the PGM2L1 gene. All had severe GDD/ID. Other features that reach the threshold for inclusion on the relevant panels (observed in at least 3 cases) are epilepsy and early obesity (99th centile at ages 2 to 3). Some functional data included.
Intellectual disability v3.1217 PIDD1 Konstantinos Varvagiannis changed review comment from: There is enough evidence to include this gene in the current panel with green rating.

Biallelic PIDD1 pathogenic variants have been reported in 26 individuals (11 families) with DD (all), variable degrees of ID (mild to severe), behavioral (eg. aggression/self-mutilation in several, ADHD) and/or psychiatric abnormalities (ASD, psychosis in 5 belonging to 3 families), well-controlled epilepsy is some (9 subjects from 6 families) and MRI abnormalities notably abnormal gyration pattern (pachygyria with predominant anterior gradient) as well as corpus callosum anomalies (commonly thinning) in several. Dysmorphic features have been reported in almost all, although there has been no specific feature suggested.

The first reports on the phenotype associated with biallelic PIDD1 mutations were made by Harripaul et al (2018 - PMID: 28397838) and Hu et al (2019 - PMID: 29302074) [both studies investigating large cohorts of individuals with ID from consanguineous families].

Sheikh et al (2021 - PMID: 33414379) provided details on the phenotype of 15 individuals from 5 families including those from the previous 2 reports and studied provided evidence on the role of PIDD1 and the effect of variants.

Zaki et al (2021 - PMID: 34163010) reported 11 additional individuals from 6 consanguineous families, summarize the features of all subjects published in the literature and review the neuroradiological features of the disorder.

PIDD1 encodes p53-induced death domain protein 1. The protein is part of the PIDDosome, a multiprotein complex also composed of the bipartite linker protein CRADD (also known as RAIDD) and the proform of caspase-2 and induces apoptosis in response to DNA damage.

There are 5 potential PIDD1 mRNA transcript variants with NM_145886.4 corresponding to the longest. Similar to the protein encoded by CRADD, PIDD1 contains a death domain (DD - aa 774-893). Constitutive post-translational processing gives PIDD1-N, PIDD1-C the latter further processed into PIDD1-CC (by auto-cleavage). Serine residues at pos. 446 and 588 are involved in this autoprocessing generating PIDD1-C (aa 446-910) and PIDD1-CC (aa 774-893). The latter is needed for caspase-2 activation.

Most (if not all) individuals belonged to consanguineous families of different origins and harbored pLoF or missense variants.

Variants reported so far include : c.2587C>T; p.Gln863* / c.1909C>T ; p.Arg637* / c.2443C>T / p.Arg815Trp / c.2275-1G>A which upon trap assay was shown to lead to skipping of ex15 with direct splicing form exon14 to the terminal exon 16 (resulting to p.Arg759Glyfs*1 with exlcusion of the entire DD) / c.2584C>T; p.Arg862Trp / c.1340G>A; p.Trp447* / c.2116_2120del; p.Val706His*, c.1564_1565del; p.Gly602fs*26

Evidence so far provided includes:
- Biallelic CRADD variants cause a NDD disorder and a highly similar gyration pattern.
- Confirmation of splicing effect (eg. for c.2275-1G>A premature stop in position 760) or poor expression (NM_145886.3:c.2587C>T; p.Gln863*). Arg815Trp did not affect autoprocessing or protein stability.
- Abnormal localization pattern, loss of interaction with CRADD and failure to activate caspase-2 (MDM2 cleavage assay) [p.Gln863* and Arg815Trp]
- Available expression data from GTEx (PIDD1 having broad expression in multiple tissues, but higher in brain cerebellum) as well as BrainSpan and PsychEncode studies suggesting high coexpression of PIDD1, CRADD and CASP2 in many regions in the developing human brain.
- Variants in other genes encoding proteins interacting with PIDD1 (MADD, FADD, DNAJ, etc) are associated with NDD.

Pidd-1 ko mice (ex3-15 removal) lack however CNS-related phenotypes. These show decreased anxiety but no motor anomalies. This has also been the case with Cradd-/- mice displaying no significant CNS phenotypes without lamination defects.

There is currently no associated phenotype in OMIM, PanelApp Australia. PIDD1 is listed in the DD panel of G2P (PIDD1-relared NDD / biallelic / loss of function / probable) . SysID includes PIDD1 among the current primary ID genes.

Overall the gene appears to be relevant for the epilepsy panel, panels for gyration and/or corpus callosum anomalies etc.
Sources: Literature, Other; to: There is enough evidence to include this gene in the current panel with green rating.

Biallelic PIDD1 pathogenic variants have been reported in 26 individuals (11 families) with DD (all), variable degrees of ID (mild to severe), behavioral (eg. aggression/self-mutilation in several, ADHD) and/or psychiatric abnormalities (ASD, psychosis in 5 belonging to 3 families), well-controlled epilepsy is some (9 subjects from 6 families) and MRI abnormalities notably abnormal gyration pattern (pachygyria with predominant anterior gradient) as well as corpus callosum anomalies (commonly thinning) in several. Dysmorphic features have been reported in almost all, although there has been no specific feature suggested.

The first reports on the phenotype associated with biallelic PIDD1 mutations were made by Harripaul et al (2018 - PMID: 28397838) and Hu et al (2019 - PMID: 29302074) [both studies investigating large cohorts of individuals with ID from consanguineous families].

Sheikh et al (2021 - PMID: 33414379) provided details on the phenotype of 15 individuals from 5 families including those from the previous 2 reports and studied provided evidence on the role of PIDD1 and the effect of variants.

Zaki et al (2021 - PMID: 34163010) reported 11 additional individuals from 6 consanguineous families, summarize the features of all subjects published in the literature and review the neuroradiological features of the disorder.

PIDD1 encodes p53-induced death domain protein 1. The protein is part of the PIDDosome, a multiprotein complex also composed of the bipartite linker protein CRADD (also known as RAIDD) and the proform of caspase-2 and induces apoptosis in response to DNA damage.

There are 5 potential PIDD1 mRNA transcript variants with NM_145886.4 corresponding to the longest. Similar to the protein encoded by CRADD, PIDD1 contains a death domain (DD - aa 774-893). Constitutive post-translational processing gives PIDD1-N, PIDD1-C the latter further processed into PIDD1-CC (by auto-cleavage). Serine residues at pos. 446 and 588 are involved in this autoprocessing generating PIDD1-C (aa 446-910) and PIDD1-CC (aa 774-893). The latter is needed for caspase-2 activation.

Most (if not all) individuals belonged to consanguineous families of different origins and harbored pLoF or missense variants.

Variants reported so far include : c.2587C>T; p.Gln863* / c.1909C>T ; p.Arg637* / c.2443C>T / p.Arg815Trp / c.2275-1G>A which upon trap assay was shown to lead to skipping of ex15 with direct splicing form exon14 to the terminal exon 16 (resulting to p.Arg759Glyfs*1 with exlcusion of the entire DD) / c.2584C>T; p.Arg862Trp / c.1340G>A; p.Trp447* / c.2116_2120del; p.Val706His*, c.1564_1565del; p.Gly602fs*26

Evidence so far provided includes:
- Biallelic CRADD variants cause a NDD disorder and a highly similar gyration pattern.
- Confirmation of splicing effect (eg. for c.2275-1G>A premature stop in position 760) or poor expression (NM_145886.3:c.2587C>T; p.Gln863*). Arg815Trp did not affect autoprocessing or protein stability.
- Abnormal localization pattern, loss of interaction with CRADD and failure to activate caspase-2 (MDM2 cleavage assay) [p.Gln863* and Arg815Trp]
- Available expression data from GTEx (PIDD1 having broad expression in multiple tissues, but higher in brain cerebellum) as well as BrainSpan and PsychEncode studies suggesting high coexpression of PIDD1, CRADD and CASP2 in many regions in the developing human brain.
- Variants in other genes encoding proteins interacting with PIDD1 (MADD, FADD, DNAJ, etc) are associated with NDD.

Pidd-1 ko mice (ex3-15 removal) lack however CNS-related phenotypes. These show decreased anxiety but no motor anomalies. This has also been the case with Cradd-/- mice displaying no significant CNS phenotypes without lamination defects.

There is currently no associated phenotype in OMIM, PanelApp Australia. PIDD1 is listed in the DD panel of G2P (PIDD1-related NDD / biallelic / loss of function / probable) . SysID includes PIDD1 among the current primary ID genes.

Overall the gene appears to be relevant for the epilepsy panel, panels for gyration and/or corpus callosum anomalies etc.
Sources: Literature, Other
Intellectual disability v3.1217 PIDD1 Konstantinos Varvagiannis gene: PIDD1 was added
gene: PIDD1 was added to Intellectual disability. Sources: Literature,Other
Mode of inheritance for gene: PIDD1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PIDD1 were set to 28397838; 29302074; 33414379; 34163010
Phenotypes for gene: PIDD1 were set to Global developmental delay; Intellectual disability; Seizures; Autism; Behavioral abnormality; Psychosis; Pachygyria; Lissencephaly; Abnormality of the corpus callosum
Penetrance for gene: PIDD1 were set to Complete
Review for gene: PIDD1 was set to GREEN
Added comment: There is enough evidence to include this gene in the current panel with green rating.

Biallelic PIDD1 pathogenic variants have been reported in 26 individuals (11 families) with DD (all), variable degrees of ID (mild to severe), behavioral (eg. aggression/self-mutilation in several, ADHD) and/or psychiatric abnormalities (ASD, psychosis in 5 belonging to 3 families), well-controlled epilepsy is some (9 subjects from 6 families) and MRI abnormalities notably abnormal gyration pattern (pachygyria with predominant anterior gradient) as well as corpus callosum anomalies (commonly thinning) in several. Dysmorphic features have been reported in almost all, although there has been no specific feature suggested.

The first reports on the phenotype associated with biallelic PIDD1 mutations were made by Harripaul et al (2018 - PMID: 28397838) and Hu et al (2019 - PMID: 29302074) [both studies investigating large cohorts of individuals with ID from consanguineous families].

Sheikh et al (2021 - PMID: 33414379) provided details on the phenotype of 15 individuals from 5 families including those from the previous 2 reports and studied provided evidence on the role of PIDD1 and the effect of variants.

Zaki et al (2021 - PMID: 34163010) reported 11 additional individuals from 6 consanguineous families, summarize the features of all subjects published in the literature and review the neuroradiological features of the disorder.

PIDD1 encodes p53-induced death domain protein 1. The protein is part of the PIDDosome, a multiprotein complex also composed of the bipartite linker protein CRADD (also known as RAIDD) and the proform of caspase-2 and induces apoptosis in response to DNA damage.

There are 5 potential PIDD1 mRNA transcript variants with NM_145886.4 corresponding to the longest. Similar to the protein encoded by CRADD, PIDD1 contains a death domain (DD - aa 774-893). Constitutive post-translational processing gives PIDD1-N, PIDD1-C the latter further processed into PIDD1-CC (by auto-cleavage). Serine residues at pos. 446 and 588 are involved in this autoprocessing generating PIDD1-C (aa 446-910) and PIDD1-CC (aa 774-893). The latter is needed for caspase-2 activation.

Most (if not all) individuals belonged to consanguineous families of different origins and harbored pLoF or missense variants.

Variants reported so far include : c.2587C>T; p.Gln863* / c.1909C>T ; p.Arg637* / c.2443C>T / p.Arg815Trp / c.2275-1G>A which upon trap assay was shown to lead to skipping of ex15 with direct splicing form exon14 to the terminal exon 16 (resulting to p.Arg759Glyfs*1 with exlcusion of the entire DD) / c.2584C>T; p.Arg862Trp / c.1340G>A; p.Trp447* / c.2116_2120del; p.Val706His*, c.1564_1565del; p.Gly602fs*26

Evidence so far provided includes:
- Biallelic CRADD variants cause a NDD disorder and a highly similar gyration pattern.
- Confirmation of splicing effect (eg. for c.2275-1G>A premature stop in position 760) or poor expression (NM_145886.3:c.2587C>T; p.Gln863*). Arg815Trp did not affect autoprocessing or protein stability.
- Abnormal localization pattern, loss of interaction with CRADD and failure to activate caspase-2 (MDM2 cleavage assay) [p.Gln863* and Arg815Trp]
- Available expression data from GTEx (PIDD1 having broad expression in multiple tissues, but higher in brain cerebellum) as well as BrainSpan and PsychEncode studies suggesting high coexpression of PIDD1, CRADD and CASP2 in many regions in the developing human brain.
- Variants in other genes encoding proteins interacting with PIDD1 (MADD, FADD, DNAJ, etc) are associated with NDD.

Pidd-1 ko mice (ex3-15 removal) lack however CNS-related phenotypes. These show decreased anxiety but no motor anomalies. This has also been the case with Cradd-/- mice displaying no significant CNS phenotypes without lamination defects.

There is currently no associated phenotype in OMIM, PanelApp Australia. PIDD1 is listed in the DD panel of G2P (PIDD1-relared NDD / biallelic / loss of function / probable) . SysID includes PIDD1 among the current primary ID genes.

Overall the gene appears to be relevant for the epilepsy panel, panels for gyration and/or corpus callosum anomalies etc.
Sources: Literature, Other
Intellectual disability v3.1216 AP1G1 Zornitza Stark gene: AP1G1 was added
gene: AP1G1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: AP1G1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: AP1G1 were set to 34102099
Phenotypes for gene: AP1G1 were set to Neurodevelopmental disorder (NDD); Intellectual Disability; Epilepsy
Review for gene: AP1G1 was set to GREEN
gene: AP1G1 was marked as current diagnostic
Added comment: Two bi-allelic homozygous missense variants were found in two distinct families with Italian and Pakistani origins; homozygous missense variants.

Eight de novo heterozygous variants were identified in nine isolated affected individuals from nine families; including five missense, two frameshift, and one intronic variant that disrupts the canonical splice acceptor site.

Knocking out AP1G1 Zebrafish model resulted in severe developmental abnormalities and increased lethality.

All individuals had neurodevelopmental disorder (NDD) including global developmental delay and ID, which varied in severity from mild to severe.

GREEN for mono-allelic, AMBER for bi-allelic.
Sources: Literature
Intellectual disability v3.1216 TP73 Zornitza Stark edited their review of gene: TP73: Added comment: New publication adds further evidence for gene-disease association, PMID 34077761:

- Seven individuals from five unrelated families homozygous for TP73 variants (includes 1x large deletion, 1x splice variant, 1x frameshift and 2x nonsense variants) and cortical malformations/ID
- In vitro ciliogenesis experiments demonstrated that epithelial cells from TP73 variant carriers had reduced number of ciliated cells and shortened cilia resulting in abnormal ciliary clearance of the airways compared to healthy controls; Changed rating: GREEN; Changed publications to: 31130284, 34077761
Intellectual disability v3.1216 CLCN3 Zornitza Stark gene: CLCN3 was added
gene: CLCN3 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: CLCN3 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: CLCN3 were set to 34186028
Phenotypes for gene: CLCN3 were set to Neurodevelopmental disorder
Mode of pathogenicity for gene: CLCN3 was set to Other
Review for gene: CLCN3 was set to GREEN
gene: CLCN3 was marked as current diagnostic
Added comment: 11 individuals reported, 9 that carried 8 different rare heterozygous missense variants in CLCN3, and 2 siblings that were homozygous for an NMD-predicted frameshift variant likely abolishing ClC-3 function. All missense variants were confirmed to be de novo in eight individuals for whom parental data was available.

The 11 individuals in the cohort share clinical features of variable severity. All 11 have GDD or ID and dysmorphic features, and a majority has mood or behavioural disorders and structural brain abnormalities:
- Structural brain abnormalities on MRI (9/11) included partial or full agenesis of the corpus callosum (6/9), disorganized cerebellar folia (4/9), delayed myelination (3/9), decreased white matter volume (3/9), pons hypoplasia (3/9), and dysmorphic dentate nuclei (3/9). Six of those with brain abnormalities also presented with seizures.
- Nine have abnormal vision, including strabismus in four and inability to fix or follow in the two with homozygous loss-of-function variants.
- Hypotonia ranging from mild to severe was reported in 7 of the 11 individuals.
- Six have mood or behavioural disorders, particularly anxiety (3/6).
- Consistent dysmorphic facial features included microcephaly, prominent forehead, hypertelorism, down-slanting palpebral fissures, full cheeks, and micrognathia.

The severity of disease in the two siblings with homozygous disruption of ClC-3 is consistent with the drastic phenotype seen in Clcn3 KO mice. The disease was more severe in two siblings carrying homozygous loss-of-function variants with the presence of GDD, absent speech, seizures, and salt and pepper fundal pigmentation in both individuals, with one deceased at 14 months of age. The siblings also had significant neuroanatomical findings including diffusely decreased white matter volume, thin corpora callosa, small hippocampi, and disorganized cerebellar folia. Supporting biallelic inheritance for LoF variants, disruption of mouse Clcn3 results in drastic neurodegeneration with loss of the hippocampus a few months after birth and early retinal degeneration. Clcn3−/− mice display severe neurodegeneration, whereas heterozygous Clcn3+/− mice appear normal.

Patch-clamp studies were used to investigate four of the missense variants. These suggested a gain of function in two variants with increased current in HEK cells, however they also showed reduced rectification of voltage and a loss of transient current, plus decreased current amplitude, glycosylation and surface expression when expressed in oocytes, and were suspected to interfere with channel gating and a negative feedback mechanism. These effects were also shown to vary depending on pH levels. The current of the remaining two variants did not differ from WT. For heterozygous missense variants, the disruption induced may be at least partially conferred to mutant/WT homodimers and mutant/ClC-4 heterodimers.

Both loss and gain of function in this gene resulted in the same phenotype.

Green for mono-allelic variants, Amber/Red for bi-allelic.
Sources: Literature
Intellectual disability v3.1216 ANK2 Zornitza Stark gene: ANK2 was added
gene: ANK2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: ANK2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ANK2 were set to 22542183; 25363768; 27479843; 28554332; 30564305; 30755392; 31981491; 33004838; 33057194
Phenotypes for gene: ANK2 were set to Complex neurodevelopmental disorder, MONDO:0100038
Review for gene: ANK2 was set to GREEN
gene: ANK2 was marked as current diagnostic
Added comment: Note link with cardiac abnormalities such as LongQT is DISPUTED.

However, more than 10 unrelated individuals reported with neurodevelopmental phenotype, comprising autism/ID and de novo truncating variants, in addition to many other individuals as part of large NDD cohorts. This association has been assessed as DEFINITIVE by ClinGen.
Sources: Literature
Intellectual disability v3.1216 LINGO4 Zornitza Stark gene: LINGO4 was added
gene: LINGO4 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: LINGO4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LINGO4 were set to 33098801
Phenotypes for gene: LINGO4 were set to Intellectual disability; speech disorder
Review for gene: LINGO4 was set to GREEN
gene: LINGO4 was marked as current diagnostic
Added comment: 3 unrelated individuals reported with bi-allelic variants in this gene and neurodevelopmental disorder:
1 x individual compound heterozygous for 2x missense variants:
c.679C>A; c.1262G>A p.Leu227Met; p.Arg421Gln. Phenotype: infancy-onset
generalized dystonia; ID, speech disorder

1 x individual homozygous for missense variant: c.679C>A p.Leu227Met Phenotype: ID, speech disorder

1 x individual homozygous for missense variant: c.1673G>A p.Ser558Asn Phenotype: ID, speech disorder
Sources: Literature
Intellectual disability v3.1216 IMPDH2 Zornitza Stark gene: IMPDH2 was added
gene: IMPDH2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: IMPDH2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: IMPDH2 were set to 33098801
Phenotypes for gene: IMPDH2 were set to Neurodevelopmental disorder with dystonia
Review for gene: IMPDH2 was set to GREEN
Added comment: 6 unrelated individuals
1x individual in a dystonia cohort index case with infancy-onset dystonia and other neurological manifestations with a de-novo missense variant, c.338G>A (p.Gly113Glu) in IMPDH2, predicted to disrupt an invariant residue within the cystathionine-β-synthase (CBS) domain pair of the encoded protein.
IMPDH2 encodes IMPDH2, a key enzyme in the purine biosynthetic pathway, expressed throughout the brain and not linked previously to any human Mendelian condition.
1x individual with a de-novo substitution, c.337G>A (p.Gly113Arg), was found in in-house whole-exome sequencing data from 500 individuals with neurodevelopmental disorders. Through GeneMatcher, de novo variants identified:
3 x missense: c.729G>C (p.Gln243His), c.619G>C (p.Gly207Arg), and c.619G>A (p.Gly207Arg)
1 x deletion: c.478_480delTCC (p.Ser160del)
The six variants were predicted to be deleterious and none of them seen in control databases. All affected conserved amino acids and resided in and around the cystathionine-β-synthase domain pair.
The described variants are situated in and around the CBS domain pair, a regulatory element in which clustering of pathogenic missense variants has already been shown for the homologue of IMPDH2, IMPDH1.

All individuals shared similar neurodevelopmental phenotypes. Apart from the dystonia cohort index case, one participant had evidence of dystonic posturing.

Modelling of the variants on 3D protein structures revealed spatial clustering near specific functional sites, predicted to result in deregulation of IMPDH2 activity. Additionally, thermal-shift assays showed that the c.619G>A (p.Gly207Arg) variant, identified as within the CBS domain pair, and c.729G>C (p.Gln243His), which is in close vicinity, affected the stability or folding behaviour of IMPDH2.
Sources: Literature
Intellectual disability v3.1216 KIF1A Arina Puzriakova Added comment: Comment on mode of inheritance: ID is most prominent in patients with NESCAV syndrome (MIM# 614255) caused by monoallelic variants in this gene. KIF1A is also associated HSP type 30 (MIM# 610357) which can be inherited recessively or dominantly - however, mostly only the dominant form has been shown to involve some variable cognitive impairment. Of the 4 families reported to date with recessive HSP (PMID: 21487076; 22258533; 28332297), only 1 presented with ID (PMID: 28332297).

Therefore, MOI should remain at 'monoallelic' only on this panel.
Intellectual disability v3.1215 KIF1A Arina Puzriakova Phenotypes for gene: KIF1A were changed from Mental Retardation, Dominant; Spastic paraplegia 30, autosomal recessive, 610357Neuropathy, hereditary sensory, type IIC, 614213Mental retardation, autosomal dominant 9, 614255; MENTAL RETARDATION, AUTOSOMAL DOMINANT 9 to NESCAV syndrome, OMIM:614255; Spastic paraplegia 30, autosomal dominant, OMIM:610357
Intellectual disability v3.1213 COG4 Arina Puzriakova Added comment: Comment on mode of inheritance: Early developmental delay (speech and motor) can be a feature of Saul-Wilson syndrome (monoallelic inheritance), however cognition is normal. Therefore, the monoallelic form is not pertinent to this panel and the MOI should remain as biallelic only which is associated with CDG-IIj, including psychomotor retardation.
Intellectual disability v3.1209 PTPN4 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not associated with a phenotype in OMIM or Gene2Phenotype. Based on the expert review, there is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Intellectual disability v3.1209 PTPN4 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not associated with a phenotype in OMIM or Gene2Phenotype. Based on the expert review, there is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Intellectual disability v3.1208 BSCL2 Arina Puzriakova Phenotypes for gene: BSCL2 were changed from Encephalopathy, progressive, with or without lipodystrophy 615924; Lipodystrophy, congenital generalized, type 2 269700; Neuropathy, distal hereditary motor, type VA 600794; Silver spastic paraplegia syndrome 270685 to Encephalopathy, progressive, with or without lipodystrophy, OMIM:615924; Lipodystrophy, congenital generalized, type 2, OMIM:269700
Intellectual disability v3.1207 BSCL2 Arina Puzriakova Added comment: Comment on mode of inheritance: Monoallelic variants lead to a motor neuropathy (MIM# 619112) or spastic paraplegia (MIM# 270685) presentation, both characterised by motor symptoms, but neither are associated with any cognitive deficits. On the other hand, biallelic variants cause encephalopathy (MIM# 615924) or generalised lipodystrophy (MIM# 269700) which do include cognitive decline and intellectual impairment, respectively.

Therefore, the MOI should be changed from 'Both mono- and biallelic' to 'Biallelic' only at the next GMS panel review.
Intellectual disability v3.1201 CAMK4 Konstantinos Varvagiannis gene: CAMK4 was added
gene: CAMK4 was added to Intellectual disability. Sources: Literature,Other
Mode of inheritance for gene: CAMK4 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CAMK4 were set to 30262571; 33098801; 33211350
Phenotypes for gene: CAMK4 were set to Global developmental delay; Intellectual disability; Autism; Behavioral abnormality; Abnormality of movement; Dystonia; Ataxia; Chorea; Myoclonus
Penetrance for gene: CAMK4 were set to Complete
Review for gene: CAMK4 was set to GREEN
Added comment: 3 publications by Zech et al (2018, 2020 - PMIDs : 30262571, 33098801, 33211350) provide clinical details on 3 individuals, each harboring a private de novo CAMK4 variant.

Overlapping features included DD, ID, behavoral issues, autism and abnormal hyperkinetic movements. Dystonia and chorea in all 3 appeared 3-20 years after initial symptoms.

CAMK4 encodes Calcium/Calmodulin-dependent protein kinase IV, an important mediator of calcium-mediated activity and dynamics, particularly in the brain. It is involved in neuronal transmission, synaptic plasticity, and neuronal gene expression required for brain development and neuronal homeostasis (summary by OMIM based on Zech et al, 2018).

The 473 aa enzyme has a protein kinase domain (aa 46-300) and a C-terminal autoregulatory domain (aa 305-341) the latter comprising an autoinhibitory domain (AID / aa 305-321) and a calmodulin-binding domain (CBD / aa 322-341) [NP_001735.1 / NM_001744.4 - also used below].

Variants in all 3 subjects were identified following trio-WES and were in all cases protein-truncating, mapping to exon 10 or exon 10-intron 10 junction, expected to escape NMD and cause selective abrogation of the autoinhibitory domain (aa 305-321) leading overall to gain-of-function.

Variation databases include pLoF CAMK4 variants albeit in all cases usptream or downstream of this region (pLI of this gene in gnomAD: 0.51). Variants leading to selective abrogation of the autoregulatory domain have not been reported.

Extensive evidence for the GoF effect of the variant has been provided in the first publication. Several previous studies have demonstrated that abrogation of the AID domain leads to consitutive activation (details below).

Mouse models - though corresponding to homozygous loss of function - support a role for CAMKIV in cognitive and motor symptoms. Null mice display tremulous and ataxic movements, deficiencies in balance and sensorimotor performance associated with reduced number of Purkinje neurons (Ribar et al 2000, PMID: 11069976 - not reviewed). Wei et al (2002, PMID: 12006982 - not reviewed) provided evidence for alteration in hippocampal physiology and memory function.

Heterozygous mutations in other genes for calcium/calmodulin-dependent protein kinases (CAMKs) e.g. CAMK2A/CAMK2B (encoding subunits of CAMKII) have been reported in individuals with ID.

---

The proband in the first publication (PMID: 30262571) was a male with DD, ID, behavioral difficulties (ASD, autoaggression, stereotypies) and hyperkinetic movement disorder (myoclonus, chorea, ataxia) with severe generalized dystonia (onset at the age of 13y). Brain MRI demonstrated cerebellar atrophy.

Extensive work-up incl. karyotyping, CMA, DYT-TOR1A, THAP1, GCH1, SCA1/2/3/6/7/8/12/17, Friedreich's ataxia and FMR1 analysis was negative.F

Trio WES identified a dn splice site variant (c.981+1G>A) in the last exon-intron junction. RT-PCR followed by gel electrophoresis and Sanger in fibroblasts from an affected and control subject revealed that the proband had - as predicted by the type/location of the variant - in equal amount 2 cDNA products, a normal as well as a truncated one.

Sequencing of the shortest revealed utilization of a cryptic donor splice site upstream of the mutated donor leading to a 77bp out-of-frame deletion and introduction of a premature stop codon in the last codon (p.Lys303Serfs*28). Western blot in fibroblast cell lines revealed 2 bands corresponding to the normal protein product as well as to the p.Lys303Serfs*28 although expression of the latter was lower than that of the full length protein.

Several previous studies have shown that mutant CAMKIV species that lack the autoinhibitory domain are consitutively active (several Refs provided). Among others Chatila et al (1996, PMID: 8702940) studied an in vitro-engineered truncation mutant (Δ1-317 - truncation at position 317 of the protein) with functionally validated gain-of-function effect.

To prove enhanced activity of the splicing variant, Zech et al assessed phosphorylation of CREB (cyclic AMP-responsive element binding protein), a downstream substrate of CAMKIV. Immunobloting revealed significant increase of CREB phosphorylation in patient fibroblasts compared to controls. Overactivation of CAMKIV signaling was reversed when cells were treated with STO-609 an inhibitor of CAMKK, the ustream activator of CAMKIV.

Overall the authors demonstrated that loss of CAMKIV autoregulatory domain due to this splice variant had a gain-of-function effect.

----

Following trio-WES, Zech et al (2020 - PMID: 33098801) identified another relevant subject within cohort of 764 individuals with dystonia. This 12-y.o. male, harboring a different variant affecting the same donor site (c.981+1G>T), presented DD, ID, dystonia (onset at 3y) and additional movement disorders (myoclonus, ataxia) as well as similar behavior (ASD, autoaggression, stereotypies). [Details in suppl. p20].

----

Finally Zech et al (2020 - PMID: 33211350) reported on a 24-y.o. woman with adolescence onset choreodystonia. Other features included DD, moderate ID, absence seizures in infancy, OCD with anxiety and later diagnosis of ASD. Trio WES revealed a dn stopgain variant (c.940C>T; p.Gln314*).

----

There is no associated phenotype in OMIM, G2P, PanelApp AUS.

In SysID CAMK4 is listed among the current primary ID genes.

----

Please consider inclusion in other relevant panels.
Sources: Literature, Other
Intellectual disability v3.1201 ATP9A Konstantinos Varvagiannis gene: ATP9A was added
gene: ATP9A was added to Intellectual disability. Sources: Literature,Other
Mode of inheritance for gene: ATP9A was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: ATP9A were set to Global developmental delay; Intellectual disability; Postnatal microcephaly; Failure to thrive; Abnormality of the abdomen
Penetrance for gene: ATP9A were set to Complete
Review for gene: ATP9A was set to AMBER
Added comment: Vogt, Verheyen et al (2021 - http://dx.doi.org/10.1136/jmedgenet-2021-107843) report 3 affected individuals from 2 unrelated consanguineous families.

Features included DD, variable ID (Fam1: sib1-mild, sib2-possible, Fam2: severe), postnatal microcephaly (-2.33 to -3.58 SD), failure to thrive as well as gastrointestinal symptoms (nausea, vomiting, GE reflux).

These subjects were homozygous for pLoF ATP9A variants private to each family.

Previous investigations incl. karyotype, aCGH and transferrin electophoresis (CDGs) and were unremarkable.

Diagnosis was made by exome sequencing and homozygosity mapping. Affected sibs from the first family were homozygous for a stopgain variant [NM_006045.3:c.868C>Τ / p.(Arg290*)]. The subject from the second family was homozygous for a variant affecting the consensus (donor) splice site [c.642+1G>A - same RefSeq]. Both variants were absent from gnomAD. Sanger sequencing was used to confirm variants, carrier status of the parents and unaffected sibs in both families.

Sequencing of cDNA from the individual homozygous for the splicing variant demonstrated skipping of exon 7 with the variant likely leading to frameshift and introduction of a premature stop codon.

qPCR in dermal fibroblasts from affected individuals from both families revealed expression downregulation of ATP9A (14% and 4% respectively for the stopgain and splice variant). Study at the protein level was not possible due to absence of antibody against endogenous ATP9A.

ATP9A encodes ATPase phospholipid transporting 9A (similarly to ATP9B) belonging to the subclass 2 of the P4-ATPase family. As the authors comment, the protein is mainly expressed in the brain although the precise function or subcellular distribution of endogenous ATP9A are unknown.

A previous study showed that overexpressed ATP9A in HeLa cells localizes to early/recycling endosomes and the trans-Golgi network, being required for endocytic recycling of the transferrin receptor to the plasma membrane. ATP9A (in complex with DOP1B and MON2) functionally interacts with the SNX3-retromer. A previous ATP9A knockdown cell line suggested dysregulation of >100 genes with ARPC3 (actin-related protein 2/3 complex subunit 3) being strongly upregulated.

Overall ATP9A appears to have a role in endosome trafficking pathways as well as to inhibit secretion of exosomes at the plasma membrane likely due to alteration of the actin cytoskeleton.

In line with the role of APT9A in early/recycling endosomes and identified interactions, the authors demonstrated overexpression of ARPC3 and SNX3. Study of genes encoding other known interacting proteins was not possible due to poor expression in fibroblasts.

As the authors note, mutations in genes encoding proteins of the Golgi and endosomal trafficking are important for brain development and have been associated with postnatal microcephaly.

In OMIM, G2P, SysID there is no associated phenotype.

The gene is included in the ID panel of PanelApp AUS with amber rating.
Sources: Literature, Other
Intellectual disability v3.1201 ZDHHC9 Ivone Leong Phenotypes for gene: ZDHHC9 were changed from Mental retardation, X-linked syndromic, Raymond type, 300799; MENTAL RETARDATION SYNDROMIC X-LINKED ZDHHC9-RELATED (MRXSZ) to Mental retardation, X-linked syndromic, Raymond type, OMIM:300799
Intellectual disability v3.1200 CEP85L Sarah Leigh edited their review of gene: CEP85L: Added comment: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least nine variants reported in nine unrelated families. PMID 32097630 comments that - the CEP85L gene as a whole is tolerant to loss of function and to missense variation. However, the 4 missense variants that have been identified in patients affect a 15-aa region of the protein that is highly intolerant to missense variation, the splicing and start-loss variants are predicted to produce a shortened protein that excludes the same 15-aa region. It is speculated that variants in this constrained region, may act through a dominant-negative mechanism.
Intellectual disability was apparent in eight of the families studied, ranging from mild (three families) to moderate (five families).
Supportive studies were also presented (PMID 32097630, 32097629).; Changed rating: GREEN
Intellectual disability v3.1198 DPYSL5 Ivone Leong changed review comment from: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in Gene2Phenotype (probable) but not in OMIM.

PMID: 33894126. 10 individuals (2 of whom are related). 7/7 had severe ID, 9/9 DD and hypotonia, 3/6 ataxia, 3/10 seizures, 6/7 cerebellar hypoplasia and 7/10 corpus callosum agenesis.

Based on literature and expert review, there is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.; to: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in Gene2Phenotype (probable) but not in OMIM.

PMID: 33894126. 10 individuals (2 of whom are related). 7/7 had severe ID, 9/9 DD and hypotonia, 3/6 ataxia, 3/10 seizures, 6/7 cerebellar hypoplasia and 7/10 corpus callosum agenesis. Age range from 2.5 years to 33 years.

Based on literature and expert review, there is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Intellectual disability v3.1198 DPYSL5 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in Gene2Phenotype (probable) but not in OMIM.

PMID: 33894126. 10 individuals (2 of whom are related). 7/7 had severe ID, 9/9 DD and hypotonia, 3/6 ataxia, 3/10 seizures, 6/7 cerebellar hypoplasia and 7/10 corpus callosum agenesis.

Based on literature and expert review, there is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Intellectual disability v3.1197 CHD5 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in Gene2Phenotype (possible) but not in OMIM.

PMID: 33944996. Age ranged from 3 years - 22 years. 9/14 individuals had ID (only 6 of 9 patients were assessed for severity with 2 moderate ID and 4 severe cases). 10/16 individuals had epilepsy. 7/14 had hypotonia and 3/7 had craniosynostosis. 16 different variants were identified (11 missense, 1 frameshift, 2 nonsense and 2 splice site variants).

There are >3 unrelated cases, therefore there is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Intellectual disability v3.1195 CEP85L Rachel Challis gene: CEP85L was added
gene: CEP85L was added to Intellectual disability. Sources: NHS GMS
Mode of inheritance for gene: CEP85L was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CEP85L were set to 32097629; 32097630
Phenotypes for gene: CEP85L were set to Intellectual disability; epilepsy, lissencephaly
Penetrance for gene: CEP85L were set to unknown
Review for gene: CEP85L was set to GREEN
gene: CEP85L was marked as current diagnostic
Added comment: Recommend adding as Green gene to GMS - R29 Intellectual disability panel.

Monoallelic missense and loss of function variants in CEP85L are associated with Lissencephaly (OMIM 618873). Over 10 unrelated families have been described with de novo and inherited rare variants in CEP85L. Functional work in cell lines and knockdown of Cep85l in mice confirms the role of CEP85L in neuronal migration.
PMID: 32097629
PMID: 32097630
Sources: NHS GMS
Intellectual disability v3.1195 PCDHGC4 Sarah Leigh changed review comment from: Not associated with a phenotype in OMIM, Gen2Phen or MONDO. At least eight variants reported in 19 members of nine unreleted families with a neurodevelopmental syndrome. Severe or moderate intellectual disabilty was found in eight families and seizures were evident in four families. Four of the variants were terminating, in silico analysis of the remaining missense (n=3) and splice variants were predicted to be pathogenic.
Sources: Literature; to: Not associated with a phenotype in OMIM, Gen2Phen or MONDO (15/7/2021). At least eight variants reported in 19 members of nine unreleted families with a neurodevelopmental syndrome. Severe or moderate intellectual disabilty was found in eight families and seizures were evident in four families. Four of the variants were terminating, in silico analysis of the remaining missense (n=3) and splice variants were predicted to be pathogenic.
Sources: Literature
Intellectual disability v3.1194 PCDHGC4 Sarah Leigh gene: PCDHGC4 was added
gene: PCDHGC4 was added to Intellectual disability. Sources: Literature
Q3_21_rating tags were added to gene: PCDHGC4.
Mode of inheritance for gene: PCDHGC4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PCDHGC4 were set to 34244665
Phenotypes for gene: PCDHGC4 were set to neurodevelopmental syndrome
Review for gene: PCDHGC4 was set to GREEN
Added comment: Not associated with a phenotype in OMIM, Gen2Phen or MONDO. At least eight variants reported in 19 members of nine unreleted families with a neurodevelopmental syndrome. Severe or moderate intellectual disabilty was found in eight families and seizures were evident in four families. Four of the variants were terminating, in silico analysis of the remaining missense (n=3) and splice variants were predicted to be pathogenic.
Sources: Literature
Intellectual disability v3.1193 ATXN2L Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not asssociated with a phenotype in OMIM or Gene2Phenotype. There is not enough evidence to support a gene-disease association. This gene has been given a Amber rating.
Intellectual disability v3.1192 EPHA7 Ivone Leong Added comment: Comment on list classification: New gene added by Konstantinos Varvagiannis (Other). This gene is not associated with a phenotype in OMIM or Gene2Phenotype. This gene has been given an Amber rating based on expert review.
Intellectual disability v3.1190 ERGIC3 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not asssociated with a phenotype in OMIM or Gene2Phenotype. There is not enough evidence to support a gene-disease association. This gene has been given an Amber rating.
Intellectual disability v3.1188 HEATR5B Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not associated with a phenotype in OMIM or Gene2Phenotype. There is currently not enough evidence to support a gene-disease association. This gene has been given an Amber rating.
Intellectual disability v3.1187 HEATR5B Ivone Leong Phenotypes for gene: HEATR5B were changed from pontocerebellar hypoplasia; intellectual disability; seizures to pontocerebellar hypoplasia, MONDO:0020135; intellectual disability, MONDO:0001071; seizures
Intellectual disability v3.1186 JPH3 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is asssociated with a phenotype in OMIM but not Gene2Phenotype. As there is only one case there is not enough evidence to support a gene-disease association. This gene has been given a Red rating.
Intellectual disability v3.1185 KIF1B Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is asssociated with a phenotype in OMIM but not Gene2Phenotype. As there is only one case there is not enough evidence to support a gene-disease association. This gene has been given a Red rating.
Intellectual disability v3.1183 SAMD9L Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in OMIM and Gene2Phenotype, but nothing related to ID. There is currently not enough evidence to support a gene-disease association. This gene has been given a Red status.
Intellectual disability v3.1180 SPTBN1 Sarah Leigh gene: SPTBN1 was added
gene: SPTBN1 was added to Intellectual disability. Sources: Literature
Q3_21_rating tags were added to gene: SPTBN1.
Mode of inheritance for gene: SPTBN1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SPTBN1 were set to 34211179
Phenotypes for gene: SPTBN1 were set to autosomal dominant neurodevelopmental syndrome
Review for gene: SPTBN1 was set to GREEN
Added comment: Not associated with a phenotype in OMIM, Gen2Phen or MONDO (as of 13/07/2021). At least 27 monoallelic variants reported in 29 individuals with neurodevelopmental abnormalities. Developmental delay was reported in 28/28 tested cases. Intellectual disabilty was reported in 21/24 tested cases (including severe in 5 cases, moderate to severe in 2 cases and moderate in 4 cases) and epilepsy/seizures was reported in 9/24 tested cases (including febrile seizures in 2 cases). Extensive supportive functional evidence was also reported (PMID 34211179).
Sources: Literature
Intellectual disability v3.1179 NAA20 Sarah Leigh changed review comment from: Not associated with a phenotype in OMIM nor Gen2Phen. Two missense variants reported as homozygotes in one family each. In silico predictions and in vitro functional studies provide evidence that these variants will adversely affect their capacity to form a NatB complex with NAA25, and in vitro acetylation assays revealed reduced catalytic activities toward different NatB substrates (PMID 34230638). Children from these two families had developmental delay, intellectual disability (mild to moderate family 1, severe family 2).
The two children in family 1 in this study had a head circumcernces of -2.3 & -1.9 SD (which is not regarded as severe microcephaly).
The three children from family 2 this study had a head circumcernces of -3.5, -3.0 & -3.5 SD (which is regarded as severe microcephaly). Subtle dysmorphic features were also reported.
Sources: Literature; to: Not associated with a phenotype in OMIM nor Gen2Phen. Two missense variants reported as homozygotes in one family each. In silico predictions and in vitro functional studies provide evidence that these variants will adversely affect their capacity to form a NatB complex with NAA25, and in vitro acetylation assays revealed reduced catalytic activities toward different NatB substrates (PMID 34230638). Children from these two families had developmental delay, intellectual disability (mild to moderate family 1, severe family 2).
The two children in family 1 in this study had a head circumcernces of -2.3 & -1.9 SD (which is not regarded as severe microcephaly).
The three children from family 2 in this study had a head circumcernces of -3.5, -3.0 & -3.5 SD (which is regarded as severe microcephaly). Subtle dysmorphic features were also reported.
Sources: Literature
Intellectual disability v3.1179 NAA20 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be amber on this panel, based on two missense variants, which have supporting in silico and experimental evidence in cases with mild to severe intellectually disability (PMID 34230638).
Intellectual disability v3.1177 NAA20 Sarah Leigh gene: NAA20 was added
gene: NAA20 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: NAA20 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NAA20 were set to 34230638
Phenotypes for gene: NAA20 were set to autosomal recessive developmental delay, intellectual disability, and microcephaly
Review for gene: NAA20 was set to AMBER
Added comment: Not associated with a phenotype in OMIM nor Gen2Phen. Two missense variants reported as homozygotes in one family each. In silico predictions and in vitro functional studies provide evidence that these variants will adversely affect their capacity to form a NatB complex with NAA25, and in vitro acetylation assays revealed reduced catalytic activities toward different NatB substrates (PMID 34230638). Children from these two families had developmental delay, intellectual disability (mild to moderate family 1, severe family 2).
The two children in family 1 in this study had a head circumcernces of -2.3 & -1.9 SD (which is not regarded as severe microcephaly).
The three children from family 2 this study had a head circumcernces of -3.5, -3.0 & -3.5 SD (which is regarded as severe microcephaly). Subtle dysmorphic features were also reported.
Sources: Literature
Intellectual disability v3.1176 CAMK2A Ivone Leong Phenotypes for gene: CAMK2A were changed from Intellectual disability to Mental retardation, autosomal dominant 53, OMIM:617798; ?Mental retardation, autosomal recessive 63, OMIM:618095
Intellectual disability v3.1175 CAMK2A Ivone Leong Added comment: Comment on publications: PMID:29784083. 2 siblings born from consanguineous parents from Jordan with homozygous missense variant. Both had severe ID.
Intellectual disability v3.1174 MYT1 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in Gene2Phenotype but not in OMIM. There is currently not enough evidence to support a gene-disease association. This gene has been given a Red rating.
Intellectual disability v3.1173 MYT1 Ivone Leong Added comment: Comment on publications: PMID:18341605. A case with de novo subtelomeric deletion on chromosome 20 containing MYT1 and PCMTD2. Both genes affect myelination and neural differentiation.

PMID:33710394. Authors also discuss that variants in MYT1 have been identified in patients with oculo-auriculo-vertebral spectrum (OAVS) who have normal intelligence.
Intellectual disability v3.1169 FLNA Arina Puzriakova Phenotypes for gene: FLNA were changed from Frontometaphyseal dysplasia, 305620Heterotopia, periventricular, ED variant, 300537FG syndrome 2, 300321Cardiac valvular dysplasia, X-linked, 314400Terminal osseous dysplasia, 300244Congenital short bowel syndrome, 300048; EPILEPTIC ENCEPHALOPATHY to Heterotopia, periventricular, 1, OMIM:300049; Otopalatodigital syndrome, type II, OMIM:304120; ?FG syndrome 2, OMIM:300321
Intellectual disability v3.1167 ACSL4 Ivone Leong changed review comment from: ACSL4 is said to be X-linked dominant in OMIM.

PMID: 12525535 - a family with 4 affected males, 1 unaffected male, 2 carrier females and 1 non-carrier female. All affected males full scale IQ (FSIQ) ranged from 43-71, unaffected male FSIQ is 116, carrier females ranged from 74-83 and non-carrier female is 133. All carrier females showed 100% skewed inactivation.

PMID: 11889465 - Family MRX63, all carrier females showed complete skewed X-inactivation. All affected males showed non-specific, non-progressive mental deficiency (moderate - severe). Carrier females showed highly variable cognitive capacities (normal to moderate).

Based on the available evidence the MOI should be 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)".; to: ACSL4 is said to be X-linked dominant in OMIM.

PMID: 12525535 - a family with 4 affected males, 1 unaffected male, 2 carrier females and 1 non-carrier female. All affected males full scale IQ (FSIQ) ranged from 43-71, unaffected male FSIQ is 116, carrier females ranged from 74-83 and non-carrier female is 133. All carrier females showed 100% skewed inactivation.

PMID: 11889465 - Family MRX63, all carrier females showed complete skewed X-inactivation. All affected males showed non-specific, non-progressive mental deficiency (moderate - severe). Carrier females showed highly variable cognitive capacities (normal to moderate).

As there are only 2 cases where carrier females have a phenotype, the MOI should be kept as "X-LINKED: hemizygous mutation in males, biallelic mutations in females".
Intellectual disability v3.1167 HID1 Zornitza Stark gene: HID1 was added
gene: HID1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: HID1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HID1 were set to 33999436
Phenotypes for gene: HID1 were set to Syndromic infantile encephalopathy; Hypopituitarism
Review for gene: HID1 was set to GREEN
Added comment: 7 individuals from 6 unrelated families reported. Clinical features included: hypopituitarism in combination with brain atrophy, thin corpus callosum, severe developmental delay, visual impairment, and epilepsy.
Sources: Literature
Intellectual disability v3.1167 KIF1B Zornitza Stark gene: KIF1B was added
gene: KIF1B was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: KIF1B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KIF1B were set to 33710394
Phenotypes for gene: KIF1B were set to Hypotonia; coloboma; hypoplasia of the corpus callosum; severe neurodevelopmental delay
Review for gene: KIF1B was set to RED
Added comment: Compound heterozygous missense variants reported in a woman with severe hypotonia, hypsarrhythmia, coloboma, hypoplasia of corpus callosum, severe neurodevelopmental delay.
Sources: Literature
Intellectual disability v3.1167 JPH3 Zornitza Stark gene: JPH3 was added
gene: JPH3 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: JPH3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: JPH3 were set to 33824468
Phenotypes for gene: JPH3 were set to Intellectual disability; dystonia
Review for gene: JPH3 was set to RED
Added comment: One homozygous truncating variant (NM_020655.4: c.1740dup; p.(Val581Argfs*137)) found in a female individual affected with neurodevelopmental anomalies (including delayed motor milestones, abnormal social communication, language difficulties and borderline cognitive impairment) and paroxysmal attacks of dystonia since her early infancy. No functional work.

STRs in this gene are associated with HD-like disorder.
Sources: Literature
Intellectual disability v3.1167 ERGIC3 Zornitza Stark gene: ERGIC3 was added
gene: ERGIC3 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: ERGIC3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ERGIC3 were set to 33710394; 31585110
Phenotypes for gene: ERGIC3 were set to Intellectual disability
Review for gene: ERGIC3 was set to AMBER
Added comment: PMID: 33710394 - two homozygous sibs with mild ID, a novel canonical splice (c.717+1G>A). Absent in gnomAD, no splice studies. Classed as a VUS.

PMID: 31585110 - 1 hom (p.Gln233Argfs*10) in a male 8yo with Growth retardation, Microcephaly, Learning disability, Facial dysmorphism, Abnormal pigmentation.
Sources: Literature
Intellectual disability v3.1167 ZC3H14 Zornitza Stark reviewed gene: ZC3H14: Rating: AMBER; Mode of pathogenicity: None; Publications: 21734151, 33710394, 28666327; Phenotypes: Mental retardation, autosomal recessive 56 MIM#617125; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1167 MYT1 Zornitza Stark gene: MYT1 was added
gene: MYT1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: MYT1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MYT1 were set to 33710394
Phenotypes for gene: MYT1 were set to Intellectual disability
Review for gene: MYT1 was set to RED
Added comment: Missense variant reported de novo in a patient with mild ID reported in a cohort study. Patient also had a COL9A2 variant and skeletal features. Authors referred to it as an extended phenotype and dual diagnosis.
Sources: Literature
Intellectual disability v3.1167 ATP1A2 Zornitza Stark changed review comment from: Although some of the symptoms of this condition are episodic, intellectual disability is a recognised feature.; to: Alternating hemiplegia: Although some of the symptoms of this condition are episodic, intellectual disability is a recognised feature.
Intellectual disability v3.1167 ATP1A2 Zornitza Stark edited their review of gene: ATP1A2: Added comment: PMID 33880529: six individuals with de novo missense variants reported and DD/EE/PMG.; Changed publications to: 33880529; Changed phenotypes to: Alternating hemiplegia of childhood 1, MIM# 104290, Developmental and epileptic encephalopathy
Intellectual disability v3.1167 HEATR5B Zornitza Stark gene: HEATR5B was added
gene: HEATR5B was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: HEATR5B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HEATR5B were set to 33824466
Phenotypes for gene: HEATR5B were set to pontocerebellar hypoplasia; intellectual disability; seizures
Review for gene: HEATR5B was set to AMBER
Added comment: Four affected children from two families presenting with pontocerebellar hypoplasiawith neonatal seizures, severe ID and motor delay. Two homozygous splice variants were reported (c.5051–1G>A and c.5050+4A>G) in intron 31 of HEATR5B gene. Aberrant splicing was found in patient fibroblasts, which correlated with reduced levels of HEATR5B protein. Homozygous knockout mice were not viable
Sources: Literature
Intellectual disability v3.1167 RING1 Eleanor Williams gene: RING1 was added
gene: RING1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: RING1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: RING1 were set to 29386386
Phenotypes for gene: RING1 were set to microcephaly; intellectual disability
Review for gene: RING1 was set to RED
Added comment: Not associated with any phenotype in OMIM.

PMID: 29386386 - Pierce et al 2018 - report a 13 yo female with a de novo RING1 p.R95Q variant and syndromic neurodevelopmental disabilities. Early motor and language development were normal but were delayed after the first year of life. Cognitive testing showed a verbal IQ of 55 and a visual performance IQ of 63. Head circumference at birth was -4.9 SD, and -4.2 SD at age 13 which falls into the severe microcephaly category. C. elegans with either the missense mutation or complete knockout of spat-3 (the suggested RING1 ortholog) were defective in monoubiquitylation of histone H2A and had defects in neuronal migration and axon guidance.
Sources: Literature
Intellectual disability v3.1166 PPP1R21 Ivone Leong Added comment: Comment on phenotypes: Previously:
Hepatosplenomegaly;Abnormality of the respiratory system;Generalized hypotonia, Feeding difficulties, Profound global developmental delay, Abnormality of the face, Abnormality of vision, Abnormal heart morphology
Intellectual disability v3.1166 PPP1R21 Ivone Leong Phenotypes for gene: PPP1R21 were changed from Hepatosplenomegaly; Abnormality of the respiratory system; Generalized hypotonia, Feeding difficulties, Profound global developmental delay, Abnormality of the face, Abnormality of vision, Abnormal heart morphology to Neurodevelopmental disorder with hypotonia, facial dysmorphism, and brain abnormalities, OMIM:619383
Intellectual disability v3.1163 SAMD9L Zornitza Stark gene: SAMD9L was added
gene: SAMD9L was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: SAMD9L was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SAMD9L were set to 33710394
Phenotypes for gene: SAMD9L were set to Intellectual disability
Review for gene: SAMD9L was set to RED
Added comment: Missense variant reported de novo in a patient with moderate ID, in a large cohort study. Authors described it as a phenotype expansion as ataxia-pancytopenia not found in that patient.
Sources: Literature
Intellectual disability v3.1163 RFX4 Zornitza Stark gene: RFX4 was added
gene: RFX4 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: RFX4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RFX4 were set to 33658631
Phenotypes for gene: RFX4 were set to ID, ASD, ADHD
Review for gene: RFX4 was set to GREEN
Added comment: Report of 38 individuals (from 33 unrelated families) with de novo or inherited loss of function variants in RFX3 (15 families), RFX4 (4 families), and RFX7 (14 families), identified through WES. Individuals share neurobehavioural features including ASD, intellectual disability, and/or ADHD; other frequent features include hypersensitivity to sensory stimuli and sleep problems. RFX3, RFX4, and RFX7 are strongly expressed in developing and adult human brain, and X-box binding motifs as well as RFX ChIP-seq peaks are enriched in the cis-regulatory regions of known ASD risk genes. These genes are potentially critical transcriptional regulators of neurobiological pathways associated with neurodevelopmental disease pathogenesis.
Sources: Literature
Intellectual disability v3.1163 RFX3 Zornitza Stark gene: RFX3 was added
gene: RFX3 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: RFX3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RFX3 were set to 33658631
Phenotypes for gene: RFX3 were set to ID, ASD, ADHD
Review for gene: RFX3 was set to GREEN
Added comment: Report of 38 individuals (from 33 unrelated families) with de novo or inherited loss of function variants in RFX3 (15 families), RFX4 (4 families), and RFX7 (14 families), identified through WES. Individuals share neurobehavioural features including ASD, intellectual disability, and/or ADHD; other frequent features include hypersensitivity to sensory stimuli and sleep problems. RFX3, RFX4, and RFX7 are strongly expressed in developing and adult human brain, and X-box binding motifs as well as RFX ChIP-seq peaks are enriched in the cis-regulatory regions of known ASD risk genes. These genes are potentially critical transcriptional regulators of neurobiological pathways associated with neurodevelopmental disease pathogenesis.
Sources: Literature
Intellectual disability v3.1163 RFX7 Zornitza Stark gene: RFX7 was added
gene: RFX7 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: RFX7 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RFX7 were set to 33658631
Phenotypes for gene: RFX7 were set to ID, ASD, ADHD
Review for gene: RFX7 was set to GREEN
Added comment: Report of 38 individuals (from 33 unrelated families) with de novo or inherited loss of function variants in RFX3 (15 families), RFX4 (4 families), and RFX7 (14 families), identified through WES. Individuals share neurobehavioural features including ASD, intellectual disability, and/or ADHD; other frequent features include hypersensitivity to sensory stimuli and sleep problems. RFX3, RFX4, and RFX7 are strongly expressed in developing and adult human brain, and X-box binding motifs as well as RFX ChIP-seq peaks are enriched in the cis-regulatory regions of known ASD risk genes. These genes are potentially critical transcriptional regulators of neurobiological pathways associated with neurodevelopmental disease pathogenesis.
Sources: Literature
Intellectual disability v3.1162 GNB2 Arina Puzriakova gene: GNB2 was added
gene: GNB2 was added to Intellectual disability. Sources: Literature
Q3_21_rating tags were added to gene: GNB2.
Mode of inheritance for gene: GNB2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: GNB2 were set to 31698099; 33971351; 34183358
Phenotypes for gene: GNB2 were set to Intellectual disability
Review for gene: GNB2 was set to GREEN
Added comment: GNB2 is not yet associated with any phenotype in OMIM, but has a 'confirmed' disease confidence rating for 'GNB2-related developmental disorder (monoallelic)' in G2P.

At least 14 unrelated individuals with de novo monoallelic variants, including 5 recurrent variants in 13 individuals (PMIDs: 31698099; 33971351; 34183358). All patients (except one fetus owing to termination of pregnancy) have DD/ID of variable severity (mild to severe) which appeared to correlate with the variant each individual harboured. Other variable features include non-specific facial dysmorphism, hypotonia, and autistic behaviour.
Sources: Literature
Intellectual disability v3.1160 ATP6V1A Arina Puzriakova Phenotypes for gene: ATP6V1A were changed from Epileptic encephalopathy, infantile or early childhood, 3 618012; Cutis laxa, autosomal recessive, type IID 617403 to Developmental and epileptic encephalopathy 93, OMIM:618012
Intellectual disability v3.1158 ATP2C2 Eleanor Williams gene: ATP2C2 was added
gene: ATP2C2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: ATP2C2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ATP2C2 were set to 33864365; 28440294
Phenotypes for gene: ATP2C2 were set to language impairment, HP:0002463
Review for gene: ATP2C2 was set to RED
Added comment: PMID: 33864365 - Martinelli et al 2021 - report a family with a missense variant NM_001286527.2:c.304G>A, p.(Val102Met) in ATP2C2 in a father and two siblings with specific language impairment. However two other affected siblings did not have this variant. This variant was also reported by Chen et al. They found that the variant had a higher frequency in language cases (1.8%, N = 360) compared with cohorts selected for dyslexia (0.8%, N = 520) and ADHD (0.7%, N = 150), which presented frequencies comparable to reference databases (0.9%, N = 24 046 gnomAD controls). They postulate that variant is not sufficient on its own to cause a disorder but is a susceptibility factor which increases the risk for language impairment.

PMID: 28440294 - Chen et al 2017 - report 2 probands with severe learning impairment, and missense variants in ATP2C2 (NM_001286527: c.G304A:p.V102M and NM_001291454:exon21: c.C1936T:p.R646W).
Sources: Literature
Intellectual disability v3.1156 ACSL4 Ivone Leong Phenotypes for gene: ACSL4 were changed from Mental retardation, X-linked 63, OMIM:300387; ALPORT SYNDROME WITH MENTAL RETARDATION MIDFACE HYPOPLASIA AND ELLIPTOCYTOSIS (ATS-MR) to Mental retardation, X-linked 63, OMIM:300387; Alport syndrome-intellectual disability-midface hypoplasia-elliptocytosis syndrome, MONDO:0010263
Intellectual disability v3.1155 ACSL4 Ivone Leong Phenotypes for gene: ACSL4 were changed from Mental retardation, X-linked 63, 300387; ALPORT SYNDROME WITH MENTAL RETARDATION MIDFACE HYPOPLASIA AND ELLIPTOCYTOSIS (ATS-MR) to Mental retardation, X-linked 63, OMIM:300387; ALPORT SYNDROME WITH MENTAL RETARDATION MIDFACE HYPOPLASIA AND ELLIPTOCYTOSIS (ATS-MR)
Intellectual disability v3.1154 EPHA7 Konstantinos Varvagiannis gene: EPHA7 was added
gene: EPHA7 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: EPHA7 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: EPHA7 were set to 34176129; 19664229
Phenotypes for gene: EPHA7 were set to Global developmental delay; Intellectual disability; Delayed speech and language development; Behavioral abnormality
Penetrance for gene: EPHA7 were set to Incomplete
Review for gene: EPHA7 was set to AMBER
Added comment: Lévy et al (2021 - PMID: 34176129) provide evidence that haploinssuficiency of EPHA7 results in a neurodevelopmental disorder.

The authors report on 12 individuals belonging to 9 unrelated families, all harboring with 6q microdeletions spanning EPHA7.

Overlapping features included DD (13/13), ID (10/10 - mild in most cases, individuals with larger CNVs/additional variants had more severe phenotype), speech delay and behavioral disorders. Variable other features incl. hypotonia (70%), non specific facial features, eye abnormalities (40%) and cardiac defects (25%).

The CNVs ranged from 152 kb to few Mb in size but in 4 subjects (P5-8) were only minimal, involving only EPHA7.

The 6q microdeletion included additional ID-related genes in at least one case (eg. ZNF292 in P12) while one subject (P4) harbored also a 7q11.23 Williams syndrome deletion.

Confirmation (e.g. with FISH or qPCR) and segregation analyses were performed. 9 out of 12 individuals had inherited the deletion (5 subjects paternal, 4 maternal), in 1 subject (P12) this occured de novo, while for 2 others inheritance was not specified. Most deletions were inherited from an unaffected parent (in 6/7 families), with unclear contribution in a further one.

Sequencing of an ID gene panel was performed for 5 subjects (P1-4 (sibs) and P9) and exome for 4 ones (P1,2,10,11). CNVs in all these subjects were not limited to EPHA7. These investigations did not reveal other variants responsible for the phenotype of these subjects.

EPHA7 encodes ephrin receptor A7. As the authors comment, ephrin receptors are the largest family of transmembrane receptor tyrosine kinases. These receptors interact with membrane bound ephrins and binding activates the tyrosine kinase activity of the receptor.

The authors discuss on previous studies suggesting an important role for EphA7 in brain development (modulation of cell-cell adhesion and repulsion, regulation of dendrite morphogenesis in early corticogenesis, role in dendritic spine formation later in development. EphA7 has also been proposed to drive neuronal maturation and synaptic function).

Haploinsufficiency for other ephrins or ephrin receptors has been implicated in other NDDs.

Finally the authors comment on a previous report of a de novo 2.16 Mb microdeletion spanning EPHA7 and another gene (TSG1). This deletion, reported by Traylor et al (2009 - PMID: 19664229) was identified in a 15-month old male with DD, microcephaly and dysmorphic features.

Overall Lévy et al promote incomplete penetrance and variable expressivity with haploinsufficiency of this gene being a risk factor for NDD. [The gene has also an %HI of 2.76% and a pLI of 1].

In DECIPHER there are 2 indivuals (DDD participants) with de novo missense variants and abnormality of the nervous system.

As a result this gene can be considered for inclusion in the ID panel with amber rating pending further evidence.
Sources: Literature
Intellectual disability v3.1154 ARHGEF9 Arina Puzriakova edited their review of gene: ARHGEF9: 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)
Intellectual disability v3.1154 ARHGEF9 Arina Puzriakova edited their review of gene: ARHGEF9: Changed publications to: 17893116, 18615734, 28589176, 27238888, 30048823, 33600053, 32939676
Intellectual disability v3.1154 ARHGEF9 Arina Puzriakova Tag Q3_21_MOI tag was added to gene: ARHGEF9.
Intellectual disability v3.1154 ARHGEF9 Arina Puzriakova Added comment: Comment on mode of inheritance: Currently, the MOI in OMIM is set to XLR. Heterozygous mothers of affected males have been reported as unaffected, which combined with the fact that the first few affected females presented a skewed XCI pattern (PMIDs: 17893116; 18615734; 28589176), led to consider this defect as an XLR disorder affecting females when XCI is skewed.

However, review of the literature revealed that the chromosomal aberrations identified in these all of cases occurred de novo with one allele remaining as normal and cases with random XCI have since been reported (PMID: 27238888; 30048823). More recently, at least 4 unrelated affected females have also been identified with heterozygous SNVs and a random XCI pattern (PMIDs: 33600053; 32939676).

Overall this indicates that monoallelic variants in ARHGEF9 can cause disease in females and so the MOI should be changed from XLR to XLD (tagged)
Intellectual disability v3.1154 ARHGEF9 Arina Puzriakova Mode of inheritance for gene: ARHGEF9 was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability v3.1153 ARHGEF9 Arina Puzriakova Phenotypes for gene: ARHGEF9 were changed from Epileptic encephalopathy, early infantile, 8, 300607; EPILEPTIC ENCEPHALOPATHY, EARLY INFANTILE, 8 to Developmental and epileptic encephalopathy 8, OMIM:300607
Intellectual disability v3.1152 AR Arina Puzriakova Phenotypes for gene: AR were changed from SPINAL AND BULBAR MUSCULAR ATROPHY to Spinal and bulbar muscular atrophy of Kennedy, OMIM:313200
Intellectual disability v3.1149 UFSP2 Sarah Leigh changed review comment from: The founder variant rs142500730 appears to the be causal for pediatric neurodevelopmental anomalies and epilepsy feautres in over seven Asian families form different locations.; to: The Q2_21_expert_review tag has been added to consider the evidence for the founder variant rs142500730, which appears to the be causal for pediatric neurodevelopmental anomalies and epilepsy feautres in over seven Asian families form different locations.
Intellectual disability v3.1146 KDM3B Ivone Leong Added comment: Comment on publications: PMID: 30929739. 8/16 patients had short stature (< -2.5 SD) and 9/15 had neonatal feeding difficulties. 5/16 had joint hypermobility, 4/17 had hearing loss.
Intellectual disability v3.1145 GEMIN5 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). There is sufficient evidence to promote this gene to Green at the next GMS panel update (see details below).
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Kour et al. 2021 (PMID: 33963192) report 30 individuals from 22 unrelated families with biallelic variants in the GEMIN5 gene. All affected individuals displayed predominantly motor DD, although cognitive and speech delays were also seen in most patients (18/19). 23/30 had central hypotonia, and variable appendicular spasticity was observed in 13/30 cases. 8 individuals were nonambulatory, while all ambulatory patients (19) had a gait ataxia. Brain MRI in all cases showed cerebellar atrophy.

Variants perturbed the subcellular distribution, stability, and expression of GEMIN5 protein and its interacting partners, and disrupted snRNP complex assembly formation in patient iPSC-derived neurons, suggesting a LoF mechanism. Knockdown in Drosophila lead to developmental defects, motor dysfunction, and a reduced lifespan

GEMIN5 is associated with a relevant phenotype in OMIM (Neurodevelopmental disorder with cerebellar atrophy and motor dysfunction, MIM# 619333) but is not yet listed in G2P.
Intellectual disability v3.1144 GEMIN5 Arina Puzriakova Phenotypes for gene: GEMIN5 were changed from Neurodevelopmental disorder with cerebellar atrophy and motor dysfunction, MIM# 619333 to Neurodevelopmental disorder with cerebellar atrophy and motor dysfunction, OMIM:619333
Intellectual disability v3.1143 BCAS3 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). There is sufficient evidence to promote this gene to Green at the next GMS panel update (see details below).
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Hengel et al. 2021 (PMID: 34022130) report 8 unrelated families, all with different biallelic variants in the BCAS3 gene. All affected individuals (15 total, +1 additional proband but with unphased variants but consistent phenotype) had severe GDD and ID, with 10 subjects having minimal vocabulary and 4 never learning to speak. All probands had a severe motor disorder with pyramidal tract involvement resulting in hyperreflexia and spasticity of the lower limbs (15/15). Other variable features observed in the cohort include microcephaly, short stature, seizures, and dysmorphic facial features.
Intellectual disability v3.1142 CPE Arina Puzriakova changed review comment from: Comment on list classification: New gene added by Zornitza Stark. Two consanguineous families in literature with different homozygous variants in the CPE gene. Affected individuals presented with obesity, intellectual disability and hypogonadotropic hypogonadism. Rating Amber, awaiting further cases (added watchlist tag); to: Comment on list classification: New gene added by Zornitza Stark. Two consanguineous families in literature to date with different homozygous variants in the CPE gene (PMIDs: 26120850; 32936766). Affected individuals presented with obesity, intellectual disability and hypogonadotropic hypogonadism. Rating Amber, awaiting further cases (added watchlist tag)
Intellectual disability v3.1142 CPE Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. Two consanguineous families in literature with different homozygous variants in the CPE gene. Affected individuals presented with obesity, intellectual disability and hypogonadotropic hypogonadism. Rating Amber, awaiting further cases (added watchlist tag)
Intellectual disability v3.1140 PIGB Arina Puzriakova Phenotypes for gene: PIGB were changed from Epileptic encephalopathy, early infantile, 80, 618580; Generalized hypotonia; Global developmental delay; Intellectual disability; Seizures; Hearing abnormality; Abnormality of vision; Elevated alkaline phosphatase; Abnormality of the head; Abnormality of the hand; Abnormality of the foot to Developmental and epileptic encephalopathy 80, OMIM:618580
Intellectual disability v3.1137 SCN8A Arina Puzriakova Phenotypes for gene: SCN8A were changed from ?Cognitive impairment with or without cerebellar ataxia,614306; Epileptic encephalopathy, early infantile,614558; Seizures, benign familial infantile,617080 to Cognitive impairment with or without cerebellar ataxia, OMIM:614306; Developmental and epileptic encephalopathy 13, OMIM:614558
Intellectual disability v3.1136 RUBCN Arina Puzriakova reviewed gene: RUBCN: Rating: ; Mode of pathogenicity: None; Publications: 32450808; Phenotypes: Spinocerebellar ataxia, autosomal recessive 15, OMIM:615705; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.1135 RUBCN Arina Puzriakova Phenotypes for gene: RUBCN were changed from SYNDROMIC MR WITH ATAXIA, DYSARTHRIA AND EPILEPSY to Spinocerebellar ataxia, autosomal recessive 15, OMIM:615705
Intellectual disability v3.1133 POLR3B Arina Puzriakova Added comment: Comment on mode of inheritance: Both biallelic and monoallelic variants have been linked to ID. There is enough evidence for a Green rating for both allelic requirements, so POLR3B has been tagged Q2_21_MOI to change the MOI from biallelic to both biallelic/monoallelic at the next GMS review.
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Biallelic variants in POLR3B are a well-established cause of hypomyelinating leukodystrophy (OMIM:614381), associated with variable ID.

Recently, heterozygous variants were also linked to ID. Djordjevic et al. 2021 (PMID:33417887) identified different de novo POLR3B variants in 6 unrelated individuals. The majority had some degree of DD, with 5/6 participants being diagnosed with intellectual disability ranging from mild to moderate severity. Four individuals required assistance with basic activities of daily living, however none had developmental regression. Protein modelling and proteomic analysis shows variants caused aberrant association of individual enzyme subunits rather than affecting overall enzyme assembly or stability.
Intellectual disability v3.1129 PHACTR1 Arina Puzriakova Phenotypes for gene: PHACTR1 were changed from Global developmental delay; Intellectual disability; Seizures:Epileptic encephalopathy, early infantile, 70 618298; PHACTR1-associated neurodevelopment disorder to Developmental and epileptic encephalopathy 70, OMIM:618298
Intellectual disability v3.1128 EIF3F Arina Puzriakova Phenotypes for gene: EIF3F were changed from Intellectual disability; Seizures; Behavioral abnormality; Sensorineural hearing impairment to Mental retardation, autosomal recessive 67, OMIM:618295
Intellectual disability v3.1127 CUX2 Arina Puzriakova Phenotypes for gene: CUX2 were changed from Epileptic encephalopathy, early infantile, 67, 618141; Seizures; Intellectual disability; Autistic behavior to Developmental and epileptic encephalopathy 67, OMIM:618141; Seizures; Intellectual disability; Autistic behaviour
Intellectual disability v3.1125 PGM2L1 Zornitza Stark gene: PGM2L1 was added
gene: PGM2L1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: PGM2L1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PGM2L1 were set to 33979636
Phenotypes for gene: PGM2L1 were set to Neurodevelopmental disorder
Review for gene: PGM2L1 was set to GREEN
Added comment: PMID: 33979636:
- Bi-allelic PTVs in 4 unrelated individuals. All four affected individuals had severe developmental and speech delay, dysmorphic facial features, ear anomalies, high arched palate, strabismus, hypotonia, and keratosis pilaris. Early obesity and seizures were present in three individuals.
- Studies on patient fibroblasts and cell lines indicated that PGM2L1 deficiency causes a decrease, but not a disappearance, of the sugar bisphosphates needed for the formation of NDP-sugars and that there is no evidence that this leads to a glycosylation defect.
Sources: Literature
Intellectual disability v3.1125 ATXN2L Zornitza Stark gene: ATXN2L was added
gene: ATXN2L was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: ATXN2L was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ATXN2L were set to 33283965; 33057194
Phenotypes for gene: ATXN2L were set to Intellectual disability; Macrocephaly
Review for gene: ATXN2L was set to AMBER
Added comment: Combined data from three large exome groups identified several de novo variants, including frameshift and missense, in ATXN2L in patients with developmental delay (Kaplanis et al., 2020). pLI=1.0 Limited other data available.
Single case report of a novel de novo missense variant in a child with macrocephaly and developmental delay. No functional work.
Sources: Literature
Intellectual disability v3.1125 SIN3B Arina Puzriakova Added comment: Comment on list classification: New gene added and reviewed by Zornitza Stark (Green) and Konstantinos Varvagiannis (Green/Amber). Overall there are sufficient unrelated cases (>3) of ID associated with SNVs in this gene to warrant a Green rating on this panel at the next GMS review. Deletions of the region containing SIN3B have also been linked to ID, lending further support to this gene-disease association.
Intellectual disability v3.1124 EMC10 Arina Puzriakova Added comment: Comment on list classification: There is now enough evidence to warrant a Green rating at the next GMS panel update.
Intellectual disability v3.1123 EMC10 Arina Puzriakova edited their review of gene: EMC10: Added comment: There are now at least 15 individuals from 8 families reported with biallelic variants in the EMC10 gene associated with disease. One variant found in a single population is likely to be a founder variant; however, the identification of a different variant in a family presenting with a similar phenotype corroborates causality. Both variants were shown to significantly reduce EMC10 RNA expression. All affected individuals show a core phenotype of GDD/ID with variable severity. Seizures were noted in 7/15 individuals, typically during childhood or in the neonatal period, and included multifocal as well as generalized tonic–clonic seizures.; Changed rating: GREEN; Changed publications to: 32869858, 33531666; Changed phenotypes to: Neurodevelopmental disorder with dysmorphic facies and variable seizures, OMIM:619264; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1123 BCAS3 Zornitza Stark gene: BCAS3 was added
gene: BCAS3 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: BCAS3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BCAS3 were set to 34022130
Phenotypes for gene: BCAS3 were set to Syndromic neurodevelopmental disorder
Review for gene: BCAS3 was set to GREEN
Added comment: 15 individuals from eight unrelated families with germline bi-allelic loss-of-function variants in BCAS3. All probands share a global developmental delay accompanied by pyramidal tract involvement, microcephaly, short stature, strabismus, dysmorphic facial features, and seizures. Patient fibroblasts confirmed absence of BCAS3 protein.
Sources: Literature
Intellectual disability v3.1123 SRCAP Zornitza Stark reviewed gene: SRCAP: Rating: GREEN; Mode of pathogenicity: None; Publications: 33909990; Phenotypes: Neurodevelopmental disorder, non-Floating Harbor; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.1122 EMC10 Arina Puzriakova Added comment: Comment on phenotypes: EMC10 is now associated with a relevant phenotype in OMIM - 'Neurodevelopmental disorder with dysmorphic facies and variable seizures, OMIM:619264' and is listed in G2P with a 'probable' disease confidence rating for 'EMC10-related neurodevelopmental disorder'
Intellectual disability v3.1122 EMC10 Arina Puzriakova Phenotypes for gene: EMC10 were changed from Neurodevelopmental disorder with dysmorphic facies and variable seizures, OMIM:619264 to Neurodevelopmental disorder with dysmorphic facies and variable seizures, OMIM:619264
Intellectual disability v3.1121 EMC10 Arina Puzriakova Phenotypes for gene: EMC10 were changed from Intellectual disability to Neurodevelopmental disorder with dysmorphic facies and variable seizures, OMIM:619264
Intellectual disability v3.1120 GEMIN5 Zornitza Stark gene: GEMIN5 was added
gene: GEMIN5 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: GEMIN5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GEMIN5 were set to 33963192
Phenotypes for gene: GEMIN5 were set to Neurodevelopmental disorder with cerebellar atrophy and motor dysfunction, MIM# 619333
Review for gene: GEMIN5 was set to GREEN
gene: GEMIN5 was marked as current diagnostic
Added comment: Neurodevelopmental disorder with cerebellar atrophy and motor dysfunction (NEDCAM) is an autosomal recessive disorder characterized by global developmental delay with prominent motor abnormalities, mainly axial hypotonia, gait ataxia, and appendicular spasticity. Affected individuals have cognitive impairment and speech delay; brain imaging shows cerebellar atrophy.

30 individuals from 22 unrelated families reported.
Sources: Literature
Intellectual disability v3.1120 PARP6 Zornitza Stark gene: PARP6 was added
gene: PARP6 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: PARP6 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PARP6 were set to 34067418
Phenotypes for gene: PARP6 were set to Intellectual disability; Epilepsy; Microcephaly
Review for gene: PARP6 was set to GREEN
Added comment: Four unrelated individuals reported with de novo variants in this gene and a neurodevelopmental phenotype. Supportive functional data. One pair of siblings with a homozygous missense: limited evidence for bi-allelic variants causing disease.
Sources: Literature
Intellectual disability v3.1120 CPE Zornitza Stark gene: CPE was added
gene: CPE was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: CPE was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CPE were set to 26120850; 32936766
Phenotypes for gene: CPE were set to Intellectual developmental disorder and hypogonadotropic hypogonadism, MIM# 619326
Review for gene: CPE was set to AMBER
Added comment: Four affected individuals from two unrelated families reported, bi-allelic LoF variants.
Sources: Literature
Intellectual disability v3.1120 SMARCA5 Zornitza Stark reviewed gene: SMARCA5: Rating: GREEN; Mode of pathogenicity: None; Publications: 33980485; Phenotypes: Neurodevelopmental disorder, microcephaly, dysmorphic features; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.1120 CAPN15 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. Sufficient number of cases presenting with DD/ID (5/7 individuals from 3 unrelated families - PMIDs: 33410501; 32885237) to warrant a Green rating on this panel.
Intellectual disability v3.1118 ANKRD17 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. There is sufficient evidence to rate this gene Green at the next GMS panel update.

Chopra et al. 2021 (PMID: 33909992) report 34 individuals from 32 families with a heterozygous variant or microdeletion of ANKRD17. GDD/ID was the most common feature, affecting 31/33 individuals with variable severity - 7 severe, 12 moderate, 5 mild, 7 borderline. Deletions of the region containing ANKRD17 have also been associated with ID.
Intellectual disability v3.1117 SMARCA5 Arina Puzriakova Tag Q2_21_rating tag was added to gene: SMARCA5.
Tag Q2_21_NHS_review tag was added to gene: SMARCA5.
Intellectual disability v3.1117 SMARCA5 Arina Puzriakova Classified gene: SMARCA5 as Amber List (moderate evidence)
Intellectual disability v3.1117 SMARCA5 Arina Puzriakova Added comment: Comment on list classification: New gene added and reviewed Green by Julia Baptista (RD&E NHS FT). SMARCA5 should be promoted to Green at the next GMS panel update.

Variants have been associated with a variable neurodevelopmental phenotype including predominantly mild DD, short stature, and microcephaly (PMID:33980485). Regarding cognition, four probands had mild ID and one had severe ID. Although relatively mild in most patients, the number of unrelated families presenting ID is sufficient for a Green rating and inclusion on this panel should increase the likelihood of detecting cases.
Intellectual disability v3.1117 SMARCA5 Arina Puzriakova Gene: smarca5 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1115 CYP7B1 Arina Puzriakova Phenotypes for gene: CYP7B1 were changed from Spastic paraplegia 5A, autosomal recessive 270800 to Spastic paraplegia 5A, autosomal recessive , OMIM:270800
Intellectual disability v3.1112 APOPT1 Arina Puzriakova Phenotypes for gene: APOPT1 were changed from MITOCHONDRIAL COMPLEX IV DEFICIENCY, 220110 to Mitochondrial complex IV deficiency, nuclear type 17, OMIM:619061
Intellectual disability v3.1111 LAMB1 Arina Puzriakova Phenotypes for gene: LAMB1 were changed from COBBLESTONE BRAIN MALFORMATION WITHOUT MUSCULAR OR OCULAR ABNORMALITIES to Lissencephaly 5, OMIM:615191
Intellectual disability v3.1110 PDCD6IP Arina Puzriakova changed review comment from: Comment on list classification: Phenotype is relevant to this panel but additional cases required to validate pathogenicity of variants in this gene. Therefore Rating Amber, awaiting further publications.; to: Comment on list classification: Phenotype is relevant to this panel with a supportive animal model that recapitulates features such as microcephaly. However, additional cases required to validate pathogenicity prior to inclusion as diagnostic-grade. Therefore Rating Amber, awaiting further publications.
Intellectual disability v3.1110 PDCD6IP Arina Puzriakova changed review comment from: Comment on list classification: Phenotype is relevant to this panel but additional cases required to validate pathogenicity of variants in this gene.; to: Comment on list classification: Phenotype is relevant to this panel but additional cases required to validate pathogenicity of variants in this gene. Therefore Rating Amber, awaiting further publications.
Intellectual disability v3.1107 FOXG1 Sarah Leigh Phenotypes for gene: FOXG1 were changed from Rett syndrome, congenital variant, 613454; CONGENITAL VARIANT OF RETT SYNDROME (RTTCV) to Rett Syndrome, congenital variant OMIM:613454; Rett syndrome, congenital variant MONDO:0013270
Intellectual disability v3.1106 SMARCE1 Arina Puzriakova Phenotypes for gene: SMARCE1 were changed from COFFIN SIRIS to Coffin-Siris syndrome 5, OMIM:616938
Intellectual disability v3.1105 SMARCC1 Arina Puzriakova Mode of inheritance for gene: SMARCC1 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.1103 DPH1 Arina Puzriakova Phenotypes for gene: DPH1 were changed from Developmental delay with short stature, dysmorphic features, and sparse hair, 616901 to Developmental delay with short stature, dysmorphic facial features, and sparse hair, OMIM:616901
Intellectual disability v3.1100 SMARCA5 Julia Baptista gene: SMARCA5 was added
gene: SMARCA5 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: SMARCA5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SMARCA5 were set to 33980485
Phenotypes for gene: SMARCA5 were set to intellectual disability; postnatal microcephaly; hypotonia; failure to thrive
Penetrance for gene: SMARCA5 were set to unknown
Review for gene: SMARCA5 was set to GREEN
Added comment: The authors identified seven missense variants, one splice-altering variant that led to exon skipping and in-frame deletion, and one recurrent in-frame deletion in 12 individuals from
10 unrelated families. The variant was de novo in nine individuals. They presented a broad range of clinical features from isolated autism to syndromic intellectual disability.
Sources: Literature
Intellectual disability v3.1100 UFSP2 Sarah Leigh changed review comment from: Comment on list classification: A founder variant (rs142500730) reported in four South Asian families (haplotype analysis available for two of the families proves relatedness). Functional studies suggest that although mRNA expression seems to be unaffected, protein stability maybe responsible for the reduced protein detected by immunoblotting in patients fibroblasts (PMID 33473208).
Homozygous rs142500730 has also been reported in individuals (2 Asian and 1 white) in the Genoimcs England 100K study, with epilepsy and intellectual disabilities.; to: Comment on list classification: A founder variant (rs142500730) reported in four South Asian families (haplotype analysis available for two of the families proves relatedness). Functional studies suggest that although mRNA expression seems to be unaffected, protein stability maybe responsible for the reduced protein detected by immunoblotting in patients fibroblasts (PMID 33473208).
Homozygous rs142500730 has also been reported in individuals (Asian and white) in the Genoimcs England 100K study, with epilepsy and intellectual disabilities.
Intellectual disability v3.1096 SCYL1 Sarah Leigh Phenotypes for gene: SCYL1 were changed from Spinocerebellar ataxia, autosomal recessive 21, 616719 to Spinocerebellar ataxia, autosomal recessive 21 OMIM:616719; acute infantile liver failure-cerebellar ataxia-peripheral sensory motor neuropathy syndrome MONDO:0014744
Intellectual disability v3.1094 UFSP2 Sarah Leigh changed review comment from: Comment on list classification: A founder variant (rs142500730) reported in four South Asian families (haplotype analysis available for two of the families proves relatedness). Functional studies suggest that although mRNA expression seems to be unaffected, protein stability maybe responsible for the reduced protein detected by immunoblotting in patients fibroblasts (PMID 33473208).
rs142500730 has also been reported in individuals in the Genoimcs England 100K study, with epilepsy and intellectual disabilities.; to: Comment on list classification: A founder variant (rs142500730) reported in four South Asian families (haplotype analysis available for two of the families proves relatedness). Functional studies suggest that although mRNA expression seems to be unaffected, protein stability maybe responsible for the reduced protein detected by immunoblotting in patients fibroblasts (PMID 33473208).
Homozygous rs142500730 has also been reported in individuals (2 Asian and 1 white) in the Genoimcs England 100K study, with epilepsy and intellectual disabilities.
Intellectual disability v3.1094 UFSP2 Sarah Leigh edited their review of gene: UFSP2: Added comment: The founder variant rs142500730 appears to the be causal for pediatric neurodevelopmental anomalies and epilepsy feautres in over seven Asian families form different locations.; Changed rating: GREEN
Intellectual disability v3.1094 UFSP2 Konstantinos Varvagiannis changed review comment from: Ni et al (2021 - PMID: 33473208) describe the phenotype of 8 children (belonging to 4 families - 2 of which consanguineous) homozygous for a UFSP2 missense variant [NM_018359.5:c.344T>A; p.(Val115Glu)].

Members of a broader consanguineous pedigree from Pakistan with 3 affected children with epilepsy and DD and ID underwent exome sequencing. All affected individuals were homozygous for the specific SNV with their parents (2 parent pairs, in both cases first cousins) being heterozygous. An unaffected sib was homozygous for the wt allele. Through genematching platforms 3 additional families with similarly affected individuals and homozygosity for the same variant were recruited. These additional families were from Pakistan (1/3) and Afganistan (2/3).

Based on ROH analysis from the broader first pedigree and an additional family the authors concluded on a single shared region of homozygosity on chr 4q. Lack of ES data did not allow verification of whether 2/4 families shared the same haplotype with the other 2.

The authors calculated the probability of the genotype-phenotype cosegragation occurring by chance (0.009) and this was lower than the recommended criterion (0.06) for strong evidence of pathogenicity.

Shared features included abnormal tone in most (hypotonia 6/8, limb hypertonia 1/8), seizures (8/8 - onset 2d - 7m), severe DD with speech delay/absent speech (8/8), ID (8/8), strabismus (6/8).

UFSP2 encodes UFM1-specific protease 2 involved in UFmylation, a post-translational protein modification. As summarized by the authors the cysteine protease encoded by this gene (as is also the case for UFSP1) cleaves UFM1 in the initial step of UFMylation. Apart from producing mature UFM1, the 2 proteases have also the ability to release UFM1 from UFMylated proteins, in the process of de-UFMylation. [several refs. provided]

UFMylation is important in brain development with mutations in genes encoding other components of the pathway reported in other NDD disorders (incl. UFM1, UBA5, UFC1).

Additional studies were carried to provide evidence for pathogenicity of this variant.

Skin biopsies from 3 individuals were carried out to establish fibroblast cultures. Immunoblotting revealed reduced UFSP2 levels relative to controls. mRNA levels measured by qRT-PCR revealed no differences compared to controls altogether suggesting normal mRNA but reduced protein stability.

The authors demonstrated increased levels of UFM1-conjugated proteins (incl. DDRGK1, or TRIP4). Ectopic expression of wt UFSP2 normalized the levels of UFMylated proteins in the fibroblasts which was not the case for the V115E variant. Further the variant was difficult to detect by immunoblotting consistent with an effect on protein destabilization.

Although disruption of UFMylation induces ER stress, this was not shown to occur in patient fibroblast lines, when assessed for ER stress markers.

Evaluation of data from the GTEx project, concerning UFSP2 as well as well as DDRGK1 or TRIP4 - an UFMylation target - revealed relevant expression in multiple regions of the human brain.

Overall the authors provide evidence for defective de-UFMylation in patient fibroblasts (presence of increased UFMylation marks). The authors stress out that the effect of the variant in UFMylation in brain is unknown, as UFSP1 or other enzymes might compensate in the presence of hypomorphic UFSP2 mutants.

Biallelic UFSP2 variants have previously been reported in 2 skeletal dysplasias [# 142669. BEUKES HIP DYSPLASIA; BHD and # 617974. SPONDYLOEPIMETAPHYSEAL DYSPLASIA, DI ROCCO TYPE; SEMDDR]. These disorders are not characterized by neurological dysfunction or epilepsy. The authors underscore the fact that variants identified in these disorders (Y290H, D526A, H428R) localize within the C-terminal catalytic (peptidase) domain [aa 278 – 461] while the variant here identified lies in the N-terminal substrate binding domain affecting protein stability/abundance.

In OMIM, only the 2 aforementioned disorders are currently associated with biallelic UFSP2 mutations. There is no associated phenotype in G2P. SysID includes UFSP2 among the primary ID genes.

You may consider inclusion in the current panel with amber/green rating.
Sources: Literature; to: Ni et al (2021 - PMID: 33473208) describe the phenotype of 8 children (belonging to 4 families - 2 of which consanguineous) homozygous for a UFSP2 missense variant [NM_018359.5:c.344T>A; p.(Val115Glu)].

Members of a broader consanguineous pedigree from Pakistan with 3 affected children with epilepsy and DD and ID underwent exome sequencing. All affected individuals were homozygous for the specific SNV with their parents (2 parent pairs, in both cases first cousins) being heterozygous. An unaffected sib was homozygous for the wt allele. Through genematching platforms 3 additional families with similarly affected individuals and homozygosity for the same variant were recruited. These additional families were from Pakistan (1/3) and Afganistan (2/3).

Based on ROH analysis from the broader first pedigree and an additional family the authors concluded on a single shared region of homozygosity on chr 4q. Lack of ES data did not allow verification of whether 2/4 families shared the same haplotype with the other 2.

The authors calculated the probability of the genotype-phenotype cosegragation occurring by chance (0.009) and this was lower than the recommended criterion (0.06) for strong evidence of pathogenicity.

Shared features included abnormal tone in most (hypotonia 6/8, limb hypertonia 1/8), seizures (8/8 - onset 2d - 7m), severe DD with speech delay/absent speech (8/8), ID (8/8), strabismus (6/8).

UFSP2 encodes UFM1-specific protease 2 involved in UFmylation, a post-translational protein modification. As summarized by the authors the cysteine protease encoded by this gene (as is also the case for UFSP1) cleaves UFM1 in the initial step of UFMylation. Apart from producing mature UFM1, the 2 proteases have also the ability to release UFM1 from UFMylated proteins, in the process of de-UFMylation. [several refs. provided]

UFMylation is important in brain development with mutations in genes encoding other components of the pathway reported in other NDD disorders (incl. UFM1, UBA5, UFC1).

Additional studies were carried to provide evidence for pathogenicity of this variant.

Skin biopsies from 3 individuals were carried out to establish fibroblast cultures. Immunoblotting revealed reduced UFSP2 levels relative to controls. mRNA levels measured by qRT-PCR revealed no differences compared to controls altogether suggesting normal mRNA but reduced protein stability.

The authors demonstrated increased levels of UFM1-conjugated proteins (incl. DDRGK1, or TRIP4). Ectopic expression of wt UFSP2 normalized the levels of UFMylated proteins in the fibroblasts which was not the case for the V115E variant. Further the variant was difficult to detect by immunoblotting consistent with an effect on protein destabilization.

Although disruption of UFMylation induces ER stress, this was not shown to occur in patient fibroblast lines, when assessed for ER stress markers.

Evaluation of data from the GTEx project, concerning UFSP2 as well as well as DDRGK1 or TRIP4 - an UFMylation target - revealed relevant expression in multiple regions of the human brain.

Overall the authors provide evidence for defective de-UFMylation in patient fibroblasts (presence of increased UFMylation marks). The authors stress out that the effect of the variant in UFMylation in brain is unknown, as UFSP1 or other enzymes might compensate in the presence of hypomorphic UFSP2 mutants.

**Monoallelic** (correction to previous review) UFSP2 variants have previously been reported in 2 skeletal dysplasias [# 142669. BEUKES HIP DYSPLASIA; BHD and # 617974. SPONDYLOEPIMETAPHYSEAL DYSPLASIA, DI ROCCO TYPE; SEMDDR]. These disorders are not characterized by neurological dysfunction or epilepsy. The authors underscore the fact that variants identified in these disorders (Y290H, D526A, H428R) localize within the C-terminal catalytic (peptidase) domain [aa 278 – 461] while the variant here identified lies in the N-terminal substrate binding domain affecting protein stability/abundance.

In OMIM, only the 2 aforementioned disorders are currently associated with biallelic UFSP2 mutations. There is no associated phenotype in G2P. SysID includes UFSP2 among the primary ID genes.

You may consider inclusion in the current panel with amber/green rating.
Sources: Literature
Intellectual disability v3.1094 UFSP2 Sarah Leigh changed review comment from: Comment on list classification: A founder variant (rs142500730) reported in four South Asian families (haplotype analysis available for two of the families proves relatedness). Functional studies suggest that although expression seems to be unaffected, immunoblotting indicates that protein stability maybe affected (PMID 33473208).
rs142500730 has also been reported in individuals in the Genoimcs England 100K study, with epilepsy and intellectual disabilities.; to: Comment on list classification: A founder variant (rs142500730) reported in four South Asian families (haplotype analysis available for two of the families proves relatedness). Functional studies suggest that although mRNA expression seems to be unaffected, protein stability maybe responsible for the reduced protein detected by immunoblotting in patients fibroblasts (PMID 33473208).
rs142500730 has also been reported in individuals in the Genoimcs England 100K study, with epilepsy and intellectual disabilities.
Intellectual disability v3.1094 UFSP2 Sarah Leigh Added comment: Comment on list classification: A founder variant (rs142500730) reported in four South Asian families (haplotype analysis available for two of the families proves relatedness). Functional studies suggest that although expression seems to be unaffected, immunoblotting indicates that protein stability maybe affected (PMID 33473208).
rs142500730 has also been reported in individuals in the Genoimcs England 100K study, with epilepsy and intellectual disabilities.
Intellectual disability v3.1093 UFSP2 Sarah Leigh Added comment: Comment on phenotypes: No OMIM reference for the pediatric neurodevelopmental anomalies and epilepsy feautres. Monoallelic variants have previously been associated with skeletal dysplasias (PMIDs 28892125;26428751;32755715), but there does not appear to be any phenotypic overlap between these and the phenotype seen for the biallelic rs142500730.
Intellectual disability v3.1092 UFSP2 Konstantinos Varvagiannis gene: UFSP2 was added
gene: UFSP2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: UFSP2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: UFSP2 were set to 33473208
Phenotypes for gene: UFSP2 were set to Abnormal muscle tone; Seizures; Global developmental delay; Delayed speech and language development; Intellectual disability; Strabismus
Penetrance for gene: UFSP2 were set to Complete
Added comment: Ni et al (2021 - PMID: 33473208) describe the phenotype of 8 children (belonging to 4 families - 2 of which consanguineous) homozygous for a UFSP2 missense variant [NM_018359.5:c.344T>A; p.(Val115Glu)].

Members of a broader consanguineous pedigree from Pakistan with 3 affected children with epilepsy and DD and ID underwent exome sequencing. All affected individuals were homozygous for the specific SNV with their parents (2 parent pairs, in both cases first cousins) being heterozygous. An unaffected sib was homozygous for the wt allele. Through genematching platforms 3 additional families with similarly affected individuals and homozygosity for the same variant were recruited. These additional families were from Pakistan (1/3) and Afganistan (2/3).

Based on ROH analysis from the broader first pedigree and an additional family the authors concluded on a single shared region of homozygosity on chr 4q. Lack of ES data did not allow verification of whether 2/4 families shared the same haplotype with the other 2.

The authors calculated the probability of the genotype-phenotype cosegragation occurring by chance (0.009) and this was lower than the recommended criterion (0.06) for strong evidence of pathogenicity.

Shared features included abnormal tone in most (hypotonia 6/8, limb hypertonia 1/8), seizures (8/8 - onset 2d - 7m), severe DD with speech delay/absent speech (8/8), ID (8/8), strabismus (6/8).

UFSP2 encodes UFM1-specific protease 2 involved in UFmylation, a post-translational protein modification. As summarized by the authors the cysteine protease encoded by this gene (as is also the case for UFSP1) cleaves UFM1 in the initial step of UFMylation. Apart from producing mature UFM1, the 2 proteases have also the ability to release UFM1 from UFMylated proteins, in the process of de-UFMylation. [several refs. provided]

UFMylation is important in brain development with mutations in genes encoding other components of the pathway reported in other NDD disorders (incl. UFM1, UBA5, UFC1).

Additional studies were carried to provide evidence for pathogenicity of this variant.

Skin biopsies from 3 individuals were carried out to establish fibroblast cultures. Immunoblotting revealed reduced UFSP2 levels relative to controls. mRNA levels measured by qRT-PCR revealed no differences compared to controls altogether suggesting normal mRNA but reduced protein stability.

The authors demonstrated increased levels of UFM1-conjugated proteins (incl. DDRGK1, or TRIP4). Ectopic expression of wt UFSP2 normalized the levels of UFMylated proteins in the fibroblasts which was not the case for the V115E variant. Further the variant was difficult to detect by immunoblotting consistent with an effect on protein destabilization.

Although disruption of UFMylation induces ER stress, this was not shown to occur in patient fibroblast lines, when assessed for ER stress markers.

Evaluation of data from the GTEx project, concerning UFSP2 as well as well as DDRGK1 or TRIP4 - an UFMylation target - revealed relevant expression in multiple regions of the human brain.

Overall the authors provide evidence for defective de-UFMylation in patient fibroblasts (presence of increased UFMylation marks). The authors stress out that the effect of the variant in UFMylation in brain is unknown, as UFSP1 or other enzymes might compensate in the presence of hypomorphic UFSP2 mutants.

Biallelic UFSP2 variants have previously been reported in 2 skeletal dysplasias [# 142669. BEUKES HIP DYSPLASIA; BHD and # 617974. SPONDYLOEPIMETAPHYSEAL DYSPLASIA, DI ROCCO TYPE; SEMDDR]. These disorders are not characterized by neurological dysfunction or epilepsy. The authors underscore the fact that variants identified in these disorders (Y290H, D526A, H428R) localize within the C-terminal catalytic (peptidase) domain [aa 278 – 461] while the variant here identified lies in the N-terminal substrate binding domain affecting protein stability/abundance.

In OMIM, only the 2 aforementioned disorders are currently associated with biallelic UFSP2 mutations. There is no associated phenotype in G2P. SysID includes UFSP2 among the primary ID genes.

You may consider inclusion in the current panel with amber/green rating.
Sources: Literature
Intellectual disability v3.1091 CAMK2B Arina Puzriakova Phenotypes for gene: CAMK2B were changed from Mental retardation, autosomal dominant 54 617799 to Mental retardation, autosomal dominant 54, OMIM:617799
Intellectual disability v3.1088 UNC80 Arina Puzriakova Phenotypes for gene: UNC80 were changed from Hypotonia, infantile, with psychomotor retardation and characteristic facies 2 616801 to Hypotonia, infantile, with psychomotor retardation and characteristic facies 2, OMIM:616801
Intellectual disability v3.1087 UGP2 Arina Puzriakova Phenotypes for gene: UGP2 were changed from Epileptic encephalopathy, early infantile, 83, 618744; Global developmental delay; Intellectual disability; Feeding difficulties; Abnormality of vision; Abnormality of the face to Developmental and epileptic encephalopathy 83, OMIM:618744
Intellectual disability v3.1085 TSEN54 Arina Puzriakova Phenotypes for gene: TSEN54 were changed from PONTOCEREBELLAR HYPOPLASIA TYPE 2 AND TYPE 4 to ?Pontocerebellar hypoplasia type 5, OMIM:610204; Pontocerebellar hypoplasia type 2A, OMIM:277470; Pontocerebellar hypoplasia type 4, OMIM:225753
Intellectual disability v3.1084 AFG3L2 Sarah Leigh commented on gene: AFG3L2: Disease causing variants are both monoallelic and biallelic
Intellectual disability v3.1084 AFG3L2 Sarah Leigh Phenotypes for gene: AFG3L2 were changed from Spastic ataxia 5, autosomal recessive, 614487 to Spastic ataxia 5, autosomal recessive OMIM:614487; spastic ataxia 5 MONDO:0013776; Spinocerebellar ataxia 28 OMIM:610246; spinocerebellar ataxia type 28 MONDO:0012450
Intellectual disability v3.1083 AFG3L2 Sarah Leigh reviewed gene: AFG3L2: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Spastic ataxia 5, autosomal recessive OMIM:614487, spastic ataxia 5 MONDO:0013776, Spinocerebellar ataxia 28 OMIM:610246, spinocerebellar ataxia type 28 MONDO:0012450; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.1083 TSEN15 Arina Puzriakova Phenotypes for gene: TSEN15 were changed from delayed developmental milestones; Pontocerebellar hypoplasia, type 2F, 617026; Intellectual disability to Pontocerebellar hypoplasia, type 2F, OMIM:617026
Intellectual disability v3.1079 TRAPPC9 Arina Puzriakova Phenotypes for gene: TRAPPC9 were changed from Mental retardation, autosomal recessive 13, 613192; Mental Retardation, Recessive; MENTAL RETARDATION AUTOSOMAL RECESSIVE TYPE 13 (MRT13) to Mental retardation, autosomal recessive 13, OMIM:613192
Intellectual disability v3.1076 MINPP1 Arina Puzriakova Entity copied from Ataxia and cerebellar anomalies - narrow panel v2.174
Intellectual disability v3.1076 MINPP1 Arina Puzriakova gene: MINPP1 was added
gene: MINPP1 was added to Intellectual disability. Sources: Literature,Expert Review Amber
Q2_21_rating tags were added to gene: MINPP1.
Mode of inheritance for gene: MINPP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MINPP1 were set to 33257696; 33168985
Phenotypes for gene: MINPP1 were set to Pontocerebellar hypoplasia
Intellectual disability v3.1073 CAD Arina Puzriakova Phenotypes for gene: CAD were changed from Epileptic encephalopathy, early infantile, 50 - MIM 616457 to Developmental and epileptic encephalopathy 50, OMIM:616457
Intellectual disability v3.1072 TMEM222 Sarah Leigh edited their review of gene: TMEM222: Added comment: Not associated with relevant phenotype in OMIM or Gen2Phen (TMEM222 not listed on OMIM 11/05/2021). At least ten variants reported in at least nine unrelated families. Moderate to severe intellectual disability was evident in all families.; Changed rating: GREEN
Intellectual disability v3.1070 FARSA Ivone Leong Entity copied from White matter disorders and cerebral calcification - narrow panel v1.79
Intellectual disability v3.1070 FARSA Ivone Leong gene: FARSA was added
gene: FARSA was added to Intellectual disability. Sources: Literature,Expert Review Red
Mode of inheritance for gene: FARSA was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FARSA were set to 31355908
Phenotypes for gene: FARSA were set to ?Rajab interstitial lung disease with brain calcifications 2, OMIM:619013
Intellectual disability v3.1069 CAPN15 Zornitza Stark gene: CAPN15 was added
gene: CAPN15 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: CAPN15 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CAPN15 were set to 33410501; 32885237
Phenotypes for gene: CAPN15 were set to Oculogastrointestinal neurodevelopmental syndrome, MIM# 619318
Review for gene: CAPN15 was set to GREEN
gene: CAPN15 was marked as current diagnostic
Added comment: 5 families reported, including DD/ID in 3. Profound in one family with bi-allelic LoF variant, PMID 33410501.
Sources: Literature
Intellectual disability v3.1069 CHD5 Zornitza Stark gene: CHD5 was added
gene: CHD5 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: CHD5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CHD5 were set to 33944996
Phenotypes for gene: CHD5 were set to Intellectual disability; Epilepsy
Review for gene: CHD5 was set to GREEN
gene: CHD5 was marked as current diagnostic
Added comment: 16 unrelated individuals reported with language deficits (81%), behavioral symptoms (69%), intellectual disability (64%), epilepsy (62%), and motor delay (56%).
Sources: Literature
Intellectual disability v3.1069 FBXO31 Zornitza Stark edited their review of gene: FBXO31: Added comment: PMIDs 33675180; 32989326: three unrelated individuals with de novo missense variant, (p.Asp334Asn) and spastic-dystonic CP, including ID.

AR ID: Single consanguineous family reported with homozygous truncating variant, limited functional evidence.; Changed rating: GREEN; Changed publications to: 24623383, 33675180, 32989326
Intellectual disability v3.1069 PTPN4 Zornitza Stark gene: PTPN4 was added
gene: PTPN4 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: PTPN4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PTPN4 were set to 17953619; 25424712; 30238967; DOI: https://doi.org/10.1016/j.xhgg.2021.100033
Phenotypes for gene: PTPN4 were set to Intellectual disability
Review for gene: PTPN4 was set to GREEN
gene: PTPN4 was marked as current diagnostic
Added comment: >3 unrelated probands and supportive mouse model
PMID: 17953619 - knockout mouse model has impaired motor learning and cerebellar synaptic plasticity
PMID: 25424712 - twins with a de novo whole gene deletion and a Rett-like neurodevelopmental disorder
PMID: 30238967 - mosaic de novo variant (p.Leu72Ser) identified in a child with developmental delay, autistic features, hypotonia, increased immunoglobulin E and dental problems. Also supporting mouse assays demonstrating loss of protein expression in dendritic spines
DOI: https://doi.org/10.1016/j.xhgg.2021.100033 - missense and truncating variants in six unrelated individuals with varying degrees of intellectual disability or developmental delay. 5 were able to undergo segregation analysis and found to be de novo.
Sources: Literature
Intellectual disability v3.1069 ANKRD17 Zornitza Stark gene: ANKRD17 was added
gene: ANKRD17 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: ANKRD17 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ANKRD17 were set to 33909992
Phenotypes for gene: ANKRD17 were set to Intellectual disability, speech delay, and dysmorphism
Review for gene: ANKRD17 was set to GREEN
gene: ANKRD17 was marked as current diagnostic
Added comment: 34 predominantly LoF variants reported - 29 de novo, 1 inherited from an affected parent, 1 inherited from a suspected mosaic parent. Main phenotypes were dev delay/ID, motor delay, and speech delay.
Sources: Literature
Intellectual disability v3.1069 SIN3B Zornitza Stark gene: SIN3B was added
gene: SIN3B was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: SIN3B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SIN3B were set to 33811806
Phenotypes for gene: SIN3B were set to Syndromic intellectual disability
Review for gene: SIN3B was set to GREEN
gene: SIN3B was marked as current diagnostic
Added comment: PMID: 33811806
- 9 affected individuals, variants all de novo (2 PTCs, 2 missense, multigenic CNVs)
- syndrome hallmarked by intellectual disability, developmental delay, and dysmorphic facial features with variably penetrant ASD, congenital malformations, corpus callosum defects, and impaired growth.
Sources: Literature
Intellectual disability v3.1069 DPYSL5 Zornitza Stark gene: DPYSL5 was added
gene: DPYSL5 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: DPYSL5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: DPYSL5 were set to 33894126
Phenotypes for gene: DPYSL5 were set to Neurodevelopmental disorder with corpus callosum agenesis and cerebellar abnormalities
Review for gene: DPYSL5 was set to GREEN
gene: DPYSL5 was marked as current diagnostic
Added comment: Nine individuals with brain malformations, including corpus callosum agenesis and/or posterior fossa abnormalities, associated with variable degrees of intellectual disability. The recurrent de novo p.Glu41Lys was found in eight unrelated patients, and a p.Gly47Arg variant was identified in one individual from the first family reported with Ritscher-Schinzel syndrome. Both impaired DPYSL5 function on dendritic outgrowth regulation by preventing the formation of the ternary complex with MAP2 and βIII-tubulin, ultimately leading to abnormal brain development.
Sources: Literature
Intellectual disability v3.1069 EMC10 Zornitza Stark edited their review of gene: EMC10: Added comment: PMID 33531666: Additional 12 individuals from 7 Middle Eastern families reported. Same variant in all, suggestive of founder effect (but different to the previously reported family).; Changed rating: GREEN; Changed publications to: 32869858, 33531666; Changed phenotypes to: Neurodevelopmental disorder with dysmorphic facies and variable seizures, MIM# 619264
Intellectual disability v3.1069 TMEM222 Konstantinos Varvagiannis gene: TMEM222 was added
gene: TMEM222 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: TMEM222 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TMEM222 were set to 33824500
Phenotypes for gene: TMEM222 were set to Motor delay; Delayed speech and language development; Intellectual disability; Generalized hypotonia; Broad-based gait; Abnormality of nervous system morphology; Seizures; Microcephaly; Behavioral abnormality
Penetrance for gene: TMEM222 were set to Complete
Review for gene: TMEM222 was set to GREEN
Added comment: Polla et al (2021 - PMID: 33824500) report 17 individuals from 9 unrelated families, with biallelic TMEM222 pathogenic variants.

The phenotype included motor, speech delay and moderate to severe ID (as universal features). Other manifestations included hypotonia (10/15), broad gait (5/12), seizures (7/17 - belonging to 6/9 families), MRI abnormalities (5/8). Variable behavioral abnormalities were observed (aggressive behavior, shy character, stereotypic movements etc). Abnormal OFC was a feature in several with microcephaly in 7 subjects from 4 families (measurements not available for all 17). Nonspecific facial features were reported in 10/17. Rare features incl. body tremors, decreased lower extremity muscle mass or disorder of motor neurons.

TMEM222 variants were identified following exome sequencing. Previous investigations incl. metabolic studies, FMR1, chromosomes by standard karyotype or CMA, SMA, CMT1A were reported to be normal (available for some individuals).

TMEM222 variants missense and pLoF ones mostly found in homozygosity (7/9 families were consanguineous, compound heterozygosity reported in a single case from the 9 families). Sanger sequencing was used for confirmation of variants, parental carrier state as well as testing of sibs (unaffected sibs tested in 4 families).

Few individuals had additional genetic findings in other genes, though classified as VUS (3 families).

The gene encodes transmembrane protein 222 (208 residues) which however has unknown function. The protein comprises 3 transmembrane domains and a domain of unknown function. TMEMs are a group of transmembrane proteins spanning membranes with - most commonly - unclear function.

The authors measured expression by qPCR mRNA analysis, demonstrating highest fetal and adult brain expression (incl. parietal and occipital cortex). Expression levels from GTEx data also support a role in neurodevelopment.

Immunocytochemistry revealed highest levels in mature human iPSC-derived glutaminergic cortical neurons and moderate in immature ones. Additional studies supported that the gene is highly expressed in dendrites and might play a role in postsynaptic vesicles (colocalization with postsynaptic and early endosomal markers).

A previous study by Riazuddin et al (2017 - PMID: 27457812) had identified TMEM222 as a candidate gene for ID. This family (PKMR213) however appears to be included as family 2 in the aforementioned publication (same pedigree, variant and phenotype in both articles).

In OMIM there is currently no associated phenotype.

The gene is listed among the primary ID genes in SysID.

Please consider inclusion in the ID panel with green (or amber) rating. This gene may also be included in other panels e.g. for epilepsy, microcephaly, etc.
Sources: Literature
Intellectual disability v3.1069 CLTC Arina Puzriakova Phenotypes for gene: CLTC were changed from Mental retardation, autosomal dominant 56, 617854; Autosomal dominant non-syndromic intellectual disability, Epilepsy and intellectual disability to Mental retardation, autosomal dominant 56, OMIM:617854
Intellectual disability v3.1068 UBTF Arina Puzriakova Mode of pathogenicity for gene: UBTF was changed from to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Intellectual disability v3.1063 DNA2 Arina Puzriakova Phenotypes for gene: DNA2 were changed from PRIMORDIAL DWARFISM SECKEL SYNDROME 8; SCKL8 to Seckel syndrome 8, OMIM:615807
Intellectual disability v3.1062 WDR4 Ivone Leong Phenotypes for gene: WDR4 were changed from Primordial dwarfism; motor and speech delay; intellectual disability; global developmental delay. to Galloway-Mowat syndrome 6, OMIM:61834; Microcephaly, growth deficiency, seizures, and brain malformations, OMIM:618347
Intellectual disability v3.1057 CDH11 Arina Puzriakova Added comment: Comment on mode of inheritance: Association with biallelic variants well-established, with ID reported in all cases to date. On the other hand, DD/ID is variable in individuals with monoallelic variants (PMID: 33811546) - 7/19 cases (4 families) presented a developmental phenotype including very mild speech delays in 5/7, mild-moderate DD in 1/7, and global delay in 1/7 individuals.

Overall, given the mostly mild degree of cognitive delay, as well as intra- and interfamilial reduced penetrance of this feature, there is currently not enough evidence to rate as Green on this panel for the monoallelic disease.
Intellectual disability v3.1056 HTT Eleanor Williams changed review comment from: PMID: 33432339 - Jung et al 2021 - further characterisation of the family previously reported in PMID: 27329733 (Rodan et al 2016) - using WGS they confirm they are the most likely cause of the LOMARS phenotype and clarify their locations as NM_002111.8(HTT): c.8157T>A (p.Phe2719Leu) and NM_002111.8(HTT)c.4469+1G>A (Note there are incorrect Clinvar entries). Functional studies show them each to be a hypomorphic mutation, resulting in severe deficiency of huntingtin in compound heterozygotes.; to: PMID: 33432339 - Jung et al 2021 - further characterisation of the family previously reported in PMID: 27329733 (Rodan et al 2016) - using WGS they confirm they are the most likely cause of the LOMARS phenotype and clarify their locations as NM_002111.8(HTT): c.8157T>A (p.Phe2719Leu) and NM_002111.8(HTT)c.4469+1G>A (Note there are incorrect Clinvar entries). Functional studies show them each to be a hypomorphic mutation, resulting in severe deficiency of huntingtin in compound heterozygotes.

Still only 2 cases reported to date (PMID: 27329733/33432339 and 26740508) with biallelic LOF variants in HTT associated with the LOMARS phenotype although this study add further weight with some functional data.
Intellectual disability v3.1056 FAR1 Arina Puzriakova Publications for gene: FAR1 were set to 25439727
Intellectual disability v3.1055 FAR1 Arina Puzriakova Tag Q2_21_expert_review tag was added to gene: FAR1.
Tag Q2_21_MOI tag was added to gene: FAR1.
Intellectual disability v3.1055 FAR1 Arina Puzriakova reviewed gene: FAR1: Rating: ; Mode of pathogenicity: None; Publications: 25439727, 30561787, 33239752; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.1054 HERC2 Arina Puzriakova Phenotypes for gene: HERC2 were changed from Mental retardation, autosomal recessive 38 to Mental retardation, autosomal recessive 38, OMIM:615516
Intellectual disability v3.1053 NUBPL Arina Puzriakova Phenotypes for gene: NUBPL were changed from MITOCHONDRIAL COMPLEX I DEFICIENCY to Mitochondrial complex I deficiency, nuclear type 21, OMIM:618242
Intellectual disability v3.1052 INPP4A Arina Puzriakova Phenotypes for gene: INPP4A were changed from AUTOSOMAL RECESSIVE MENTAL RETARDATION to Intellectual disability; Seizures
Intellectual disability v3.1050 INPP4A Arina Puzriakova Added comment: Comment on list classification: Upgraded from Red to Amber. 2 unrelated families with severe ID and biallelic variants in this gene reported to date (PMIDs: 25338135; 31978615)
Intellectual disability v3.1049 UBE4A Arina Puzriakova changed review comment from: Comment on list classification: New gene added by Zornitza Stark. Sufficient evidence to rate this gene Green at the next GMS panel update - 4 unrelated families with different homozygous LoF variants in UBE4A, supported by some functional data and animal model. Severe ID and GDD was a feature in all affected individuals (8 total).

UBE4A is not associated with any phenotype in OMIM (last edited on 17/09/2010) but has a 'probable' disease confidence rating for 'UBE4A-associated neurodevelopmental disorder' in Gene2Phenotype.; to: Comment on list classification: New gene added by Zornitza Stark. Sufficient evidence to rate this gene Green at the next GMS panel update - PMID:33420346 report 4 unrelated families with different homozygous LoF variants in UBE4A, supported by some functional data and animal model. Severe ID and GDD was a feature in all affected individuals (8 total).

UBE4A is not associated with any phenotype in OMIM (last edited on 17/09/2010) but has a 'probable' disease confidence rating for 'UBE4A-associated neurodevelopmental disorder' in Gene2Phenotype.
Intellectual disability v3.1049 UBE4A Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. Sufficient evidence to rate this gene Green at the next GMS panel update - 4 unrelated families with different homozygous LoF variants in UBE4A, supported by some functional data and animal model. Severe ID and GDD was a feature in all affected individuals (8 total).

UBE4A is not associated with any phenotype in OMIM (last edited on 17/09/2010) but has a 'probable' disease confidence rating for 'UBE4A-associated neurodevelopmental disorder' in Gene2Phenotype.
Intellectual disability v3.1048 NCDN Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. Sufficient evidence to rate this gene as Green with 'monoallelic' MOI at next GMS panel update.

- PMID: 33711248 (2021) - Six affected individuals (3 sibs with homozygous missense, and 3 unrelated patients with different de novo missense variants) with variable degrees of DD, ID, and seizures. Severity of ID in individuals with heterozygous variants is severe, moderate, and mild (but also learning disabilities), respectively. ID in the 3 sibs was determined as mild. Supportive functional data included.

NCDN is not yet associated with any phenotype in OMIM (last edited on 08/08/2012) but in Gene2Phenotype monoallelic disease has a 'probable' confidence rating while biallelic variants have a 'possible' disease confidence rating.
Intellectual disability v3.1047 NCDN Arina Puzriakova Added comment: Comment on mode of inheritance: Setting MOI to 'Monoallelic' as only one biallelic case reported to date, and patients with biallelic variants would still be picked up by the Genomics England pipeline.
Intellectual disability v3.1045 MAPKAPK5 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. Rating Amber, awaiting further cases (added watchlist tag)

- PMID: 33442026 report on 2 unrelated families with a comparable phenotype including severe GDD, who harbour different homozygous truncating variants in MAPKAPK5. Some functional evidence indicating the variants impact expression and function of MAPKAPK5 protein.

MAPKAPK5 is not yet associated with any phenotype in OMIM (last edited on 06/04/2016) but has a 'probable' disease confidence rating for 'MAPKAPK5-associated syndrome with synpolydactyly' in Gene2Phenotype.
Intellectual disability v3.1044 COPB1 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. PMID:33632302 reports on six individuals from two unrelated families with different homozygous variants in this gene. All affected patients had severe ID. Rating Amber, awaiting further cases.
Intellectual disability v3.1043 COPB1 Arina Puzriakova Phenotypes for gene: COPB1 were changed from Baralle-Macken syndrome, MIM# 619255; Severe intellectual disability; variable microcephaly; cataracts to Baralle-Macken syndrome, OMIM:619255; Severe intellectual disability; Cataracts; Variable microcephaly
Intellectual disability v3.1041 PIGC Arina Puzriakova Added comment: Comment on list classification: There are now at least 3 unrelated families with biallelic variants in this gene, and severe DD/ID is evident in all cases (PMIDs: 27694521; 32707268) . Therefore, PIGC can be upgraded to Green status at the next GMS panel update.
Intellectual disability v3.1038 MTFMT Sarah Leigh Phenotypes for gene: MTFMT were changed from Combined oxidative phosphorylation deficiency 15, 614947 to Combined oxidative phosphorylation deficiency 15 OMIM:614947; combined oxidative phosphorylation defect type 15 MONDO:0013987; Mitochondrial complex I deficiency, nuclear type 27 OMIM:618248; mitochondrial complex 1 deficiency, nuclear type 27 MONDO:0032631
Intellectual disability v3.1037 JMJD1C Zornitza Stark gene: JMJD1C was added
gene: JMJD1C was added to Intellectual disability. Sources: Expert Review
Mode of inheritance for gene: JMJD1C was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: JMJD1C were set to 26181491; 32996679
Phenotypes for gene: JMJD1C were set to Intellectual disability
Review for gene: JMJD1C was set to GREEN
gene: JMJD1C was marked as current diagnostic
Added comment: Reported in ID cohort (with Rett-like phenotypic overlap) with supporting functional studies (PMID: 26181491). 7 individuals with rare variants identified, and variants demonstrated to be de novo in 2, one with a Rett-like phenotype and the other with ID. Functional study of the JMJD1C mutant Rett syndrome patient demonstrated that the altered protein had abnormal subcellular localization, diminished activity to demethylate the DNA damage-response protein MDC1, and reduced binding to MECP2. JMJD1C protein shown to be widely expressed in brain regions and that its depletion compromised dendritic activity.

Splice-disrupting JMJD1C variant reported in association with learning disability and myoclonic epilepsy (PMID 32996679).

Disruption of gene due to balanced translocation (PMID 33591602) implicated in autism spectrum disease phenotype.
Sources: Expert Review
Intellectual disability v3.1037 LAMA1 Sarah Leigh Phenotypes for gene: LAMA1 were changed from CEREBELLAR DYSPLASIA WITH CYSTS WITH OR WITHOUT RETINAL DYSTROPHY to Poretti-Boltshauser syndrome OMIM:615960; ataxia - intellectual disability - oculomotor apraxia - cerebellar cysts syndrome MONDO:0014419
Intellectual disability v3.1035 NEUROD2 Arina Puzriakova Added comment: Comment on list classification: There is enough evidence to rate this gene as Green at the next GMS panel update - sufficient number of unrelated cases (4, plus 1 unpublished), all presenting GDD as an early feature. Particularly pertinent to less severely affected individuals who do not develop seizures.
Intellectual disability v3.1034 NEUROD2 Arina Puzriakova gene: NEUROD2 was added
gene: NEUROD2 was added to Intellectual disability. Sources: Literature
Q2_21_rating tags were added to gene: NEUROD2.
Mode of inheritance for gene: NEUROD2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: NEUROD2 were set to 16504944; 30323019; 33438828
Phenotypes for gene: NEUROD2 were set to Developmental and epileptic encephalopathy 72, OMIM:618374
Review for gene: NEUROD2 was set to GREEN
Added comment: NEUROD2 is associated with a relevant phenotype in OMIM (MIM# 618374), but is not yet listed in Gene2Phenotype.

- PMID: 30323019 (2019) - Two unrelated children with refractory early-infantile epileptic encephalopathy. Developmental delay (DD) preceded onset of seizures in both cases, with signs of DD becoming evident at 2-4 months and seizures arising at 5 months of age. Patient 1 became seizure-free after introducing a ketogenic diet at 16 months; however, an EEG at 22 months remained abnormal and she continues to have severe GDD with no independent sitting, walking or speaking at the chronological age of 3 years and 2 months. Patient 2 became seizure-free when a vagal nerve stimulator (VNS) was placed at 16 months of age. He displayed significant improvement on EEG and subsequently began regaining neurodevelopmental milestones.
WES revealed different de novo variants in the NEUROD2 gene (P1: c.388G>C, p.E130Q; P2: c.401T>C, p.M134T, respectively). Knockdown of the neurod2 in Xenopus tropicalis tadpoles resulted in abnormal swimming behaviour and progressive seizures followed by periods of immobility. Overexpression of wild-type human NEUROD2 in tadpoles induced non-neuronal cells to differentiate into neurons - on the other hand, overexpression of the mutant alleles failed to to cause any (p.E130Q) or a comparable degree (p.M134T) of ectopic neuronal induction as seen with the wild-type protein.

- Conference poster (Genomics of Rare Disease 2021) - 'Neuronal Differentiation Factor 2 (NEUROD2) Pathogenic Variant as a Molecular Aetiology of Infantile Spasm ' by Sakpichaisakul et al, QSNICH, Thailand -
In a 15 month-old female with infantile spasm, trio exome sequencing revealed a de novo variant in NEUROD2 (c.388G>C, p.E130Q). She was born of non-consanguineous healthy parents with no family history of epilepsy. Poor eye contact and no social smile were noted in the first few months, followed by the first infantile spasm at 5 months of age. This was initially controlled by combined vigabatrin and prednisolone therapy - however relapsing seizures were detected at 15 months. Sequential treatment with vigabatrin following prednisolone resulted in cessation of seizures, and subsequently regaining of neurodevelopmental milestones (sitting without support, grabbing objects without pincer grasp and speaking one single word)

----- Cases without seizures -

- PMID: 33438828 (2021) - Adolescent (14 yrs old) with GDD but without seizures who was found to have a novel de novo NEUROD2 missense variant (c.488 T > C, p.L163P). An additional individual (12 yrs) with DD and a different missense NEUROD2 (c.703G>A, p.A235T) was also identified, but lacking parental samples for segregation analysis.
Functional analysis in Xenopus laevis revealed that injection of the p.L163P mRNA variant resulted in a defective ability to induce ectopic neurons in tadpoles as compared with wild-type NEUROD2 mRNA, while the p.A235T variant functioned similarly to wild-type.
Sources: Literature
Intellectual disability v3.1033 NCKAP1 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update. Guo et al 2020 (PMID:33157009) describe multiple families with inherited and de novo deleterious NCKAP1 variants. Neurodevelopmental features represent the core phenotypes, including autistic features, psychomotor delays, and ID or learning disabilities (10/16 individuals had a diagnosis of mild to severe ID)
Intellectual disability v3.1028 DPYS Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. Overall variable clinical presentation, even including asymptomatic subjects. However, DD and/or ID have been reported in multiple published cases (PMIDs: 9266350; 17383919; 20362666; 27604308; 26771602; 29054612). Sufficient unrelated cases (>3) to rate Green but will seek opinion from the GMS expert group due to highly variable penetrance of this phenotype.
Intellectual disability v3.1022 B4GALT1 Arina Puzriakova Added comment: Comment on list classification: Upgraded from Red to Amber as now there are 2 families (4 total) exhibiting severe cognitive impairment, albeit this resolved in the singleton by age 11 (remaining patients were age 2.5, 11 and 11 years at the time of reporting)
Intellectual disability v3.1018 UBE4A Zornitza Stark gene: UBE4A was added
gene: UBE4A was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: UBE4A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: UBE4A were set to 33420346
Phenotypes for gene: UBE4A were set to Intellectual disability
Review for gene: UBE4A was set to GREEN
gene: UBE4A was marked as current diagnostic
Added comment: 8 individuals, from 4 unrelated families, with syndromic intellectual disability and global developmental delay (other clinical features included hypotonia, short stature, seizures, and behaviour disorder. Exome sequencing identified biallelic loss-of-function variants in UBE4A in the 4 families, with variants segregating with disease and parents carriers. They demonstrated that UBE4A loss-of-function variants reduced RNA expression and protein levels in clinical samples. Mice generated to mimic patient-specific Ube4a loss-of-function variant exhibited muscular and neurological/behavioural abnormalities, some of which are suggestive of the clinical abnormalities seen in the affected individuals.
Sources: Literature
Intellectual disability v3.1018 MAPKAPK5 Zornitza Stark gene: MAPKAPK5 was added
gene: MAPKAPK5 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: MAPKAPK5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MAPKAPK5 were set to 3344202
Phenotypes for gene: MAPKAPK5 were set to Developmental delay, variable brain anomalies, congenital heart defects, dysmorphism
Review for gene: MAPKAPK5 was set to GREEN
gene: MAPKAPK5 was marked as current diagnostic
Added comment: 3 individuals from 2 families with severe developmental delay, variable brain anomalies, congenital heart defects, dysmorphic facial features, and a distinctive type of synpolydactyly with an additional hypoplastic digit between the fourth and fifth digits of hands and/or feet. Exome sequencing identified different homozygous truncating variants in MAPKAPK5 in both families, segregating with disease and unaffected parents as carriers.

Patient-derived cells showed no expression of MAPKAPK5 protein isoforms and reduced levels of the MAPKAPK5-interacting protein ERK3. F-actin recovery after latrunculin B treatment was found to be less efficient in patient-derived fibroblasts than in control cells, supporting a role of MAPKAPK5 in F-actin polymerization.

Borderline Amber/Green but high impact variants and a distinctive phenotype with some functional data.
Sources: Literature
Intellectual disability v3.1018 FAR1 Zornitza Stark edited their review of gene: FAR1: Added comment: PMID 33239752: 12 patients with paediatric onset spastic paraparesis and bilateral congenital/juvenile cataracts. Most also had speech and gross motor developmental delay and truncal hypotonia. Exome sequencing identified de novo variants affecting the Arg480 residue in FAR1 (p.Arg480Cys/His/Leu). Further functional studies in fibroblasts showed that these variants cause a disruption of the plasmalogen-dependent feedback regulation of FAR1 protein levels leading to uncontrolled ether lipid production.; Changed rating: GREEN; Changed publications: 25439727, 33239752; Changed phenotypes: Peroxisomal fatty acyl-CoA reductase 1 disorder, MIM#616154, spastic paraparesis and bilateral cataracts; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.1018 NCDN Zornitza Stark gene: NCDN was added
gene: NCDN was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: NCDN was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: NCDN were set to 33711248
Phenotypes for gene: NCDN were set to Intellectual disability; epilepsy
Review for gene: NCDN was set to GREEN
Added comment: Four families reported, all with de novo missense variants except for 1 consanguineous family where 3 affecteds were homozygous and carrier parents unaffected. ID ranged from mild to severe, several had seizures. Green for mono-allelic disease, Red for bi-allelic.
Sources: Literature
Intellectual disability v3.1017 KCNH1 Arina Puzriakova Phenotypes for gene: KCNH1 were changed from Temple-Baraitser syndrome, OMIM:611816; Temple-Baraitser syndrome, MONDO:0012735; Zimmermann-Laband syndrome 1, OMIM:135500; Zimmermann-Laband syndrome 1, MONDO:0024526 to Temple-Baraitser syndrome, OMIM:611816; Zimmermann-Laband syndrome 1, OMIM:135500; Intellectual disability; Encephalopathy without features of TBS/ZLS
Intellectual disability v3.1015 COPB1 Zornitza Stark gene: COPB1 was added
gene: COPB1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: COPB1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COPB1 were set to 33632302
Phenotypes for gene: COPB1 were set to Baralle-Macken syndrome, MIM# 619255; Severe intellectual disability; variable microcephaly; cataracts
Review for gene: COPB1 was set to AMBER
Added comment: Two unrelated families, some supportive functional data.
Sources: Literature
Intellectual disability v3.1010 KCNQ2 Arina Puzriakova Phenotypes for gene: KCNQ2 were changed from Seizures, benign neonatal, 1, 121200Myokymia, 121200Epileptic encephalopathy, early infantile, 7, 613720; BENIGN NEONATAL EPILEPSY TYPE 1 (EBN1) to Developmental and epileptic encephalopathy 7, OMIM:613720
Intellectual disability v3.1009 FAR1 Arina Puzriakova Publications for gene: FAR1 were set to 0
Intellectual disability v3.1008 FAR1 Arina Puzriakova Phenotypes for gene: FAR1 were changed from SEVERE INTELLECTUAL DISABILITY, EPILEPSY, AND CATARACTS to Peroxisomal fatty acyl-CoA reductase 1 disorder, OMIM:616154
Intellectual disability v3.1007 LARS2 Arina Puzriakova Publications for gene: LARS2 were set to
Intellectual disability v3.1006 LARS2 Arina Puzriakova changed review comment from: Comment on list classification: While are a few cases with neurological symptoms including developmental delay have been reported, this manifestation is part of a broader phenotype where cognitive impairment is unlikely to represent a main feature. In the majority of cases, cognitive function is preserved.

Therefore, rating Amber on this panel. The phenotypes associated with LARS2 are better represented in other panels (e.g. Hearing loss) where this gene is already Green.; to: Comment on list classification: While a few cases with neurological symptoms including developmental delay or neurologic decline have been reported (PMID: 29205794; 30737337; 32442335), this manifestation is part of a broader phenotype where cognitive impairment is unlikely to represent the main feature. In the majority of cases, cognitive function is preserved.

Therefore, rating Amber on this panel. The phenotypes associated with LARS2 are better represented in other panels (e.g. Hearing loss) where this gene is already Green.
Intellectual disability v3.1006 LARS2 Arina Puzriakova Classified gene: LARS2 as Amber List (moderate evidence)
Intellectual disability v3.1006 LARS2 Arina Puzriakova Added comment: Comment on list classification: While are a few cases with neurological symptoms including developmental delay have been reported, this manifestation is part of a broader phenotype where cognitive impairment is unlikely to represent a main feature. In the majority of cases, cognitive function is preserved.

Therefore, rating Amber on this panel. The phenotypes associated with LARS2 are better represented in other panels (e.g. Hearing loss) where this gene is already Green.
Intellectual disability v3.1006 LARS2 Arina Puzriakova Gene: lars2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1005 LARS2 Arina Puzriakova Phenotypes for gene: LARS2 were changed from to Perrault syndrome 4, OMIM:615300; Hydrops, lactic acidosis, and sideroblastic anemia, OMIM:617021; Leukodystrophy
Intellectual disability v3.1004 LARS2 Arina Puzriakova Mode of inheritance for gene: LARS2 was changed from to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1003 LARS2 Zornitza Stark reviewed gene: LARS2: Rating: GREEN; Mode of pathogenicity: None; Publications: 29205794, 32423379, 30737337, 26537577, 23541342; Phenotypes: Perrault syndrome 4, Hydrops, lactic acidosis, and sideroblastic anemia, MIM# 617021, Leukodystrophy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1003 DPYS Zornitza Stark gene: DPYS was added
gene: DPYS was added to Intellectual disability. Sources: Expert Review
Mode of inheritance for gene: DPYS was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: DPYS were set to Dihydropyrimidinuria, MIM#222748
Review for gene: DPYS was set to GREEN
gene: DPYS was marked as current diagnostic
Added comment: Highly variable phenotype, but many have ID.
Sources: Expert Review
Intellectual disability v3.1003 DPM2 Zornitza Stark edited their review of gene: DPM2: Added comment: Further unrelated individual reported, main clinical features were truncal hypotonia, hypertonicity, congenital heart defects, intellectual disability, and generalized muscle wasting.; Changed rating: GREEN; Changed publications: 23109149, 33129689
Intellectual disability v3.1001 BBS1 Sarah Leigh Phenotypes for gene: BBS1 were changed from Bardet-Biedl syndrome 1, 209900; BARDET-BIEDL SYNDROME TYPE 1 (BBS1) to Bardet-Biedl syndrome 1 OMIM:209900; Bardet-Biedl syndrome 1 MONDO:0008854
Intellectual disability v3.998 ATP8A2 Sarah Leigh Phenotypes for gene: ATP8A2 were changed from ?Cerebellar ataxia, mental retardation, and dysequilibrium syndrome 4 615268; intellectual disability to ?Cerebellar ataxia, mental retardation, and dysequilibrium syndrome 4 OMIM:615268; cerebellar ataxia, mental retardation, and dysequilibrium syndrome 4 MONDO:0014104
Intellectual disability v3.996 SPEN Arina Puzriakova Added comment: Comment on list classification: There is now enough evidence to promote this gene to Green at the next review - sufficient cases (>20) with truncating SPEN variants and GDD/ID of relevant severity to this panel.
Intellectual disability v3.995 MED27 Arina Puzriakova Phenotypes for gene: MED27 were changed from Intellectual disability; cerebellar hypoplasia; dystonia to Intellectual disability; Axial hypotonia; Spasticity; Dystonia; Cerebellar hypoplasia; Cataracts; Epilepsy
Intellectual disability v3.994 MED27 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next review - at least 11 unrelated families reported with MED27 variants presenting overlapping phenotypes that include ID of relevant severity to this panel.
Intellectual disability v3.993 MED27 Arina Puzriakova reviewed gene: MED27: Rating: GREEN; Mode of pathogenicity: None; Publications: 33443317; Phenotypes: Intellectual disability, Axial hypotonia, Spasticity, Dystonia, Cerebellar hypoplasia, Cataracts, Epilepsy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.993 EIF5A Arina Puzriakova Added comment: Comment on list classification: There is enough evidence to rate this gene Green at the next review - PMID: 33547280 (2021) reports 7 unrelated individuals with different de novo heterozygous variants in the EIF5A gene. All were affected by variable degrees of DD and/or ID, mostly within the moderate severity range. Other features such as microcephaly and craniofacial dysmorphism were prominent but overall, the phenotype is best represented by this panel. Supportive functional data included.

EIF5A is currently not associated with any phenotype in OMIM (last edited on 18/07/2019), but is listed in Gene2Phenotype with a 'probable' disease confidence rating for 'EIF5A-related craniofacial-neurodevelopmental disorder'
Intellectual disability v3.990 RAD50 Arina Puzriakova edited their review of gene: RAD50: Added comment: - PMID: 33378670 (2020) - single patient described with bone marrow failure, immunodeficiency and developmental defects, who was compound heterozygous for a frameshift and premature stop codon (c.2165dup; p.Glu723Glyfs∗5 - maternally inherited) and in-frame deletion (c.3109_3111del; p.Glu1035del - de novo) in the RAD50 gene.
Functional characterisation using patient-derived fibroblasts indicated defects in DNA replication, DNA repair, and DNA end resection; however, ATM-dependent DNA damage response remained intact. Studies in yeast modelling the variant corresponding to p.Glu1035del produced defects in both DNA repair and Tel1ATM-dependent signalling following thermal activation.

This is the third case published with biallelic variants in the RAD50 gene. Although authors report 'developmental defects', it is unclear whether this individual displayed cognitive impairment. Therefore, maintaining the Red gene rating on this panel.; Changed rating: RED; Changed publications: 19409520, 32212377, 33378670; Changed phenotypes: Nijmegen breakage syndrome-like disorder, OMIM:613078; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.988 GNB1 Arina Puzriakova Phenotypes for gene: GNB1 were changed from Intellectual disability; developmental delay; Global developmental delay to Mental retardation, autosomal dominant 42, OMIM:616973
Intellectual disability v3.987 ADPRHL2 Sarah Leigh Phenotypes for gene: ADPRHL2 were changed from Developmental regression; Seizures; Ataxia; Intellectual disability to Neurodegeneration, childhood-onset, stress-induced, with variable ataxia and seizures OMIM:618170; neurodegeneration, childhood-onset, stress-induced, with variable ataxia and seizures MONDO:0100095
Intellectual disability v3.984 TMPRSS9 Arina Puzriakova gene: TMPRSS9 was added
gene: TMPRSS9 was added to Intellectual disability. Sources: Other
watchlist tags were added to gene: TMPRSS9.
Mode of inheritance for gene: TMPRSS9 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TMPRSS9 were set to 31943016
Phenotypes for gene: TMPRSS9 were set to Progressive intellectual and neurological deterioration; Global developmental delay; Intellectual disability; Autism; Epilepsy
Review for gene: TMPRSS9 was set to RED
Added comment: TMPRSS9 is currently not associated with any phenotype in OMIM or Gene2Phenotype.

- PMID: 31943016 (2020) - Single female subject with compound heterozygous nonsense variants (paternal: c.286C>T, p.R96*; maternal: c.1267C>T; p.R423*) in TMPRSS9. Early childhood development was normal until 2.5 years of age when she experienced profound developmental regression, including speech, social interaction and motor skills, resulting in ASD and profound ID. Knockout mice showed decreased social interest and recognition, and additionally borderline recognition memory deficit in aged female mice.

- Conference poster (Genomics of Rare Disease 2021) - 'ZOEMBA: combining metabolomics and genomics data to solve the unsolved' by Oud et al, United for Metabolic Diseases (UMD), Netherlands -
Trio WES revealed compound heterozygous variants (paternal: c.143-1G>A, p.?; maternal: c.1864G>A; p.V622M) in the TMPRSS9 gene in a female proband with GDD, PIND, aggression, autism and epilepsy. The individual was recruited on the basis of 'suspicion of an inherited metabolic disorder and extensive genetic and metabolic work-up with no diagnosis'.
Sources: Other
Intellectual disability v3.983 DDB1 Arina Puzriakova Added comment: Comment on list classification: There is enough evidence to promote this gene to Green at the next review - sufficient unrelated cases (8) presenting consistent features primarily characterised by ID/DD and hypotonia, supported by functional data (PMID:33743206)
Intellectual disability v3.982 DDB1 Arina Puzriakova changed review comment from: - PMID: 33743206 (2021) - 8 unrelated individuals with de novo variants in DDB1, including one recurrent variant in four individuals (c.637G>A, p.Glu213Lys) and two different substitutions at the same amino acid residue (p.Arg188Trp and p.Arg188Gln). Clinical features were consistent and include hypotonia (7/8) and mild-moderate developmental delay or intellectual disability (8/8) and similar facial gestalt. Brachydactyly was common and most noticeable in the feet (6/8), and two individuals had cutaneous toe syndactyly. All three older individuals had a BMI in the obese range for their age. Functional studies using patient-derived lymphoblasts showed altered DDB1 function resulting in abnormal DNA damage signatures and histone methylation following UV-induced DNA damage.
Sources: Literature; to: - PMID: 33743206 (2021) - 8 unrelated individuals with de novo variants in DDB1, including one recurrent variant in four individuals (c.637G>A, p.Glu213Lys) and two different substitutions at the same amino acid residue (p.Arg188Trp and p.Arg188Gln). Clinical features were consistent and include hypotonia (7/8) and mild-moderate developmental delay or intellectual disability (8/8) and similar facial gestalt. Brachydactyly was common and most noticeable in the feet (6/8), and two individuals had cutaneous toe syndactyly. All three older individuals had a BMI in the obese range for their age. Functional studies using patient-derived lymphoblasts showed altered DDB1 function resulting in abnormal DNA damage signatures and histone methylation following UV-induced DNA damage.

Variants in other CRL4 complex components, such as CUL4B (MIM# 300304) and PHIP (MIM# 612870), have been shown to cause overlapping phenotypes consisting of syndromic ID with hypotonia and obesity.
Sources: Literature
Intellectual disability v3.982 DDB1 Arina Puzriakova gene: DDB1 was added
gene: DDB1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: DDB1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: DDB1 were set to 33743206
Phenotypes for gene: DDB1 were set to Intellectual disability
Review for gene: DDB1 was set to GREEN
Added comment: - PMID: 33743206 (2021) - 8 unrelated individuals with de novo variants in DDB1, including one recurrent variant in four individuals (c.637G>A, p.Glu213Lys) and two different substitutions at the same amino acid residue (p.Arg188Trp and p.Arg188Gln). Clinical features were consistent and include hypotonia (7/8) and mild-moderate developmental delay or intellectual disability (8/8) and similar facial gestalt. Brachydactyly was common and most noticeable in the feet (6/8), and two individuals had cutaneous toe syndactyly. All three older individuals had a BMI in the obese range for their age. Functional studies using patient-derived lymphoblasts showed altered DDB1 function resulting in abnormal DNA damage signatures and histone methylation following UV-induced DNA damage.
Sources: Literature
Intellectual disability v3.981 PIGU Arina Puzriakova Phenotypes for gene: PIGU were changed from Glycosylphosphatidylinositol biosynthesis defect 2, 618590; Global developmental delay; Intellectual disability; Seizures; Cerebral atrophy; Cerebellar hypoplasia; Scoliosis to Neurodevelopmental disorder with brain anomalies, seizures, and scoliosis, OMIM:618590
Intellectual disability v3.980 SMARCB1 Arina Puzriakova Phenotypes for gene: SMARCB1 were changed from Rhabdoid tumors, somatic, 609322Rhabdoid predisposition syndrome 1, 609322Mental retardation, autosomal dominant 15, 614608; RHABDOID PREDISPOSITION SYNDROME 1 to Coffin-Siris syndrome 3, OMIM:614608
Intellectual disability v3.979 SMARCA4 Arina Puzriakova Phenotypes for gene: SMARCA4 were changed from Rhabdoid tumor predisposition syndrome 2, 613325Mental retardation, autosomal dominant 16, 614609; COFFIN SIRIS to Coffin-Siris syndrome 4, OMIM:614609
Intellectual disability v3.978 POLD1 Arina Puzriakova Phenotypes for gene: POLD1 were changed from {Colorectal cancer, susceptibility to, 10}, 612591; Mandibular; hypoplasia, deafness, progeroid features, and lipodystrophy syndrome, 615381 to {Colorectal cancer, susceptibility to, 10}, 612591; Mandibular hypoplasia, deafness, progeroid features, and lipodystrophy syndrome, 615381
Intellectual disability v3.977 SIAH1 Arina Puzriakova Added comment: Comment on list classification: There are sufficient unrelated cases (5) to promote this gene to Green at the next GMS panel update. Developmental delay, including cognitive impairment, was a key presenting feature of the disease phenotype. Inclusion on this panel would also cover the infantile hypotonia element as the ID panel is a component panel of the 'Hypotonic infant, R69' super panel.
Intellectual disability v3.976 SIAH1 Arina Puzriakova gene: SIAH1 was added
gene: SIAH1 was added to Intellectual disability. Sources: Literature
Q2_21_rating tags were added to gene: SIAH1.
Mode of inheritance for gene: SIAH1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SIAH1 were set to 32430360
Phenotypes for gene: SIAH1 were set to Developmental delay; Infantile hypotonia; Dysmorphic features; Laryngomalacia
Review for gene: SIAH1 was set to GREEN
Added comment: - PMID: 32430360 (2021) - Five unrelated individuals with shared features of developmental delay, infantile hypotonia, dysmorphic features and laryngomalacia. All had speech delay and where cognitive assessment was age appropriate individuals exhibited learning difficulties. Trio WES revealed distinct de novo variants in SIAH1. In vitro assays demonstrated that SIAH1 mutants induce loss of Wnt stimulatory activity.
Sources: Literature
Intellectual disability v3.975 EIF5A Zornitza Stark gene: EIF5A was added
gene: EIF5A was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: EIF5A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: EIF5A were set to 33547280
Phenotypes for gene: EIF5A were set to Intellectual disability; microcephaly; dysmorphism
Review for gene: EIF5A was set to GREEN
Added comment: 7 unrelated individuals reported with de novo variants in this gene and variable combinations of developmental delay, microcephaly, micrognathia and dysmorphism.
Sources: Literature
Intellectual disability v3.975 MED27 Zornitza Stark gene: MED27 was added
gene: MED27 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: MED27 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MED27 were set to 33443317
Phenotypes for gene: MED27 were set to Intellectual disability; cerebellar hypoplasia; dystonia
Review for gene: MED27 was set to GREEN
gene: MED27 was marked as current diagnostic
Added comment: 16 patients from 11 families reported
Sources: Literature
Intellectual disability v3.975 SPEN Zornitza Stark edited their review of gene: SPEN: Added comment: PMID: 33596411
- 34 individuals with truncating variants in SPEN reported, most are de novo variants.
- Clinical profile includes developmental delay/intellectual disability, autism spectrum disorder, anxiety, aggressive behavior, attention deficit disorder, hypotonia, brain and spine anomalies, congenital heart defects, high/narrow palate, facial dysmorphisms, and obesity/increased BMI, especially in females.
- Authors showed haploinsufficiency of SPEN is associated with a distinctive DNA methylation episignature of the X chromosome in affected females.; Changed rating: GREEN; Changed publications: 33057194, 33596411; Changed phenotypes: Developmental delay/intellectual disability, autism spectrum disorder, anxiety, aggressive behavior, attention deficit disorder, hypotonia, brain and spine anomalies, congenital heart defects, high/narrow palate, facial dysmorphisms, and obesity/increased BMI; Set current diagnostic: yes
Intellectual disability v3.973 ERBB4 Sarah Leigh changed review comment from: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review depending on the interpretation of structural variants.; to: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review depending on the interpretation of copy number variants.
Intellectual disability v3.973 ERBB4 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review depending on the interpretation of structural variants.
Intellectual disability v3.972 ERBB4 Sarah Leigh Added comment: Comment on phenotypes: Amyotrophic lateral sclerosis 19 615515 is not appropriate for this panel At present there is no precise ID phenotype associated with variants in this gene.
Intellectual disability v3.968 ACO2 Arina Puzriakova Phenotypes for gene: ACO2 were changed from INFANTILE CEREBELLAR-RETINAL DEGENERATION to Infantile cerebellar-retinal degeneration, OMIM:614559; Infantile cerebellar-retinal degeneration, MONDO:0013802
Intellectual disability v3.966 KCNN3 Arina Puzriakova edited their review of gene: KCNN3: Added comment: Now at least 6 unrelated individuals with different gain-of-function KCNN3 variants (PMIDs: 31155282 and 33594261). Phenotypes include mild-to-moderate DD and/or ID.; Changed publications: 31155282, 33594261
Intellectual disability v3.966 KCNN3 Arina Puzriakova changed review comment from: Comment on mode of pathogenicity: Gain-of-function variants identified in all patients, reported to date.; to: Comment on mode of pathogenicity: Gain-of-function variants identified in all patients reported to date.
Intellectual disability v3.964 KCNH1 Arina Puzriakova Phenotypes for gene: KCNH1 were changed from TEMPLE BARRAISTER SYNDROME to Temple-Baraitser syndrome, OMIM:611816; Temple-Baraitser syndrome, MONDO:0012735; Zimmermann-Laband syndrome 1, OMIM:135500; Zimmermann-Laband syndrome 1, MONDO:0024526
Intellectual disability v3.963 ARMC4 Catherine Snow Tag new-gene-name tag was added to gene: ARMC4.
Intellectual disability v3.963 ARMC4 Catherine Snow commented on gene: ARMC4
Intellectual disability v3.963 ERBB4 Julia Baptista gene: ERBB4 was added
gene: ERBB4 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: ERBB4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ERBB4 were set to 33603162
Phenotypes for gene: ERBB4 were set to intellectual disability; epilepsy
Penetrance for gene: ERBB4 were set to Incomplete
Review for gene: ERBB4 was set to GREEN
Added comment: Heterozygous intragenic multi-exonic ERBB4 deletions were identified in nine individuals from five unrelated families. Affected individuals had either non-syndromic ID or generalised epilepsy.
The deletion segregated with the phenotype in five affected individuals in one family, it was de novo in a second family and the inheritance was unknown in two families. In the fifth family, the deletion was inherited from a normal parent.
Sources: Literature
Intellectual disability v3.963 KCNH1 Julia Baptista reviewed gene: KCNH1: Rating: GREEN; Mode of pathogenicity: None; Publications: 33594261; Phenotypes: Temple-Baraitser syndrome, Zimmermann-Laband syndrome 1; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Intellectual disability v3.963 KCNN3 Julia Baptista reviewed gene: KCNN3: Rating: GREEN; Mode of pathogenicity: Other; Publications: 33594261; Phenotypes: developmental delay, ID, hypotonia, gingival enlargement, hypertrichosis, nail anomalies; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Intellectual disability v3.963 CDK19 Julia Baptista changed review comment from: De novo missense variants mapped to the kinase domain of CDK19 were described in 11 unrelated individuals (age range: 9 months to 14 years).Two recurrent changes at residues Tyr32 and Gly28 were identified.
One additional case report (PMID:33568421) described a 10-month-old male patient who presented with a neurodevelopmental syndrome characterized by infantile spasms and a de novo missense variant c.92C>A (p.Thr31Asn) (also in the kinase domain). This brings the total of cases reported in the literature to 15.; to: De novo missense variants mapped to the kinase domain of CDK19 were described in 11 unrelated individuals (age range: 9 months to 14 years).Two recurrent changes at residues Tyr32 and Gly28 were identified.
One additional case report (PMID:33568421) described a 10-month-old male patient who presented with a neurodevelopmental syndrome characterized by infantile spasms and a de novo missense variant c.92C>A (p.Thr31Asn) (also in the kinase domain). This brings the total of cases reported in the literature to 15.
Intellectual disability v3.963 CLP1 Sarah Leigh Phenotypes for gene: CLP1 were changed from PONTOCEREBELLAR HYPOPLASIA, TYPE 10 to Pontocerebellar hypoplasia 10 OMIM:615803; Pontocerebellar hypoplasia type 10 MONDO:0014349
Intellectual disability v3.949 SMARCD2 Catherine Snow Source: Expert Review Red was removed from gene: SMARCD2
Intellectual disability v3.929 TARDBP Arina Puzriakova Source: Expert Review Amber was removed from gene: TARDBP
Intellectual disability v3.920 PARK7 Sarah Leigh Source: Expert Review Amber was removed from gene: PARK7
Intellectual disability v3.919 SIGMAR1 Arina Puzriakova Source: Expert Review Amber was removed from gene: SIGMAR1
Intellectual disability v3.910 SCARB2 Arina Puzriakova Source: Expert Review Amber was removed from gene: SCARB2
Intellectual disability v3.895 MARS2 Sarah Leigh Source: Expert Review Amber was removed from gene: MARS2
Intellectual disability v3.848 ERMARD Catherine Snow Source: Expert Review Red was removed from gene: ERMARD
Intellectual disability v3.833 QARS Ivone Leong Source: Expert Review Red was removed from gene: QARS
Intellectual disability v3.803 SPART Catherine Snow Source: Expert Review Amber was removed from gene: SPART
Intellectual disability v3.787 PARN Catherine Snow Source: Expert Review Amber was removed from gene: PARN
Intellectual disability v3.787 ARL13B Ivone Leong Source: Expert Review Red was removed from gene: ARL13B
Intellectual disability v3.786 ARID2 Ivone Leong Source: Expert Review Red was removed from gene: ARID2
Intellectual disability v3.780 CCDC186 Sarah Leigh changed review comment from: Not associated with relevant phenotype in OMIM or Gen2Phen. At least 2 terminating variants reported in unrelated cases.
Sources: Literature; to: Not associated with a relevant phenotype in OMIM or Gen2Phen. At least 2 terminating variants reported in cases with failure to thrive and developmental delay.
Sources: Literature
Intellectual disability v3.780 CCDC186 Sarah Leigh gene: CCDC186 was added
gene: CCDC186 was added to Intellectual disability. Sources: Literature
watchlist tags were added to gene: CCDC186.
Mode of inheritance for gene: CCDC186 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CCDC186 were set to 33259146; 28600779
Phenotypes for gene: CCDC186 were set to failure to thrive and developmental delay
Review for gene: CCDC186 was set to AMBER
Added comment: Not associated with relevant phenotype in OMIM or Gen2Phen. At least 2 terminating variants reported in unrelated cases.
Sources: Literature
Intellectual disability v3.779 LMBRD2 Sarah Leigh Added comment: Comment on mode of pathogenicity: Both of the references for this entry suggest a gain-of-function action for LMBRD2 variants.
Intellectual disability v3.779 LMBRD2 Sarah Leigh Mode of pathogenicity for gene: LMBRD2 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
Intellectual disability v3.778 ADAM22 Sarah Leigh Added comment: Comment on list classification: There is just enough evidence for this gene to be rated GREEN at the next major review, which may make it a boarderline case.
Intellectual disability v3.777 KCNN2 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. There is enough evidence to promote this gene to Green at the next GMS panel update - variable degrees of cognitive impairment were a universal feature amongst individuals with KCNN2 variants (at least 10 unrelated cases with unique variants). Pathogenicity was supported by functional data.
Intellectual disability v3.774 OTUD5 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. There is enough evidence to rate this gene Green at the next GMS panel update.

At least 8 families reported with a multiple congenital anomaly disorder and distinct hemizygous variants in this gene. GDD/ID is part of the disease presentation and was noted in all cases of relevant age (PMIDs: 33131077 and 33523931).
Intellectual disability v3.773 OTUD5 Zornitza Stark changed review comment from: PMID 33523931: Another 10 individuals from 7 families reported, promote to Green. X-linked multiple congenital anomalies-neurodevelopmental syndrome (MCAND) is an X-linked recessive congenital multisystemic disorder characterized by poor growth, global developmental delay with impaired intellectual development, and variable abnormalities of the cardiac, skeletal, and genitourinary systems. Most affected individuals also have hypotonia and dysmorphic craniofacial features. Brain imaging typically shows enlarged ventricles and thin corpus callosum; some have microcephaly, whereas others have hydrocephalus. The severity of the disorder is highly variable, ranging from death in early infancy to survival into the second or third decade.; to: PMID 33523931: Another 10 individuals from 7 families reported. Key features include poor growth, global developmental delay with impaired intellectual development, and variable abnormalities of the cardiac, skeletal, and genitourinary systems. Most affected individuals also have hypotonia and dysmorphic craniofacial features. Brain imaging typically shows enlarged ventricles and thin corpus callosum; some have microcephaly, whereas others have hydrocephalus. The severity of the disorder is highly variable, ranging from death in early infancy to survival into the second or third decade.
Intellectual disability v3.773 OTUD5 Zornitza Stark edited their review of gene: OTUD5: Added comment: PMID 33523931: Another 10 individuals from 7 families reported, promote to Green. X-linked multiple congenital anomalies-neurodevelopmental syndrome (MCAND) is an X-linked recessive congenital multisystemic disorder characterized by poor growth, global developmental delay with impaired intellectual development, and variable abnormalities of the cardiac, skeletal, and genitourinary systems. Most affected individuals also have hypotonia and dysmorphic craniofacial features. Brain imaging typically shows enlarged ventricles and thin corpus callosum; some have microcephaly, whereas others have hydrocephalus. The severity of the disorder is highly variable, ranging from death in early infancy to survival into the second or third decade.; Changed rating: GREEN; Changed publications: 33131077, 33523931
Intellectual disability v3.773 PIGF Arina Puzriakova changed review comment from: Comment on list classification: New gene added by Zornitza Stark. Rating Red as 2 families with the same (likely founder) variant reported at present (PMID: 33386993). Phenotypes did include severe ID or DD, respectively - but additional cases with other variants in the LRRC32 gene required to substantiate causation (added founder-effect tag); to: Comment on list classification: New gene added by Zornitza Stark. Rating Red as 2 families with the same (likely founder) variant reported at present (PMID: 33386993). Phenotypes did include severe ID or DD, respectively - but additional cases with other variants in the PIGF gene required to substantiate causation (added founder-effect tag)
Intellectual disability v3.773 PIGF Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. Rating Red as 2 families with the same (likely founder) variant reported at present (PMID: 33386993). Phenotypes did include severe ID or DD, respectively - but additional cases with other variants in the LRRC32 gene required to substantiate causation (added founder-effect tag)
Intellectual disability v3.771 OTUD5 Arina Puzriakova Phenotypes for gene: OTUD5 were changed from X-linked severe neurodevelopmental delay, hydrocephalus, and early lethality to Multiple congenital anomalies-neurodevelopmental syndrome, X-linked, OMIM:301056
Intellectual disability v3.770 METAP1 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. Rating Red as only one family reported at present (PMID:32764695). Phenotypes do include ID/DD, but additional cases required to corroborate this gene-disease association.
Intellectual disability v3.767 HPDL Arina Puzriakova Phenotypes for gene: HPDL were changed from spastic paraplegia; spastic tetraplegia; microcephaly; brain atrophy; epilepsy; severe intellectual; motor disability to Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities, OMIM:619026; Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities, MONDO:0033613
Intellectual disability v3.766 HIRA Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. At least 4 unrelated individuals with heterozygous variants in this gene - however, only 1 presented moderate ID (2 had ASD rather than ID, while the phenotype is unclear for the fourth individual). HIRA is a good candidate for neurodevelopmental impairment, supported by an animal model, but additional cases are required to ascertain the relevance of ID.

Therefore, at present there is only enough evidence to rate Amber awaiting further cases/clinical evidence (added 'watchlist' tag)
Intellectual disability v3.765 VPS4A Arina Puzriakova Phenotypes for gene: VPS4A were changed from developmental delay; intellectual disability; cerebellar hypoplasia; pontine hypoplasia; thin corpus callosum; microcephaly; growth retardation; congenital anaemia; dyserythropeoitic anaemia; dystonia; congenital cataracts; deafness to CIMDAG syndrome
Intellectual disability v3.764 B4GALNT1 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least eight variants reported in at least eight unrelated cases.
Intellectual disability v3.762 B4GALNT1 Sarah Leigh Phenotypes for gene: B4GALNT1 were changed from ID; Spastic paraplegia 26, autosomal recessive to Spastic paraplegia 26, autosomal recessive OMIM:609195; hereditary spastic paraplegia 26 MONDO:0012213
Intellectual disability v3.761 PIGF Zornitza Stark gene: PIGF was added
gene: PIGF was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: PIGF was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PIGF were set to 33386993
Phenotypes for gene: PIGF were set to Glycosylphosphatidylinositol deficiency, onychodystrophy, osteodystrophy, intellectual disability, and seizures
Review for gene: PIGF was set to RED
Added comment: The same homozygous missense variant identified in 2 individuals from different families from the same region of India. Individuals had a phenotype similar to DOORS syndrome without deafness. Impaired glycosylphosphatidylinositol (GPI) biosynthesis was demonstrated.

Rated Red as the two families are likely to be related (founder mutation?).
Sources: Literature
Intellectual disability v3.761 DDX58 Arina Puzriakova reviewed gene: DDX58: Rating: ; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.760 HPDL Evan Reid gene: HPDL was added
gene: HPDL was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: HPDL was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HPDL were set to PMID: 32707086; 33188300
Phenotypes for gene: HPDL were set to spastic paraplegia; spastic tetraplegia; microcephaly; brain atrophy; epilepsy; severe intellectual; motor disability
Penetrance for gene: HPDL were set to Complete
Review for gene: HPDL was set to GREEN
Added comment: Newly identified gene that can give a phenotype ranging from infantile epileptic encephalopathy with severe developmental delay/intellectual disability to juvenile onset progressive spastic paraplegia.
Sources: Literature
Intellectual disability v3.759 TCTN3 Arina Puzriakova changed review comment from: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update (added 'for-review' tag).

At least 3 unrelated cases with Joubert syndrome, presenting with ID, and biallelic variants in this gene (PMIDs: 22883145; 25118024; 26092869); to: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update (added 'for-review' tag).

Independent reports of at least 3 unrelated cases with Joubert syndrome, presenting with ID, and different biallelic variants in this gene (PMIDs: 22883145; 25118024; 26092869)
Intellectual disability v3.759 TCTN3 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update (added 'for-review' tag).

At least 3 unrelated cases with Joubert syndrome, presenting with ID, and biallelic variants in this gene (PMIDs: 22883145; 25118024; 26092869)
Intellectual disability v3.758 PRUNE1 Eleanor Williams Phenotypes for gene: PRUNE1 were changed from Neurodevelopmental disorder with microcephaly, hypotonia, and variable brain anomalies, 617481; NMIHBA; Complex neurological syndrome to Neurodevelopmental disorder with microcephaly, hypotonia, and variable brain anomalies OMIM:617481; neurodevelopmental disorder with microcephaly, hypotonia, and variable brain anomalies MONDO:0060490; NMIHBA; Complex neurological syndrome
Intellectual disability v3.756 PRUNE1 Eleanor Williams reviewed gene: PRUNE1: Rating: GREEN; Mode of pathogenicity: None; Publications: 33105479; Phenotypes: Neurodevelopmental disorder with microcephaly, hypotonia, and variable brain anomalies OMIM:617481, neurodevelopmental disorder with microcephaly, hypotonia, and variable brain anomalies MONDO:0060490; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.756 VPS4A Arina Puzriakova Added comment: Comment on list classification: New gene added by Evan Reid (University of Cambridge). At least 5 different variants reported in 10 unrelated individuals with a comparable phenotype, including severe-to-profound ID/DD. Pathogenicity is supported by functional data.

There is enough evidence to promote this gene to Green at the next GMS panel update (added 'for-review' tag)
Intellectual disability v3.755 VPS4A Arina Puzriakova Added comment: Comment on mode of inheritance: Setting MOI to 'Monoallelic' as only one biallelic case reported to date, and patients with biallelic variants would still be picked up by the Genomics England pipeline.
Intellectual disability v3.754 VPS4A Arina Puzriakova reviewed gene: VPS4A: 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: 33186545, 33186543; Phenotypes: CIMDAG syndrome; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.752 ADAM22 Sarah Leigh Phenotypes for gene: ADAM22 were changed from to ?Epileptic encephalopathy, early infantile, 61 OMIM:617933; developmental and epileptic encephalopathy, 61 MONDO:0033370
Intellectual disability v3.751 VPS4A Evan Reid changed review comment from: Multiple families (now 10) described with a consistent phenotype (we have termed it CIMDAG as an acronym for the major features). All have de novo heterozygous missense mutations of VPS4A, with a distinct mutational hotspot (R284) in many families. Mechanism is likely dominant negative. Haplo-insufficiency of VPS4A is tolerated and present in general population databases, so loss of function mutations likely do not cause this disease.
Sources: Literature, Research; to: Multiple families (now 10) described with a consistent phenotype (termed CIMDAG as an acronym for the major features). All have de novo heterozygous missense mutations of VPS4A, with a distinct mutational hotspot (R284) in many families. Mechanism is likely dominant negative. Haplo-insufficiency of VPS4A is tolerated and present in general population databases, so loss of function mutations likely do not cause this disease.
Sources: Literature, Research
Intellectual disability v3.751 VPS4A Evan Reid gene: VPS4A was added
gene: VPS4A was added to Intellectual disability. Sources: Literature,Research
Mode of inheritance for gene: VPS4A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: VPS4A were set to (PMID: 33186545; 33186543; 33460484)
Phenotypes for gene: VPS4A were set to developmental delay; intellectual disability; cerebellar hypoplasia; pontine hypoplasia; thin corpus callosum; microcephaly; growth retardation; congenital anaemia; dyserythropeoitic anaemia; dystonia; congenital cataracts; deafness
Penetrance for gene: VPS4A were set to Complete
Mode of pathogenicity for gene: VPS4A 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: VPS4A was set to GREEN
Added comment: Multiple families (now 10) described with a consistent phenotype (we have termed it CIMDAG as an acronym for the major features). All have de novo heterozygous missense mutations of VPS4A, with a distinct mutational hotspot (R284) in many families. Mechanism is likely dominant negative. Haplo-insufficiency of VPS4A is tolerated and present in general population databases, so loss of function mutations likely do not cause this disease.
Sources: Literature, Research
Intellectual disability v3.750 PIGK Sarah Leigh Phenotypes for gene: PIGK were changed from Neurodevelopmental disorder with hypotonia and cerebellar atrophy, with or without seizures 618879 to Neurodevelopmental disorder with hypotonia and cerebellar atrophy, with or without seizures OMIM:618879
Intellectual disability v3.749 HIRA Zornitza Stark gene: HIRA was added
gene: HIRA was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: HIRA was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: HIRA were set to 33417013; 28135719; 25363760
Phenotypes for gene: HIRA were set to Neurodevelopmental disorder
Review for gene: HIRA was set to GREEN
gene: HIRA was marked as current diagnostic
Added comment: Two unrelated patients with different de novo loss of function variants identified in PMID 33417013:

Individual 1: intragenic deletion, phenotype included psychomotor retardation, ID, growth retardation, microcephaly, and facial features reminiscent of 22q deletion syndrome.
Individual 2: canonical splice variant, phenotype mostly confined to ASD

Another two de novo variants were identified in the literature by the authors of that paper, one stop-gain (DDD study, PMID 28135719) and one missense (large autism cohort, PMID 25363760).

PMID 33417013 also showed that HIRA knockdown in mice results in neurodevelopmental abnormalities.

Rated Green due to 4 unrelated individuals (albeit 2 in large cohort studies) and a mouse model. NB: HIRA is within the common 22q deletion region.
Sources: Literature
Intellectual disability v3.749 SATB1 Zornitza Stark changed review comment from: PMID: 33513338: 42 patients with SNVs. 28 de novo, 3 inherited from an affected parent.
Missense variants - more severe, profound ID
NMD PTCs - milder disease; to: PMID: 33513338: 42 patients with SNVs. 28 de novo, 3 inherited from an affected parent.
Missense variants - more severe, profound ID
NMD PTCs - milder disease

Consider adding to epilepsy and ataxia panels.
Intellectual disability v3.749 SATB1 Zornitza Stark edited their review of gene: SATB1: Added comment: PMID: 33513338: 42 patients with SNVs. 28 de novo, 3 inherited from an affected parent.
Missense variants - more severe, profound ID
NMD PTCs - milder disease; Changed rating: GREEN; Changed publications: 33057194, 33513338; Changed phenotypes: Neurodevelopmental disorder; Set current diagnostic: yes
Intellectual disability v3.749 METAP1 Zornitza Stark gene: METAP1 was added
gene: METAP1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: METAP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: METAP1 were set to 32764695
Phenotypes for gene: METAP1 were set to Intellectual disability, aggression, neurodevelopmental delay
Review for gene: METAP1 was set to RED
Added comment: Biallelic nonsense (NMD-predicted) variant identified in 4 sibs in a consanguineous family with dev delay. One sib had bilateral clinodactyly of her toes and her left 3rd finger, other sibs were not dysmorphic. Rated red due to single consanguineous family.
Sources: Literature
Intellectual disability v3.749 KCNN2 Zornitza Stark gene: KCNN2 was added
gene: KCNN2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: KCNN2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KCNN2 were set to 33242881
Phenotypes for gene: KCNN2 were set to Intellectual disability; seizures; movement disorder
Review for gene: KCNN2 was set to GREEN
gene: KCNN2 was marked as current diagnostic
Added comment: - 11 probands all de novo except for 1 mother-daughter pair.
- a mix of null and missense variants
- 2/11 with microcephaly, 10/11 motor delay, 7/11 language delay (excluding 2 with regression), all with varying degrees of ID, 3/11 seizures, 7/11 movement disorder, 4/11 cerebellar ataxia, 6/11 MRI anomalies
Sources: Literature
Intellectual disability v3.749 OTUD5 Zornitza Stark gene: OTUD5 was added
gene: OTUD5 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: OTUD5 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: OTUD5 were set to 33131077
Phenotypes for gene: OTUD5 were set to X-linked severe neurodevelopmental delay, hydrocephalus, and early lethality
Review for gene: OTUD5 was set to RED
Added comment: 13 male patients from a single family with three generations affected. Patients presented prenatally or during the neonatal period with IUGR, ventriculomegaly, hydrocephalus, hypotonia, congenital heart defects, hypospadias, and severe neurodevelopmental delay. The disease is typically fatal during infancy, mainly due to sepsis (pneumonias). Female carriers are asymptomatic. WGS in four individuals identified a unique candidate variant in the OTUD5 gene (NM_017602.3:c.598G > A, p.Glu200Lys). The variant cosegregated with the disease in 10 tested individuals.
Sources: Literature
Intellectual disability v3.749 MSMO1 Arina Puzriakova Phenotypes for gene: MSMO1 were changed from Microcephaly, congenital cataract, and psoriasiform dermatitis, 616834 to Microcephaly, congenital cataract, and psoriasiform dermatitis, OMIM:616834; Microcephaly-congenital cataract-psoriasiform dermatitis syndrome, MONDO:0014793
Intellectual disability v3.748 MEIS2 Arina Puzriakova Phenotypes for gene: MEIS2 were changed from Cleft palate, cardiac defects, and mental retardation; Oral cleft; Abnormal heart morphology; Intellectual disability; Cleft palate, cardiac defects, and mental retardation, 600987 to Cleft palate, cardiac defects, and mental retardation, OMIM:600987; Cardiac malformation, cleft lip/palate, microcephaly, and digital anomalies, MONDO:0010970
Intellectual disability v3.747 KNL1 Arina Puzriakova Phenotypes for gene: KNL1 were changed from Microcephaly 4, primary, autosomal recessive 604321 to Microcephaly 4, primary, autosomal recessive, OMIM:604321; Microcephaly 4, primary, autosomal recessive, MONDO:0011437
Intellectual disability v3.745 TOR1A Arina Puzriakova Added comment: Comment on list classification: Upgraded from Red to Amber, but there is sufficient evidence linking biallelic variants to a relevant phenotype to rate this gene Green at the next GMS panel update (added 'for-review' tag)
Intellectual disability v3.744 TOR1A Arina Puzriakova reviewed gene: TOR1A: Rating: GREEN; Mode of pathogenicity: None; Publications: 30244176, 29053766, 28516161; Phenotypes: Arthrogryposis multiplex congenita 5, OMIM:618947, Arthrogryposis multiplex congenita 5, MONDO:0100218; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.743 TOR1A Arina Puzriakova Phenotypes for gene: TOR1A were changed from Dystonia-1, torsion, 128100; Dystonia, early-onset atypical, with myoclonic features; {Dystonia-1, modifier of} to Arthrogryposis multiplex congenita 5, OMIM:618947; Arthrogryposis multiplex congenita 5, MONDO:0100218
Intellectual disability v3.740 ABCC9 Arina Puzriakova changed review comment from: Comment on list classification: Intellectual impairment as been reported in individuals with loss-of-function variants and a percentage of those with gain-of-function variants. However, this is less prominent than other features of the disease presentation (e.g. cardiac, skeletal defects) and often ID is perhaps too mild.

Therefore, ABCC9 will be flagged for review by the GMS team with regards to phenotypic fit for this panel and determine whether it should be demoted from Green to Amber (added for-review tag).; to: Comment on list classification: Intellectual impairment has been reported in individuals with loss-of-function variants and a percentage of those with gain-of-function variants. ID is typically mild, however it is plausible that patients may still be tested for this panel, particularly if recruited under Coffin-Siris-like coarse facial features which can be associated with this gene. Therefore, maintaining Green gene rating.

Comment on mode of inheritance: Leaving MOI as Monoallelic as only 2 families with the same biallelic variant (possible founder variant) reported to date (PMID:31575858), and patients with biallelic variants would still be picked up by the Genomics England pipeline.
Intellectual disability v3.740 UBR7 Arina Puzriakova Added comment: Comment on list classification: In view of recent expert review by Zornitza Stark, upgraded from Red to Amber but with a recommendation of rating Green at the next GMS panel update (added 'for-review' tag)

At least 6 SNVs and 1 intragenic deletion reported in 7 individuals from 6 families with a comparable neurodevelopmental disorder. DD/ID was a feature in all cases (PMID:33340455)
Intellectual disability v3.738 UBR7 Arina Puzriakova Phenotypes for gene: UBR7 were changed from AUTOSOMAL RECESSIVE MENTAL RETARDATION to Intellectual disability; epilepsy; hypothyroidism; congenital anomalies; dysmorphic features
Intellectual disability v3.737 RNU7-1 Arina Puzriakova Added comment: Comment on list classification: Various degrees of cognitive impairment reported (PMID:33230297). However, DD is an early feature often preceding other neurological concerns, and there are enough cases with sufficiently severe ID for inclusion on this panel.

Rating Amber but should be promoted to Green at the next GMS panel update (added 'for-review' tag)
Intellectual disability v3.736 RNU7-1 Arina Puzriakova Phenotypes for gene: RNU7-1 were changed from Aicardi–Goutières syndrome-like to Aicardi–Goutières syndrome-like; Type I interferonopathy
Intellectual disability v3.734 RNU7-1 Arina Puzriakova reviewed gene: RNU7-1: Rating: GREEN; Mode of pathogenicity: None; Publications: 33230297; Phenotypes: Aicardi–Goutières syndrome-like, Type I interferonopathy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.734 FGFR1 Arina Puzriakova Phenotypes for gene: FGFR1 were changed from Hartsfield syndrome, OMIM:615465; Pfeiffer syndrome, OMIM:101600 to Hartsfield syndrome, OMIM:615465; Pfeiffer syndrome, OMIM:101600; Encephalocraniocutaneous lipomatosis, somatic mosaic, OMIM:613001
Intellectual disability v3.732 FGFR1 Arina Puzriakova Phenotypes for gene: FGFR1 were changed from Encephalocraniocutaneous lipomatosis, 613001; KALLMANN SYNDROME TYPE 2; Pfeiffer syndrome,101600 to Hartsfield syndrome, OMIM:615465; Pfeiffer syndrome, OMIM:101600
Intellectual disability v3.731 TANC2 Arina Puzriakova Added comment: Comment on list classification: This gene should be promoted to Green at the next GMS panel update - multiple unrelated families with a comparable neurodevelopmental disorder (including ID). As highlighted in review by Zornitza Stark, most reported SNVs are de novo putative disruptive variants, or missense variants that are predicted in silico to have a damaging or possibly damaging effect. Gene expression and function are neurodevelopmentally-relevant, and there is some limited functional data.

Gene-disease association is also now listed in both OMIM and Gene2Phenotype.
Intellectual disability v3.729 ATP1A3 Arina Puzriakova Added comment: Comment on list classification: Maintaining Amber rating on this panel, in line with the previous comments by Louise Daugherty (Genomics England) and internal clinical review.

Heterozygous variants are associated with several phenotypes, not all of which include cognitive impairment. Gain from inclusion on the ID panel is likely smaller than the risk of incidental information for the majority of the ID cohort. Patients are expected to be tested under the paroxysmal central nervous system disorders or dystonia GMS panels.
Intellectual disability v3.728 PPIL1 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. Currently not associated with any phenotype in OMIM (last edited on: 10/07/2001) but has a 'probable' gene rating for 'PPIL1-related Neurodegenerative Pontocerebellar Hypoplasia with Microcephaly' in Gene2Phenotype.

At least 12 variants identified in 17 individuals from 9 unrelated families (PMID: 33220177). All displayed pontocerebellar hypoplasia and congenital microcephaly. Severe ID, with or without seizures, was noted in all subjects (14) where information was provided (see table S1). Pathogenicity is supported by animal model.

Sufficient evidence to promote this gene to Green at the next GMS panel update (added 'for-review' tag)
Intellectual disability v3.727 PPIL1 Arina Puzriakova Phenotypes for gene: PPIL1 were changed from Pontocerebellar hypoplasia; microcephaly; seizures; intellectual disbility to PPIL1-related Neurodegenerative Pontocerebellar Hypoplasia with Microcephaly
Intellectual disability v3.726 FGF13 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. Three variants (c.31C>T, c.41G>C, c.32G>C) identified by WES/WGS in seven individuals from five unrelated families who presented with severe infantile-onset seizures and severe-to-profound ID. Supportive functional data.

Sufficient number of unrelated cases with relevant phenotype; however, early-onset epilepsy represents the main feature of the disorder and ID appears to be a secondary manifestation (see supplemental note in PMID:33245860 for clinical details). Therefore, rating Amber on this panel but will add the FGF13 gene to 'Genetic epilepsy syndromes'
Intellectual disability v3.723 FBRSL1 Arina Puzriakova Phenotypes for gene: FBRSL1 were changed from Intellectual disability; congenital anomalies to Intellectual disability; Microcephaly; Heart defect; Cleft palate; Contractures; Hearing impairment; Skin creases
Intellectual disability v3.722 FBRSL1 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. There is enough evidence to promote this gene to Green at the next GMS panel update (added 'for-review' tag) - sufficient number of unrelated cases with distinct variants and relevant phenotype, supported by functional data.

Currently not associated with any phenotype in OMIM or Gene2Phenotype.
Intellectual disability v3.721 DPH2 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. Currently not associated with any phenotype in OMIM or Gene2Phenotype.

At least 2 unrelated families with biallelic variants in this gene. Phenotypes included DD with expressive language delays in the 19-month-old male in PMID: 32576952 (2020); and intellectual disability in both sibs in PMID: 27421267 (2016), albeit within the mild range (Stanford-Binet scale IQ = 58 and 68, respectively). However in the latter case, KALRN was proposed as the causative gene at the time of publication, as scarce data was known for the DPH2 gene.

Additional cases would help corroborate this gene-disease association and so rating Amber, awaiting further cases/clinical evidence.
Intellectual disability v3.720 CDC40 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. CDC40 currently not associated with any phenotype in OMIM (last edited: 23/08/19) but has a 'possible' disease confidence for 'CDC40-related Neurodegenerative Pontocerebellar Hypoplasia with Microcephaly' in Gene2Phenotype.

Rating Red as currently only a single individual reported in PMID: 33220177 (2021). There is some functional and animal model data to support pathogenicity, so have added 'watchlist' tag. If additional cases arise, CDC40 may also be considered for other panels (e.g. Malformations of cortical development, Genetic epilepsy syndromes, Cytopenia - NOT Fanconi anaemia, etc)
Intellectual disability v3.719 CDC40 Arina Puzriakova Phenotypes for gene: CDC40 were changed from Pontocerebellar hypoplasia; microcephaly; seizures; intellectual disability to CDC40-related Neurodegenerative Pontocerebellar Hypoplasia with Microcephaly
Intellectual disability v3.718 ABCC9 Arina Puzriakova Added comment: Comment on list classification: Intellectual impairment as been reported in individuals with loss-of-function variants and a percentage of those with gain-of-function variants. However, this is less prominent than other features of the disease presentation (e.g. cardiac, skeletal defects) and often ID is perhaps too mild.

Therefore, ABCC9 will be flagged for review by the GMS team with regards to phenotypic fit for this panel and determine whether it should be demoted from Green to Amber (added for-review tag).
Intellectual disability v3.717 ABCC9 Arina Puzriakova reviewed gene: ABCC9: Rating: ; Mode of pathogenicity: None; Publications: 31575858; Phenotypes: mild ID, similar facies, myopathy, cerebral white matter hyperintensities, cardiac systolic dysfunction; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.716 TRAPPC12 Arina Puzriakova Phenotypes for gene: TRAPPC12 were changed from Encephalopathy, progressive, early-onset, with brain atrophy and spasticity, 617669; Developmental delay to Encephalopathy, progressive, early-onset, with brain atrophy and spasticity, OMIM:617669; Early-onset progressive encephalopathy-hearing loss-pons hypoplasia-brain atrophy syndrome, MONDO:0044696
Intellectual disability v3.714 TRAPPC12 Arina Puzriakova reviewed gene: TRAPPC12: Rating: GREEN; Mode of pathogenicity: None; Publications: 32369837; Phenotypes: Encephalopathy, progressive, early-onset, with brain atrophy and spasticity, OMIM:617669, Early-onset progressive encephalopathy-hearing loss-pons hypoplasia-brain atrophy syndrome, MONDO:0044696; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.714 NARS Ivone Leong Tag for-review tag was added to gene: NARS.
Intellectual disability v3.714 GLS_GCA Arina Puzriakova changed review comment from: Comment on list classification: Early developmental delay, which preceded other progressive neurological concerns, was reported in the three unrelated cases from PMID:30970188. Following discussion with Helen Brittain (Genomics England Clinical Team) it was agreed that this is sufficient for inclusion on this panel.

However, detection of this 5' UTR triplet expansion must first be internally validated for the interpretation pipeline. In the meantime, rating Red but will raise the STR for validation with the Rare Disease team.; to: Comment on list classification: Early developmental delay, which preceded other progressive neurological concerns, was reported in the three unrelated cases from PMID:30970188. Following discussion with Helen Brittain (Genomics England Clinical Team) it was agreed that this is sufficient for inclusion on this panel.

However, detection of this 5' UTR triplet expansion must first be validated within the Genomics England pipeline. In the meantime, rating Red but will raise the STR for validation with the Rare Disease team.
Intellectual disability v3.714 GLS_GCA Arina Puzriakova Added comment: Comment on list classification: Early developmental delay, which preceded other progressive neurological concerns, was reported in the three unrelated cases from PMID:30970188. Following discussion with Helen Brittain (Genomics England Clinical Team) it was agreed that this is sufficient for inclusion on this panel.

However, detection of this 5' UTR triplet expansion must first be internally validated for the interpretation pipeline. In the meantime, rating Red but will raise the STR for validation with the Rare Disease team.
Intellectual disability v3.713 GLS Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. Early developmental delay, which preceded other progressive neurological concerns, was reported in the three unrelated cases from PMID:30970188. Following discussion with Helen Brittain (Genomics England Clinical Team) it was agreed that this is sufficient for inclusion on this panel.

However, detection of the 5' UTR triplet expansion must first be internally validated for the interpretation pipeline. In the meantime, rating Amber but will raise the STR for validation with the Rare Disease team.
Intellectual disability v3.712 GLS Arina Puzriakova Phenotypes for gene: GLS were changed from Global developmental delay, progressive ataxia, and elevated glutamine, MIM# 618412 to Global developmental delay, progressive ataxia, and elevated glutamine, OMIM:618412; Global developmental delay, progressive ataxia, and elevated glutamine, MONDO:0032733; ?Infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development, OMIM:618339; Infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development, MONDO:0032685
Intellectual disability v3.712 GLS Arina Puzriakova Added comment: Comment on phenotypes: Global developmental delay, progressive ataxia, and elevated glutamine, OMIM:618412; Global developmental delay, progressive ataxia, and elevated glutamine, MONDO:0032733; ?Infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development, OMIM:618339; Infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development, MONDO:0032685
Intellectual disability v3.710 GLS Arina Puzriakova Added comment: Comment on mode of inheritance: As evidence for pathogenicity of monoallelic variants is limited (currently only 1 case), MOI will remain as 'Biallelic' until further cases emerge that support an association between monoallelic variants and disease.
Intellectual disability v3.709 GLS Arina Puzriakova edited their review of gene: GLS: Added comment: One case reported with a de novo (i.e. monoallelic) gain-of-function variant, associated with profound developmental delay, infantile cataract, skin abnormalities, and glutamate excess. Functional analysis showed the variant causes hyperactivity and compensatory downregulation of GLS expression combined with upregulation of the counteracting enzyme GS (PMID: 30239721).; Changed publications: 30970188, 30239721; Changed phenotypes: Global developmental delay, progressive ataxia, and elevated glutamine, OMIM:618412, Global developmental delay, progressive ataxia, and elevated glutamine, MONDO:0032733
Intellectual disability v3.709 GLS_GCA Arina Puzriakova STR: GLS_GCA was added
STR: GLS_GCA was added to Intellectual disability. Sources: Literature
Mode of inheritance for STR: GLS_GCA was set to BIALLELIC, autosomal or pseudoautosomal
Publications for STR: GLS_GCA were set to 30970188
Phenotypes for STR: GLS_GCA were set to Global developmental delay, progressive ataxia, and elevated glutamine, OMIM:618412; Global developmental delay, progressive ataxia, and elevated glutamine, MONDO:0032733
Review for STR: GLS_GCA was set to GREEN
Added comment: - PMID: 30970188 (2019) - Three unrelated cases who presented with an early-onset global developmental delay, progressive ataxia, and elevated levels of glutamine. One patient also showed cerebellar atrophy.

All 3 individuals harboured a large trinucleotide (GCA) repeat expansion in the 5' UTR (length: 680-1,500-copy repeats). The repeat expansion was found in homozygosity in 1 case, and occurred in compound heterozygosity with an SNV in the other two cases (missense and frameshift variant, respectively). Functional analysis showed the repeat expansion results in reduced expression and glutaminase deficiency.
Sources: Literature
Intellectual disability v3.708 MN1 Arina Puzriakova Phenotypes for gene: MN1 were changed from Central hypotonia; Feeding difficulties; Global developmental delay; Intellectual disability; Hearing impairment; Abnormality of facial skeleton; Craniosynostosis; Abnormality of the face; Abnormality of the cerebellum; Abnormality of the corpus callosum; Polymicrogyria to CEBALID syndrome, OMIM:618774; CEBALID syndrome, MONDO:0032908
Intellectual disability v3.707 KIF14 Arina Puzriakova Phenotypes for gene: KIF14 were changed from Microcephaly 20, primary, autosomal recessive, 617914 to Microcephaly 20, primary, autosomal recessive, OMIM:617914; Microcephaly 20, primary, autosomal recessive, MONDO:0054761
Intellectual disability v3.700 TLK2 Arina Puzriakova Phenotypes for gene: TLK2 were changed from intellectual disability to Mental retardation, autosomal dominant 57, OMIM:618050; Mental retardation, autosomal dominant 57, MONDO:0054837
Intellectual disability v3.699 ZNF526 Arina Puzriakova Added comment: Comment on list classification: Upgraded from Red to Amber but can be rated Green at the next GMS panel update (added 'for-review' tag).

Truncating variants associated with a more severe disease presentation; however, ID is the universal feature among individuals with biallelic variants in this gene.
Intellectual disability v3.698 ZNF526 Arina Puzriakova Phenotypes for gene: ZNF526 were changed from Non-syndromic autosomal recessive intellectual disability to Intellectual disability; Microcephaly; Cataracts; Epilepsy; Hypertonia; Dystonia
Intellectual disability v3.696 ZNF526 Arina Puzriakova reviewed gene: ZNF526: Rating: GREEN; Mode of pathogenicity: None; Publications: 21937992, 25558065, 33397746; Phenotypes: Intellectual disability, Microcephaly, Cataracts, Epilepsy, Hypertonia, Dystonia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.694 FGF13 Zornitza Stark gene: FGF13 was added
gene: FGF13 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: FGF13 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: FGF13 were set to 33245860
Phenotypes for gene: FGF13 were set to Intellectual disability; epilepsy
Mode of pathogenicity for gene: FGF13 was set to Other
Review for gene: FGF13 was set to GREEN
gene: FGF13 was marked as current diagnostic
Added comment: Two sibling pairs and three unrelated males reported who presented in infancy with intractable focal seizures and severe developmental delay. The variants were located in the N-terminal domain of the A isoform of FGF13/FHF2 (FHF2A). The X-linked FHF2 gene (also known as FGF13) has alternative first exons which produce multiple protein isoforms that differ in their N-terminal sequence. The variants were located at highly conserved residues in the FHF2A inactivation particle that competes with the intrinsic fast inactivation mechanism of Nav channels. Functional characterization of mutant FHF2A co-expressed with wild-type Nav1.6 (SCN8A) revealed that mutant FHF2A proteins lost the ability to induce rapid-onset, long-term blockade of the channel while retaining pro-excitatory properties. These gain-of-function effects are likely to increase neuronal excitability consistent with the epileptic potential of FHF2 variants.
Sources: Literature
Intellectual disability v3.694 RNU7-1 Zornitza Stark gene: RNU7-1 was added
gene: RNU7-1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: RNU7-1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RNU7-1 were set to 33230297
Phenotypes for gene: RNU7-1 were set to Aicardi–Goutières syndrome-like
Review for gene: RNU7-1 was set to GREEN
gene: RNU7-1 was marked as current diagnostic
Added comment: Review originally submitted by Ming Wong
- 16 affected individuals from 11 families
- Compared to control fibroblasts, patient fibroblasts were enriched for misprocessed forms of
replication-dependent histone (RDH) mRNAs
Sources: Literature
Intellectual disability v3.694 DPH2 Zornitza Stark gene: DPH2 was added
gene: DPH2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: DPH2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DPH2 were set to 32576952; 27421267
Phenotypes for gene: DPH2 were set to Diphthamide-deficiency syndrome
Review for gene: DPH2 was set to AMBER
Added comment: One 19 month old reported (PMID:32576952) with biallelic (one missense, one nonsense) variants in DPH2, with phenotype similar to DPH1 deficiency (gross motor delay, not walking, fine motor and expressive language delays, macrocephaly)

Another family (sibs) was previously reported with biallelic nonsense variants (PMID:27421267) with a comparable phenotype, this family also has biallelic variants in KALRN and the authors thought those variants more likely causative. Patients had ID and microcephaly (in contrast to the 19 month old above).

In vitro functional assays support reduced diphthamide synthesis activity for the variants identified in PMID:32576952.
Sources: Literature
Intellectual disability v3.694 FBRSL1 Zornitza Stark gene: FBRSL1 was added
gene: FBRSL1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: FBRSL1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FBRSL1 were set to 32424618
Phenotypes for gene: FBRSL1 were set to Intellectual disability; congenital anomalies
Review for gene: FBRSL1 was set to GREEN
gene: FBRSL1 was marked as current diagnostic
Added comment: Three children with de novo PTCs that escape NMD, and an overlapping syndromic phenotype with respiratory insufficiency, postnatal growth restriction, microcephaly, global developmental delay and other malformations. 2/3 had heart defects, cleft palate and hearing impairement.
Supported by Xenopus oocyte functional studies
Sources: Literature
Intellectual disability v3.694 CDC40 Zornitza Stark gene: CDC40 was added
gene: CDC40 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: CDC40 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CDC40 were set to 33220177
Phenotypes for gene: CDC40 were set to Pontocerebellar hypoplasia; microcephaly; seizures; intellectual disability
Review for gene: CDC40 was set to RED
Added comment: Single individual reported with bi-allelic variants in the gene and PCH, microcephaly, hypotonia, seizures, severe DD/ID, thrombocytopaenia, anaemia. Interaction with PPIL1 and mouse model support gene-disease association.

Gene referred to as PRP17 in paper.
Sources: Literature
Intellectual disability v3.694 CCDC40 Zornitza Stark changed review comment from: ID is not part of the phenotype.; to: ID is not part of the phenotype.
Intellectual disability v3.694 CCDC40 Zornitza Stark edited their review of gene: CCDC40: Added comment: New publication: Single individual reported with bi-allelic variants in the gene and PCH, microcephaly, hypotonia, seizures, severe DD/ID, thrombocytopaenia, anaemia. Interaction with PPIL1 and mouse model support gene-disease association.; Changed publications: 33220177
Intellectual disability v3.694 PPIL1 Zornitza Stark gene: PPIL1 was added
gene: PPIL1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: PPIL1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PPIL1 were set to 33220177
Phenotypes for gene: PPIL1 were set to Pontocerebellar hypoplasia; microcephaly; seizures; intellectual disbility
Review for gene: PPIL1 was set to GREEN
Added comment: 17 individuals from 9 unrelated families reported with bi-allelic variants in the gene and PCH, microcephaly, hypotonia, seizures, severe DD/ID. Mouse models support gene-disease association.
Sources: Literature
Intellectual disability v3.694 AP4E1 Arina Puzriakova Phenotypes for gene: AP4E1 were changed from Spastic paraplegia 51, autosomal recessive, 613744; CEREBRAL PALSY SPASTIC QUADRIPLEGIC TYPE 4 to Spastic paraplegia 51, autosomal recessive, OMIM:613744; Hereditary spastic paraplegia 51, MONDO:0013401
Intellectual disability v3.693 AP4B1 Arina Puzriakova Phenotypes for gene: AP4B1 were changed from Spastic paraplegia 47, autosomal recessive, 614066; CEREBRAL PALSY SPASTIC QUADRIPLEGIC TYPE 5 to Spastic paraplegia 47, autosomal recessive, OMIM:614066; Hereditary spastic paraplegia 47, MONDO:0013551
Intellectual disability v3.692 TBCD Arina Puzriakova Phenotypes for gene: TBCD were changed from Encephalopathy, progressive, early-onset, with brain atrophy and thin corpus callosum 617193 to Encephalopathy, progressive, early-onset, with brain atrophy and thin corpus callosum, OMIM:617193; Early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome, MONDO:0044646
Intellectual disability v3.690 SLC9A7 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. Associated with relevant phenotype in OMIM and Gene2Phenotype. However, only 2 unrelated families reported at present (PMID: 30335141) and therefore only sufficient for an Amber rating, awaiting further publications/clinical evidence (added 'watchlist' tag)
Intellectual disability v3.686 AGO2 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. All patients reported in PMID: 33199684 presented GDD/ID, while other features were relatively heterogenous. However, cognitive impairment was perhaps too mild in majority of cases. Tagged 'for-review' to assess whether there is sufficient evidence for a Green rating in light of the scope of the ID panel.
Intellectual disability v3.685 ZNF407 Arina Puzriakova Added comment: Comment on list classification: New gene added by Konstantinos Varvagiannis. Some evidence linking both mono- and biallelic variants with disease but currently not sufficient for a Green rating. Further cases would help validate this gene-disease association (added 'watchlist' tag)
Intellectual disability v3.683 SMG8 Arina Puzriakova Added comment: Comment on list classification: Additional cases reported in recent publication (PMID: 33242396) extend the total to at least 5 unrelated families with GDD/ID and different homozygous variants in the SMG8 gene. Also some supporting functional data provided.

Upgraded from Red to Amber, but there is sufficient evidence to promote to Green at the next GMS panel update (added 'for-review' tag)
Intellectual disability v3.681 SMG8 Arina Puzriakova edited their review of gene: SMG8: Added comment: PMID: 33242396 (2020) - 9 affected individuals from 4 consanguineous families with different biallelic variants in the SMG8 gene. Clinical features include GDD (8/8), dysmorphic features (9/9) microcephaly (6/9), short stature (4/9), brain imaging anomalies (4/5), congenital heart disease (3/9) and cataract (3/8). Only two sibs from Family 2 had a formal ID diagnosis, but this can be inferred from the clinical reports of the other cases demonstrating severe language delays, difficulties to follow simple instructions or perform daily activities.
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Several features described here overlap with those in the previously reported cases from PMID: 31130284 (e.g. microcephaly, ID, cataract, VSD); Changed rating: GREEN; Changed publications: 31130284, 33242396
Intellectual disability v3.681 LSS Eleanor Williams changed review comment from: In light of the recent expert review green by Zornitza Stark, this gene should be considered for a green rating by the GMS. The phenotype is variable with the ID phenotype being part of the presentation in approx half the families.; to: In light of the recent expert review green by Zornitza Stark, this gene should be considered for a green rating by the GMS, as agreed with Genomics England clinicians. The phenotype is variable with the ID phenotype being part of the presentation in approx half the families.
Intellectual disability v3.681 LSS Eleanor Williams edited their review of gene: LSS: Added comment: In light of the recent expert review green by Zornitza Stark, this gene should be considered for a green rating by the GMS. The phenotype is variable with the ID phenotype being part of the presentation in approx half the families.; Changed rating: GREEN
Intellectual disability v3.681 KCNMA1 Arina Puzriakova changed review comment from: Multiple individuals reported with either mono- or biallelic variants. Developmental delay and intellectual disability of relevant severity to this panel has been reported in a sufficient number of cases for inclusion on this panel. Although in most cases the phenotypes are primarily characterised by seizures or dyskinesia, it is plausible that these individuals may still be tested under the ID panel.

Furthermore, several individuals have been reported with severe GDD/ID and other variable feature such as craniofacial dysmorphism, ataxia, bone dysplasia, visceral malformations, and brain imaging anomalies, but without epilepsy or paroxysmal dyskinesia (namely Liang-Wang syndrome, PMID: 31152168). In less severely affected cases DD with significant speech delay has been noted as the main clinical indication of the presenting phenotypes, further indicating benefit of inclusion on a diagnostic ID panel.; to: Multiple individuals reported with either mono- or biallelic variants. Developmental delay and intellectual disability of relevant severity has been reported in a sufficient number of cases for inclusion on this panel. Although in most cases the phenotypes are primarily characterised by seizures or dyskinesia, it is plausible that these individuals may still be tested under the ID panel in context of the severe intellectual impairment that may be observed.

Furthermore, several individuals have been reported with severe GDD/ID and other variable feature such as craniofacial dysmorphism, ataxia, bone dysplasia, visceral malformations, and brain imaging anomalies, but without epilepsy or paroxysmal dyskinesia (namely Liang-Wang syndrome, PMID: 31152168). In less severely affected cases DD with significant speech delay has been noted as the main clinical indication of the presenting phenotypes, further indicating benefit of inclusion on a diagnostic ID panel.
Intellectual disability v3.681 KCNMA1 Arina Puzriakova Phenotypes for gene: KCNMA1 were changed from Cerebellar atrophy, developmental delay, and seizures, 617643; Paroxysmal nonkinesigenic dyskinesia, 3, with or without generalized epilepsy, 609446 to Cerebellar atrophy, developmental delay, and seizures, OMIM:617643; Cerebellar atrophy, developmental delay, and seizures, MONDO:0060551; Paroxysmal nonkinesigenic dyskinesia, 3, with or without generalized epilepsy, OMIM:609446; Generalized epilepsy-paroxysmal dyskinesia syndrome, MONDO:0012276; Liang-Wang syndrome, OMIM:618729; Liang-Wang syndrome, MONDO:0032886; {Epilepsy, idiopathic generalized, susceptibility to, 16}, OMIM:618596; Epilepsy, idiopathic generalized, susceptibility to, 16, MONDO:0032827
Intellectual disability v3.678 KCNMA1 Arina Puzriakova reviewed gene: KCNMA1: Rating: GREEN; Mode of pathogenicity: None; Publications: 26195193, 27567911, 29330545, 29545233, 31152168, 31427379; Phenotypes: Cerebellar atrophy, developmental delay, and seizures, OMIM:617643, Cerebellar atrophy, developmental delay, and seizures, MONDO:0060551, Paroxysmal nonkinesigenic dyskinesia, 3, with or without generalized epilepsy, OMIM:609446, Generalized epilepsy-paroxysmal dyskinesia syndrome, MONDO:0012276, Liang-Wang syndrome, OMIM:618729, Liang-Wang syndrome, MONDO:0032886, {Epilepsy, idiopathic generalized, susceptibility to, 16}, OMIM:618596, Epilepsy, idiopathic generalized, susceptibility to, 16, MONDO:0032827; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.678 GRIA1 Arina Puzriakova Added comment: Comment on list classification: Maintaining Amber rating as no new evidence has been published since previous review. Most commonly reported as a candidate gene in large screening studies with limited segregation/phenotype/functional data. Also variable penetrance of the ID phenotype. Therefore, there is currently not enough evidence to classify as Green.
Intellectual disability v3.677 H3F3B Arina Puzriakova changed review comment from: Currently not associated with any phenotype in OMIM or Gene2Phenotype.

- PMID: 33268356 (2020) - De novo missense variants identified in 13 unrelated individuals with a shared phenotype of GDD/ID, usually severe and often progressive, with mostly minor congenital anomalies. 8/13 patients showed abnormalities on brain MRI including hypomyelination (5), cortical atrophy (4), arachnoid cysts (3), and a thin corpus collosum (2). Variable seizure phenotypes were reported in 6/13 cases, all early-onset where specified, mostly during infancy (latest onset at 10 years of age).; to: Currently not associated with any phenotype in OMIM or Gene2Phenotype.

- PMID: 33268356 (2020) - De novo missense variants identified in 13 unrelated individuals with a shared phenotype of GDD/ID, usually severe and often progressive, with mostly minor congenital anomalies. One individual was reported to have a normal IQ at 15 years. 8/13 patients showed abnormalities on brain MRI including hypomyelination (5), cortical atrophy (4), arachnoid cysts (3), and a thin corpus collosum (2). Variable seizure phenotypes were reported in 6/13 cases, all early-onset where specified, mostly during infancy (latest onset at 10 years of age).
Intellectual disability v3.674 H3F3B Arina Puzriakova Added comment: Comment on list classification: Upgraded from Red to Amber, but there is sufficient evidence to promoted to Green at the next GMS panel update (added 'for-review' tag).

Multiple unrelated cases (at least 12) with GDD/ID associated with de novo variants in this gene.
Intellectual disability v3.670 H3F3A Arina Puzriakova Added comment: Comment on list classification: Upgraded from Red to Amber, but there is sufficient evidence to promoted to Green at the next GMS panel update (added 'for-review' tag).

Multiple unrelated cases (>30) with GDD/ID associated with de novo variants in this gene.
Intellectual disability v3.670 H3F3A Arina Puzriakova Added comment: Comment on list classification: Upgraded from Red to Amber, but there is sufficient evidence to promoted to Green at the next GMS panel update (added 'for-review' tag).

Multiple unrelated cases (>30) with GDD/ID associated with de novo variants in this gene.
Intellectual disability v3.669 KDM4B Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. Rating Amber but may be promoted to Green at the next GMS panel update (added 'for-review' tag).

9 unrelated individuals reported at present (PMID: 33232677). Although all presented GDD, only 1 individual had severe ID (IQ = 50) and 3 had mild ID. Although ID is too mild in majority of cases, developmental delay was the universal feature amongst affected individuals and other phenotypes were heterogenous (e.g. seizures, brain malformations). Therefore, there may be value in inclusion on this panel for capturing this phenotype.
Intellectual disability v3.668 HSPG2 Arina Puzriakova Phenotypes for gene: HSPG2 were changed from Schwartz-Jampel syndrome, type 1, 255800 to Schwartz-Jampel syndrome, type 1, OMIM:255800; Schwartz-Jampel syndrome, MONDO:0009717
Intellectual disability v3.667 HSPG2 Arina Puzriakova Added comment: Comment on list classification: While there are sufficient cases to support a gene-disease association, DD/ID is part of a broader phenotype and cognitive impairment is unlikely to represent a main feature of the disease presentation.

Maintaining Amber rating as the disorder is better represented in other panels (e.g. Skeletal dysplasia, Arthrogryposis, etc) where this gene is already Green.
Intellectual disability v3.666 CSNK1G1 Arina Puzriakova Added comment: Comment on list classification: Upgraded from Red to Amber as now at least 5 unrelated individuals reported (PMID: 33009664). All present developmental delay of varying severity, although a formal ID assessment was not performed. Tagged 'for-review' to evaluate relevance of the phenotypes to this panel.
Intellectual disability v3.665 SHMT2 Arina Puzriakova Added comment: Comment on list classification: New gene added by Konstantinos Varvagiannis. Sufficient number of unrelated cases (>3) with ID of relevant severity to this panel. Some functional data indicating variants result in impaired SHMT2 enzymatic function. Rating Amber but should be promoted to Green at the next GMS panel update (added 'for-review' tag)

SHMT2 is listed in Gene2Phenotype with a 'probable' disease confidence rating for 'SHMT2-related neurodevelopmental syndrome', and is also associated with 'Neurodevelopmental disorder with cardiomyopathy, spasticity, and brain abnormalities, MIM# 619121' in OMIM.
Intellectual disability v3.664 SHMT2 Arina Puzriakova Phenotypes for gene: SHMT2 were changed from Congenital microcephaly; Infantile axial hypotonia; Spastic paraparesis; Global developmental delay; Intellectual disability; Abnormality of the corpus callosum; Abnormal cortical gyration; Hypertrophic cardiomyopathy; Abnormality of the face; Proximal placement of thumb; 2-3 toe syndactyly to Neurodevelopmental disorder with cardiomyopathy, spasticity, and brain abnormalities, OMIM:619121
Intellectual disability v3.662 ITFG2 Arina Puzriakova Added comment: Comment on list classification: New gene added by Konstantinos Varvagiannis. Rating Amber as ITFG2 can only be classified as a possible candidate gene based present evidence. Clinical and pedigree details are limited and there is no supporting functional data. Additional cases required to corroborate this gene-disease association.
Intellectual disability v3.661 RAP1B Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in Gene2Phenotype but not OMIM.

PMID: 32627184 describes 2 patients.
36 yo patient of non-consanguineous parents. Had unclear pancytopenia, multiple congenital malformations, mild intellectual disability, endocrine disorders (short stature with growth hormone deficiency), dysmorphism and other features. Parents and sibling unaffected.
13 yo of non-consanguineous parents with thrombocytopenia, multiple congenital anomalies and learning difficulties. He had normal developmental milestones, walk was achieved at 14 months and there was no speech delay. He attended mainstream school with auxiliary help because of learning difficulties with graphism, syntaxic comprehension, logical reasoning and attention deficit. Parents and siblings unaffected.

PMID: 26280580 describes another patient with variant in RAP1B. The clinical features can be found in supplementary table 2. The table lists ID, but doesn't say severity and lists a host of other features including short stature, facial dysmorphism and skeletal findings.

All 3 cases seem to have a very wide spectrum of differing phenotypes and therefore, this gene has been given an Amber rating until further evidence is available.
Intellectual disability v3.659 AARS Arina Puzriakova Phenotypes for gene: AARS were changed from EARLY-ONSET EPILEPTIC ENCEPHALOPATHY WITH PERSISTENT MYELINATION DEFECT. to Developmental and epileptic encephalopathy 29, OMIM:616339; Developmental and epileptic encephalopathy, 29, MONDO:0014593
Intellectual disability v3.657 GOT2 Arina Puzriakova Phenotypes for gene: GOT2 were changed from Global developmental delay; Intellectual disability; Seizures; Increased serum lactate; Hyperammonemia; Microcephaly; Failure to thrive; Feeding difficulties; Abnormality of nervous system morphology to Epileptic encephalopathy, early infantile, 82, OMIM:618721; Developmental and epileptic encephalopathy, 82, MONDO:0032880
Intellectual disability v3.656 GOT2 Arina Puzriakova Added comment: Comment on list classification: ID of relevant severity to this panel (severe-to-profound) is reported in 4/4 individuals (PMID:31422819). However, intellectual impairment was secondary to epilepsy and there is no evidence of neurodevelopmental delay preceding the onset of seizures. Therefore, maintaining Amber rating on this panel (GOT2 is already Green on the Genetic epilepsy syndromes (v2.236) panel)
Intellectual disability v3.655 GATA6 Arina Puzriakova Added comment: Comment on list classification: Developmental delay has been reported in some patients with GATA6 variants. However, in view of the pancreatic and cardiac abnormalities that constitute the main phenotypes, cognitive impairment is unlikely to represent a key feature of the disease presentation.

Maintaining Amber rating as the disorder is better represented in other panels (e.g. Diabetes, Severe Paediatric Disorders, etc) where this gene is already Green.
Intellectual disability v3.654 HS2ST1 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not associated with a relevant phenotype in OMIM or Gene2Phenotype. Only 2 of 3 unrelated families with affected individuals described in PMID: 33159882 were reported to have ID. The affected individuals in the third family could not be assessed for ID. Therefore, there is currently not enough evidence to support a gene-disease association. This gene has been given an Amber rating.
Intellectual disability v3.653 BICRA Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not associated with any phenotypes in OMIM or Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Intellectual disability v3.652 EMC10 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not associated with any phenotypes in OMIM or Gene2Phenotype. As there is only 1 case, this gene has been given a Red rating.
Intellectual disability v3.651 CSNK1G1 Ivone Leong Phenotypes for gene: CSNK1G1 were changed from severe non-syndromic early-onset epilepsy to severe non-syndromic early-onset epilepsy; Global developmental delay; Intellectual disability; Autism; Seizures; Abnormality of the face; Abnormality of limbs
Intellectual disability v3.648 NARS Arina Puzriakova changed review comment from: Associated with relevant phenotype in OMIM, and in Gene2Phenotype with 'confirmed' disease confidence for 'NARS1 Neurodevelopmental Disorder (monoallelic)' and 'probable' for 'NARS1 Neurodevelopmental Disorder (biallelic)'

Total of 23 patients from 13 unrelated families with biallelic variants in the NARS1 gene (PMIDs: 32738225 and 32788587) and 8 unrelated patients with de novo heterozygous nonsense variants (PMIDs: 32738225). All individuals had GDD and ID, which varied in severity from moderate to profound. Other features include microcephaly, seizures, ataxia, and dysmorphism. Supportive functional data.; to: Associated with relevant phenotype in OMIM, and in Gene2Phenotype with 'confirmed' disease confidence for 'NARS1 Neurodevelopmental Disorder (monoallelic)' and 'probable' for 'NARS1 Neurodevelopmental Disorder (biallelic)'

Total of 24 patients from 13 unrelated families with biallelic variants in the NARS1 gene (PMIDs: 32738225 and 32788587) and 8 unrelated patients with de novo heterozygous variants (PMIDs: 32738225). All individuals had GDD and ID, which varied in severity from moderate to profound. Other features include microcephaly, seizures, ataxia, and dysmorphism. Supportive functional data.
Intellectual disability v3.648 NARS Arina Puzriakova changed review comment from: Associated with relevant phenotype in OMIM, and in Gene2Phenotype with 'confirmed' disease confidence for 'NARS1 Neurodevelopmental Disorder (monoallelic)' and 'probable' for 'NARS1 Neurodevelopmental Disorder (biallelic)'

Total of 23 patients from 13 unrelated families with biallelic variants in the NARS1 gene (PMIDs: 32738225 and 32788587) and 6 unrelated patients with de novo heterozygous nonsense variants (PMIDs: 32738225). All individuals had GDD and ID, which varied in severity from moderate to profound. Other features include microcephaly, seizures, ataxia, and dysmorphism. Supportive functional data.; to: Associated with relevant phenotype in OMIM, and in Gene2Phenotype with 'confirmed' disease confidence for 'NARS1 Neurodevelopmental Disorder (monoallelic)' and 'probable' for 'NARS1 Neurodevelopmental Disorder (biallelic)'

Total of 23 patients from 13 unrelated families with biallelic variants in the NARS1 gene (PMIDs: 32738225 and 32788587) and 8 unrelated patients with de novo heterozygous nonsense variants (PMIDs: 32738225). All individuals had GDD and ID, which varied in severity from moderate to profound. Other features include microcephaly, seizures, ataxia, and dysmorphism. Supportive functional data.
Intellectual disability v3.648 NARS Arina Puzriakova commented on gene: NARS: Added new-gene-name tag, new approved HGNC gene symbol for NARS is NARS1
Intellectual disability v3.648 NARS Arina Puzriakova Classified gene: NARS as Amber List (moderate evidence)
Intellectual disability v3.648 NARS Arina Puzriakova Gene: nars has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.647 NARS Arina Puzriakova reviewed gene: NARS: Rating: GREEN; Mode of pathogenicity: None; Publications: 32738225, 32788587; Phenotypes: Neurodevelopmental disorder with microcephaly, impaired language, and gait abnormalities, autosomal recessive, OMIM:619091, Neurodevelopmental disorder with microcephaly, impaired language, epilepsy, and gait abnormalities, autosomal dominant, OMIM:619092; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.647 NARS Arina Puzriakova Publications for gene: NARS were set to 32738225
Intellectual disability v3.646 NARS Arina Puzriakova Phenotypes for gene: NARS were changed from Abnormal muscle tone; Microcephaly; Global developmental delay; Intellectual disability; Seizures; Ataxia; Abnormality of the face; Demyelinating peripheral neuropathy to Neurodevelopmental disorder with microcephaly, impaired language, and gait abnormalities, autosomal recessive, OMIM:619091; Neurodevelopmental disorder with microcephaly, impaired language, epilepsy, and gait abnormalities, autosomal dominant, OMIM:619092
Intellectual disability v3.645 ISCA-37418-Loss Arina Puzriakova Phenotypes for Region: ISCA-37418-Loss were changed from Potocki-Lupski syndrome; hypotonia, poor feeding, failure to thrive, developmental delay particularly cognitive and language deficity, mild-moderate intellectual deficit, and neuropsychiatric disorders; Smith-Magenis syndrome; Structural cardiovascular anomalies (dilated aortic root, bicommissural aortic valve, atrial/ventricular and septal defects) and sleep disturbance; 182290; moderate intellectual disability, delayed speech and language skills, distinctive facial features, sleep disturbances, and behavioral problems; hypotonia, failure to thrive, mental retardation, pervasive developmental disorders, congenital anomalies; Dental abnormalities to Smith-Magenis syndrome, OMIM:182290; Smith-Magenis syndrome, MONDO:0008434
Intellectual disability v3.644 RAP1B Zornitza Stark gene: RAP1B was added
gene: RAP1B was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: RAP1B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RAP1B were set to 32627184; 26280580
Phenotypes for gene: RAP1B were set to Syndromic intellectual disability
Review for gene: RAP1B was set to GREEN
Added comment: Three unrelated individuals reported with de novo variants, some functional data. One of them described as Kabuki-like but lacks typical facial gestalt.
Sources: Literature
Intellectual disability v3.644 EMC10 Zornitza Stark gene: EMC10 was added
gene: EMC10 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: EMC10 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EMC10 were set to 32869858
Phenotypes for gene: EMC10 were set to Intellectual disability
Review for gene: EMC10 was set to RED
Added comment: Homozygous variants of EMC1 are associated with GDD, scoliosis, and cerebellar atrophy, indicating the relevance of this pathway for neurogenetic disorders.

One Saudi family with 2 affected individuals with mild ID, speech delay, and GDD.
WES and Sanger sequencing revealed a homozygous splice acceptor site variant (c.679‐1G>A) in EMC10 . Variant segregated within the family. RT‐qPCR showed a substantial decrease in the relative EMC10 gene expression in the patients.
Sources: Literature
Intellectual disability v3.644 BICRA Zornitza Stark gene: BICRA was added
gene: BICRA was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: BICRA was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: BICRA were set to 33232675
Phenotypes for gene: BICRA were set to Developmental delay, intellectual disability, autism spectrum disorder,behavioral abnormalities, dysmorphic features
Review for gene: BICRA was set to GREEN
Added comment: 12 individuals reported, 11 de novo (1 not resolved), with neurodevelopmental phenotypes—developmental delay (HP:0001263), intellectual disability (HP:0001249), autism spectrum disorder (HP:0000729), and/or behavioral phenotypes (HP:0000708)—and variable structural birth defects and dysmorphic features. Mostly LoF or gene deletions, but 2 missense reported. Zebrafish model supports the gene-disease association.
Sources: Literature
Intellectual disability v3.644 HS2ST1 Zornitza Stark gene: HS2ST1 was added
gene: HS2ST1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: HS2ST1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HS2ST1 were set to 33159882
Phenotypes for gene: HS2ST1 were set to Intellectual disability; dysmorphic features; congenital anomalies
Review for gene: HS2ST1 was set to GREEN
Added comment: Four affected individuals from 3 unrelated families. 3 unique missense and 2 PTCs. Clinical features included developmental delay, corpus callosum hypoplasia or aplasia, and skeletal and renal abnormalities as well as joint contractures/arthrogryposis.
Sources: Literature
Intellectual disability v3.644 KDM4B Zornitza Stark gene: KDM4B was added
gene: KDM4B was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: KDM4B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KDM4B were set to 33232677
Phenotypes for gene: KDM4B were set to Global developmental delay, intellectual disability and neuroanatomical defects
Review for gene: KDM4B was set to GREEN
Added comment: Nine individuals with mono-allelic de novo or inherited variants in KDM4B.

All individuals presented with dysmorphic features and global developmental delay (GDD) with language and motor skills most affected. Three individuals had a history of seizures, and four had anomalies on brain imaging ranging from agenesis of the corpus callosum with hydrocephalus to cystic formations, abnormal hippocampi, and polymicrogyria.

In a knockout mouse the total brain volume was significantly reduced with decreased
size of the hippocampal dentate gyrus, partial agenesis of the corpus callosum, and ventriculomegaly.
Sources: Literature
Intellectual disability v3.644 AGO2 Zornitza Stark gene: AGO2 was added
gene: AGO2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: AGO2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: AGO2 were set to 33199684
Phenotypes for gene: AGO2 were set to Intellectual disability; regression; seizures
Review for gene: AGO2 was set to GREEN
Added comment: 21 individuals reported, five variants (p.L192P, p.G201V, p.T357M, p.M364T, p.C751Y) were recurrent. Variable ID.
Sources: Literature
Intellectual disability v3.643 SMARCA2 Arina Puzriakova Phenotypes for gene: SMARCA2 were changed from Nicolaides-Baraitser syndrome, 601358; COFFIN SIRIS to Nicolaides-Baraitser syndrome, OMIM:601358; Coffin-siris syndrome; Blepharophimosis intellectual disability syndrome
Intellectual disability v3.642 SMARCA2 Arina Puzriakova Publications for gene: SMARCA2 were set to
Intellectual disability v3.641 MORC2 Arina Puzriakova Phenotypes for gene: MORC2 were changed from Charcot-Marie-Tooth disease, axonal, type 2Z, MIM #616688 to Developmental delay; Intellectual disability; Growth retardation; Microcephaly; Craniofacial dysmorphism; Charcot-Marie-Tooth disease, axonal, type 2Z, OMIM:616688
Intellectual disability v3.639 MORC2 Arina Puzriakova Added comment: Comment on list classification: Though signs suggestive of neuropathy were observed in the cohort presented by Sacoto et al (PMID:32693025), these were not the predominant feature of the disease presentation or the primary indication for diagnostic testing. Inclusion on this panel would be of value for detecting such cases, and so this gene should be promoted to Green at the next GMS panel update (added 'for-review' tag)
Intellectual disability v3.638 MORC2 Arina Puzriakova reviewed gene: MORC2: Rating: GREEN; Mode of pathogenicity: None; Publications: 32693025; Phenotypes: Developmental delay, Intellectual disability, Growth retardation, Microcephaly, Craniofacial dysmorphism; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.638 LARS Arina Puzriakova commented on gene: LARS: Added new-gene-name tag, new approved HGNC gene symbol for LARS is LARS1
Intellectual disability v3.638 LARS Arina Puzriakova Classified gene: LARS as Amber List (moderate evidence)
Intellectual disability v3.638 LARS Arina Puzriakova Added comment: Comment on list classification: New gene added by Konstantinos Varvagiannis. Developmental delay is prevalent among affected individuals, and there are sufficient unrelated cases (>3) presenting with relevant severity to this panel. This may serve as a possible route for diagnostic testing as currently there are no relevant panels for detecting the hepatic phenotype of the disease presentation, and so there may be value in rating Green at the next major panel review (added 'for-review tag).
Intellectual disability v3.638 LARS Arina Puzriakova Gene: lars has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.637 LARS Arina Puzriakova Tag new-gene-name tag was added to gene: LARS.
Tag for-review tag was added to gene: LARS.
Intellectual disability v3.636 SOX3 Arina Puzriakova Phenotypes for gene: SOX3 were changed from Mental retardation, X-linked, with isolated growth hormone deficiency, 300123Panhypopituitarism, X-linked, 312000; SEX REVERSAL TYPE 3 (SRXX3) to Mental retardation, X-linked, with isolated growth hormone deficiency, OMIM:300123; Intellectual disability, X-linked, with panhypopituitarism, MONDO:0010252
Intellectual disability v3.633 PRKAR1A Arina Puzriakova Phenotypes for gene: PRKAR1A were changed from Gene2Phenotype confirmed gene with ID HPO to Acrodysostosis 1, with or without hormone resistance, OMIM:101800
Intellectual disability v3.632 SH3PXD2B Arina Puzriakova Added comment: Comment on list classification: Following discussion with the Genomics England clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark (Australian Genomics)
Intellectual disability v3.631 SEC23B Arina Puzriakova Added comment: Comment on list classification: Following discussion with the Genomics England clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark (Australian Genomics)
Intellectual disability v3.630 SCN11A Arina Puzriakova Added comment: Comment on list classification: Following discussion with the Genomics England clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark (Australian Genomics)
Intellectual disability v3.629 SCARF2 Arina Puzriakova Classified gene: SCARF2 as Red List (low evidence)
Intellectual disability v3.629 SCARF2 Arina Puzriakova Added comment: Comment on list classification: Following discussion with the Genomics England clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark (Australian Genomics)
Intellectual disability v3.629 SCARF2 Arina Puzriakova Gene: scarf2 has been classified as Red List (Low Evidence).
Intellectual disability v3.628 SBDS Arina Puzriakova Added comment: Comment on list classification: Following discussion with the Genomics England clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark (Australian Genomics)
Intellectual disability v3.627 SALL4 Arina Puzriakova Added comment: Comment on list classification: Following discussion with the Genomics England clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark (Australian Genomics)
Intellectual disability v3.626 PRSS56 Arina Puzriakova Added comment: Comment on list classification: Following discussion with the Genomics England clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark (Australian Genomics)
Intellectual disability v3.625 PROP1 Arina Puzriakova Added comment: Comment on list classification: Following discussion with the Genomics England clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark (Australian Genomics)
Intellectual disability v3.624 PRDM12 Arina Puzriakova Added comment: Comment on list classification: Following discussion with the Genomics England clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark (Australian Genomics)
Intellectual disability v3.623 PPA2 Arina Puzriakova Added comment: Comment on list classification: Following discussion with the Genomics England clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark (Australian Genomics)
Intellectual disability v3.622 POLR1D Arina Puzriakova Added comment: Comment on list classification: Following discussion with the Genomics England clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark (Australian Genomics)
Intellectual disability v3.621 POLD1 Arina Puzriakova Added comment: Comment on list classification: Following discussion with the Genomics England clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark (Australian Genomics)
Intellectual disability v3.620 POC1B Arina Puzriakova Added comment: Comment on list classification: Following discussion with the Genomics England clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark (Australian Genomics)
Intellectual disability v3.619 PMS2 Arina Puzriakova Added comment: Comment on list classification: Following discussion with the Genomics England clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark (Australian Genomics)
Intellectual disability v3.618 PLOD2 Arina Puzriakova Added comment: Comment on list classification: Following discussion with the Genomics England clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark (Australian Genomics)
Intellectual disability v3.617 PKHD1 Arina Puzriakova Added comment: Comment on list classification: Following discussion with the Genomics England clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark (Australian Genomics)
Intellectual disability v3.616 PKD1L1 Arina Puzriakova Added comment: Comment on list classification: Following discussion with the Genomics England clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark (Australian Genomics)
Intellectual disability v3.615 PITX3 Arina Puzriakova Added comment: Comment on list classification: Following discussion with the Genomics England clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark (Australian Genomics)
Intellectual disability v3.614 PITX2 Arina Puzriakova Added comment: Comment on list classification: Following discussion with the Genomics England clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark (Australian Genomics)
Intellectual disability v3.613 PIK3R1 Arina Puzriakova Added comment: Comment on list classification: Following discussion with the Genomics England clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark
Intellectual disability v3.610 POLR1C Arina Puzriakova Added comment: Comment on list classification: Cognitive impairment (ID and/or cognitive regression) may be variable amongst affected individuals; however, there are sufficient unrelated cases (>3) for inclusion on this panel as Green.
Intellectual disability v3.608 PNPT1 Arina Puzriakova Added comment: Comment on list classification: GDD/ID is a prominent feature of the disease presentation and there are sufficient unrelated cases (>3) presenting with relevant severity to this panel. This is a possible route for diagnostic testing and so there may be value in classifying as Green - PNPT1 will be flagged for review at the next GMS panel update (added 'for-review' tag)
Intellectual disability v3.607 SCN1B Arina Puzriakova Added comment: Comment on list classification: Biallelic variants associated with developmental epileptic encephalopathy characterised by early onset epileptic seizures followed by cognitive decline. At least 5 unrelated families in literature (PMIDs: 19710327; 23148524; 28218389).

Rating Amber as seizures are the prominent feature of the disease presentation, to which cognitive impairment is secondary. Cases would be detected via the epilepsy route (SCN1B is already Green on Genetic epilepsy syndromes panel).
Intellectual disability v3.601 ZFHX4 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in OMIM. Based on the available evidence there is enough evidence to support a gene-disease association. This gene should be promoted to Green at the next review.
Intellectual disability v3.599 UPF1 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics).

PMID: 28539120 describes a patient with significant ID. The patient has SNVs in SQSTM1 and UPF1. The authors suggests that it is plausible that the haploinsufficiency of SQSTM1 may have caused neurofunctional defects, which the haploinsufficiency of UPF1 may have exacerbated.

As the patient in the second case has another variant in another gene, there is not enough evidence to support a gene-disease association so this gene has been given an Amber rating.
Intellectual disability v3.597 U2AF2 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). There is not enough evidence to support a gene-disease association so this gene has been given an Amber rating.
Intellectual disability v3.596 TCF7L2 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). There is not enough evidence to support a gene-disease association so this gene has been given an Amber rating.
Intellectual disability v3.595 SRRM2 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). There is not enough evidence to support a gene-disease association so this gene has been given an Amber rating.
Intellectual disability v3.594 SPEN Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). There is not enough evidence to support a gene-disease association so this gene has been given an Amber rating.
Intellectual disability v3.590 MSL2 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). There is not enough evidence to support a gene-disease association so this gene has been given an Amber rating.
Intellectual disability v3.590 MSL2 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). There is not enough evidence to support a gene-disease association so this gene has been given an Amber rating.
Intellectual disability v3.589 RAB14 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). There is not enough evidence to support a gene-disease association so this gene has been given an Amber rating.
Intellectual disability v3.588 PSMC5 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). There is not enough evidence to support a gene-disease association so this gene has been given an Amber rating.
Intellectual disability v3.587 MMGT1 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). There is not enough evidence to support a gene-disease association so this gene has been given an Amber rating.
Intellectual disability v3.586 HNRNPD Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). There is not enough evidence to support a gene-disease association so this gene has been given an Amber rating.
Intellectual disability v3.585 FBXO31 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). There is not enough evidence to support a gene-disease association so this gene has been given an Amber rating.
Intellectual disability v3.584 PIK3C2A Arina Puzriakova Added comment: Comment on list classification: Maintaining Amber rating as only 2/2 individuals assessed for ID (both from the same family) are reported with it (PMID:31034465). Although authors state that 'most affected individuals exhibited neurological involvement including developmental delay', this was not formally assessed or otherwise reported on in the remaining cases.
Intellectual disability v3.583 FBXO31 Ivone Leong Phenotypes for gene: FBXO31 were changed from Mental retardation, autosomal recessive 45, MIM#615979; Intellectual disability, autosomal dominant to ?Mental retardation, autosomal recessive 45, OMIM:615979; Intellectual disability, autosomal dominant
Intellectual disability v3.582 FOXP4 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). As ID is not present in the majority of affected patients, and the affected individuals only show mild ID, this gene has been given an Amber rating.
Intellectual disability v3.581 DHX32 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). There is not enough evidence to support a gene-disease association so this gene has been given an Amber rating.
Intellectual disability v3.580 GIGYF1 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). There is not enough evidence to support a gene-disease association so this gene has been given an Amber rating.
Intellectual disability v3.579 ATP6V0A1 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). There is not enough evidence to support a gene-disease association so this gene has been given an Amber rating.
Intellectual disability v3.578 DDX23 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). There is not enough evidence to support a gene-disease association so this gene has been given an Amber rating.
Intellectual disability v3.577 ARHGAP35 Ivone Leong Classified gene: ARHGAP35 as Amber List (moderate evidence)
Intellectual disability v3.577 ARHGAP35 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). There is not enough evidence to support a gene-disease association so this gene has been given an Amber rating.
Intellectual disability v3.577 ARHGAP35 Ivone Leong Gene: arhgap35 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.576 ARHGAP35 Ivone Leong Tag watchlist tag was added to gene: ARHGAP35.
Intellectual disability v3.575 AP2S1 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). There is not enough evidence to support a gene-disease association so this gene has been given an Amber rating.
Intellectual disability v3.574 TFE3 Arina Puzriakova Phenotypes for gene: TFE3 were changed from to TFE3-related intellectual disability with pigmentary mosaicism
Intellectual disability v3.573 CDH2 Arina Puzriakova reviewed gene: CDH2: Rating: GREEN; Mode of pathogenicity: None; Publications: 31650526; Phenotypes: Agenesis of corpus callosum, cardiac, ocular, and genital syndrome, OMIM:618929; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.573 CDH2 Arina Puzriakova Phenotypes for gene: CDH2 were changed from Agenesis of corpus callosum, cardiac, ocular, and genital syndrome 618929 to Agenesis of corpus callosum, cardiac, ocular, and genital syndrome, OMIM:618929; Agenesis of corpus callosum, cardiac, ocular, and genital syndrome, MONDO:0030065
Intellectual disability v3.569 RNPC3 Ivone Leong gene: RNPC3 was added
gene: RNPC3 was added to Intellectual disability. Sources: Expert Review,Literature
Mode of inheritance for gene: RNPC3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RNPC3 were set to 24480542; 29866761; 32462814
Phenotypes for gene: RNPC3 were set to isolated growth hormone deficiency; ?Growth hormone deficiency, isolated, type V, 618160; developmental delay/intellectual deficiency and delayed puberty
Review for gene: RNPC3 was set to RED
Added comment: This gene is an Amber gene on the Growth failure in early childhood panel (v1.16). The following reviews are present for this gene on that panel:

"Comment on list classification: Based on the available evidence and expert review, this gene has been promoted from Red to Amber. This gene is associated with a relevant phenotype on OMIM. The family described in PMIDs 24480542 and 29866761 are the same. The 3 sisters in this family had GH deficiency only. PMID: 32462814 had GH deficiency and almost undetectable levels of prolactin as well.
Ivone Leong (Genomics England Curator), 15 Oct 2020

Two families reported. PMID 29866761: isolated growth deficiency and pituitary hypoplasia. PMID 32462814: growth hormone deficiency, central congenital hypothyroidism, congenital cataract, developmental delay/intellectual deficiency and delayed puberty. Full spectrum of phenotype unclear at present.
Zornitza Stark (Australian Genomics), 5 Oct 2020"

As only 1 affected family has developmental delay/intellectual deficiency, this gene is given a Red rating.
Sources: Expert Review, Literature
Intellectual disability v3.567 DNMT3A Sarah Leigh Added comment: Comment on mode of pathogenicity: Tatton-Brown-Rahman syndrome 615879 is associated with loss of function variants and Heyn-Sproul-Jackson syndrome OMIM:618724 is associated with gain of function variants.
Intellectual disability v3.564 DDC Arina Puzriakova Phenotypes for gene: DDC were changed from AROMATIC L-AMINO-ACID DECARBOXYLASE DEFICIENCY to Aromatic L-amino acid decarboxylase deficiency, OMIM:608643; Aromatic L-amino acid decarboxylase deficiency, MONDO:0012084
Intellectual disability v3.563 AGAP1 Arina Puzriakova Added comment: Comment on list classification: New gene added as Amber. Clinical reports are generally limited and the contribution of secondary variants in other genes in 2 subjects cannot be ruled out. Additional cases necessary to corroborate this gene-disease association.
Intellectual disability v3.562 MPP5 Arina Puzriakova Added comment: Comment on list classification: New gene added by Konstantinos Varvagiannis. ased on the evidence provided in PMID:33073849, this gene should be promoted to Green at the next GMS panel update (added 'for-review' tag) - 3 unrelated individuals with de novo variants in the MPP5 gene associated with ID/GDD, language delay/regression and behavioural changes. Supportive animal model.
Intellectual disability v3.561 JARID2 Arina Puzriakova Classified gene: JARID2 as Amber List (moderate evidence)
Intellectual disability v3.561 JARID2 Arina Puzriakova Gene: jarid2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.560 JARID2 Arina Puzriakova Phenotypes for gene: JARID2 were changed from Intellectual disability to Intellectual disability; Neurodevelopmental syndrome
Intellectual disability v3.559 JARID2 Arina Puzriakova Tag for-review tag was added to gene: JARID2.
Intellectual disability v3.559 JARID2 Arina Puzriakova reviewed gene: JARID2: Rating: GREEN; Mode of pathogenicity: None; Publications: 33077894; Phenotypes: Neurodevelopmental syndrome; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.559 LMNB1 Sarah Leigh changed review comment from: Not associated with relevant phenotype in OMIM (19/11/2020), but as confirmed Gen2Phen gene for LMNB1-associated developmental disorder. At least 7 variants reported in at least 7 unrelated cases. Each variant was associated with intellectual disability and microcephaly (PMID 32910914; 33033404).; to: Not associated with relevant phenotype in OMIM (19/11/2020), but as confirmed Gen2Phen gene for LMNB1-associated developmental disorder. At least 5 variants reported in at least 5 unrelated cases. Each variant was associated with intellectual disability and microcephaly (PMID 32910914; 33033404).
Intellectual disability v3.558 LMNB1 Sarah Leigh edited their review of gene: LMNB1: Added comment: Not associated with relevant phenotype in OMIM (19/11/2020), but as confirmed Gen2Phen gene for LMNB1-associated developmental disorder. At least 7 variants reported in at least 7 unrelated cases. Each variant was associated with intellectual disability and microcephaly (PMID 32910914; 33033404).; Changed rating: GREEN; Changed phenotypes: LMNB1-associated developmental disorder
Intellectual disability v3.557 PJA1 Arina Puzriakova Added comment: Comment on list classification: Upgraded rating from Red to Amber - 7 individuals reported in PMID:32530565 all with ID, albeit due to a founder variant. Some cases with deletions encompassing this gene reported with mild DD, however contribution of other affected genes cannot be ruled out. Evidence of pathogenicity of other PJA1 variants is required prior to inclusion on a diagnostic panel.
Intellectual disability v3.553 MAPK1 Catherine Snow reviewed gene: MAPK1: 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: 32721402; Phenotypes: Noonan syndrome 13, OMIM:619087, MONDO:0018997; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.553 FAM50A Arina Puzriakova Phenotypes for gene: FAM50A were changed from Mental retardation syndrome, X-linked, Armfield type (MIM #300261) to Mental retardation syndrome, X-linked, Armfield type, OMIM:300261; Armfield syndrome, MONDO:0010284
Intellectual disability v3.552 FAM50A Arina Puzriakova Added comment: Comment on list classification: New gene added by Konstantinos Varvagiannis. Based on the evidence provided in PMID:32703943, this gene should be promoted to Green at the next GMS panel update (added 'for-review' tag) - 6 individuals from 5 families, all exhibiting GDD/ID as the common presenting feature.
Intellectual disability v3.551 PRKACB Arina Puzriakova Added comment: Comment on list classification: New gene added by Konstantinos Varvagiannis. Rating Amber based on the evidence provided in one publication (PMID:33058759) reporting 2/4 unrelated individuals with ID among other features, although this presentation was mild in one of these cases.
Intellectual disability v3.550 PIGQ Sarah Leigh Added comment: Comment on phenotypes: According to Joanna Peas-Welch (OMIM), Multiple congenital anomalies-hypotonia-seizures syndrome-4 (MCAHS4) will replace Epileptic encephalopathy, early infantile, 77, OMIM:618548 as the name for this phenotype (12/11/2020).
Intellectual disability v3.550 PIGQ Sarah Leigh Phenotypes for gene: PIGQ were changed from Epileptic encephalopathy, early infantile 77, OMIM:618548 to Multiple congenital anomalies-hypotonia-seizures syndrome-4 OMIM:618548
Intellectual disability v3.549 NARS Sarah Leigh Tag new-gene-name tag was added to gene: NARS.
Intellectual disability v3.549 PIGQ Sarah Leigh edited their review of gene: PIGQ: Added comment: Associated with relevant phenotype in OMIM and as possible Gen2Phen gene for severe early onset epilepsy. At least 11 variants reported in seven unrelated cases of multiple congenital anomalies-hypotonia-seizures syndrome-4 (MCAHS4)(Epileptic encephalopathy, early infantile, 77 618548)(OMIM:618548).; Changed rating: GREEN; Changed phenotypes: OMIM:618548; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.548 COX6B1 Arina Puzriakova Phenotypes for gene: COX6B1 were changed from MITOCHONDRIAL COMPLEX IV DEFICIENCY (MT-C4D) to Mitochondrial complex IV deficiency, nuclear type 7, OMIM:619051
Intellectual disability v3.546 COX6B1 Arina Puzriakova Added comment: Comment on list classification: This gene should be demoted from Green to Red and will be flagged for evaluation at the next GMS panel update (added 'for-review' tag) in view of the recent review by Zornitza Stark. As discussed the disease presentation is not prominent for ID, and rather is primarily characterised by lactate acidosis and encephalopathy which should be sufficient indications for diagnostic testing - COX6B1 is already Green on relevant metabolic/mitochondrial panels.
Intellectual disability v3.545 PIGQ Sarah Leigh Phenotypes for gene: PIGQ were changed from Epileptic encephalopathy, early infantile 77, 618548 to Epileptic encephalopathy, early infantile 77, OMIM:618548
Intellectual disability v3.544 PIGQ Sarah Leigh Phenotypes for gene: PIGQ were changed from SEVERE EARLY-ONSET EPILEPSY; Epileptic encephalopathy, early infantile, 77, 618548 to Epileptic encephalopathy, early infantile 77, 618548
Intellectual disability v3.542 TFE3 Sarah Leigh changed review comment from: Not associated with a relevant phenotype in OMIM, but as a confirmed Gen2Phen gene for X-linked dominant Intellectual disability with pigmentary mosaicism and storage disorder and hemizygous TFE3-related intellectual disability with pigmentary mosaicism. At least 14 variants reported as de novo events in 17 unrelated cases of severe intellectual disability with pigmentary mosaicism and storage disorder-like features (no relevant OMIM or MONDO title as of 16/11/2020).

There is enough evidence for this gene to be rated GREEN at the next major review.; to: Not associated with a relevant phenotype in OMIM, but as a confirmed Gen2Phen gene for X-linked dominant Intellectual disability with pigmentary mosaicism and storage disorder and hemizygous TFE3-related intellectual disability with pigmentary mosaicism. At least 14 variants reported as de novo events in 17 unrelated cases of severe intellectual disability with pigmentary mosaicism and storage disorder-like features (no relevant OMIM or MONDO title as of 16/11/2020).
Intellectual disability v3.541 TFE3 Sarah Leigh changed review comment from: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least 14 variants reported as de novo events in 17 unrelated cases of severe intellectual disability with pigmentary mosaicism and storage disorder-like features (no OMIM or MONDO title as of 16/11/2020).

There is enough evidence for this gene to be rated GREEN at the next major review.; to: Not associated with a relevant phenotype in OMIM, but as a confirmed Gen2Phen gene for X-linked dominant Intellectual disability with pigmentary mosaicism and storage disorder and hemizygous TFE3-related intellectual disability with pigmentary mosaicism. At least 14 variants reported as de novo events in 17 unrelated cases of severe intellectual disability with pigmentary mosaicism and storage disorder-like features (no relevant OMIM or MONDO title as of 16/11/2020).

There is enough evidence for this gene to be rated GREEN at the next major review.
Intellectual disability v3.541 SCO1 Arina Puzriakova Phenotypes for gene: SCO1 were changed from MITOCHONDRIAL COMPLEX IV DEFICIENCY (MT-C4D) to Mitochondrial complex IV deficiency, nuclear type 4, OMIM:619048
Intellectual disability v3.540 SCO1 Arina Puzriakova Added comment: Comment on list classification: This gene should be demoted from Green to Red and will be flagged for evaluation at the next GMS panel update (added 'for-review' tag), in view of the recent review by Zornitza Stark. As discussed the phenotype is primarily characterised by lactate acidosis and encephalopathy which should be sufficient indications for diagnostic testing - SCO1 is already Green on relevant metabolic/mitochondrial panels.
Intellectual disability v3.537 EXOC2 Arina Puzriakova Added comment: Comment on list classification: New gene added by Konstantinos Varvagiannis. Updating rating from Grey to Amber based on one publication (PMID:32639540) reporting 2 families with EXOC2 variants and variable ID, among other features. Additional cases with a significant ID phenotype are required before inclusion of this gene on a diagnostic panel.
Intellectual disability v3.536 TBC1D2B Arina Puzriakova Added comment: Comment on list classification: New gene added by Konstantinos Varvagiannis. Updating rating from Grey to Amber based on one publication (PMID:32623794). Manifestation of ID is variable amongst cases, but is mostly within the mild range. Additional cases would help determine the relevance of ID to the overall disease presentation (added 'watchlist' tag)
Intellectual disability v3.535 PAX1 Arina Puzriakova Added comment: Comment on list classification: New gene added and rated Amber by Konstantinos Varvagiannis. Updating rating from Grey to Amber based on 2 papers (PMID:29681087 and PMID:23851939) reporting 2 unrelated cases with mild ID.
Intellectual disability v3.532 CEP120 Arina Puzriakova Added comment: Comment on list classification: New gene added by Konstantinos Varvagiannis. Based on the evidence provided, this gene should be promoted to Green at the next GMS panel update (added 'for-review' tag)

4 unrelated individuals with distinct variants in the CEP120 gene and Joubert syndrome, including a neurological phenotype in all consisting of hypotonia, developmental delay and cognitive impairment (PMID:27208211).
Intellectual disability v3.531 NUS1 Eleanor Williams edited their review of gene: NUS1: Added comment: As reported by reviewer Konstantinos Varvagiannis another 2 cases now reported by Den et al 2019 (PMID: 31656175). 2 unrelated Japanese patients with a novel, recurrent, de novo NUS1 variant, who presented with epileptic seizures with involuntary movement, ataxia, intellectual disability and scoliosis. The variant c.691 + 1C > A, creates a new splice donor site resulting in a 91 bp deletion in exon 3.

This now gives a total of 5 families with heterozygous variants in NUS1 and a presentation of developmental delay and epileptic encephalopathy.; Changed publications: 31656175
Intellectual disability v3.531 PET100 Eleanor Williams Added comment: Comment on list classification: Leaving this gene rating as amber until the next GMS review, but as reviewer Zornitza Stark notes there are 8 Lebanese familes with the same variant, plus an Asian British family with a similar phenotype and a different variant, plus functional data to support the disease causation, so would recommend Green rating.
Intellectual disability v3.530 PET100 Eleanor Williams Added comment: Comment on phenotypes: Removing MIM# 220110 as this is associated with variants in SURF1
Intellectual disability v3.530 PET100 Eleanor Williams Phenotypes for gene: PET100 were changed from Mitochondrial complex IV deficiency,220110; Intellectual disability; Complex IV-deficient Leigh syndrome to Intellectual disability; Complex IV-deficient Leigh syndrome; Mitochondrial complex IV deficiency, nuclear type 12 OMIM:619055
Intellectual disability v3.528 PET100 Eleanor Williams reviewed gene: PET100: Rating: GREEN; Mode of pathogenicity: None; Publications: 24462369, 25293719, 31406627; Phenotypes: Mitochondrial complex IV deficiency, nuclear type 12 OMIM:619055, Leigh syndrome; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.527 PIGH Eleanor Williams Added comment: Comment on list classification: Leaving as amber for now, but this gene should be reviewed at the next GMS update. It is borderline green as there are 5 families reported with DD/ID but only two without epilepsy.
Intellectual disability v3.525 PRKAR1B Ivone Leong Tag watchlist tag was added to gene: PRKAR1B.
Intellectual disability v3.525 PRKAR1B Ivone Leong Classified gene: PRKAR1B as Amber List (moderate evidence)
Intellectual disability v3.525 PRKAR1B Ivone Leong Added comment: Comment on list classification: New gene added by Konstantinos Varvagiannis. Based on the provided evidence this gene has been given an Amber rating.
Intellectual disability v3.525 PRKAR1B Ivone Leong Gene: prkar1b has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.524 KCNC3 Catherine Snow Phenotypes for gene: KCNC3 were changed from Spinocerebellar ataxia 13, OMIM:605259; MONDO:0011529 to Spinocerebellar ataxia 13, OMIM:605259; MONDO:0011529
Intellectual disability v3.523 KCNC3 Catherine Snow Phenotypes for gene: KCNC3 were changed from SPINOCEREBELLAR ATAXIA TYPE 13 (SCA13) to Spinocerebellar ataxia 13, OMIM:605259; MONDO:0011529
Intellectual disability v3.522 KCNC3 Catherine Snow reviewed gene: KCNC3: Rating: AMBER; Mode of pathogenicity: None; Publications: 32655623; Phenotypes: Spinocerebellar ataxia 13, OMIM:605259, MONDO:0011529; Mode of inheritance: None
Intellectual disability v3.522 TMEM106B Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to rate this gene Green at the next GMS panel update (added 'for-review' tag) in view of 6 cases with the same variant and phenotype, supported by some evidence of altered gene function.

Inclusion on this panel would also cover the hypotonia feature exhibited by most cases in the neonatal period (as ID is a sub-panel of the Hypotonic Infant super panel)
Intellectual disability v3.520 TMEM106B Arina Puzriakova reviewed gene: TMEM106B: 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: 29186371, 29444210, 30643851, 32595021; Phenotypes: Leukodystrophy, hypomyelinating, 16 OMIM:617964; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.520 AFF3 Sarah Leigh changed review comment from: Not associated with relevant phenotype in OMIM and as probable Gen2Phen gene for Skeletal dysplasia with severe neurological disease. At least 2 variants have been reported in peer reviewed literature, further four variants have been reported in a preprint (July 2019). This preprint has not been published in a peer reviewed (as of 06/08/2020). There are convincing aminal models; to: Not associated with relevant phenotype in OMIM and as probable Gen2Phen gene for Skeletal dysplasia with severe neurological disease. At least 2 variants have been reported in peer reviewed literature, further four variants have been reported in a preprint (July 2019). This preprint has not been published in a peer reviewed (as of 06/08/2020). There are convincing aminal models. If the preprint is peer reviewed and the evidence is relevant, then this gene could be rated green at the next major review (as of 12/11/2020).
Intellectual disability v3.520 ZMYM2 Ivone Leong Added comment: Comment on list classification: New gene added by Konstantinos Varvagiannis. This gene is probably associated with a phenotype on Gene2Phenotype. This gene has been given an Amber rating based on the expert review and the evidence provided. As ID is not an identifying part of the phenotype and not all affected individuals had ID, this gene has been given an Amber rating.
Intellectual disability v3.519 AFF3 Sarah Leigh changed review comment from: Not associated with relevant phenotype in OMIM and as probable Gen2Phen gene for Skeletal dysplasia with severe neurological disease. At least 2 variants have been reported in peer reviewed literature, further four variants have been reported in a preprint (July 2019). This preprint has not been published in a peer reviewed (as of 06/08/2020). There are confvincing aminal models; to: Not associated with relevant phenotype in OMIM and as probable Gen2Phen gene for Skeletal dysplasia with severe neurological disease. At least 2 variants have been reported in peer reviewed literature, further four variants have been reported in a preprint (July 2019). This preprint has not been published in a peer reviewed (as of 06/08/2020). There are convincing aminal models
Intellectual disability v3.514 MAPRE2 Arina Puzriakova Added comment: Comment on list classification: There are sufficient cases to promote this gene rating to Green at the next GMS panel update (added 'for-review' tag). Also not all patients present other associated features for which this gene is on a panel (e.g. Clefting, Structural eye disease) and so ID should be a sufficient indication for detecting these cases.
Intellectual disability v3.513 MAP1B Arina Puzriakova Added comment: Comment on list classification: Maintaining Amber rating as although cognitive impairment is reported in multiple (but not all) cases, often this is mild and not sufficient for a clinical diagnosis of ID. Affected individuals are more likely to be assessed in view of the brain malformations - MAP1B will be added to the 'Malformations of cortical development' panel.
Intellectual disability v3.512 MAP1B Arina Puzriakova Phenotypes for gene: MAP1B were changed from Intellectual disability; No OMIM number to Periventricular nodular heterotopia 9, 618918
Intellectual disability v3.510 MAP1B Arina Puzriakova commented on gene: MAP1B: Only one homozygous case identified in a screening study of a congenital microcephaly cohort. Other features included hypochromic microcytic anaemia, lymphocytic colitis, retinal coloboma, dysmorphic features, and normal brain MRI. As this is only considered a candidate variant and the phenotype is not compatible with other monoallelic reports, the evidence is currently insufficient for a disease association with biallelic variants (PMID:30214071)
Intellectual disability v3.510 MAP1B Arina Puzriakova reviewed gene: MAP1B: Rating: AMBER; Mode of pathogenicity: None; Publications: 30150678, 29738522, 30214071, 31317654; Phenotypes: Periventricular nodular heterotopia 9, 618918; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.510 SPTBN4 Arina Puzriakova commented on gene: SPTBN4: Review by Helen Brittain (Genomics England Clinical Team): the phenotype is characterised by marked hypotonia in infancy and developmental delay / ID. Adding as Green to the ID panel would therefore cover both of these GMS indications (as the Hypotonic Infant super panel has the ID panel as a sub-panel).
Intellectual disability v3.510 HDAC4 Sarah Leigh changed review comment from: There are many cases of 2q37.3 terminal region (includes HDAC4) loss in PMID 30848064, however, there are only two intragenic variants in HDAC4, with a rating of VUS and as such this gene should be rated as amber.; to: There are many cases of 2q37.3 terminal region (includes HDAC4) loss in PMID 30848064, however, there are only two intragenic variants in HDAC4, with a rating of VUS.
This gene should be rated as amber at the next major review.
Intellectual disability v3.510 HDAC4 Sarah Leigh changed review comment from: There are many cases of 2q37.3 terminal region (includes HDAC4) loss in PMID 30848064, however, there are only two intragenic variants in HDAC4, with a rating of VUS and as such the this gene should be rated as amber.; to: There are many cases of 2q37.3 terminal region (includes HDAC4) loss in PMID 30848064, however, there are only two intragenic variants in HDAC4, with a rating of VUS and as such this gene should be rated as amber.
Intellectual disability v3.510 UPF1 Zornitza Stark gene: UPF1 was added
gene: UPF1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: UPF1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: UPF1 were set to 33057194
Phenotypes for gene: UPF1 were set to Developmental disorders
Review for gene: UPF1 was set to AMBER
Added comment: PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio study from the Deciphering Developmental Disorders study. 16 de novo variants (1 frameshift, 11 missense, 4 synonymous) identified in ~10,000 cases with developmental disorders (no other phenotype info provided, hence Amber rating).
Sources: Literature
Intellectual disability v3.510 U2AF2 Zornitza Stark gene: U2AF2 was added
gene: U2AF2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: U2AF2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: U2AF2 were set to 33057194
Phenotypes for gene: U2AF2 were set to Developmental disorders
Review for gene: U2AF2 was set to AMBER
Added comment: PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio study from the Deciphering Developmental Disorders study. 10 de novo variants (1 in-frame, 8 missense, 1 synoymous) identified in ~10,000 cases with developmental disorders (no other phenotype info provided, hence Amber rating).
Sources: Literature
Intellectual disability v3.510 TCF7L2 Zornitza Stark gene: TCF7L2 was added
gene: TCF7L2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: TCF7L2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TCF7L2 were set to 33057194
Phenotypes for gene: TCF7L2 were set to Developmental disorders
Review for gene: TCF7L2 was set to AMBER
Added comment: A diabetes susceptibility locus associated with common SNVs, see OMIM for details.

PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio study from the Deciphering Developmental Disorders study. 12 de novo variants (2 frameshift, 6 missense, 1 splice acceptor, 2 stopgain, 1 synonymous) identified in ~10,000 cases with developmental disorders (no other phenotype info provided, hence Amber rating).
Sources: Literature
Intellectual disability v3.510 SRRM2 Zornitza Stark gene: SRRM2 was added
gene: SRRM2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: SRRM2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SRRM2 were set to 33057194
Phenotypes for gene: SRRM2 were set to Developmental disorders
Review for gene: SRRM2 was set to AMBER
Added comment: PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio study from the Deciphering Developmental Disorders study. 28 de novo variants (11 frameshift, 7 missense, 1 splice acceptor, 5 stopgain, 4 synonymous) identified in ~10,000 cases with developmental disorders (no other phenotype info provided hence Amber rating).
Sources: Literature
Intellectual disability v3.510 SPEN Zornitza Stark gene: SPEN was added
gene: SPEN was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: SPEN was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SPEN were set to 33057194
Phenotypes for gene: SPEN were set to Developmental disorders
Review for gene: SPEN was set to AMBER
Added comment: PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio study from the Deciphering Developmental Disorders study. 25 de novo variants (6 frameshift, 1 in-frame, 7 missense, 8 stopgain, 3 synonymous) identified in ~10,000 cases with developmental disorders (no other phenotype info provided, hence Amber rating).
Sources: Literature
Intellectual disability v3.510 RAB14 Zornitza Stark gene: RAB14 was added
gene: RAB14 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: RAB14 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RAB14 were set to 33057194
Phenotypes for gene: RAB14 were set to Developmental disorders
Review for gene: RAB14 was set to AMBER
Added comment: PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio study from the Deciphering Developmental Disorders study. 8 de novo variants (1 in-frame, 7 missense) identified in ~10,000 cases with developmental disorders (no other phenotype info provided hence Amber rating).
Sources: Literature
Intellectual disability v3.510 PSMC5 Zornitza Stark gene: PSMC5 was added
gene: PSMC5 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: PSMC5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PSMC5 were set to 33057194
Phenotypes for gene: PSMC5 were set to Developmental disorders
Review for gene: PSMC5 was set to AMBER
Added comment: PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio study from the Deciphering Developmental Disorders study. 10 de novo variants (1 in-frame, 9 missense) identified in ~10,000 cases with developmental disorders (no other phenotype info provided hence Amber rating).
Sources: Literature
Intellectual disability v3.510 MSL2 Zornitza Stark gene: MSL2 was added
gene: MSL2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: MSL2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MSL2 were set to 31332282; 33057194
Phenotypes for gene: MSL2 were set to Developmental disorders; autism
Review for gene: MSL2 was set to AMBER
Added comment: PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio study from the Deciphering Developmental Disorders study. 13 de novo variants (9 frameshift, 4 missense) identified in ~10,000 cases with developmental disorders (no other phenotype info provided hence Amber rating).
PMID: 31332282 - candidate gene in a single autism study, with recurrent de novo variants in a potential oligogenic model
Sources: Literature
Intellectual disability v3.510 MMGT1 Zornitza Stark gene: MMGT1 was added
gene: MMGT1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: MMGT1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MMGT1 were set to 33057194
Phenotypes for gene: MMGT1 were set to Developmental disorders
Review for gene: MMGT1 was set to AMBER
Added comment: PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio study from the Deciphering Developmental Disorders study. 3 de novo missense identified in ~10,000 cases with developmental disorders (no other phenotype info provided hence Amber rating).
Sources: Literature
Intellectual disability v3.510 HNRNPD Zornitza Stark gene: HNRNPD was added
gene: HNRNPD was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: HNRNPD was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: HNRNPD were set to 33057194
Phenotypes for gene: HNRNPD were set to Developmental disorders
Review for gene: HNRNPD was set to AMBER
Added comment: PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio study from the Deciphering Developmental Disorders study. 8 de novo variants (5 frameshift, 1 missense, 1 splice acceptor, 1 synonymous) identified in ~10,000 cases with developmental disorders (no other phenotype info provided hence Amber rating).
Sources: Literature
Intellectual disability v3.510 GIGYF1 Zornitza Stark gene: GIGYF1 was added
gene: GIGYF1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: GIGYF1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: GIGYF1 were set to 33057194
Phenotypes for gene: GIGYF1 were set to Developmental disorder
Review for gene: GIGYF1 was set to AMBER
Added comment: PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio study from the Deciphering Developmental Disorders study. 14 de novo variants (4 frameshift, 5 missense, 1 splice donor, 3 stopgain, 1 synonymous) identified in ~10,000 cases with developmental disorders (no other phenotype info provided hence Amber rating).
Sources: Literature
Intellectual disability v3.510 FOXP4 Zornitza Stark gene: FOXP4 was added
gene: FOXP4 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: FOXP4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FOXP4 were set to 33110267
Phenotypes for gene: FOXP4 were set to Neurodevelopmental disorder; multiple congenital abnormalities
Review for gene: FOXP4 was set to AMBER
Added comment: This gene is a little bit difficult to place, may be Green on Fetal Anomalies panel?

Eight unrelated individuals reported, seven de novo missense, and one individual with a truncating variant. Detailed phenotypic information available on 6. Overlapping features included speech and language delays, growth abnormalities, congenital diaphragmatic hernia (2/6), cervical spine abnormalities, and ptosis. Intellectual disability described as mild in 2, some had normal intellect despite the early speech and language delays, hence Amber rating here.
Sources: Literature
Intellectual disability v3.510 DHX32 Zornitza Stark gene: DHX32 was added
gene: DHX32 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: DHX32 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: DHX32 were set to 32989326
Phenotypes for gene: DHX32 were set to Intellectual disability, spastic diplegia, dystonia, brain abnormalities
Review for gene: DHX32 was set to AMBER
Added comment: PMID: 32989326 - Large cohort study of cerebral palsy cases identified two de novo variants in two unrelated patients with intellectual disability, one with spastic diplegia, and the other characterised as generalised dystonia. Brain abnormalities were identified also.
Sources: Literature
Intellectual disability v3.510 FBXO31 Zornitza Stark edited their review of gene: FBXO31: Changed phenotypes: Mental retardation, autosomal recessive 45, MIM#615979, Intellectual disability, spasticity, autosomal dominant
Intellectual disability v3.510 FBXO31 Zornitza Stark gene: FBXO31 was added
gene: FBXO31 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: FBXO31 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: FBXO31 were set to 24623383; 32989326
Phenotypes for gene: FBXO31 were set to Mental retardation, autosomal recessive 45, MIM#615979; Intellectual disability, autosomal dominant
Review for gene: FBXO31 was set to AMBER
Added comment: Bi-allelic variants: Single consanguineous family reported with homozygous truncating variant, limited functional evidence.

Mono-allelic variants: 2 unrelated probands reported as part of a 'cerebral palsy' cohort harbouring the same de novo missense variant (p.Asp334Asn). The variant affects the cyclin D interaction site, leading to an apparent gain of function of cyclin D degradation, supported by Western blots from patient fibroblasts which showed decreased cyclin D expression.

Patient phenotypes: Spastic diplegia, with esotropia, ID, dysarthria, mixed receptive/expressive language disorder, ADHD, cleft palate, intestinal malrotation and midgut volvulus (patient 1); Spastic paraplegia with ventricular dilation and thin corpus callosum, ID, attention deficit, anxiety, language impairments, strabismus, severe constipation (patient 2).
Sources: Literature
Intellectual disability v3.510 AP2S1 Zornitza Stark gene: AP2S1 was added
gene: AP2S1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: AP2S1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: AP2S1 were set to 33057194
Phenotypes for gene: AP2S1 were set to Developmental disorder
Review for gene: AP2S1 was set to AMBER
Added comment: Established hypercalcaemia gene. PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio developmental disorder study. 5 de novo missense identified in ~10,000 cases with developmental disorders (no other phenotype info provided, hence Amber rating).
Sources: Literature
Intellectual disability v3.510 ARHGAP35 Zornitza Stark gene: ARHGAP35 was added
gene: ARHGAP35 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: ARHGAP35 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ARHGAP35 were set to 33057194
Phenotypes for gene: ARHGAP35 were set to Developmental disorder
Review for gene: ARHGAP35 was set to AMBER
Added comment: Has been identified as a gene with significant de novo enrichment in a large trio developmental disorder study. 16 de novo variants (3 frameshift, 2 in-frame, 10 missense, 1 stopgain) identified in ~10,000 cases with developmental disorders (no other phenotype info provided, hence Amber rating).
Sources: Literature
Intellectual disability v3.510 ATP6V0A1 Zornitza Stark gene: ATP6V0A1 was added
gene: ATP6V0A1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: ATP6V0A1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ATP6V0A1 were set to 30842224; 33057194
Phenotypes for gene: ATP6V0A1 were set to Developmental disorder; Rett syndrome-like
Review for gene: ATP6V0A1 was set to AMBER
Added comment: PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio developmental disorder study. 11 de novo missense identified in ~10,000 cases with developmental disorders (no other phenotype info provided hence Amber rating).
PMID: 30842224 - identified a de novo missense variant in a single individual with atypical Rett syndrome phenotype
Sources: Literature
Intellectual disability v3.510 DDX23 Zornitza Stark gene: DDX23 was added
gene: DDX23 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: DDX23 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: DDX23 were set to 33057194
Phenotypes for gene: DDX23 were set to Developmental disorder
Review for gene: DDX23 was set to AMBER
Added comment: PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio developmental disorder study. 6 de novo missense identified in ~10,000 cases with developmental disorders (rated Amber as no other phenotype info provided).
Sources: Literature
Intellectual disability v3.510 NUDT2 Arina Puzriakova Added comment: Comment on list classification: This gene should be promoted to Green at the next GMS panel update (added 'for-review' tag). There are now at least 2 biallelic variants reported in 6 families - 3 of which present GDD and ID, while the remaining had delay but borderline intelligence.
Intellectual disability v3.509 NUDT2 Arina Puzriakova Phenotypes for gene: NUDT2 were changed from Muscular hypotonia; Global developmental delay; Intellectual disability; no OMIM number to Muscular hypotonia; Global developmental delay; Intellectual disability; Polyneuropathy; no OMIM number
Intellectual disability v3.505 NEMF Arina Puzriakova Added comment: Comment on mode of inheritance: Set MOI to 'Biallelic' as currently only 1 case (total 14) with a monoallelic variant described but with normal intellectual development.
Intellectual disability v3.504 NEMF Arina Puzriakova commented on gene: NEMF: At least 14 unrelated families reported with variants in NEMF (13 biallelic, 1 monoallelic). GDD/ID is reported in all but 2 cases (USA1 and USA3 in PMID: 32934225) albeit mostly within the mild range. Nonetheless, there are sufficient cases with moderate-severe ID to warrant a Green rating on this panel. Some cases also do not present all other features associated with NEMF variants (e.g. neuropathy) providing further support for inclusion.
Intellectual disability v3.504 SETD1A Arina Puzriakova Phenotypes for gene: SETD1A were changed from Schizophrenia; developmental disorder; Intellectual disability to Neurodevelopmental disorder with speech impairment and dysmorphic facies, 619056; Epilepsy, early-onset, with or without developmental delay, 618832
Intellectual disability v3.502 JARID2 Konstantinos Varvagiannis reviewed gene: JARID2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.502 ARID2 Arina Puzriakova Added comment: Comment on publications: Added new publication (Kang et al. 2020) reviewing phenotypes of patients with ARID2 variants, and supporting the current Green rating on this panel.
Intellectual disability v3.502 ARID2 Arina Puzriakova Publications for gene: ARID2 were set to 28124119; 26238514
Intellectual disability v3.501 ARID2 Arina Puzriakova Phenotypes for gene: ARID2 were changed from Coffin-Siris syndrome-like phenotype to Coffin-Siris syndrome 6, 617808; ARID2-Coffin-Siris like disorder
Intellectual disability v3.500 JARID2 Zornitza Stark gene: JARID2 was added
gene: JARID2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: JARID2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: JARID2 were set to 23294540; 33077894
Phenotypes for gene: JARID2 were set to Intellectual disability
Review for gene: JARID2 was set to GREEN
gene: JARID2 was marked as current diagnostic
Added comment: 13 individuals reported recently, note CNVs common but LOF sequence variants identified too.
Sources: Literature
Intellectual disability v3.500 NUDT2 Zornitza Stark reviewed gene: NUDT2: Rating: GREEN; Mode of pathogenicity: None; Publications: 27431290, 30059600, 33058507; Phenotypes: Muscular hypotonia, Global developmental delay, Intellectual disability, Polyneuropathy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability v3.500 AGAP1 Zornitza Stark gene: AGAP1 was added
gene: AGAP1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: AGAP1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: AGAP1 were set to 31700678; 25666757; 30472483
Phenotypes for gene: AGAP1 were set to Cerebral palsy
Review for gene: AGAP1 was set to AMBER
Added comment: Two individuals reported with de novo variants in this gene and a CP phenotype. Rare variants over-represented in a case-control study. Supportive zebrafish model. Another individual with a deletion (+1 other gene) reported with ID and autism. This seems the most appropriate panel?
Sources: Literature
Intellectual disability v3.500 PRKAR1B Konstantinos Varvagiannis gene: PRKAR1B was added
gene: PRKAR1B was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: PRKAR1B was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: PRKAR1B were set to https://doi.org/10.1101/2020.09.10.20190314; 25414040
Phenotypes for gene: PRKAR1B were set to Global developmental delay; Intellectual disability; Autism; Attention deficit hyperactivity disorder; Aggressive behavior; Abnormality of movement; Upslanted palpebral fissure
Penetrance for gene: PRKAR1B were set to unknown
Review for gene: PRKAR1B was set to AMBER
Added comment: Please consider inclusion of this gene with amber rating pending publication of the preprint and/or additional evidence.

Marbach et al. (2020 - medRxiv : https://doi.org/10.1101/2020.09.10.20190314 - last author : C. Schaaf) report 6 unrelated individuals with heterozygous missense PRKAR1B variants.

All presented formal ASD diagnosis (6/6), global developmental delay (6/6) and intellectual disability (all - formal evaluations were lacking though). Additional features included neurologic anomalies (movement disorders : dyspraxia, apraxia, clumsiness in all, with tremor/dystonia or involuntary movements as single occurrences). Three displayed high pain tolerance. Regression in speech was a feature in two. Additional behavior anomalies included ADHD (4-5/6) or aggression (3/6). There was no consistent pattern of malformations, physical anomalies or facial features (with the exception of uplsanted palpebral fissures reported in 4).

3 different missense variants were identified (NM_00116470:c.1003C>T - p.Arg335Trp, c.586G>A - p.Glu196Lys, c.500_501delAAinsTT - p.Gln167Leu) with Arg355Trp being a recurrent one within this cohort (4/6 subjects). A possible splicing effect may apply for the MNV. All variants are absent from gnomAD and the SNVs had CADD scores > 24.

In all cases were parental samples were available (5/6), the variant had occurred as a de novo event.

Protein kinase A (PKA) is a tetrameric holoenzyme formed by the association of 2 catalytic (C) subunits with a regulatory (R) subunit dimer. Activation of PKA is achieved through binding of 2 cAMP molecules to each R-subunit, and unleashing(/dissociation) of C-subunits to engage substrates. PRKACA/B genes encode the Cα- and Cβ-subunits while the 4 functionally non-redundant regulatory subunits are encoded by PRKAR1A/1B/2A/2B genes. As the authors comment, the RIβ subunit is primarily expressed in brain with higher expression in cortex and hypothalamus.

The functional consequences of the variants at cellular level were not studied.

Previous studies have demonstrated that downregulation of RIβ in murine hippocampal cultures, reduced phosphorylation of CREB, a transcription factor involved in long-term memory formation. The authors speculate that a similar effect on cAMP/PKA/CREB cascade may mediate the cognitive effects in humans. RIβ deficient mice also display diminished nociceptive pain, similar to the human phenotype. [Several refs provided].

The authors cite the study by Kaplanis et al (2020 - PMID: 33057194), where in a large sample of 31,058 trio exomes of children with developmental disorders, PRKAR1B was among the genes with significant enrichment for de novo missense variants. [The gene has a pLI score of 0.18 in gnomAD / o/e = 0.26 - so pLoF variants may not be deleterious].

Please note that a specific PRKAR1B variant (NM_002735.2:c.149T>G - p.Leu50Arg) has been previous reported to segregate with a late-onset neurodegenerative disorder characterized by dementia and/or parkinsonism within a large pedigree with 12 affected individuals [Wong et al 2014 - PMID: 25414040].
Sources: Literature
Intellectual disability v3.500 MPP5 Konstantinos Varvagiannis gene: MPP5 was added
gene: MPP5 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: MPP5 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: MPP5 were set to 33073849
Phenotypes for gene: MPP5 were set to Global developmental delay; Intellectual disability; Delayed speech and language development; Developmental regression; Behavioral abnormality
Penetrance for gene: MPP5 were set to unknown
Review for gene: MPP5 was set to GREEN
Added comment: Sterling et al (2020 - PMID: 33073849) provide information on the phenotype of 3 individuals with de novo MPP5 variants.

Common features included global developmental delay, intellectual disability (3/3 - severe in 2/3), speech delay/regression (the latter in at least 2) and behavioral abnormalities. Variable other features were reported, among others microcephaly (1/3), abnormal vision (1/3 : CVI, retinal dystrophy, nystagmus), brain MRI abnormalities (2/3), late-onset seizures (1/3). These subjects displayed variable and non-specific dysmorphic features.

All were investigated by exome sequencing (previous tests not mentioned).

One subject was found to harbor a de novo mosaic (5/25 reads) stopgain variant, further confirmed by Sanger sequencing [NM_022474.4:c.1555C>T - p.(Arg519Ter). The specific variant is reported once in gnomAD (1/251338). Two de novo missense variants were identified in the remaining individuals [c.1289A>G - p.Glu430Gly / c.974A>C - p.His325Pro).

All variants had in silico predictions in favor of a deleterious effect (CADD score >24).

The authors comment that MPP5 encodes an apical complex protein with asymmetric localization to the apical side of polarized cells. It is expressed in brain, peripheral nervous system and other tissues. MPP5 is a member of the membrane-associated guanylate kinase family of proteins (MAGUK, p55 subfamily), determining cell polarity at tight junctions.

Previous animal models suggest that complete Mpp5(Pals1) KO in mice leads to near absence of cerebral cortical neurons. Htz KO mice display reduction in size of cerebral cortex and hippocampus. The gene is expressed in proliferating cell populations of cerebellum and important for establishment cerebellar architecture. Conditional KO of Mpp5(Pals1) in retinal progenitor cells mimics the retinal pathology observed in LCA. [Several refs. provided]

The authors studied a heterozygous CNS-specific Mpp5 KO mouse model. These mice presented microcephaly, decreased cerebellar volume and cortical thickness, decreased ependymal cells and Mpp5 at the apical surface of cortical vertrical zone. The proportion of cortical cells undergoing apoptotic cell death was increased. Mice displayed behavioral abnormalities (hyperactivity) and visual deficits, with ERG traces further suggesting retinal blindness.

Overall the mouse model was thought to recapitulate the behavioral abnormalities observed in affected subjects as well as individual rare features such as microcephaly and abnormal vision.

Haploinsufficiency (rather than a dominant negative effect) is favored as the underlying disease mechanism. This is also in line with a dose dependent effect observed in mice.
Sources: Literature
Intellectual disability v3.493 NPHP3 Arina Puzriakova Added comment: Comment on list classification: Kept rating Amber as affected individuals are more likely to be assessed under renal and ciliopathy panels, for which this gene is already Green.
Intellectual disability v3.491 ZIC1 Arina Puzriakova changed review comment from: Associated with phenotype in OMIM, and a 'confirmed' gene for Craniosynostosis 6 in Gene2Phenotype.

At least 5 variants reported in 6 unrelated families with intellectual disability (2 mild, 1 moderate, 2 moderate-severe, 1 severe) among other variable CNS abnormalities including craniosynostosis, callosal dysgenesis, anomaly in cerebellar hemispheres, vermis and pons, spinal dysraphism, as well as skull abnormalities not associated with craniosynostosis.

; to: Associated with phenotype in OMIM, and a 'confirmed' gene for Craniosynostosis 6 in Gene2Phenotype.

At least 5 variants reported in 6 unrelated families with intellectual disability (2 mild, 1 moderate, 2 moderate-severe, 1 severe) among other variable CNS abnormalities including craniosynostosis, callosal dysgenesis, anomaly in cerebellar hemispheres, vermis and pons, spinal dysraphism, as well as skull abnormalities not associated with craniosynostosis.

Predicted that both gain- and loss-of-function variants can be deleterious.
Intellectual disability v3.491 ZIC1 Arina Puzriakova changed review comment from: Associated with phenotype in OMIM, and a 'confirmed' gene for Craniosynostosis 6 in Gene2Phenotype.

At least 5 variants reported in 6 unrelated families with craniosynostosis and associated variable intellectual disability (2 mild, 1 moderate, 2 moderate-severe, 1 severe); to: Associated with phenotype in OMIM, and a 'confirmed' gene for Craniosynostosis 6 in Gene2Phenotype.

At least 5 variants reported in 6 unrelated families with intellectual disability (2 mild, 1 moderate, 2 moderate-severe, 1 severe) among other variable CNS abnormalities including craniosynostosis, callosal dysgenesis, anomaly in cerebellar hemispheres, vermis and pons, spinal dysraphism, as well as skull abnormalities not associated with craniosynostosis.
Intellectual disability v3.489 ZIC1 Arina Puzriakova reviewed gene: ZIC1: 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: 26340333, 30391508; Phenotypes: ?Craniosynostosis 6, 616602, Structural brain anomalies with impaired intellectual development and craniosynostosis, 618736; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.487 ZNF335 Arina Puzriakova commented on gene: ZNF335: Removed 'watchlist' tag as there are now sufficient cases to support a gene-disease association, and for this gene to be rated Green.
Intellectual disability v3.487 ZNF335 Arina Puzriakova reviewed gene: ZNF335: Rating: GREEN; Mode of pathogenicity: None; Publications: 23178126, 27540107, 29652087, 30500859, 31187448; Phenotypes: Microcephaly 10, primary, autosomal recessive, 615095; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.487 ZNF335 Arina Puzriakova Phenotypes for gene: ZNF335 were changed from ?Microcephaly 10, primary, autosomal recessive, 615095; developmental delay; intellectual disability to Microcephaly 10, primary, autosomal recessive, 615095
Intellectual disability v3.484 COX6B1 Zornitza Stark reviewed gene: COX6B1: Rating: RED; Mode of pathogenicity: None; Publications: 18499082, 24781756; Phenotypes: Mitochondrial complex IV deficiency, nuclear type 7, MIM# 619051; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.484 SCO1 Zornitza Stark reviewed gene: SCO1: Rating: RED; Mode of pathogenicity: None; Publications: 11013136, 19295170, 31352446, 23878101; Phenotypes: Mitochondrial complex IV deficiency, nuclear type 4, MIM# 619048; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.484 PRKACB Konstantinos Varvagiannis gene: PRKACB was added
gene: PRKACB was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: PRKACB was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: PRKACB were set to 33058759
Phenotypes for gene: PRKACB were set to Postaxial hand polydactyly; Postaxial foot polydactyly; Common atrium; Atrioventricular canal defect; Narrow chest; Abnormality of the teeth; Intellectual disability
Penetrance for gene: PRKACB were set to unknown
Mode of pathogenicity for gene: PRKACB 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: PRKACB was set to AMBER
Added comment: ID was a feature in 2/4 individuals with PRKACB pathogenic variant reported to date.

Please consider inclusion of PRKACB (and PRKACA) in other relevant gene panels e.g. for polydactyly, congenital heart defects. The disorder may be considered in the DD of ciliopathies.

-----


Palencia-Campos et al (2020 - PMID: 33058759) report on the phenotype of 3 individuals heterozygous for PRKACA and 4 individuals heterozygous for PRKACB pathogenic variants.

The most characteristic features in all individuals with PRKACA/PRKACB mutation, included postaxial polydactyly of hands (6/7 bilateral, 1/7 unilateral) and feet (4/7 bilateral, 1/7 unilateral), brachydactyly and congenital heart defects (CHD 5/7) namely a common atrium or AVSD. Two individuals with PRKACA variant who did not have CHD had offspring with the same variant and an AVSD.

Other variably occurring features included short stature, limbs, narrow chest, abnormal teeth, oral frenula, nail dysplasia. One individual with PRKACB variant presented tumors.

Intellectual disability was reported in 2/4 individuals with PRKACB variant (1/4: mild, 1/4: severe). The 3 individuals with PRKACA variant did not present ID.

As the phenotype was overall suggestive of Ellis-van Creveld syndrome (or the allelic Weyers acrofacial dysostosis), although these diagnoses were ruled out following analysis of EVC and EVC2 genes.

WES was carried out in all.

PRKACA : A single heterozygous missense variant was identified in 3 individuals from 3 families (NM_002730.4:c.409G>A / p.Gly137Arg) with 1 of the probands harboring the variant in mosaic state (28% of reads) and having 2 similarly affected offspring. The variant was de novo in one individual and inherited in a third one having a similarly affected fetus (narrow thorax, postaxial polyd, AVSD).

PRKACB : 4 different variants were identified (NM_002731.3: p.His88Arg/Asn, p.Gly235Arg, c.161C>T - p.Ser54Leu). One of the individuals was mosaic for the latter variant, while in all other cases the variant had occurred de novo.

Protein kinase A (PKA) is a tetrameric holoenzyme formed by the association of 2 catalytic (C) subunits with a regulatory (R) subunit dimer. Activation of PKA is achieved through binding of 2 cAMP molecules to each R-subunit, and unleashing(/dissociation) of C-subunits to engage substrates. PRKACA/B genes encode the Cα- and Cβ-subunits while the 4 functionally non-redundant regulatory subunits are encoded by PRKAR1A/1B/2A/2B genes.

The authors provide evidence that the variants confer increased sensitivity of PKA holoenzymes to activation by cAMP (compared to wt).

By performing ectopic expression of wt or mt PRKACA/B (variants studied : PRKACA p.Gly137Arg / PRKACB p.Gly235Arg) in NIH 3T3 fibroblasts, the authors demonstrate that inhibition of hedgehog signaling likely underlyies the developmental defects observed in affected individuals.

As for PRKACA, the authors cite another study where a 31-month old female with EvC syndrome diagnosis was found to harbor the aforementioned variant (NM_001304349.1:c.637G>A:p.Gly213Arg corresponding to NM_002730.4:c.409G>A / p.Gly137Arg) as a de novo event. Without additional evidence at the time, the variant was considered to be a candidate for this subject's phenotype (Monies et al 2019 – PMID: 31130284).
Sources: Literature
Intellectual disability v3.484 CDH2 Sarah Leigh Phenotypes for gene: CDH2 were changed from Abnormality of the corpus callosum; Abnormality of neuronal migration; Bimanual synkinesia; Duane anomaly; Abnormality of cardiovascular system; Abnormality of the eye; Abnormality of the genital system; Global developmental delay; Intellectual disability to Agenesis of corpus callosum, cardiac, ocular, and genital syndrome 618929
Intellectual disability v3.480 RARS Arina Puzriakova Classified gene: RARS as Amber List (moderate evidence)
Intellectual disability v3.480 RARS Arina Puzriakova Gene: rars has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.479 RARS Arina Puzriakova Tag for-review tag was added to gene: RARS.
Intellectual disability v3.463 HSPG2 Ivone Leong Phenotypes for gene: HSPG2 were changed from Schwartz-Jampel syndrome, type 1, 255800; Dyssegmental dysplasia, Silverman-Handmaker type, 224410 to Schwartz-Jampel syndrome, type 1, 255800
Intellectual disability v3.461 KCNK4 Ivone Leong commented on gene: KCNK4: As the 2 unrelated patients who have the same de novo variants have severe ID/DD and 3rd patient has low average ID, this gene will be kept as Amber until further evidence is available. Watchlist tag has been added as well.
Intellectual disability v3.461 LMBRD2 Arina Puzriakova changed review comment from: Comment on list classification: There is a sufficient number of unrelated cases to rate this gene GREEN at the next major review.; to: Comment on list classification: New gene added by Konstantinos Varvagiannis. Rating Amber but there is a sufficient number of unrelated cases with the relevant phenotype to rate this gene GREEN at the next major review.
Intellectual disability v3.456 LMNB2 Konstantinos Varvagiannis gene: LMNB2 was added
gene: LMNB2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: LMNB2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: LMNB2 were set to 33033404
Phenotypes for gene: LMNB2 were set to Congenital microcephaly; Global developmental delay; Intellectual disability
Penetrance for gene: LMNB2 were set to Complete
Mode of pathogenicity for gene: LMNB2 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: LMNB2 was set to GREEN
Added comment: Parry et al (2020 - PMID: 33033404) in a study to identify novel microcephaly genes using the DDD and 100k genomes project (100kGP) patient cohort, report on the phenotype of 13 individuals with heterozygous variant in LMNB1 (N=7) and LMNB2 (N=6).

LMNB1 : The authors identified 3 recurrent variants (c.97A>G - p.Lys33Glu (3), c.97_99del - p.Lys33del (2) , c.269G>C - p.Arg90Pro (2) / NM_005573.4) in seven individuals (3 from the DDD study, 4 from the 100kGP). In all cases were segregation studies were possible, the variant had occurred as a de novo event.

LMNB2 : 4 individuals from the DDD cohort and 1 from the 100kGP were found to harbor the same missense SNV (NM_032737.4:c.1192G>A, p.Glu398Lys). The variant had occurred de novo in 3 subjects and was inherited from a mosaic - unaffected - parent in a further case. Another individual was found to harbor c.160A>C - p.Asn54His.

LMNB1/2 common phenotypes :
All cases had congenital microcephaly (OFC -5.85 +/- 1.14 SD) apart from one individual, without history of IUGR or postnatally abnormal height (the latter in most).

Neuroimaging suggested structurally normal brain without abnormal migration. Gyral simplification / global reduction in white matter / increased extra axial spaces / enlarged ventricles were reported in 2.

LMNB1 - Global developmental delay was a feature in all (mild to severe) with some having occasional words at 7y (P3), absent speech (P9 - age category 5-10y) or ID not further specified (P13).

LMNB2 - DD was a feature in all 6 subjects (5/6 moderate to severe - 1/6 GDD). 5/6 were 10y or older with language (in 3 language not achieved) and motor deficits (walking not achieved in 1/6 - occurred at the age of 6y in 1/6).

Facial features were not consistent nor suggestive of a syndromic diagnosis (sloping forehead in some).

Overall, as the authors comment, the phenotype corresponded to a severe nonsyndromic microcephaly (although additional features were reported in some).

Animal model:
Microcephaly is supported by Lmnb1 ko mouse model. Lmnb1/2 ko mice however display migration defects, while Lmnb2 ko mice do not have reduced size at birth. Heterozygous Lmnb1 mice do not present microcephaly. It is suggested that while animal models support a similar (to the human) phenotype the underlying mechanism is different.

Variant effect :
variants were shown to affect highly conserved residues within the lamin a-helical rod-domain. As affected residues are conserved in LMNA, modelling with available LMNA PDB structures, suggested disrupted interactions required for higher-order assembly of lamin filaments.

Recurrence of specific variants at specific residues, absence of pLoF ones, the htz mouse Lmnb1 phenotype (absence of microcephaly) and the proposed mechanism (perturbation of complex formation) suggest a gain-of-function/dominant-negative effect rather than happloinsufficiency.

[Please also note the additional OMIM phenotypes for LMNB1 / LMNB2 - not here reviewed]
Sources: Literature
Intellectual disability v3.456 LMNB1 Konstantinos Varvagiannis edited their review of gene: LMNB1: Added comment: There is an additional report on LMBN1/2-associated phenotypes supporting green rating of the gene in the current panel.

Parry et al (2020 - PMID: 33033404) in a study to identify novel microcephaly genes using the DDD and 100k genomes project (100kGP) patient cohort, report on the phenotype of 13 individuals with heterozygous variant in LMNB1 (N=7) and LMNB2 (N=6).

LMNB1 : The authors identified 3 recurrent variants (c.97A>G - p.Lys33Glu (3), c.97_99del - p.Lys33del (2) , c.269G>C - p.Arg90Pro (2) / NM_005573.4) in seven individuals (3 from the DDD study, 4 from the 100kGP). In all cases were segregation studies were possible, the variant had occurred as a de novo event.

LMNB2 : 4 individuals from the DDD cohort and 1 from the 100kGP were found to harbor the same missense SNV (NM_032737.4:c.1192G>A, p.Glu398Lys). The variant had occurred de novo in 3 subjects and was inherited from a mosaic - unaffected - parent in a further case. Another individual was found to harbor c.160A>C - p.Asn54His.

LMNB1/2 common phenotypes :
All cases had congenital microcephaly (OFC -5.85 +/- 1.14 SD) appart from one individual, without history of IUGR or postnatally abnormal height (the latter in most).

Neuroimaging suggested structurally normal brain without abnormal migration. Gyral simplification / global reduction in white matter / increased extra axial spaces / enlarged ventricles were reported in 2.

LMNB1 - Global developmental delay was a feature in all (mild to severe) with some having occasional words at 7y (P3), absent speech (P9 - age category 5-10y) or ID not further specified (P13).

LMNB2 - DD was a feature in all 6 subjects (5/6 moderate to severe - 1/6 GDD). 5/6 were 10y or older with language (in 3 language not achieved) and motor deficits (walking not achieved in 1/6 - occured at the age of 6y in 1/6).

Facial features were not consistent nor suggestive of a syndromic diagnosis (sloping forehead in some).

Overall, as the authors comment, the phenotype corresponded to a severe nonsyndromic microcephaly (although additional features were reported in some).

Animal model:
Microcephaly is supported by Lmnb1 ko mouse model. Lmnb1/2 ko mice however display migration defects, while Lmnb2 ko mice do not have reduced size at birth. Heterozygous Lmnb1 mice do not present microcephaly. It is suggested that while animal models support a similar (to the human) phenotype the underlying mechanism is different.

Variant effect :
variants were shown to affect highly conserved residues within the lamin a-helical rod-domain. As affected residues are conserved in LMNA, modelling with available LMNA PDB structures, suggested disrupted interactions required for higher-order assembly of lamin filaments.

Recurrence of specific variants at specific residues, absence of pLoF ones, the htz mouse Lmnb1 phenotype (absence of microcephaly) and the proposed mechanism (perturbation of complex formation) suggest a gain-of-function/dominant-negative effect rather than happloinsufficiency.

[Please also note the additional OMIM phenotypes for LMNB1 / LMNB2 - not here reviewed]; Changed publications: 32910914, 33033404
Intellectual disability v3.456 CNPY3 Arina Puzriakova Added comment: Comment on list classification: New gene added and reviewed by Konstantinos Varvagiannis. Although there are sufficient cases to support a gene-disease association, this disorder is mainly characterised by severe epileptic encephalopathy and ID manifests secondarily to seizures.

Rating Amber, but this may be reviewed if new evidence emerges indicating that neurodevelopmental impairment precedes onset of seizures.
Intellectual disability v3.451 STT3A Arina Puzriakova Added comment: Comment on list classification: There is enough evidence to support a gene-disease association, and so STT3A should be promoted from Amber to Green at the next GMS panel update (added 'for-review' tag).

ID/DD reported in all cases (at least 7 individuals from 3 unrelated families, with 2 different homozygous variants in STT3A)
Intellectual disability v3.448 CARS2 Arina Puzriakova changed review comment from: Comment on list classification: Kept rating Amber as developmental regression and progressive cognitive decline appear secondary to seizures, which represent the key phenotypic feature of this disorder.

This gene is Green on the Inborn errors of metabolism (v2.2) panel, a component the Epilepsy super panel, which should be a sufficient route for detecting these cases.; to: Comment on list classification: Kept rating Amber as developmental regression and progressive cognitive decline appear secondary to seizures, which represent the key phenotypic feature of this disorder.

This gene is Green on Inborn errors of metabolism (v2.3) and has been added to the Genetic epilepsy syndromes (v2.176) panel, which should be sufficient routes for detecting these cases.
Intellectual disability v3.448 TRPM3 Arina Puzriakova Added comment: Comment on list classification: Excluding the individual harbouring a VUS, 8 unrelated individuals with ID and the same p.Val837Met variant have been reported (PMID:31278393, 32439617). Also now available is functional data demonstrating variants render the channel overactive.

With addition of the recent publications, there is enough evidence to support a Green rating on this panel. Therefore added 'for-review' tag, for reassessment at next GMS panel update.
Intellectual disability v3.446 TRPM3 Arina Puzriakova reviewed gene: TRPM3: Rating: ; 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: 32439617, 32343227, 32427099; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.446 FGF14 Arina Puzriakova Added comment: Comment on list classification: Cognitive impairment has been reported in several patients, mostly mild but few cases with moderate deficits have also been described. However, the phenotype is mainly characterised by ataxia which would be the expected CI for diagnostic testing - FGF14 is already Green on Ataxia panels.

The utility of calling variants in this gene in a cohort of ID patients without the ataxic component is unlikely to be of benefit, and therefore the rating has been kept Amber on this panel.
Intellectual disability v3.443 DENND5A Arina Puzriakova Phenotypes for gene: DENND5A were changed from EPILEPTIC ENCEPHALOPATHY to Epileptic encephalopathy, early infantile, 49 617281
Intellectual disability v3.442 DENND5A Arina Puzriakova Added comment: Comment on list classification: Kept rating Amber as disorder is mainly characterised by severe early-infantile encephalopathy, and cognitive arrest appears secondary to the onset of seizures.

This gene is Green on the Genetic epilepsy syndromes (v2.170) panel, which should be a sufficient route for detecting cases.
Intellectual disability v3.438 CACNA2D2 Arina Puzriakova Added comment: Comment on list classification: Kept rating Amber as severe GDD is a neurodegenerative manifestation that is secondary to the onset of seizures, which represent the key phenotypic feature of this disorder.

This gene is Green on the Genetic epilepsy syndromes (v2.170) panel, which should be a sufficient route for detecting these cases.
Intellectual disability v3.437 CARS2 Arina Puzriakova Publications for gene: CARS2 were set to 25787132
Intellectual disability v3.436 CARS2 Arina Puzriakova Classified gene: CARS2 as Amber List (moderate evidence)
Intellectual disability v3.436 CARS2 Arina Puzriakova Added comment: Comment on list classification: Kept rating Amber as developmental regression and progressive cognitive decline appear secondary to seizures, which represent the key phenotypic feature of this disorder.

This gene is Green on the Inborn errors of metabolism (v2.2) panel, a component the Epilepsy super panel, which should be a sufficient route for detecting these cases.
Intellectual disability v3.436 CARS2 Arina Puzriakova Gene: cars2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.435 C2CD3 Arina Puzriakova Added comment: Comment on list classification: Despite phenotypic diversity among cases with C2CD3 variants, ID/DD is consistently reported in living patients.

Therefore, this gene could be promoted from Amber to Green at the next GMS panel update (added 'for-review' tag).
Intellectual disability v3.432 C2CD3 Arina Puzriakova changed review comment from: - PMID: 24997988 (2014) - Two unrelated cases with OFD syndrome and biallelic variants (p.Arg62* and p.Cys1029Gly; p.Ala1304Valfs*3, respectively) in C2CD3. In a 4-year-old male, additional manifestations included severe microcephaly (-5 SD), severe ID, micropenis, and brain malformations including Molar Tooth Sign. In the second patient, a terminated foetus, severe microcephaly (-4 SD) was combined with canonical OFD symptoms, but assessment of ID was not possible. No functional studies of the variants; however, some data supporting a role of C2CD3 in cilium assembly and function.

- PMID: 26092869 (2015) - Two unrelated individuals with biallelic variants in C2CD3. Clinical details are limited but both had features of Joubert syndrome (as JBTS screening study), as well as oral features including oral frenulae and/or cleft palate. No report on ID status, but could possibly be present in view of the JBTS diagnosis. One patient also harboured biallelic variants in TTC21B.

- PMID: 26477546 (2015) - Compound het variants identified in two affected sibs with a classic form of JBTS and severe GDD but without any extraneural manifestations, as described in previous cases.

- PMID: 27094867 (2016) - Two sibling fetuses with skeletal dysplasia, brain malformations but no microcephaly, in association with compound het variants in C2CD3. Due to termination of pregnancies, ID status could not be established. Analysis of patient-derived fibroblasts showed impaired cilium assembly.

- PMID: 30097616 (2018) - Four individuals from three unrelated families with different biallelic variants in C2CD3. Each family exhibited distinct clinical phenotypes and severity of disease:
Family 1: two sibs with a diagnosis of OFD including polydactyly, cleft palate and/or incomplete cleft lip, microcephaly, brain malformations and bilateral colobomas. GDD was noted in both sibs.
Family 2: fetus with occipital encephalocele and a ventricular septal defect. Similar abnormalities were identified in another sib (also a terminated fetus), but DNA analysis was not performed on the latter.
Family 3: one male with various fetal anomalies, and subsequent diagnosis of JBTS following identification of consistent findings on brain MRI. Other features included DD and bilateral retina colobomas.; to: - PMID: 24997988 (2014) - Two unrelated cases with OFD syndrome and biallelic variants (p.Arg62* and p.Cys1029Gly; p.Ala1304Valfs*3, respectively) in C2CD3. In a 4-year-old male, additional manifestations included severe microcephaly (-5 SD), severe ID, micropenis, and brain malformations including Molar Tooth Sign. In the second patient, a terminated foetus, severe microcephaly (-4 SD) was combined with canonical OFD symptoms, but assessment of ID was not possible. No functional studies of the variants; however, some data supporting a role of C2CD3 in cilium assembly and function.

- PMID: 26092869 (2015) - Two unrelated individuals with biallelic variants in C2CD3. Clinical details are limited but both had features of Joubert syndrome (as JBTS screening study), as well as oral features including oral frenulae and/or cleft palate. No report on ID status, but could possibly be present in view of the JBTS diagnosis. One patient also harboured biallelic variants in TTC21B.

- PMID: 26477546 (2015) - Compound het variants identified in two affected sibs with a classic form of JBTS and severe GDD but without any extraneural manifestations, as described in previous cases.

- PMID: 27094867 (2016) - Two sibling fetuses with skeletal dysplasia, brain malformations but no microcephaly, in association with compound het variants in C2CD3. Due to termination of pregnancies, ID status could not be established. Analysis of patient-derived fibroblasts showed impaired cilium assembly.

- PMID: 30097616 (2018) - Four individuals from three unrelated families with different biallelic variants in C2CD3. Each family exhibited distinct clinical phenotypes and severity of disease:
Family 1: two sibs with a diagnosis of OFD including polydactyly, cleft palate and/or incomplete cleft lip, microcephaly, brain malformations and bilateral colobomas. GDD was noted in both sibs.
Family 2: fetus with encephalocele and a ventricular septal defect. Similar abnormalities were identified in a sib (also a terminated fetus), but DNA analysis was not performed on the latter.
Family 3: one male with various fetal anomalies, and subsequent diagnosis of JBTS following identification of consistent findings on brain MRI. Other features included DD and bilateral retina colobomas.
Intellectual disability v3.429 MPV17 Ivone Leong Added comment: Comment on list classification: Promoted from Red to Amber. While there are enough cases to support a gene-disease association, ID is part of a broader phenotype for this disorder. Affected individuals will more likely be assessed under mitchondrial panels. This gene is green in Mitochondrial liver disease, inborn errors of metabolism, possible mitochondrial disorder - nuclear genes and mitochondrial disorders panels.
Intellectual disability v3.426 LAS1L Ivone Leong changed review comment from: Comment on list classification: Based on the expert reviews and available evidence, this gene has been promoted from Red to Amber. As the ID severity in the second case in (PMID: 25644381) is unknown and the variant in 1 case reported by (PMID: 26358559) is predicted to be benign. Until there is further evidence this gene has been given an Amber rating.; to: Comment on list classification: Based on the expert reviews and available evidence, this gene has been promoted from Red to Amber. This gene is listed in OMIM and Gene2Phenotype with a relevant phenotype. In Gene2Phenotype it has been classified as probable course for the phenotype. As the ID severity in the second case in (PMID: 25644381) is unknown and the variant in 1 case reported by (PMID: 26358559) is predicted to be benign. Until there is further evidence this gene has been given an Amber rating.
Intellectual disability v3.426 LAS1L Ivone Leong Added comment: Comment on list classification: Based on the expert reviews and available evidence, this gene has been promoted from Red to Amber. As the ID severity in the second case in (PMID: 25644381) is unknown and the variant in 1 case reported by (PMID: 26358559) is predicted to be benign. Until there is further evidence this gene has been given an Amber rating.
Intellectual disability v3.423 TINF2 Arina Puzriakova Added comment: Comment on list classification: Although DD can be a feature, the condition is expected to present in a syndromic manner with cytopenia, cerebellar hypoplasia and retinopathy representing key characteristics. It is expected that these indications should be sufficient for detecting cases - TINF2 is already Green on the relevant panels.

Calling variants in this gene in a cohort of ID patients is therefore unlikely to be of benefit and so the rating has been kept Red.
Intellectual disability v3.421 STAR Arina Puzriakova Source Expert Review Red was added to STAR.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 ARHGEF6 Arina Puzriakova Source Expert Review Red was added to ARHGEF6.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.420 ITFG2 Konstantinos Varvagiannis gene: ITFG2 was added
gene: ITFG2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: ITFG2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ITFG2 were set to 28397838; https://doi.org/10.1038/s41525-020-00150-z
Phenotypes for gene: ITFG2 were set to Neurodevelopmental abnormality; Intellectual disability; Developmental regression; Ataxia
Penetrance for gene: ITFG2 were set to Complete
Review for gene: ITFG2 was set to AMBER
Added comment: ITFG2 was suggested to be a candidate gene for autosomal recessive ID in the study by Harripaul et al (2018 - PMID: 28397838). The authors performed microarray and exome sequencing in 192 consanguineous families and identified a homozygous ITGF2 stopgain variant (NM_018463.3:c.472G>T / p.Glu158*) along with 3 additional variants segregating with ID within an investigated family (PK51).

Cheema et al (2020 - https://doi.org/10.1038/s41525-020-00150-z) report briefly on a male, born to consanguineous parents presenting with NDD, seizures, regression and ataxia. There was a similarly affected female sibling. Evaluation of ROH revealed a homozygous ITFG2 nonsense variant [NM_018463.3:c.361C>T / p.(Gln121*)]. Families in this study were investigated by trio WES or WGS.

Evaluation of data of the same lab revealed 3 additional unrelated subjects with overlapping phenotypes, notably NDD and ataxia. These individuals were - each - homozygous for pLoF variants [NM_018463.3:c.848-1G>A; NM_018463.3:c.704dupC, p.(Ala236fs), NM_018463.3:c.1000_1001delAT, p.(Ile334fs)].

As discussed in OMIM, ITFG2 encodes a subunit of the KICSTOR protein complex, having a role in regulating nutrient sensing by MTOR complex-1 (Wolfson et al 2017 - PMID : 28199306).

Please consider inclusion in the ID panel with amber rating, pending further details.
Sources: Literature
Intellectual disability v3.420 SHMT2 Konstantinos Varvagiannis gene: SHMT2 was added
gene: SHMT2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: SHMT2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SHMT2 were set to 33015733
Phenotypes for gene: SHMT2 were set to Congenital microcephaly; Infantile axial hypotonia; Spastic paraparesis; Global developmental delay; Intellectual disability; Abnormality of the corpus callosum; Abnormal cortical gyration; Hypertrophic cardiomyopathy; Abnormality of the face; Proximal placement of thumb; 2-3 toe syndactyly
Penetrance for gene: SHMT2 were set to Complete
Review for gene: SHMT2 was set to GREEN
Added comment: García‑Cazorla et al. (2020 - PMID: 33015733) report 5 individuals (from 4 families) with a novel brain and heart developmental syndrome caused by biallelic SHMT2 pathogenic variants.

All affected subjects presented similar phenotype incl. microcephaly at birth (5/5 OFC < -2 SD though in 2/5 cases N OFC was observed later), DD and ID (1/5 mild-moderate, 1/5 moderate, 3/5 severe), motor dysfunction in the form of spastic (5/5) paraparesis, ataxia/dysmetria (3/4), intention tremor (in 3/?) and/or peripheral neuropathy (2 sibs). They exhibited corpus callosum hypoplasia (5/5) and perisylvian microgyria-like pattern (4/5). Cardiac problems were reported in all, with hypertrophic cardiomyopathy in 4/5 (from 3 families) and atrial-SD in the 5th individual (1/5). Common dysmorphic features incl. long palpebral/fissures, eversion of lateral third of lower eylids, arched eyebrows, long eyelashes, thin upper lip, short Vth finger, fetal pads, mild 2-3 toe syndactyly, proximally placed thumbs.

Biallelic variants were identified following exome sequencing in all (other investigations not mentioned). Identified variants were in all cases missense SNVs or in-frame del, which together with evidence from population databases and mouse model might suggest a hypomorphic effect of variants and intolerance/embryonic lethality for homozygous LoF ones.

SHMT2 encodes the mitohondrial form of serine hydroxymethyltransferase. The enzyme transfers one-carbon units from serine to tetrahydrofolate (THF) and generates glycine and 5,10,methylene-THF.

Mitochondrial defect was suggested by presence of ragged red fibers in myocardial biopsy of one patient. Quadriceps and myocardial biopsies of the same individual were overall suggestive of myopathic changes.

While plasma metabolites were within N range and SHMT2 protein levels not significantly altered in patient fibroblasts, the authors provide evidence for impaired enzymatic function eg. presence of the SHMT2 substrate (THF) in patient but not control (mitochondria-enriched) fibroblasts , decrease in glycine/serine ratios, impared folate metabolism. Patient fibroblasts displayed impaired oxidative capacity (reduced ATP levels in a medium without glucose, diminished oxygen consumption rates). Mitochondrial membrane potential and ROS levels were also suggestive of redox malfunction.

Shmt2 ko in mice was previously shown to be embryonically lethal attributed to severe mitochondrial respiration defects, although there was no observed brain metabolic defect.

The authors performed Shmt2 knockdown in motoneurons in Drosophila, demonstrating neuromuscular junction (# of satellite boutons) and motility defects (climbing distance/velocity).

Overall this gene can be considered for inclusion with (probably) green rating in gene panels for ID, metabolic / mitochondrial disorders, cardiomyopathy, congenital microcephaly, corpus callosum anomalies, etc.
Sources: Literature
Intellectual disability v3.420 ABCB11 Arina Puzriakova Added comment: Comment on list classification: Downgraded from Amber to Red in context of the review by Konstantinos Varvagiannis
Intellectual disability v3.419 ACAN Arina Puzriakova Added comment: Comment on list classification: Downgraded from Amber to Red in context of the review by Konstantinos Varvagiannis
Intellectual disability v3.417 ATP8B1 Arina Puzriakova changed review comment from: Following discussion with the clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark; to: Following discussion with the clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark and Konstantinos Varvagiannis
Intellectual disability v3.412 SCAF4 Arina Puzriakova Added comment: Comment on list classification: At least 8 unrelated individuals reported in PMID:32730804 with a neurodevelopmental disorder characterised by DD/ID, mostly in the mild range (severe in only one individual).

Rating Amber in view of the mild ID presentation. This may be reviewed if further cases are reported with more severe manifestations of relevant phenotypes.
Intellectual disability v3.410 NEDD4L Eleanor Williams changed review comment from: Associated with Periventricular nodular heterotopia 7 #617201 (AD) in OMIM.

PMID: 27694961 - Broix et al 2016 - report 4 different de novo missense changes in NEDD4L in a total of five unrelated patients with periventricular nodular heterotopia and neurodevelopmental delay, and in a additional familial case with a similar phenotype and a previously found missense variant. In the familial case, two affected siblings were found to be heterozygous for the variant, the father and an unaffected sibling did not carry the variant, and the mother was found to show somatic mosaicism of NEDD4L variant. Functional studies showed a sensitivity of PNH-associated mutants to proteasome degradation.; to: Associated with Periventricular nodular heterotopia 7 #617201 (AD) in OMIM.

PMID: 27694961 - Broix et al 2016 - report 4 different de novo missense changes in NEDD4L in a total of five unrelated patients with periventricular nodular heterotopia and neurodevelopmental delay, and in a additional familial case with a similar phenotype and a previously found missense variant. In the familial case, two affected siblings were found to be heterozygous for the variant, the father and an unaffected sibling did not carry the variant, and the mother was found to show somatic mosaicism of NEDD4L variant. Functional studies showed a sensitivity of PNH-associated mutants to proteasome degradation. Seizures were reported in some but not all affected individuals.
Intellectual disability v3.409 NEDD4L Eleanor Williams Added comment: Comment on list classification: Promoting this gene from red to amber, but there are sufficient cases with a severe developmental delay phenotype for it to be rated green. It should therefore be reviewed at the next GMS update.
Intellectual disability v3.408 NEDD4L Eleanor Williams Phenotypes for gene: NEDD4L were changed from EPILEPTIC ENCEPHALOPATHY to Periventricular nodular heterotopia 7, 617201
Intellectual disability v3.407 NEDD4L Eleanor Williams reviewed gene: NEDD4L: Rating: GREEN; Mode of pathogenicity: None; Publications: 27694961; Phenotypes: Periventricular nodular heterotopia 7, 617201; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.405 NUP214 Eleanor Williams changed review comment from: Associated with {Encephalopathy, acute, infection-induced, susceptibility to, 9} 618426 in OMIM and Gene2Phenotype (probable).

PMID: 31178128 - Fichtman et al 2019 - report on two families one of Palestinian decent, the other Northern European (not Finnish descent). Each had two affected siblings in which neurological decline was seen after febrile events. The older son in family A, exhibited minor developmental delay from infancy. A homozygous missense variant was identified in NUP214 (p.Arg38Cys) in family A and segregated with the disease in available family members. In family B affected sisters were compound heterozygous for a frameshift and a missense variant in NUP214 (p.Pro387Ser and p.Pro525Leufs∗6). Functional studies with fibroblasts from one patient in family A showed a decrease in NUP214 and NUP88 levels compared to controls,

PMID: 30758658 - Shamseldin et al 2019 - describe a multiplex consanguineous family in which four affected members presented with severe neonatal hypotonia, profound global developmental delay, progressive microcephaly and early death. Whole exome sequencing revealed the presence of a novel homozygous missense variant in NUP214, p.D154G.

PMID: 29483668 - Egloff et al 2018 - report a 4-year-old girl presenting with developmental delay, growth retardation and facial dysmorphism. She was found to have a 9q deletion inherited from her healthy mother and a a hemizygous one-base pair deletion in the NUP214 gene inherited from her father. From patient leukocytes it was found that the expression level of the NUP214 transcript was significantly decreased and close to zero in the patient compared to the controls. ; to: Associated with {Encephalopathy, acute, infection-induced, susceptibility to, 9} 618426 in OMIM and Gene2Phenotype (probable).

PMID: 31178128 - Fichtman et al 2019 - report on two families one of Palestinian decent, the other Northern European (not Finnish descent). Each had two affected siblings in which neurological decline was seen after febrile events. The older son in family A, exhibited minor developmental delay from infancy. A homozygous missense variant was identified in NUP214 (p.Arg38Cys) in family A and segregated with the disease in available family members. In family B affected sisters were compound heterozygous for a frameshift and a missense variant in NUP214 (p.Pro387Ser and p.Pro525Leufs∗6). Functional studies with fibroblasts from one patient in family A showed a decrease in NUP214 and NUP88 levels compared to controls,

PMID: 30758658 - Shamseldin et al 2019 - describe a multiplex consanguineous family in which four affected members presented with severe neonatal hypotonia, profound global developmental delay, progressive microcephaly and early death (<2 year old). Whole exome sequencing revealed the presence of a novel homozygous missense variant in NUP214, p.D154G.

PMID: 29483668 - Egloff et al 2018 - report a 4-year-old girl presenting with developmental delay, growth retardation and facial dysmorphism. She was found to have a 9q deletion inherited from her healthy mother and a hemizygous one-base pair deletion in the NUP214 gene inherited from her father. From patient leukocytes it was found that the expression level of the NUP214 transcript was significantly decreased and close to zero in the patient compared to the controls.
Intellectual disability v3.405 NUP214 Eleanor Williams changed review comment from: Associated with {Encephalopathy, acute, infection-induced, susceptibility to, 9} 618426 in OMIM and Gene2Phenotype (probable).

PMID: 31178128 - Fichtman et al 2019 - report on two families. Family A have first-cousin parents of Palestinian descent. The proband exhibited minor developmental delay from infancy, presented with ataxia, mental retardation, and intractable epilepsy and died at 11 years. He suffered deterioration in association with febrile illnesses. His cousin presented at 5.5 months with partially reversible encephalopathy and developmental regression after a febrile illness. Family B were sisters born to non-consanguineous parents of Northern European (non-Finnish) descent. The older sister had nystagmus at 2 months and mild hypotonia, but she was otherwise meeting milestones appropriately . At 15 months of age, she developed a fever that led to a rapid neurological decline, seizures, and abnormal movements. The younger sister presented at 7 months with failure to thrive and hyponatremia but was meeting developmental milestones appropriately. By 24 months of age, she had motor and speech delay, ataxic gait, and occasional very mild head bobbing. In family A a homozygous NUP214 p.Arg38Cys variant segregated with the disease in available family members. In family B the sisters were found to be compound heterozygous for a frameshift and a missense variant in NUP214 (p.Pro387Ser and p.Pro525Leufs∗6).; to: Associated with {Encephalopathy, acute, infection-induced, susceptibility to, 9} 618426 in OMIM and Gene2Phenotype (probable).

PMID: 31178128 - Fichtman et al 2019 - report on two families one of Palestinian decent, the other Northern European (not Finnish descent). Each had two affected siblings in which neurological decline was seen after febrile events. The older son in family A, exhibited minor developmental delay from infancy. A homozygous missense variant was identified in NUP214 (p.Arg38Cys) in family A and segregated with the disease in available family members. In family B affected sisters were compound heterozygous for a frameshift and a missense variant in NUP214 (p.Pro387Ser and p.Pro525Leufs∗6). Functional studies with fibroblasts from one patient in family A showed a decrease in NUP214 and NUP88 levels compared to controls,

PMID: 30758658 - Shamseldin et al 2019 - describe a multiplex consanguineous family in which four affected members presented with severe neonatal hypotonia, profound global developmental delay, progressive microcephaly and early death. Whole exome sequencing revealed the presence of a novel homozygous missense variant in NUP214, p.D154G.

PMID: 29483668 - Egloff et al 2018 - report a 4-year-old girl presenting with developmental delay, growth retardation and facial dysmorphism. She was found to have a 9q deletion inherited from her healthy mother and a a hemizygous one-base pair deletion in the NUP214 gene inherited from her father. From patient leukocytes it was found that the expression level of the NUP214 transcript was significantly decreased and close to zero in the patient compared to the controls.
Intellectual disability v3.404 GPSM2 Eleanor Williams Added comment: Comment on list classification: Leaving this gene as green just now, but as there are only 2 families out of 19 in which mild cognitive delay is seen then the recommendation would be to rate this gene amber. This gene should be reviewed at the next GMS update.
Intellectual disability v3.401 GPSM2 Eleanor Williams changed review comment from: Associated with Chudley-McCullough syndrome604213 in OMIM

Summary: From 19 reported families, 3 individuals from 2 families showed cognitive delay.

PMID: 27180139 - Hemzeh et al 2016 - report two brothers from a Yemeni family who were diagnosed clinically with CMS then tested for GPSM2 mutations using Sanger sequencing. A homozygous mutation in GPSM2 was found in both brothers (c.1055C > A) leading to a truncating protein change; (p.Ser352*). The 12 year old brother showed cognitive delay, noted by the inability to tell the time in minutes, or to follow complex commands. The 11 year old brother could speak in sentences but with poor articulation, and could not respond to complex commands.

PMID: 23494849 - Almomani et al 2013 - report three patients from two unrelated Dutch families with CMS were investigated in which the same c.1473delG variant observed in 4 of the Menonite families by Doherty et al was observed. All three patients had normal cognitive abilities.

PMID: 22578326 - Doherty et al 2012 - report on 5 Menonite, 1 European-American, 1 Dutch and 1 Mexican-American family in which probands had severe/profound hearing loss and ventriculomegaly (total of 12 affected individuals). They also look again at the patients reported with autosomal recessive nonsyndromic deafness (DFNB82) by Walsh et al 2010 (PMID: 20602914, 1 proband ina Pakistani family) and Yariz et al 2012 (PMID: 21348867, 3 probands in a Turkish family) who they found had brain abnormalities consistent with with a diagnosis of Chudley-McCullough syndrome.
Oout of the 16 patients reported, only one had developmental issues beyond what is typically seen in individuals with severe hearing loss.



- -; to: Associated with Chudley-McCullough syndrome604213 in OMIM

Summary: From 19 reported families, 3 individuals from 2 families showed cognitive delay.

PMID: 27180139 - Hemzeh et al 2016 - report two brothers from a Yemeni family who were diagnosed clinically with CMS then tested for GPSM2 mutations using Sanger sequencing. A homozygous mutation in GPSM2 was found in both brothers (c.1055C > A) leading to a truncating protein change; (p.Ser352*). The 12 year old brother showed cognitive delay, noted by the inability to tell the time in minutes, or to follow complex commands. The 11 year old brother could speak in sentences but with poor articulation, and could not respond to complex commands. The poor articulation was thought to be due to late cochlear implant surgery.

PMID: 23494849 - Almomani et al 2013 - report three patients from two unrelated Dutch families with CMS were investigated in which the same c.1473delG variant observed in 4 of the Menonite families by Doherty et al was observed. All three patients had normal cognitive abilities.

PMID: 22578326 - Doherty et al 2012 - report on 5 Menonite, 1 European-American, 1 Dutch and 1 Mexican-American family in which probands had severe/profound hearing loss and ventriculomegaly (total of 12 affected individuals). They also look again at the patients reported with autosomal recessive nonsyndromic deafness (DFNB82) by Walsh et al 2010 (PMID: 20602914, 1 proband ina Pakistani family) and Yariz et al 2012 (PMID: 21348867, 3 probands in a Turkish family) who they found had brain abnormalities consistent with with a diagnosis of Chudley-McCullough syndrome.
Oout of the 16 patients reported, only one had developmental issues beyond what is typically seen in individuals with severe hearing loss.



- -
Intellectual disability v3.401 USP18 Arina Puzriakova Added comment: Comment on list classification: DD reported in one surviving patient. However, this only became apparent following treatment which was administered after genetic diagnosis was already achieved. DD is therefore unlikely represent the clinical indication to prompt testing in the neonatal period.

Therefore keeping rating Red on the ID panel. USP18 is Green on other relevant panels (White matter disorders and cerebral calcification, PID) which should be adequate for detecting these cases.
Intellectual disability v3.393 MADD Ivone Leong Added comment: Comment on list classification: Based on expert review provided by Konstantinos Varvagiannis and Zornitza Stark, there is enough evidence to support a gene-disease association. This gene has been promoted from Red to Amber and will be promoted to Green status at next panel review.
Intellectual disability v3.384 CTNND1 Eleanor Williams Added comment: Comment on list classification: Rating as amber but could potentially be green. Individuals from 5/9 families have reported developmental delay/learning difficulty. This gene should be reviewed at the next GMS update.
Intellectual disability v3.382 CTNND1 Eleanor Williams gene: CTNND1 was added
gene: CTNND1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: CTNND1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CTNND1 were set to 32196547
Review for gene: CTNND1 was set to GREEN
Added comment: PMID: 32196547 - Alharatani et al 2020 - report an expanded phenotype for CTNND1 patients. They report 13 individuals from nine families with novel protein-truncating variants in CTNND1 identified by WES. The mutations were not previously described in blepharocheilodontic (BCD), orofacial cleft cases nor in gnomAD. 8 patients had de novo variants, 2 inherited from affected parents, 2 participants inherited a variant from a parent with a mild phenotype. 8/13 patients showed cleft palate. Additional phenotypic features seen include mild limb phenotypes (9/13), cardiovascular anomalies (6/13) and Developmental delay and other neurodevelopmental problems (8/13)
Sources: Literature
Intellectual disability v3.381 WDR83OS Ivone Leong gene: WDR83OS was added
gene: WDR83OS was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: WDR83OS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: WDR83OS were set to 30250217
Phenotypes for gene: WDR83OS were set to Intellectual disability
Review for gene: WDR83OS was set to RED
Added comment: One consanguineous family with three affected individuals with homozygous split site variant in this gene. All three have ID.
Sources: Literature
Intellectual disability v3.380 YIF1B Arina Puzriakova changed review comment from: Comment on list classification: There is a sufficient number of cases to rate this gene Green at the next GMS panel update.

GDD was reported in all 6 patients (5 families). At ages 4-11yrs, the best achieved social and language skills were limited to sounds in 4 individuals, and partial babbling or vocalisation in the remaining two, respectively.; to: Comment on list classification: There is a sufficient number of cases to rate this gene Green at the next GMS panel update.

- PMID: 32006098: GDD was reported in all 6 patients (5 families). At ages 4-11yrs, the best achieved social and language skills were limited to sounds in 4 individuals, and partial babbling or vocalisation in the remaining two, respectively.
Intellectual disability v3.380 YIF1B Arina Puzriakova changed review comment from: Comment on list classification: There are a sufficient number of cases to rate this gene Green at the next GMS panel update.

GDD was reported in all 6 patients (5 families). At ages 4-11yrs, the best achieved social and language skills were limited to sounds in 4 individuals, and partial babbling or vocalisation in the remaining two, respectively.; to: Comment on list classification: There is a sufficient number of cases to rate this gene Green at the next GMS panel update.

GDD was reported in all 6 patients (5 families). At ages 4-11yrs, the best achieved social and language skills were limited to sounds in 4 individuals, and partial babbling or vocalisation in the remaining two, respectively.
Intellectual disability v3.380 YIF1B Arina Puzriakova Added comment: Comment on list classification: There are a sufficient number of cases to rate this gene Green at the next GMS panel update.

GDD was reported in all 6 patients (5 families). At ages 4-11yrs, the best achieved social and language skills were limited to sounds in 4 individuals, and partial babbling or vocalisation in the remaining two, respectively.
Intellectual disability v3.379 UGDH Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to rate this gene Green at the next GMS panel update.

Multiple patients from over 20 unrelated families, all with moderate-to-severe ID in association with biallelic variants in UGDH.
Intellectual disability v3.378 SPTBN4 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to rate this gene Green at the next GMS panel update.

Severe-to-profound DD and/or ID reported in all but one family with a milder phenotype (at least 9 total families described with different biallelic variants in SPTBN4).
Intellectual disability v3.377 NR4A2 Arina Puzriakova Added comment: Comment on list classification: This gene will be flagged for review at the date of next GMS panel update (added 'for-review' tag).

The recent paper flagged by Konstantinos Varvagiannis (PMID:32366965) includes 2 unrelated patients with severe ID and 2 with moderate-severe ID. This is within the scope of the panel and the number of cases now reach threshold for inclusion with a Green rating.
Intellectual disability v3.375 TNRC6B Arina Puzriakova Added comment: Comment on list classification: This is a borderline Amber/Green gene, and should be reviewed at the date of next GMS panel update (added 'for-review' tag).

Phenotype is primarily characterised by neurobehavioral abnormalities, including DD (particularly speech impairment) in all cases, as well as variable features of autism, ADHD, impulsivity, anger and aggressiveness. Cognitive abilities were varied, and a formal diagnosis of ID was only attained in 4 patients. Nonetheless, this likely represents the most appropriate panel for capturing these cases and therefore a Green rating should be considered.
Intellectual disability v3.371 STS Arina Puzriakova changed review comment from: Following discussion with the clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark; to: Following discussion with the clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark and Helen Brittain
Intellectual disability v3.369 NEMF Konstantinos Varvagiannis changed review comment from: Martin et al (2020 - PMID:32934225) report on 8 individuals from 6 families with a juvenile neuromuscular disease due to biallelic NEMF variants. (In one of these 8 cases it could not be ruled out that a de novo and maternally inherited variant were on the same allele, as phase was not determined). A ninth individual with similar presentation was found to harbor a single NEMF missense SNV as de novo event (due to a speculated dominant-negative effect). This individual had a similar presentation.

Features incl. hypotonia (4/8 with biallelic variant (B) | 1/1 monoallelic (M) ), DD/ID (7/8B | 0/1M) with speech delay as universal feature (8/8B | 1/1M), axonal neuropathy (3/3B | 1/1M), ataxia (3/8B | 0/1M). Other findings included tremor (1/7B | 1/1M), abnormal brain imaging (2/6B / ?/1M), kyphosis/scoliosis (4/8B | 0/1M), respiratory distress (1/8B | 0/1M).

NEMF (Rqc2 in yeast) encodes the nuclear export mediator factor, a component of the Ribosome-associated Quality Control (RCQ) complex which is involved in proteolytic targeting of incomplete polypeptides prodduced by ribosome stalling. NEMF facilitates the recruitment of E3 ligase Listerin (LTN1) which ubiquitinates nascent polypeptide chains for subsequent proteasomal degradation.

The author provide evidence that mice homozygous for Nemf missense mutations display progressive motor phenotypes, exhibit neurogenic atrophy and progressive axonal degeneration. A further NEMF-null mouse model displayed more severe phenotype (with heterozygous mice being unaffected).

Equivalent mutations (of those in the above mouse model) in yeast (Rqc2) were shown to interfere with its ability to modify aberrant translation products with C-terminal tails which assist RQC-mediated protein degradation.

Mutation of Ltn1 (belonging to the same protein control pathway) has been also shown to lead to neurodegeneration im mice.

Overall NEMF is thought to play a role in neuronal translational homeostasis and the disorder to be mediated by dysfunction of the RQC pathway (normally protecting neurons against degeneration).
Sources: Literature; to: Martin et al (2020 - PMID:32934225) report on 8 individuals from 6 families with a juvenile neuromuscular disease due to biallelic NEMF variants. (In one of these 8 cases it could not be ruled out that a de novo and maternally inherited variant were on the same allele, as phase was not determined). A ninth individual with similar presentation was found to harbor a single NEMF missense SNV as de novo event (due to a speculated dominant-negative effect). This individual had a similar presentation.

Features incl. hypotonia (4/8 with biallelic variant (B) | 1/1 monoallelic (M) ), DD/ID (7/8B | 0/1M) with speech delay as universal feature (8/8B | 1/1M), axonal neuropathy (3/3B | 1/1M), ataxia (3/8B | 0/1M). Other findings included tremor (1/7B | 1/1M), abnormal brain imaging (2/6B / ?/1M), kyphosis/scoliosis (4/8B | 0/1M), respiratory distress (1/8B | 0/1M).

NEMF (Rqc2 in yeast) encodes the nuclear export mediator factor, a component of the Ribosome-associated Quality Control (RCQ) complex which is involved in proteolytic targeting of incomplete polypeptides produced by ribosome stalling. NEMF facilitates the recruitment of E3 ligase Listerin (LTN1) which ubiquitinates nascent polypeptide chains for subsequent proteasomal degradation.

The author provide evidence that mice homozygous for Nemf missense mutations display progressive motor phenotypes, exhibit neurogenic atrophy and progressive axonal degeneration. A further NEMF-null mouse model displayed more severe phenotype (with heterozygous mice being unaffected).

Equivalent mutations (of those in the above mouse model) in yeast (Rqc2) were shown to interfere with its ability to modify aberrant translation products with C-terminal tails which assist RQC-mediated protein degradation.

Mutation of Ltn1 (belonging to the same protein control pathway) has been also shown to lead to neurodegeneration in mice.

Overall NEMF is thought to play a role in neuronal translational homeostasis and the disorder to be mediated by dysfunction of the RQC pathway (normally protecting neurons against degeneration).
Sources: Literature
Intellectual disability v3.369 NEMF Konstantinos Varvagiannis changed review comment from: Martin et al (2020 - PMID:32934225) report on 8 individuals from 6 families with a juvenile neuromuscular disease due to biallelic NEMF variants. (In one of these 8 cases it could be ruled out that the de novo and maternally inherited variants were on the same allele, as phase was not been determined). A ninth individual with similar presentation was found to harbor a single NEMF missense SNV as de novo event (due to a speculated dominant-negative effect). This individual had a similar presentation.

Features incl. hypotonia (4/8 with biallelic variant (B) | 1/1 monoallelic (M) ), DD/ID (7/8B | 0/1M) with speech delay as universal feature (8/8B | 1/1M), axonal neuropathy (3/3B | 1/1M), ataxia (3/8B | 0/1M). Other findings included tremor (1/7B | 1/1M), abnormal brain imaging (2/6B / ?/1M), kyphosis/scoliosis (4/8B | 0/1M), respiratory distress (1/8B | 0/1M).

NEMF (Rqc2 in yeast) encodes the nuclear export mediator factor, a component of the Ribosome-associated Quality Control (RCQ) complex which is involved in proteolytic targeting of incomplete polypeptides prodduced by ribosome stalling. NEMF facilitates the recruitment of E3 ligase Listerin (LTN1) which ubiquitinates nascent polypeptide chains for subsequent proteasomal degradation.

The author provide evidence that mice homozygous for Nemf missense mutations display progressive motor phenotypes, exhibit neurogenic atrophy and progressive axonal degeneration. A further NEMF-null mouse model displayed more severe phenotype (with heterozygous mice being unaffected).

Equivalent mutations (of those in the above mouse model) in yeast (Rqc2) were shown to interfere with its ability to modify aberrant translation products with C-terminal tails which assist RQC-mediated protein degradation.

Mutation of Ltn1 (belonging to the same protein control pathway) has been also shown to lead to neurodegeneration im mice.

Overall NEMF is thought to play a role in neuronal translational homeostasis and the disorder to be mediated by dysfunction of the RQC pathway (normally protecting neurons against degeneration).
Sources: Literature; to: Martin et al (2020 - PMID:32934225) report on 8 individuals from 6 families with a juvenile neuromuscular disease due to biallelic NEMF variants. (In one of these 8 cases it could not be ruled out that a de novo and maternally inherited variant were on the same allele, as phase was not determined). A ninth individual with similar presentation was found to harbor a single NEMF missense SNV as de novo event (due to a speculated dominant-negative effect). This individual had a similar presentation.

Features incl. hypotonia (4/8 with biallelic variant (B) | 1/1 monoallelic (M) ), DD/ID (7/8B | 0/1M) with speech delay as universal feature (8/8B | 1/1M), axonal neuropathy (3/3B | 1/1M), ataxia (3/8B | 0/1M). Other findings included tremor (1/7B | 1/1M), abnormal brain imaging (2/6B / ?/1M), kyphosis/scoliosis (4/8B | 0/1M), respiratory distress (1/8B | 0/1M).

NEMF (Rqc2 in yeast) encodes the nuclear export mediator factor, a component of the Ribosome-associated Quality Control (RCQ) complex which is involved in proteolytic targeting of incomplete polypeptides prodduced by ribosome stalling. NEMF facilitates the recruitment of E3 ligase Listerin (LTN1) which ubiquitinates nascent polypeptide chains for subsequent proteasomal degradation.

The author provide evidence that mice homozygous for Nemf missense mutations display progressive motor phenotypes, exhibit neurogenic atrophy and progressive axonal degeneration. A further NEMF-null mouse model displayed more severe phenotype (with heterozygous mice being unaffected).

Equivalent mutations (of those in the above mouse model) in yeast (Rqc2) were shown to interfere with its ability to modify aberrant translation products with C-terminal tails which assist RQC-mediated protein degradation.

Mutation of Ltn1 (belonging to the same protein control pathway) has been also shown to lead to neurodegeneration im mice.

Overall NEMF is thought to play a role in neuronal translational homeostasis and the disorder to be mediated by dysfunction of the RQC pathway (normally protecting neurons against degeneration).
Sources: Literature
Intellectual disability v3.369 NEMF Konstantinos Varvagiannis changed review comment from: Martin et al (2020 - PMID:32934225) report on 8 individuals from 6 families with a juvenile neuromuscular disease due to biallelic NEMF variants. A ninth individual with similar presentation was found to harbor a single NEMF missense SNV as de novo event (due to a speculated dominant-negative effect). This individual had a similar presentation.

Features incl. hypotonia (4/8 with biallelic variant (B) | 1/1 monoallelic (M) ), DD/ID (7/8B | 0/1M) with speech delay as universal feature (8/8B | 1/1M), axonal neuropathy (3/3B | 1/1M), ataxia (3/8B | 0/1M). Other findings included tremor (1/7B | 1/1M), abnormal brain imaging (2/6B / ?/1M), kyphosis/scoliosis (4/8B | 0/1M), respiratory distress (1/8B | 0/1M).

NEMF (Rqc2 in yeast) encodes the nuclear export mediator factor, a component of the Ribosome-associated Quality Control (RCQ) complex which is involved in proteolytic targeting of incomplete polypeptides prodduced by ribosome stalling. NEMF facilitates the recruitment of E3 ligase Listerin (LTN1) which ubiquitinates nascent polypeptide chains for subsequent proteasomal degradation.

The author provide evidence that mice homozygous for Nemf missense mutations display progressive motor phenotypes, exhibit neurogenic atrophy and progressive axonal degeneration. A further NEMF-null mouse model displayed more severe phenotype (with heterozygous mice being unaffected).

Equivalent mutations (of those in the above mouse model) in yeast (Rqc2) were shown to interfere with its ability to modify aberrant translation products with C-terminal tails which assist RQC-mediated protein degradation.

Mutation of Ltn1 (belonging to the same protein control pathway) has been also shown to lead to neurodegeneration im mice.

Overall NEMF is thought to play a role in neuronal translational homeostasis and the disorder to be mediated by dysfunction of the RQC pathway (normally protecting neurons against degeneration).
Sources: Literature; to: Martin et al (2020 - PMID:32934225) report on 8 individuals from 6 families with a juvenile neuromuscular disease due to biallelic NEMF variants. (In one of these 8 cases it could be ruled out that the de novo and maternally inherited variants were on the same allele, as phase was not been determined). A ninth individual with similar presentation was found to harbor a single NEMF missense SNV as de novo event (due to a speculated dominant-negative effect). This individual had a similar presentation.

Features incl. hypotonia (4/8 with biallelic variant (B) | 1/1 monoallelic (M) ), DD/ID (7/8B | 0/1M) with speech delay as universal feature (8/8B | 1/1M), axonal neuropathy (3/3B | 1/1M), ataxia (3/8B | 0/1M). Other findings included tremor (1/7B | 1/1M), abnormal brain imaging (2/6B / ?/1M), kyphosis/scoliosis (4/8B | 0/1M), respiratory distress (1/8B | 0/1M).

NEMF (Rqc2 in yeast) encodes the nuclear export mediator factor, a component of the Ribosome-associated Quality Control (RCQ) complex which is involved in proteolytic targeting of incomplete polypeptides prodduced by ribosome stalling. NEMF facilitates the recruitment of E3 ligase Listerin (LTN1) which ubiquitinates nascent polypeptide chains for subsequent proteasomal degradation.

The author provide evidence that mice homozygous for Nemf missense mutations display progressive motor phenotypes, exhibit neurogenic atrophy and progressive axonal degeneration. A further NEMF-null mouse model displayed more severe phenotype (with heterozygous mice being unaffected).

Equivalent mutations (of those in the above mouse model) in yeast (Rqc2) were shown to interfere with its ability to modify aberrant translation products with C-terminal tails which assist RQC-mediated protein degradation.

Mutation of Ltn1 (belonging to the same protein control pathway) has been also shown to lead to neurodegeneration im mice.

Overall NEMF is thought to play a role in neuronal translational homeostasis and the disorder to be mediated by dysfunction of the RQC pathway (normally protecting neurons against degeneration).
Sources: Literature
Intellectual disability v3.369 NEMF Konstantinos Varvagiannis gene: NEMF was added
gene: NEMF was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: NEMF was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: NEMF were set to 32934225
Phenotypes for gene: NEMF were set to Hypotonia; Global developmental delay; Intellectual disability; Axonal neuropathy; Ataxia; Abnormal brain imaging; Kyphosis; Scoliosis; Tremor; Respiratory distress
Penetrance for gene: NEMF were set to Complete
Review for gene: NEMF was set to GREEN
Added comment: Martin et al (2020 - PMID:32934225) report on 8 individuals from 6 families with a juvenile neuromuscular disease due to biallelic NEMF variants. A ninth individual with similar presentation was found to harbor a single NEMF missense SNV as de novo event (due to a speculated dominant-negative effect). This individual had a similar presentation.

Features incl. hypotonia (4/8 with biallelic variant (B) | 1/1 monoallelic (M) ), DD/ID (7/8B | 0/1M) with speech delay as universal feature (8/8B | 1/1M), axonal neuropathy (3/3B | 1/1M), ataxia (3/8B | 0/1M). Other findings included tremor (1/7B | 1/1M), abnormal brain imaging (2/6B / ?/1M), kyphosis/scoliosis (4/8B | 0/1M), respiratory distress (1/8B | 0/1M).

NEMF (Rqc2 in yeast) encodes the nuclear export mediator factor, a component of the Ribosome-associated Quality Control (RCQ) complex which is involved in proteolytic targeting of incomplete polypeptides prodduced by ribosome stalling. NEMF facilitates the recruitment of E3 ligase Listerin (LTN1) which ubiquitinates nascent polypeptide chains for subsequent proteasomal degradation.

The author provide evidence that mice homozygous for Nemf missense mutations display progressive motor phenotypes, exhibit neurogenic atrophy and progressive axonal degeneration. A further NEMF-null mouse model displayed more severe phenotype (with heterozygous mice being unaffected).

Equivalent mutations (of those in the above mouse model) in yeast (Rqc2) were shown to interfere with its ability to modify aberrant translation products with C-terminal tails which assist RQC-mediated protein degradation.

Mutation of Ltn1 (belonging to the same protein control pathway) has been also shown to lead to neurodegeneration im mice.

Overall NEMF is thought to play a role in neuronal translational homeostasis and the disorder to be mediated by dysfunction of the RQC pathway (normally protecting neurons against degeneration).
Sources: Literature
Intellectual disability v3.369 PRKD1 Arina Puzriakova changed review comment from: Gene included previously in context of publication by Sifrim et al. (2016) (PMID: 27479907).
However, re-evaluation of this paper showed that only two of the three patients had ID, which may possibly be associated with microcephaly. The two individuals carried a c.1774G>A and c.896T>G variant, respectively; however, a third patient also harbouring the c.1774G>A variant did not display any neuropsychological signs (or microcephaly) at 4.86 years (see supplementary table 12).

A recent report (PMID: 32817298, 2020) describes two additional unrelated cases with de novo variants, c.1774G>C and c.1808G>A, respectively. These patients shared cardiac and ectodermal abnormalities, as with the previously described patients; however, mental development was normal in both individuals.; to: Gene included previously in context of publication by Sifrim et al. (2016) (PMID: 27479907).
However, re-evaluation of this paper showed that only two of the three patients had ID, which may possibly be associated with microcephaly. The two individuals carried a c.1774G>A and c.896T>G variant, respectively; however, a third patient also harbouring the c.1774G>A variant did not display any neuropsychological signs (or microcephaly) at 4.86 years (see supplementary table 12, and figure 3).

A recent report (PMID: 32817298, 2020) describes two additional unrelated cases with de novo variants, c.1774G>C and c.1808G>A, respectively. These patients shared cardiac and ectodermal abnormalities, as with the previously described patients; however, mental development was normal in both individuals.
Intellectual disability v3.369 PRKD1 Arina Puzriakova Added comment: Comment on list classification: This gene has been flagged for review at the date of next GMS panel update (added 'for-review' tag).

Only 2/5 patients exhibit features of ID, both of whom were also the only microcephalic cases, indicating the possibility of additional contributing factors. Therefore, a rating downgrade from Green to Amber may be warranted.
Intellectual disability v3.367 PRKD1 Arina Puzriakova reviewed gene: PRKD1: Rating: AMBER; Mode of pathogenicity: None; Publications: 27479907, 32817298; Phenotypes: Congenital heart defects and ectodermal dysplasia, 617364; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.367 CUL3 Arina Puzriakova Phenotypes for gene: CUL3 were changed from to Global developmental delay; Intellectual disability; Autism Spectrum Disorder; Seizures; Abnormality of cardiovascular system morphology; Abnormality of the palate; Pseudohypoaldosteronism, type IIE, 614496
Intellectual disability v3.364 CUL3 Arina Puzriakova Added comment: Comment on list classification: Upgraded from Red to Amber, as some cases reported with severe features of ID but not yet reaching the threshold for inclusion. Additional cases/publications would also enable clarification regarding the contribution of seizures to this phenotype.
Intellectual disability v3.363 CUL3 Arina Puzriakova commented on gene: CUL3: Literature search showed that CUL3 variants are often found in ASD patients, however the association with ID is much less discernible. Only two cases reported to date with severe ID features, but the same two individuals were also the only ones to present early-onset seizures. Therefore, it is difficult to distinguish whether these findings were independent of one another.
Intellectual disability v3.363 CUL3 Arina Puzriakova changed review comment from: - PMID: 25969726 (2015) - Determined as a candidate gene following discovery of a de novo missense variant (c.2156A>G, p.H719R) in an autistic patient with mild ID, sleep disturbances and ADHD.; to: - PMID: 25969726 (2015) - Determined as a candidate gene following discovery of a de novo missense variant (c.2156A>G, p.H719R) in an autistic patient with mild ID, sleep disturbances, ADHD, and no seizures. No functional analysis was undertaken.
Intellectual disability v3.363 NHP2 Arina Puzriakova Added comment: Comment on list classification: Rating upgraded from Red to Amber as 2/3 cases described in literature present cognitive impairment. This does not yet meet the threshold for inclusion with a Green rating, but may be reviewed if further cases are published.
Intellectual disability v3.362 NHP2 Arina Puzriakova Phenotypes for gene: NHP2 were changed from Dyskeratosis congenita, autosomal recessive 2, 613987 to Dyskeratosis congenita, autosomal recessive 2, 613987; Høyeraal-Hreidarsson syndrome
Intellectual disability v3.360 SETD1A Zerin Hyder reviewed gene: SETD1A: Rating: GREEN; Mode of pathogenicity: None; Publications: 32346159; Phenotypes: Epilepsy, early-onset, with or without developmental delay, craniofacial dysmorphisms, behavioural/psychiatric abnormalities; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.360 CYP2U1 Eleanor Williams Added comment: Comment on list classification: Leaving this gene as green for now, but after consultation with the Genomics England clinical team it was felt that it should be considered for downgrade to amber at the next GMS review. It is a spastic paraplegia gene and seems to mainly present in that manner. Amber rating would be appropriate as cognitive impairment is a feature and new cases may emerge which support that as a primary presentation.
Intellectual disability v3.356 NUP188 Arina Puzriakova Added comment: Comment on list classification: At least six unrelated families exhibiting a strikingly similar phenotype due to biallelic truncating variants in the NUP188 gene. Only 1/8 individuals survived beyond the first year of life and exhibited severe ID.

It is anticipated that other surviving patients would likely present the same phenotype; however, for now NUP188 will be rated Amber on the ID panel, awaiting further publications to corroborate the relevance of this manifestation.
Intellectual disability v3.355 INTS6 Arina Puzriakova Added comment: Comment on list classification: The Red review by Konstantinos Varvagiannis supports the current Red rating of CPD. There is currently no evidence to support this gene-disease association, and therefore have kept rating as Red.
Intellectual disability v3.354 CPD Arina Puzriakova Added comment: Comment on list classification: The Red review by Konstantinos Varvagiannis supports the current Red rating of CPD. There is currently no evidence to support this gene-disease association, and therefore have kept rating as Red.
Intellectual disability v3.352 KDM6B Arina Puzriakova Phenotypes for gene: KDM6B were changed from Neurodevelopmental disorder with coarse facies and mild distal skeletal abnormalities, 618505 to Neurodevelopmental disorder with coarse facies and mild distal skeletal abnormalities, 618505
Intellectual disability v3.352 KDM6B Arina Puzriakova Phenotypes for gene: KDM6B were changed from AUTOSOMAL RECESSIVE MENTAL RETARDATION to Neurodevelopmental disorder with coarse facies and mild distal skeletal abnormalities, 618505
Intellectual disability v3.349 KDM6B Arina Puzriakova reviewed gene: KDM6B: Rating: GREEN; Mode of pathogenicity: None; Publications: 31124279; Phenotypes: Neurodevelopmental disorder with coarse facies and mild distal skeletal abnormalities, 618505; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.349 HADH Arina Puzriakova Added comment: Comment on list classification: As ID is a secondary finding, reported in only a subset of patients, this gene should be downgraded from Green to Amber/Red at the next major review.
Intellectual disability v3.337 AHCY Arina Puzriakova Added comment: Comment on list classification: DD may occasionally be mild, however is an early and consistent finding amongst surviving patients. Inclusion on this panel may benefit detection of patients who would otherwise not be considered for testing via other routes (e.g. where metabolic abnormalities become apparent later).

Therefore, recommending a GREEN rating at the next major review.
Intellectual disability v3.336 AHCY Arina Puzriakova commented on gene: AHCY: Added 'treatable' tag as some patients have shown improvement following dietary management (particularly methionine restriction and supplementation with creatine and phosphatidylcholine)
Intellectual disability v3.335 CYP2U1 Eleanor Williams reviewed gene: CYP2U1: Rating: AMBER; Mode of pathogenicity: None; Publications: 23176821; Phenotypes: Spastic paraplegia 56, autosomal recessive, 615030; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.333 AGPS Arina Puzriakova Added comment: Comment on list classification: Though some relevant phenotypic features have been reported, the relationship with ID is not clear from literature. Patients are more likely to be recognised in context of the skeletal phenotype.

Therefore, suggesting a rating downgrade from Green to Amber at the next major review.
Intellectual disability v3.332 UPF3B Arina Puzriakova reviewed gene: UPF3B: Rating: GREEN; Mode of pathogenicity: None; Publications: 32667670; Phenotypes: Mental retardation, X-linked, syndromic 14, 300676; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability v3.331 STAT1 Arina Puzriakova changed review comment from: Following discussion with the clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark; to: Following discussion with the clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark and Konstantinos Varvagiannis
Intellectual disability v3.331 RASA1 Arina Puzriakova changed review comment from: Following discussion with the clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark; to: Following discussion with the clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark and Konstantinos Varvagiannis
Intellectual disability v3.330 ABCC6 Arina Puzriakova changed review comment from: Following discussion with the clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark; to: Following discussion with the clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark and Konstantinos Varvagiannis
Intellectual disability v3.330 RAD50 Arina Puzriakova changed review comment from: Comment on list classification: Borderline ID in second patient (at age 15 estimated IQ: 85). Therefore, keeping rating Red awaiting further cases to clarify the relevance of ID to the overall phenotype. ; to: Comment on list classification: Note uncertainty regarding ID in the first patient - PMID:1887849 states 'lack of mental retardation', while a later report PMID:19409520 describes 'mild to moderate retardation of psychomotor development'. ID was borderline in the second patient (at age 15 estimated IQ: 85).

Therefore, keeping rating Red awaiting further cases to clarify the relevance of ID to the phenotype associated with RAD50 variants.
Intellectual disability v3.330 RAD50 Arina Puzriakova changed review comment from: Comment on list classification: Borderline ID in second patient (at age 15 estimated IQ: 85). Therefore, keeping rating Red awaiting further cases to ascertain the contribution of RAD50 variants to an ID phenotype.; to: Comment on list classification: Borderline ID in second patient (at age 15 estimated IQ: 85). Therefore, keeping rating Red awaiting further cases to clarify the relevance of ID to the overall phenotype.
Intellectual disability v3.328 RAD50 Arina Puzriakova Added comment: Comment on list classification: Borderline ID in second patient (at age 15 estimated IQ: 85). Therefore, keeping rating Red awaiting further cases to ascertain the contribution of RAD50 variants to an ID phenotype.
Intellectual disability v3.327 WASHC4 Arina Puzriakova Phenotypes for gene: WASHC4 were changed from Mental retardation, autosomal recessive 43, MIM #615817 to Mental retardation, autosomal recessive 43, 615817
Intellectual disability v3.325 WASHC4 Arina Puzriakova reviewed gene: WASHC4: Rating: ; Mode of pathogenicity: None; Publications: 21498477, 31953988; Phenotypes: Mental retardation, autosomal recessive 43, 615817; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.325 AFG3L2 Arina Puzriakova Phenotypes for gene: AFG3L2 were changed from SPINOCEREBELLAR ATAXIA 28 to Spastic ataxia 5, autosomal recessive, 614487
Intellectual disability v3.324 AFG3L2 Arina Puzriakova Added comment: Comment on list classification: This gene should be downgraded from Green to Red at the next major review, in accordance with the review by Zornitza Stark.
Intellectual disability v3.321 LRP5 Sarah Leigh Added comment: Comment on mode of inheritance: Other phenotypes associated with LRP5 variants (https://www.omim.org/entry/603506?search=LRP5&highlight=lrp5#geneMap) have monoallelic inheritance, however, these phenotypes are not relevant for this panel as ID has not been reported.
Intellectual disability v3.319 TRAK1 Arina Puzriakova Phenotypes for gene: TRAK1 were changed from to Epileptic encephalopathy, early infantile, 68, 618201
Intellectual disability v3.316 TRAK1 Arina Puzriakova changed review comment from: Comment on list classification: Rating Amber - with ID seemingly following seizures, and being in association with a single recurrent variant, there is currently insufficient evidence to say that variants in this gene cause ID. This may, however, be reviewed if new evidence emerges.

All cases have presented with seizures which should be an adequate indication for diagnostic testing (this gene is rated Green on the Genetic epilepsy syndromes (v2.152) panel).; to: Comment on list classification: Rating Amber - with ID seemingly following seizures, and being in association with a single recurrent variant, TRAK1 currently does not meet the threshold to say that variants cause ID. This may, however, be reviewed if new evidence emerges.

All cases have presented with seizures which should be an adequate indication for diagnostic testing (this gene is rated Green on the Genetic epilepsy syndromes (v2.152) panel).
Intellectual disability v3.316 TRAK1 Arina Puzriakova Added comment: Comment on list classification: Rating Amber - with ID seemingly following seizures, and being in association with a single recurrent variant, there is currently insufficient evidence to say that variants in this gene cause ID. This may, however, be reviewed if new evidence emerges.

All cases have presented with seizures which should be an adequate indication for diagnostic testing (this gene is rated Green on the Genetic epilepsy syndromes (v2.152) panel).
Intellectual disability v3.315 TRAK1 Arina Puzriakova reviewed gene: TRAK1: Rating: ; Mode of pathogenicity: None; Publications: 28940097, 28364549, 29846532; Phenotypes: Epileptic encephalopathy, early infantile, 68, 618201; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.315 ZMYM2 Konstantinos Varvagiannis gene: ZMYM2 was added
gene: ZMYM2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: ZMYM2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ZMYM2 were set to 32891193
Phenotypes for gene: ZMYM2 were set to Abnormality of the urinary system; Global developmental delay; Intellectual disability; Microcephaly; Abnormality of the cardiovascular system; Autism; Seizures; Abnormality of the head or neck; Abnormality of the nail; Small hand; Short foot; Clinodactyly
Penetrance for gene: ZMYM2 were set to unknown
Review for gene: ZMYM2 was set to AMBER
Added comment: Heterozygous pathogenic (pLoF) ZMYM2 variants have been reported in individuals with syndromic presentation including CAKUT (in several cases) and variable neurological manifestations among extra-renal features. DD and ID were reported in some of the families described to date as summarized below. You might consider inclusion with green/amber rating in the ID panel and green in the panel for CAKUT.

--

Connaughton et al (2020 - PMID: 32891193) report on 19 individuals (from 15 unrelated families) with heterozygous pathogenic ZMYM2 variants. [Article not reviewed in detail].

Affected individuals from 7 families presented with CAKUT while all of them displayed extra-renal features. Neurological manifestations were reported in 16 individuals from 14 families (data not available for 1 fam), among others hypotonia (3/14 fam), speech delay (4/14 fam), global DD (9/14 fam), ID (4/14 fam), microcephaly (4/14 fam). ASD was reported in 4 fam (4 indiv). Seizures were reported in 2 fam (2 indiv). Variable other features included cardiac defects, facial dysmorphisms, small hands and feet with dys-/hypo-plastic nails and clinodactyly.

14 pLoF variants were identified, in most cases as de novo events (8 fam). In 2 families the variant was inherited from an affected parent. Germline mosaicism occurred in 1 family.

The human disease features were recapitulated in a X. tropicalis morpholino knockdown, with expression of truncating variants failing to rescue renal and craniofacial defects. Heterozygous Zmym2-deficient mice also recapitulated the features of CAKUT.

ZMYM2 (previously ZNF198) encodes a nuclear zinc finger protein localizing to the nucleus (and PML nuclear body).

It has previously been identified as transcriptional corepressor interacting with nuclear receptors and the LSD1-CoREST-HDAC1 complex. It has also been shown to interact with FOXP transcription factors.

The authors provide evidence for loss of interaction of the truncated ZMYM2 with FOXP1 (mutations in the latter having recently been reported in syndromic CAKUT).
Sources: Literature
Intellectual disability v3.315 DHX37 Arina Puzriakova changed review comment from: Comment on list classification: There is enough evidence to rate this gene GREEN at the next major review - at least 6 unrelated cases with ID associated with variants in this gene.; to: Comment on list classification: There is enough evidence to rate this gene GREEN at the next major review - at least 6 unrelated cases with ID associated with variants in this gene (albeit association with monoallelic variants in 2 cases warrants further investigation).
Intellectual disability v3.315 DHX37 Arina Puzriakova Added comment: Comment on list classification: There is enough evidence to rate this gene GREEN at the next major review - at least 6 unrelated cases with ID associated with variants in this gene.
Intellectual disability v3.314 DHX37 Arina Puzriakova reviewed gene: DHX37: Rating: GREEN; Mode of pathogenicity: None; Publications: 26539891, 31256877; Phenotypes: Neurodevelopmental disorder with brain anomalies and with or without vertebral or cardiac anomalies, 618731; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.314 LMNB1 Konstantinos Varvagiannis gene: LMNB1 was added
gene: LMNB1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: LMNB1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: LMNB1 were set to 32910914
Phenotypes for gene: LMNB1 were set to Global developmental delay; Intellectual disability; Microcephaly; Short stature; Seizures; Abnormality of the corpus callosum; Cortical gyral simplification; Feeding difficulties; Scoliosis
Penetrance for gene: LMNB1 were set to unknown
Mode of pathogenicity for gene: LMNB1 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: LMNB1 was set to GREEN
Added comment: Cristofoli et al (2020 - PMID: 32910914) report 7 individuals (from 5 families) harboring mostly de novo LMNB1 variants.

The common phenotype consisted of primary microcephaly (7/7 ranging from -4.4 to -10 SD), DD/ID (7/7), relative short stature in most (+0.7 to -4 SD). Additional features included brain MRI abnormalities (abnormal CC in 3, simplified gyral pattern in 3, small structurally normal brain, etc), seizures (4 individuals from 2 families), limb spasticity (1/7), cortical visual impairment (in 3), feeding difficulties (5/7), scoliosis (4/7). Non-overlapping dysmorphic features were reported in some.

Variants were identified by WES or custom-designed gene panel and included 3 missense variants, 1 in-frame deletion and a splice variant. The in-frame deletion was inherited from a similarly affected parent in whom the variant occurred as a dn event. The splice SNV(NM_005573.3:c.939+1G>A) occurred in 3 sibs and was present as mosaic variant (15%) in the parent. This variant was predicted to result to extension of exon 5 by 6 amino-acids (samples were unavailable for mRNA studies).

LMNB1 encodes a B-type lamin (the other being encoded by LMNB2). A- and B- type lamins are major components of the nuclear lamina. As the authors comment, LMNB1 is expressed in almost all cell types beginning at the earliest stages of development.

Lamin-deficient mouse models support an essential role of B-type lamins in organogenesis, neuronal migration, patterning during brain development.

Functional studies performed, demonstrated impaired formation of LMNB1 nuclear lamina in LMNB1-null HeLa cells transfected with cDNAs for 3 missense variants.

Two variants (Lys33Glu/Arg42Trp) were shown to result in decreased nuclear localization with increased abundance in the cytosolic fraction. In patient derived LCLs these variants led to abnormal nuclear morphology. A missense variant in another domain (Ala152Gly - 1st coil domain) resulted also in lower abundance of lamin B1, irregular lamin A/C nuclear lamina, as well as more condensed nuclei (HeLa cells).

LMNB1 duplications or missense mutations increasing LMNB1 expression are associated with a different presentation of AD leuodystrophy. A variant previously associated with leukodystrophy (Arg29Trp) was shown to behave differently (present in the nuclear extract but not in the cytosol, lamin B1 to A/C ratio in nuclear extract was not significantly altered compared to wt as was the case for Arg42Trp, Lys33Glu).

Given the pLI score of 0.55 as well as the phenotype of individuals with deletions (not presenting microcephaly) the authors predict that a dominant-negative effect applies (rather than haploinsufficiency).

Consider inclusion in the following panels : DD/ID (green), epilepsy (amber - 4 of 7 patients belonging to 2 families), primary microcephaly (green), callosome (amber/green - 3 individuals belonging to 3 families), mendeliome (green), etc.
Sources: Literature
Intellectual disability v3.313 CAMK2G Arina Puzriakova Phenotypes for gene: CAMK2G were changed from to Mental retardation, autosomal dominant 59, 618522
Intellectual disability v3.312 CAMK2G Arina Puzriakova Mode of pathogenicity for gene: CAMK2G was changed from to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Intellectual disability v3.311 CAMK2G Arina Puzriakova Added comment: Comment on list classification: Rating has been upgraded from Red to Amber based on the review by Konstantinos Varvagiannis - two unrelated individuals with severe ID, associated with de novo CAMK2G variants, with addition of functional data.
Intellectual disability v3.310 FIBP Arina Puzriakova Added comment: Comment on list classification: Rating upgraded from Red to Amber based on review by Zornitza Stark.
Intellectual disability v3.304 VAMP1 Arina Puzriakova Added comment: Comment on list classification: Literature search revealed that developmental delay primarily affects motor function, and it is unclear whether patients exhibit any cognitive deficit. Additional cases would help delineate the association with this phenotype.

Therefore, recommending a rating downgrade from Green to Amber/Red at the next major review, awaiting further publications/clinical evidence.
Intellectual disability v3.303 TRIM32 Arina Puzriakova Phenotypes for gene: TRIM32 were changed from BARDET-BIEDL SYNDROME TYPE 11 (BBS11) to Bardet-Biedl syndrome 11, 615988
Intellectual disability v3.301 TRIM32 Arina Puzriakova Added comment: Comment on list classification: Recommended Green-to-Red rating downgrade on the next major review - only one family reported to date for association with BBS. Currently also Red on the Bardet-Biedl Syndrome (Version 1.5) gene panel.
Intellectual disability v3.300 VARS2 Arina Puzriakova Classified gene: VARS2 as Amber List (moderate evidence)
Intellectual disability v3.300 VARS2 Arina Puzriakova Added comment: Comment on list classification: There is enough evidence to rate this gene GREEN at the next major review - >3 unrelated families with different variants. Severe psychomotor delay was an early and significant manifestation on clinical evaluation.
Intellectual disability v3.300 VARS2 Arina Puzriakova Gene: vars2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.299 VARS2 Arina Puzriakova Tag for-review tag was added to gene: VARS2.
Intellectual disability v3.299 SUCLA2 Arina Puzriakova Added comment: Comment on list classification: Although sufficient number of cases with relevant clinical presentation, psychomotor delay is a component of a broader phenotype. Patients are more likely to be recognised via other routes (Metabolic/White Matter Disorders/Mitochondrial) - SUCLA2 is already Green on these PanelApp panels.

Therefore, rating Amber on the ID panel.
Intellectual disability v3.295 ELN Arina Puzriakova changed review comment from: Following discussion with the clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark; to: Following discussion with the clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark and Konstantinos Varvagiannis.
Intellectual disability v3.295 ATP1A3 Zornitza Stark edited their review of gene: ATP1A3: Added comment: Four additional individuals with dystonia, dysmorphism, encephalopathy with developmental delay, brain MRI abnormalities always including cerebellar hypoplasia, no hemiplegia, and neonatal onset. All had de novo missense variants. All are described to have global developmental delay, hence supporting upgrade in rating on this panel.; Changed rating: GREEN; Changed publications: https://doi.org/10.1212/NXG.0000000000000466; Changed phenotypes: Alternating hemiplegia of childhood 2, MIM#614820, Neurodevelopmental disorder; Set current diagnostic: yes
Intellectual disability v3.295 WASHC4 Zornitza Stark gene: WASHC4 was added
gene: WASHC4 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: WASHC4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: WASHC4 were set to 31953988; 21498477
Phenotypes for gene: WASHC4 were set to Mental retardation, autosomal recessive 43, MIM #615817
Review for gene: WASHC4 was set to GREEN
gene: WASHC4 was marked as current diagnostic
Added comment: Three unrelated families reported.
Sources: Literature
Intellectual disability v3.295 ATP1A2 Sarah Leigh edited their review of gene: ATP1A2: Added comment: Associated with phenotype in OMIM and in G2P for MIGRAINE, FAMILIAL HEMIPLEGIC, ATP1A2-related. Three variants associated with congnitive impairment in 2/7 and 1/5 members of two families with Migraine, familial hemiplegic, 2 602481. At least 12 variants have been reported in Migraine, familial hemiplegic, 2 602481 families (PMID 15159495). An additional variant was reported in a case of Alternating hemiplegia of childhood 1, 104290 with impared cognitive function (PMID 29610157).; Changed rating: GREEN
Intellectual disability v3.294 TNR Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to rate this gene GREEN at the next major review - at least 7 unrelated cases with cognitive impairment associated with variants in this gene.
Intellectual disability v3.293 EARS2 Sarah Leigh Tag for-review tag was added to gene: EARS2.
Intellectual disability v3.293 EARS2 Sarah Leigh edited their review of gene: EARS2: Added comment: There is enough evidence for this gene to be rated GREEN at the next major review.; Changed rating: GREEN
Intellectual disability v3.293 EARS2 Sarah Leigh changed review comment from: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 15 variants reported in at least 12 unrelated cases, with variable degrees of psycomotor motor delay or regression and little or no language.; to: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 14 variants reported in at least 11 unrelated cases, with variable degrees of psycomotor motor delay or regression and little or no language.
Intellectual disability v3.293 EARS2 Sarah Leigh Publications for gene: EARS2 were set to 22492562
Intellectual disability v3.292 EARS2 Sarah Leigh changed review comment from: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 14 variants reported in at least 11 unrelated cases, with variable degrees of psycomotor motor delay or regression and little or no language.; to: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 15 variants reported in at least 12 unrelated cases, with variable degrees of psycomotor motor delay or regression and little or no language.
Intellectual disability v3.292 EARS2 Sarah Leigh Classified gene: EARS2 as Amber List (moderate evidence)
Intellectual disability v3.292 EARS2 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 14 variants reported in at least 11 unrelated cases, with variable degrees of psycomotor motor delay or regression and little or no language.
Intellectual disability v3.292 EARS2 Sarah Leigh Gene: ears2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.289 SLC12A2 Arina Puzriakova changed review comment from: Comment on list classification: There is sufficient evidence to rate this gene GREEN at the next major review - at least three unrelated cases presenting a relevant phenotype in association with biallelic variants in SLC12A2.; to: Comment on list classification: There is sufficient evidence to rate this gene GREEN at the next major review - at least nine unrelated cases presenting a relevant phenotype in association with variants in SLC12A2.
Intellectual disability v3.289 SLC12A2 Arina Puzriakova changed review comment from: - PMID: 28940097 (2017) - SLC12A2 first identified as a novel candidate gene in a 3.3-year-old male with GDD, failure to thrive, hypotonia, microcephaly, neonatal respiratory distress, recurrent aspiration pneumonia, and osteopenia. Sequencing revealed a homozygous variant (c.2617-2A>G) that segregated within the family.

- PMID: 30740830 (2019) - Homozygous 22kb deletion identified in a 5-year-old male with GDD, sensorineural hearing loss, gastrointestinal abnormalities, early postnatal respiratory distress, generalised hypotonia, and absent salivation. Neuropsychological testing demonstrated profound delays in all developmental areas, with skills ranging from 1 to 6 months. The deletion was the result of uniparental paternal isodisomy.

Functional studies using patient-derived fibroblasts showed truncated SLC12A2 transcripts and markedly reduced protein levels compared to control. Knockout mouse model recapitulated phenotypic features such as deafness, abnormal neuronal growth and migration, gastrointestinal abnormalities, and absent salivation.

- PMID: 32754646 (2020) - Compound heterozygous variants (c.1431delT and c.2006-1G>A) were identified in two sibs. The proband, an 8-year-old girl, presented a severe neurodevelopmental disorder (including severe ID), hearing impairment, gastrointestinal problems, hypotonia, and absent tear fluid, saliva, and sweat. Phenotypic overlap was noted in an affected older sister, who died at 22 days of age.; to: - PMID: 28940097 (2017) - SLC12A2 first identified as a novel candidate gene in a 3.3-year-old male with GDD, failure to thrive, hypotonia, microcephaly, neonatal respiratory distress, recurrent aspiration pneumonia, and osteopenia. Sequencing revealed a homozygous variant (c.2617-2A>G) that segregated within the family.

- PMID: 30740830 (2019) - Homozygous 22kb deletion identified in a 5-year-old male with GDD, sensorineural hearing loss, gastrointestinal abnormalities, early postnatal respiratory distress, generalised hypotonia, and absent salivation. Neuropsychological testing demonstrated profound delays in all developmental areas, with skills ranging from 1 to 6 months. The deletion was the result of uniparental paternal isodisomy.

Functional studies using patient-derived fibroblasts showed truncated SLC12A2 transcripts and markedly reduced protein levels compared to control. Knockout mouse model recapitulated phenotypic features such as deafness, abnormal neuronal growth and migration, gastrointestinal abnormalities, and absent salivation.

- PMID: 32754646 (2020) - Compound heterozygous variants (c.1431delT and c.2006-1G>A) were identified in two sibs. The proband, an 8-year-old girl, presented a severe neurodevelopmental disorder (including severe ID), hearing impairment, gastrointestinal problems, hypotonia, and absent tear fluid, saliva, and sweat. Phenotypic overlap was noted in an affected older sister, who died at 22 days of age.

- PMID: 32658972 (2020) - Six unrelated children, all with mild-severe ID/DD, associated with de novo variants in SLC12A2. Additional clinical features included bilateral sensorineural hearing loss (2/6), abnormalities on brain MRI (2/4), and cerebral palsy (2/6). Some functional data in Xenopus laevis oocytes, indicating a role of SLC12A2 in neurogenesis.
Intellectual disability v3.289 DHX37 Zornitza Stark gene: DHX37 was added
gene: DHX37 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: DHX37 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: DHX37 were set to 26539891; 31256877
Phenotypes for gene: DHX37 were set to Neurodevelopmental disorder with brain anomalies and with or without vertebral or cardiac anomalies, MIM#618731
Review for gene: DHX37 was set to GREEN
gene: DHX37 was marked as current diagnostic
Added comment: Overall, 5 unrelated families with bi-allelic variants, all with ID as part of the phenotype. Green for bi-allelic disease

Much less clear association between mono-allelic variants and ID, two missense variants reported. Note one was mosaic, and for the other, paternal sample was not available, so not confirmed to be de novo. No mechanism for mono-allelic vs bi-allelic disease proposed. Overall, Red for mono-allelic variants causing a neurodevelopmental phenotype at this stage. Note there is a separate association between mono allelic variants and DSD.
Sources: Literature
Intellectual disability v3.288 SLC12A2 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to rate this gene GREEN at the next major review - at least three unrelated cases presenting a relevant phenotype in association with biallelic variants in SLC12A2.
Intellectual disability v3.286 HNRNPH1 Arina Puzriakova changed review comment from: Comment on list classification: Two studies report de novo variants in at least 7 unrelated cases with moderate-severe GDD/ID.; to: Comment on list classification: There is enough evidence to rate this gene GREEN at the next major review - two studies report de novo variants in at least 7 unrelated cases with moderate-severe GDD/ID.
Intellectual disability v3.286 HNRNPH1 Arina Puzriakova Added comment: Comment on list classification: Two studies report de novo variants in at least 7 unrelated cases with moderate-severe GDD/ID.
Intellectual disability v3.285 HARS Arina Puzriakova commented on gene: HARS: Added new-gene-name tag, new approved HGNC gene symbol for HARS is HARS1
Intellectual disability v3.285 HARS Arina Puzriakova Tag new-gene-name tag was added to gene: HARS.
Intellectual disability v3.285 HARS Arina Puzriakova Classified gene: HARS as Amber List (moderate evidence)
Intellectual disability v3.285 HARS Arina Puzriakova Gene: hars has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.284 CCDC88A Arina Puzriakova Added comment: Comment on list classification: This gene has been upgraded from Red to Amber based on the external reviews by Konstantinos Varvagiannis and Zornitza Stark.
Intellectual disability v3.283 CCDC174 Arina Puzriakova Added comment: Comment on list classification: Rating Red as only one founder variant reported to-date in a single publication - currently no evidence that other variants in this gene are disease-causing.

Added 'founder-effect' tag
Intellectual disability v3.281 TRAPPC2L Arina Puzriakova Added comment: Comment on list classification: Rating Amber as additional cases required to delineate the genotype-phenotype relationship. Total of three families, but two share a founder variant, and there are some disparities between the clinical presentations reported in the two publications.
Intellectual disability v3.280 TRAPPC2L Arina Puzriakova gene: TRAPPC2L was added
gene: TRAPPC2L was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: TRAPPC2L was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TRAPPC2L were set to 30120216; 32843486
Phenotypes for gene: TRAPPC2L were set to Encephalopathy, progressive, early-onset, with episodic rhabdomyolysis, 618331
Review for gene: TRAPPC2L was set to AMBER
Added comment: Gene is associated with Encephalopathy, progressive, early-onset, with episodic rhabdomyolysis in OMIM, but not in G2P.

PMID: 30120216 (2018) - Two unrelated probands with an identical 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.

The mutant protein was expressed in patient fibroblasts, but displayed membrane trafficking delays. Studies in yeast showed that the variant impaired interaction with TRAPPC10, and increased levels of the active RAB11.


PMID: 32843486 (2020) - In an 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.

Comparable to the previous study, the variant resulted in delayed ER-to-Golgi trafficking and elevated levels of active RAB11. Studies using yeast and in vitro binding, showed that the variant disrupted interaction with another core TRAPP protein, TRAPPC6a.
Sources: Literature
Intellectual disability v3.276 ADARB1 Arina Puzriakova Publications for gene: ADARB1 were set to 32220291
Intellectual disability v3.275 ADARB1 Arina Puzriakova Phenotypes for gene: ADARB1 were changed from Intellectual disability; microcephaly; seizures to Neurodevelopmental disorder with hypotonia, microcephaly, and seizures, 618862
Intellectual disability v3.274 ADARB1 Arina Puzriakova edited their review of gene: ADARB1: Added comment: PMID: 32719099 (2020) - Three additional patients from two consanguineous families with novel biallelic variants in the ADARB1 gene. All affected individuals presented global DD, severe-profound ID, intractable early infantile-onset seizures, severe microcephaly, axial hypotonia and progressive appendicular spasticity. In vitro RNA editing assays showed that both variants resulted in severe impairment or loss of ADAR2 enzymatic activity.; Changed publications: 32220291, 32719099
Intellectual disability v3.274 HARS Zornitza Stark edited their review of gene: HARS: Changed publications: 32333447
Intellectual disability v3.273 TKFC Arina Puzriakova Phenotypes for gene: TKFC were changed from Developmental delay; cataracts; liver dysfunction to Triokinase and FMN cyclase deficiency syndrome, 618805
Intellectual disability v3.270 RAP1GDS1 Arina Puzriakova Added comment: Comment on list classification: The same variant identified in two families from the region, indicating a possible founder effect. Therefore rated Red as there is not currently enough evidence that other variants in the RAP1GDS1 gene are disease causing.
Intellectual disability v3.269 PDCD6IP Arina Puzriakova Added comment: Comment on list classification: Phenotype is relevant to this panel but additional cases required to validate pathogenicity of variants in this gene.
Intellectual disability v3.268 TUBGCP2 Arina Puzriakova changed review comment from: Comment on list classification: Although the phenotype is relevant for this panel, additional cases would help determine the aetiology of the ID presentation. This gene has been added to other panels (Malformations of cortical development/Epilepsy), in view of which these patients are more likely to be recognised.

Rating Amber, awaiting further publications (added to watchlist).; to: Comment on list classification: Although the phenotype is relevant for this panel, additional cases would help determine the aetiology of the ID presentation. This gene has been added to other panels (Malformations of cortical development/Epilepsy/Microcephaly), in view of which these patients are more likely to be recognised.

Rating Amber, awaiting further publications (added to watchlist).
Intellectual disability v3.268 TUBGCP2 Arina Puzriakova Added comment: Comment on list classification: Although the phenotype is relevant for this panel, additional cases would help determine the aetiology of the ID presentation. This gene has been added to other panels (Malformations of cortical development/Epilepsy), in view of which these patients are more likely to be recognised.

Rating Amber, awaiting further publications (added to watchlist).
Intellectual disability v3.268 TUBGCP2 Arina Puzriakova Added comment: Comment on list classification: Although the phenotype is relevant for this panel, additional cases would help determine the aetiology of the ID presentation. This gene has been added to other panels (Malformations of cortical development/Epilepsy), in view of which these patients are more likely to be recognised.

Rating Amber, awaiting further publications (added to watchlist).
Intellectual disability v3.267 PPP1R12A Arina Puzriakova Phenotypes for gene: PPP1R12A were changed from Intellectual disability; holoprosencephaly; disorder of sex development to Genitourinary and/or/brain malformation syndrome, 618820
Intellectual disability v3.266 PPP1R12A Arina Puzriakova Added comment: Comment on list classification: There is enough evidence to rate this gene GREEN at the next major review - DD reported in at least 7 unrelated patients with PPP1R12A variants.
Intellectual disability v3.265 PPP1R12A Arina Puzriakova changed review comment from: PMID: 31883643 (2020) - Screening cohorts of patients with holoprosencephaly and patients with disorders of sex development revealed 12 unrelated individuals with de novo LoF variants in the PPP1R12A gene. Variants were associated with a broad spectrum of manifestations, and a clear genotype-phenotype correlation was not observed - most commonly presentation included either malformations of the brain or the genitourinary tract (two individuals exhibited both brain and genitourinary anomalies). 7/12 individuals exhibited developmental delay, which warrants inclusion on this panel.; to: Associated with phenotype in OMIM, and a probable gene for PPP1R12A-related Holoprosencephaly Spectrum and Urogenital Malformations in G2P.

PMID: 31883643 (2020) - Screening cohorts of patients with holoprosencephaly and patients with disorders of sex development revealed 12 unrelated individuals with de novo LoF variants in the PPP1R12A gene. Variants were associated with a broad spectrum of manifestations, and a clear genotype-phenotype correlation was not observed - most commonly presentation included either malformations of the brain or the genitourinary tract (two individuals exhibited both brain and genitourinary anomalies). 7/12 individuals exhibited developmental delay, which warrants inclusion on this panel.
Intellectual disability v3.265 PPP1R12A Arina Puzriakova reviewed gene: PPP1R12A: Rating: GREEN; Mode of pathogenicity: None; Publications: 31883643; Phenotypes: Genitourinary and/or/brain malformation syndrome, 618820; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.264 TRNT1 Arina Puzriakova Added comment: Comment on list classification: There is enough evidence to rate this gene GREEN at the next major review - sufficient number of cases with (mild-profound) developmental delay, associated with biallelic variants in TRNT1.
Intellectual disability v3.262 KAT5 Konstantinos Varvagiannis reviewed gene: KAT5: 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: 32822602; Phenotypes: Severe global developmental delay, Intellectual disability, Seizures, Microcephaly, Behavioral abnormality, Sleep disturbance, Morphological abnormality of the central nervous system, Short stature, Oral cleft, Abnormality of the face; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.262 LMBRD2 Konstantinos Varvagiannis gene: LMBRD2 was added
gene: LMBRD2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: LMBRD2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: LMBRD2 were set to 32820033; https://doi.org/10.1101/797787
Phenotypes for gene: LMBRD2 were set to Global developmental delay; Intellectual disability; Microcephaly; Seizures; Abnormality of nervous system morphology; Abnormality of the eye
Penetrance for gene: LMBRD2 were set to unknown
Review for gene: LMBRD2 was set to AMBER
Added comment: You may consider inclusion with green (13 individuals with dn missense SNVs overall, overlapping features for 10 with available phenotype / a recurring variant has been identified in 2 different studies) or amber rating (role of the gene not known, no variant studies, animal model probably not available).

► Malhotra et al (2020 - PMID: 32820033) report on 10 unrelated individuals with de novo missense LMBRD2 variants.

Features included DD (9/10), ID (6/8 of relevant age), microcephaly (7/10), seizures (5/10 - >=3 different variants), structural brain abnormalities (e.g. thin CC in 6/9), highly variable ocular abnormalities (5/10) and dysmorphic features in some (7/10 - nonspecific).

All had variable prior non-diagnostic genetic tests (CMA, gene panel, mendeliome, karyotype). WES/WGS revealed LMBRD2 missense variants, in all cases de novo. A single individual had additional variants with weaker evidence of pathogenicity.

5 unique missense SNVs and 2 recurrent ones (NM_001007527:c.367T>C - p.Trp123Arg / c.1448G>A - p.Arg483His) were identified. These occurred in different exons. Variants were not present in gnomAD and all had several in silico predictions in favor of a deleterious effect.

There was phenotypic variability among individuals with the same variant (e.g. seizures in 1/3 and microchephaly in 2/3 of those harboring R483H).

The gene has a pLI of 0 (although o/e ranges from 0.23 to 0.55), %HI of 15.13 and z-score of 2.27. The authors presume that haploinsufficiency may not apply, and consider a gain-of-function/dominant-negative effect more likely.

As the authors comment LMBRD2 (LMBR1 domain containing 2) encodes a membrane bound protein with poorly described function. It is widely expressed across tissues with notable expression in human brain (also in Drosophila, or Xenopus laevis). It displays high interspecies conservation.

It has been suggested (Paek et al - PMID: 28388415) that LMBRD2 is a potential regulator of β2 adrenoreceptor signalling through involvement in GPCR signalling.

► Kaplanis et al (2020 - https://doi.org/10.1101/797787) in a dataset of 31058 parent-offspring trios (WES) previously identified 3 individuals with developmental disorder, harboring c.1448G>A - p.Arg483His. These individuals (1 from the DDD study, and 2 GeneDx patients) appear in Decipher. [ https://decipher.sanger.ac.uk/ddd/research-variant/40e17c78cc9655a6721006fc1e0c98db/overview ]. The preprint by Kaplanis et al is cited by Malhotra et al, with Arg483His reported in 6 patients overall in both studies.
Sources: Literature
Intellectual disability v3.262 SPOP Arina Puzriakova changed review comment from: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.

Associated with Nabais Sa-de Vries syndrome in OMIM, and a probable gene for SPOP-related Neurodevelopmental Disorder in G2P.

At least 7 unrelated individuals with mild-severe ID, associated with de novo missense variants in the SPOP gene. Additional variable features include craniofacial dysmorphisms, cardiovascular abnormalities, hearing impairment, and endocrine abnormalities. Functional studies show differing effects of the variants (gain-of-function or dominant-negative) that correspond to the different clinical manifestations.; to: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.

Associated with Nabais Sa-de Vries syndrome in OMIM, and a probable gene for SPOP-related Neurodevelopmental Disorder in G2P.

At least 7 unrelated individuals with mild-severe ID, associated with de novo missense variants in the SPOP gene. Additional variable features include craniofacial dysmorphisms, cardiovascular abnormalities, hearing impairment, and endocrine abnormalities. Functional studies show differing effects of the variants (gain-of-function or dominant-negative) that correspond to differences in additional clinical manifestations.
Intellectual disability v3.262 TASP1 Arina Puzriakova Added comment: Comment on list classification: Sufficient cases for a GREEN rating at the next major review.

Associated with phenotype in OMIM, and a possible gene for Developmental delay, happy demeanor, distinctive facial features, and congenital anomalies in G2P.

Four unrelated patients with homozygous LOF variants in this gene all exhibited a consistent phenotype which included global developmental delay. All variants segregated with disease, but no functional studies of the variants or patient cells were not performed.
Intellectual disability v3.260 SPOP Arina Puzriakova Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.

Associated with Nabais Sa-de Vries syndrome in OMIM, and a probable gene for SPOP-related Neurodevelopmental Disorder in G2P.

At least 7 unrelated individuals with mild-severe ID, associated with de novo missense variants in the SPOP gene. Additional variable features include craniofacial dysmorphisms, cardiovascular abnormalities, hearing impairment, and endocrine abnormalities. Functional studies show differing effects of the variants (gain-of-function or dominant-negative) that correspond to the different clinical manifestations.
Intellectual disability v3.258 POMK Arina Puzriakova Added comment: Comment on list classification: Sufficient cases to support causation; however, ID is unlikely to be the main presenting feature of this phenotype - therefore, rating Amber on this panel.

POMK is rated Green on other relevant panels including Congenital muscular dystrophy, Hydrocephalus, and Arthrogryposis.
Intellectual disability v3.257 PISD Arina Puzriakova Added comment: Comment on list classification: Four families presenting a DD/ID phenotype, but three share the same founder variant - Rating Amber until further cases are reported (added to watchlist).
Intellectual disability v3.256 PISD Arina Puzriakova reviewed gene: PISD: Rating: ; Mode of pathogenicity: None; Publications: 31263216, 30858161, 30488656, 3561949; Phenotypes: Liberfarb syndrome, 618889; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.256 PIBF1 Arina Puzriakova Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review - at least 7 families (4 with same founder variant) with Joubert syndrome, which is associated with global DD/ID.
Intellectual disability v3.255 TAF1C Konstantinos Varvagiannis gene: TAF1C was added
gene: TAF1C was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: TAF1C was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TAF1C were set to 32779182
Phenotypes for gene: TAF1C were set to Global developmental delay; Intellectual disability; Spasticity; Strabismus; Seizures; Abnormality of nervous system morphology
Penetrance for gene: TAF1C were set to Complete
Review for gene: TAF1C was set to AMBER
Added comment: Knuutinen et al (2020 - PMID: 32779182) report on 2 individuals from 2 consanguineous families, homozygous for TAF1C missense variants.

Both presented with an early onset neurological phenotype with severe global DD, ID (2/2 - moderate and profound), spasticity (2/2), ophthalmic findings (strabismus 2/2, nystagmus 1/2). Epilepsy, abnormal brain MRI (cerebral and cerebellar atrophy and white matter hyperintensities) as well and additional findings were reported in one (always the same individual).

Following a normal CMA, exome in the first case revealed a homozygous missense SNV (NM_005679.3:c.1165C>T / p.Arg389Cys) supported by in silico predictions. mRNA and protein levels were substantially reduced in fibroblasts from this subject. Only the patient and parents were tested for the variant but not 3 unaffected sibs (fig1).

The second individual was homozygous for another missense variant (p.Arg405Cys) also supported by in silico predictions. The girl was the single affected person within the family with an unaffected sib and parents heterozygous for the variant. Several other unaffected relatives in the extended pedigree were either carriers for this variant or homozygous for the wt allele.

TAF1C encodes the TATA-box binding protein associated factor (TAF) RNA polymerase I subunit.

RNA polymerase I (Pol I) transcribes genes to produce rRNA. For Pol I to initiate transcription, two transcription factors are required : UBF (upstream binding factor encoded by UBTF) and SL1 (selectivity factor 1). The latter is formed by TBP (TATA-binding protein) and 3 Pol I-specific TBP-associated factors (TAFs).

A recurrent de novo missense variant in UBTF (encoding the other Pol I transcription factor) causes a disorder with highly similar features. The specific variant acts through a gain-of-function mechanism (and not by LoF which appears to apply for TAF1C based on expression data).

The authors hypothesize that altered Pol I activity and resulting ribosomal stress could cause the microcephaly and leukodystrophy (both reported in 1 - the same - individual).

As a result, TAF1C may be considered for inclusion in the ID panel with amber rating pending further evidence.
Sources: Literature
Intellectual disability v3.254 STAR Arina Puzriakova commented on gene: STAR
Intellectual disability v3.251 ERMARD Arina Puzriakova commented on gene: ERMARD
Intellectual disability v3.250 ARHGEF6 Arina Puzriakova commented on gene: ARHGEF6
Intellectual disability v3.247 PDP1 Arina Puzriakova Added comment: Comment on list classification: Rating Amber, given the mild delay in psychomotor development seen in these patients. This gene is Green on other panels which are more relevant to the phenotype.
Intellectual disability v3.244 CNTNAP1 Sarah Leigh changed review comment from: Comment on list classification: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least four variants reported four unrelated cases of Lethal congenital contracture syndrome 7 616286 and seven variants reported in four cases of Hypomyelinating neuropathy, congenital, 3 618186. Both of these conditions include intellectual disability.; to: Comment on list classification: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene for Lethal congenital contracture syndrome 7 61628. At least four variants reported four unrelated cases of Lethal congenital contracture syndrome 7 616286 and seven variants reported in four cases of Hypomyelinating neuropathy, congenital, 3 618186. Both of these conditions include intellectual disability.
Intellectual disability v3.244 CNTNAP1 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least four variants reported four unrelated cases of Lethal congenital contracture syndrome 7 616286 and seven variants reported in four cases of Hypomyelinating neuropathy, congenital, 3 618186. Both of these conditions include intellectual disability.
Intellectual disability v3.242 B9D2 Sarah Leigh edited their review of gene: B9D2: Added comment: Three variants were reported in two unrelated cases of Joubert syndrome 34, which includes intellectual impairment, together with supportive functional studies (PMID 21763481).; Changed rating: GREEN
Intellectual disability v3.242 B9D2 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least five variants reported in four unrelated cases. Three of the variants were reported in two unrelated cases of Joubert syndrome 34, which includes intellectual impairment and the remaining three variants were found in two unrelated fetuses with Meckel syndrome 10, with brain malformations.
Intellectual disability v3.241 B9D2 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least five variants reported in four unrelated cases. Three of the variants were reported in two unrelated cases of Joubert syndrome 34, which includes intellectual impairment and the remaining three variants were found in two unrelated fetuses with Meckel syndrome 10, with brain malformations.
Intellectual disability v3.239 MADD Konstantinos Varvagiannis reviewed gene: MADD: Rating: GREEN; Mode of pathogenicity: None; Publications: 28940097, 29302074, 32761064; Phenotypes: Global developmental delay / Intellectual disability / Seizures, Global developmental delay / Intellectual disability / Seizures / Abnormality of the endocrine system / Exocrine pancreatic insufficiency / Constipation / Diarrhea / Anemia / Thrombocytopenia / Abnormality of the autonomic nervous system; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.239 FAM50A Konstantinos Varvagiannis gene: FAM50A was added
gene: FAM50A was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: FAM50A 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: FAM50A were set to 32703943
Phenotypes for gene: FAM50A were set to Mental retardation syndrome, X-linked, Armfield type (MIM #300261)
Penetrance for gene: FAM50A were set to unknown
Review for gene: FAM50A was set to GREEN
Added comment: Lee et al (2020 - PMID: 32703943) provide evidence that Armfield X-Linked intellectual disability syndrome is caused by monoallelic FAM50A pathogenic variants. The current review is based only on this reference.

The authors provide clinical details on 6 affected individuals from 5 families.

Features included postnatal growth delay, DD and ID (6/6 - also evident for those without formal IQ assesment), seizures (3/6 from 2 families), prominent forehead with presence of other facial features and variable head circumference (5th to >97th %le), ocular anomalies (5/6 - strabismus/nystagmus/Axenfeld-Rieger), cardiac (3/6 - ASD/Fallot) and genitourinary anomalies (3/6).

In the first of these families (Armfield et al 1999 - PMID: 10398235), linkage analysis followed by additional studies (Sanger, NGS of 718 genes on chrX, X-exome NGS - several refs provided) allowed the identification of a FAM50A variant. Variants in other families were identified by singleton (1 fam) or trio-ES (3 fam).

In affected individuals from 3 families, the variant had occurred de novo. Carrier females in the other families were unaffected (based on pedigrees and/or the original publication). XCI was rather biased in most obligate carrier females from the 1st family (although this ranged from 95:5 to 60:40).

Missense variants were reported in all affected subjects incl. Trp206Gly, Asp255Gly, Asp255Asn (dn), Glu254Gly (dn), Arg273Trp (dn) (NM_004699.3).

Previous studies have demonstrated that FAM50A has ubiquitous expression in human fetal and adult tissues (incl. brain in fetal ones).

Immunostaining suggests a nuclear localization for the protein (NIH/3T3 cells). Comparison of protein levels in LCLs from affected males and controls did not demonstrate significant differences. Protein localization for 3 variants (transfection of COS-7 cells) was shown to be similar to wt.

Complementation studies in zebrafish provided evidence that the identified variants confer partial loss of function (rescue of the morpholino phenotype with co-injection of wt but not mt mRNA). The zebrafish ko model seemed to recapitulate the abnormal development of cephalic structures and was indicative of diminished/defective neurogenesis. Transcriptional dysregulation was demonstrated in zebrafish (altered levels and mis-splicing). Upregulation of spliceosome effectors was demonstrated in ko zebrafish.

Similarly, mRNA expression and splicing defects were demonstrated in LCLs from affected individuals. FAM50A pulldown followed by mass spectrometry in transfected HEK293T cells demonstrated enrichment of binding proteins involved in RNA processing and co-immunoprecipitation assays (transfected U-87 cells) suggested that FAM50A interacts with spliceosome U5 and C-complex proteins.

Overall aberrant spliceosome C-complex function is suggested as the underlying pathogenetic mechanism.

Several other neurodevelopmental syndromes are caused by variants in genes encoding C-complex affiliated proteins (incl. EFTUD2, EIF4A3, THOC2, etc.).

Please consider inclusion in the ID panel with green rating and epilepsy panel with amber (seizures in individuals from 2 families).
Sources: Literature
Intellectual disability v3.239 TET3 Sarah Leigh changed review comment from: Comment on list classification: Associated with relevant phenotype including mild to severe intellectual disability in OMIM and as probable Gen2Phen gene for TET3 DNA Demethylation Disorder biallelic and TET3 DNA Demethylation Disorder monoallelic. At least 9 variants reported in total, with 5 variants associated with the biallelic version of the condition in 3 unrelated cases and 4 variants associated with the monoallelic version in 4 unrelated cases.; to: Comment on list classification: Associated with relevant phenotype OMIM and as probable Gen2Phen gene for TET3 DNA Demethylation Disorder biallelic and TET3 DNA Demethylation Disorder monoallelic. At least 9 variants reported in total, with 5 variants associated with the biallelic version of the condition in 3 unrelated cases and 4 variants associated with the monoallelic version in 4 unrelated cases. Mild to severe intellectual disability was reported in 2 unrelated cases of monoallelic and 2 unrelated cases of biallelic 2 cases TET3 DNA Demethylation Disorder.
Intellectual disability v3.239 TET3 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype including mild to severe intellectual disability in OMIM and as probable Gen2Phen gene for TET3 DNA Demethylation Disorder biallelic and TET3 DNA Demethylation Disorder monoallelic. At least 9 variants reported in total, with 5 variants associated with the biallelic version of the condition in 3 unrelated cases and 4 variants associated with the monoallelic version in 4 unrelated cases.
Intellectual disability v3.238 TET3 Sarah Leigh Added comment: Comment on phenotypes: This recognized as TET3 DNA Demethylation Disorder biallelic and TET3 DNA Demethylation Disorder monoallelic in Gen2Phen (https://www.ebi.ac.uk/gene2phenotype/search?panel=ALL&search_term=TET3#).
Intellectual disability v3.236 SUZ12 Sarah Leigh Phenotypes for gene: SUZ12 were changed from Overgrowth; Global developmental delay; Intellectual disability; Accelerated skeletal maturation; Abnormality of the skeletal system; Abnormality of the genitourinary system; Abnormality of the corpus callosum; Abnormality of the respiratory system; Abnormality of the abdominal wall to Imagawa-Matsumoto syndrome 618786
Intellectual disability v3.235 SUZ12 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least 5 variants reported in at least 13 affected individuals from 12 families, of whome 7 had mostly mild intellectual disability.
Intellectual disability v3.234 OXR1 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene for Autosomal-Recessive Neurological Disease with Cerebellar Atrophy and Lysosomal Dysfunction. At least 4 variants reported in at least 3 unrelated cases, who all had epilepsy and global developmental delay.
Intellectual disability v3.234 OXR1 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene for Autosomal-Recessive Neurological Disease with Cerebellar Atrophy and Lysosomal Dysfunction. At least 4 variants reported in at least 3 unrelated cases, who all had epilepsy and global developmental delay.
Intellectual disability v3.232 OXR1 Sarah Leigh Phenotypes for gene: OXR1 were changed from Central hypotonia; Global developmental delay; Delayed speech and language development; Intellectual disability; Seizures; Abnormality of the cerebellum to Cerebellar hypoplasia/atrophy, epilepsy, and global developmental delay 213000
Intellectual disability v3.230 SFXN4 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 5 variants reported in at least 3 unreleated cases, with mild to severe intellectual disability.
Intellectual disability v3.228 MTHFS Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 4 variants reported in at least 3 unrelated cases.
Intellectual disability v3.227 YARS Sarah Leigh Added comment: Comment on phenotypes: Monoallelic variants are associated with Charcot-Marie-Tooth disease, dominant intermediate C 608323, while biallelic variants are associated with a complex phenotype that may include intellectual disability, hearing loss and liver damage.
Intellectual disability v3.227 YARS Sarah Leigh Phenotypes for gene: YARS were changed from Intellectual disability; deafness; nystagmus; liver dysfunction to Charcot-Marie-Tooth disease, dominant intermediate C 608323; Intellectual disability; deafness; nystagmus; liver dysfunction
Intellectual disability v3.226 YARS Sarah Leigh Tag watchlist tag was added to gene: YARS.
Intellectual disability v3.226 PIGQ Konstantinos Varvagiannis reviewed gene: PIGQ: Rating: GREEN; Mode of pathogenicity: None; Publications: 32588908, 24463883, 25558065, 31148362; Phenotypes: Epileptic encephalopathy, early infantile, 77 (MIM #618548); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.225 FARSB Arina Puzriakova Classified gene: FARSB as Amber List (moderate evidence)
Intellectual disability v3.225 FARSB Arina Puzriakova Added comment: Comment on list classification: Rating Amber following consultation with the clinical team in view of the inconsistent phenotype. Patients are more likely to be recognised on the basis of other phenotypic features, for which FARSB has been rated Green
Intellectual disability v3.225 FARSB Arina Puzriakova Gene: farsb has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.224 FARSB Arina Puzriakova reviewed gene: FARSB: Rating: AMBER; Mode of pathogenicity: None; Publications: 29573043, 29979980, 30014610; Phenotypes: Rajab interstitial lung disease with brain calcifications, 613658; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.224 IREB2 Arina Puzriakova Added comment: Comment on list classification: Phenotype is appropriate for this panel, but additional cases necessary to support causation. Therefore rated Amber, awaiting further publications/clinical evidence (added to watchlist).
Intellectual disability v3.223 CHD1 Arina Puzriakova changed review comment from: Gene is associated with Pilarowski-Bjornsson syndrome in OMIM, but not in G2P.

Pilarowski et al (2018) (PMID: 28866611) reported heterozygous missense variants in five individuals (two sibs and three singletons) as the cause of developmental delay, speech apraxia, hypotonia, and facial dysmorphic features. Two variants were confirmed de novo, while segregation for others could not be determined (including the two sibs who were conceived by egg donor). Developmental delay was noted for all participants; however, ID was only reported in the two sibs.; to: Gene is associated with Pilarowski-Bjornsson syndrome in OMIM, but not in G2P.

Pilarowski et al (2018) (PMID: 28866611) reported heterozygous missense variants in five individuals (two sibs and three singletons) as the cause of developmental delay, speech apraxia, hypotonia, and facial dysmorphic features. Two variants were confirmed de novo, while segregation for others could not be determined (including the two sibs who were conceived by egg donor). Developmental delay was noted for all participants; however, ID was only reported in the two sibs. Further insight may be gained from re-evaluation of the two patients in the present study who were too young for a formal neurocognitive evaluation at the time of publication.
Intellectual disability v3.222 PAM16 Arina Puzriakova Added comment: Comment on list classification: Three unrelated cases, but two share the same founder mutation - Rating Amber until further cases are reported (added to watchlist).
Intellectual disability v3.221 PAM16 Arina Puzriakova reviewed gene: PAM16: Rating: ; Mode of pathogenicity: None; Publications: 24786642, 27354339; Phenotypes: Spondylometaphyseal dysplasia, Megarbane-Dagher-Melike type, 613320; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.220 NDUFA2 Arina Puzriakova reviewed gene: NDUFA2: Rating: GREEN; Mode of pathogenicity: None; Publications: 18513682, 28857146, 32154054; Phenotypes: Mitochondrial complex I deficiency, nuclear type 13, 618235; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.219 NDUFAF1 Arina Puzriakova reviewed gene: NDUFAF1: Rating: ; Mode of pathogenicity: None; Publications: 17557076, 21931170, 24963768; Phenotypes: Mitochondrial complex I deficiency, nuclear type 11, 618234; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.219 NARS Konstantinos Varvagiannis changed review comment from: [Please note that HGNC Approved Gene Symbol for this gene is NARS1]

Manole et al (2020 - PMID: 32738225) provide evidence that both biallelic and monoallelic (de novo) pathogenic NARS1 variants cause a neurodevelopmental disorder. In total 32 individuals from 21 families are reported, with biallelic variants identified in individuals from 13 families and de novo in 8 families.

Similar features were reported for AR/AD occurrences of the disorder and included of microcephaly (90% - most often primary), epilepsy (23/32 or 74% - variable semiology incl. partial/myoclonic/generalized tonic-clonic seizures), DD and ID (as a universal feature), abnormal tone in several (hypotonia/spasticity), ataxia, demyelinating peripheral neuropathy (in 3 or more for each inheritance mode - or a total of 25%). Some individuals had dysmorphic features.

NARS1 encodes an aminoacyl-tRNA synthetase (ARS) [asparaginyl-tRNA synthetase 1]. Aminoacyl-tRNA synthetases constitute a family of enzymes catalyzing attachment of amino-acids to their cognate tRNAs. As the authors comment, mutations in genes encoding several other ARSs result in neurological disorders ranging from peripheral neuropathy to severe multi-systemic NDD. Dominant, recessive or both modes for inheritance for mutations in the same gene (e.g. AARS1, YARS1, MARS1, etc) have been reported.

Some variants were recurrent, e.g. the c.1600C>T / p.Arg534* which occurred in 6 families as a de novo event or c.1633C>T p.Arg545Cys (homozygous in 6 families). 3 different variants were reported to have occured de novo (c.965G>T - p.Arg322Leu, c.1525G>A - p.Gly509Ser, p.Arg534*) with several other variants identified in hmz/compound htz individuals. A single SNV (c.1067A>C - p.Asp356Ala) was suggested to be acting as modifier and pathogenic only when in trans with a severe variant. [NM_004539.4 used as RefSeq for all].

The authors provide several lines of evidence for a partial loss-of-function effect (e.g. reduction in mRNA expression, enzyme levels and activity in fibroblasts or iNPCs) underlying pathogenicity of the variants identified in individuals with biallelic variants. A gain-of-function (dominant-negative) effect is proposed for de novo variants (such effect also demonstrated for the p.Arg534* in a zebrafish model).

As also Manole et al suggest, NARS1 can be considered for inclusion in gene panels for DD/ID, epilepsy and/or demyelinating neuropathy.
Sources: Literature; to: [Please note that HGNC Approved Gene Symbol for this gene is NARS1]

Manole et al (2020 - PMID: 32738225) provide evidence that both biallelic and monoallelic (de novo) pathogenic NARS1 variants cause a neurodevelopmental disorder. In total 32 individuals from 21 families are reported, with biallelic variants identified in individuals from 13 families and de novo in 8 families.

Similar features were reported for AR/AD occurrences of the disorder and included microcephaly (90% - most often primary), epilepsy (23/32 or 74% - variable semiology incl. partial/myoclonic/generalized tonic-clonic seizures), DD and ID (as a universal feature), abnormal tone in several (hypotonia/spasticity), ataxia, demyelinating peripheral neuropathy (in 3 or more for each inheritance mode - or a total of 25%). Some individuals had dysmorphic features.

NARS1 encodes an aminoacyl-tRNA synthetase (ARS) [asparaginyl-tRNA synthetase 1]. Aminoacyl-tRNA synthetases constitute a family of enzymes catalyzing attachment of amino-acids to their cognate tRNAs. As the authors comment, mutations in genes encoding several other ARSs result in neurological disorders ranging from peripheral neuropathy to severe multi-systemic NDD. Dominant, recessive or both modes for inheritance for mutations in the same gene (e.g. AARS1, YARS1, MARS1, etc) have been reported.

Some variants were recurrent, e.g. the c.1600C>T / p.Arg534* which occurred in 6 families as a de novo event or c.1633C>T p.Arg545Cys (homozygous in 6 families). 3 different variants were reported to have occured de novo (c.965G>T - p.Arg322Leu, c.1525G>A - p.Gly509Ser, p.Arg534*) with several other variants identified in hmz/compound htz individuals. A single SNV (c.1067A>C - p.Asp356Ala) was suggested to be acting as modifier and pathogenic only when in trans with a severe variant. [NM_004539.4 used as RefSeq for all].

The authors provide several lines of evidence for a partial loss-of-function effect (e.g. reduction in mRNA expression, enzyme levels and activity in fibroblasts or iNPCs) underlying pathogenicity of the variants identified in individuals with biallelic variants. A gain-of-function (dominant-negative) effect is proposed for de novo variants (such effect also demonstrated for the p.Arg534* in a zebrafish model).

As also Manole et al suggest, NARS1 can be considered for inclusion in gene panels for DD/ID, epilepsy and/or demyelinating neuropathy.
Sources: Literature
Intellectual disability v3.219 NARS Konstantinos Varvagiannis gene: NARS was added
gene: NARS was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: NARS was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: NARS were set to 32738225
Phenotypes for gene: NARS were set to Abnormal muscle tone; Microcephaly; Global developmental delay; Intellectual disability; Seizures; Ataxia; Abnormality of the face; Demyelinating peripheral neuropathy
Penetrance for gene: NARS were set to Complete
Review for gene: NARS was set to GREEN
Added comment: [Please note that HGNC Approved Gene Symbol for this gene is NARS1]

Manole et al (2020 - PMID: 32738225) provide evidence that both biallelic and monoallelic (de novo) pathogenic NARS1 variants cause a neurodevelopmental disorder. In total 32 individuals from 21 families are reported, with biallelic variants identified in individuals from 13 families and de novo in 8 families.

Similar features were reported for AR/AD occurrences of the disorder and included of microcephaly (90% - most often primary), epilepsy (23/32 or 74% - variable semiology incl. partial/myoclonic/generalized tonic-clonic seizures), DD and ID (as a universal feature), abnormal tone in several (hypotonia/spasticity), ataxia, demyelinating peripheral neuropathy (in 3 or more for each inheritance mode - or a total of 25%). Some individuals had dysmorphic features.

NARS1 encodes an aminoacyl-tRNA synthetase (ARS) [asparaginyl-tRNA synthetase 1]. Aminoacyl-tRNA synthetases constitute a family of enzymes catalyzing attachment of amino-acids to their cognate tRNAs. As the authors comment, mutations in genes encoding several other ARSs result in neurological disorders ranging from peripheral neuropathy to severe multi-systemic NDD. Dominant, recessive or both modes for inheritance for mutations in the same gene (e.g. AARS1, YARS1, MARS1, etc) have been reported.

Some variants were recurrent, e.g. the c.1600C>T / p.Arg534* which occurred in 6 families as a de novo event or c.1633C>T p.Arg545Cys (homozygous in 6 families). 3 different variants were reported to have occured de novo (c.965G>T - p.Arg322Leu, c.1525G>A - p.Gly509Ser, p.Arg534*) with several other variants identified in hmz/compound htz individuals. A single SNV (c.1067A>C - p.Asp356Ala) was suggested to be acting as modifier and pathogenic only when in trans with a severe variant. [NM_004539.4 used as RefSeq for all].

The authors provide several lines of evidence for a partial loss-of-function effect (e.g. reduction in mRNA expression, enzyme levels and activity in fibroblasts or iNPCs) underlying pathogenicity of the variants identified in individuals with biallelic variants. A gain-of-function (dominant-negative) effect is proposed for de novo variants (such effect also demonstrated for the p.Arg534* in a zebrafish model).

As also Manole et al suggest, NARS1 can be considered for inclusion in gene panels for DD/ID, epilepsy and/or demyelinating neuropathy.
Sources: Literature
Intellectual disability v3.219 ZNF407 Konstantinos Varvagiannis gene: ZNF407 was added
gene: ZNF407 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: ZNF407 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: ZNF407 were set to 24907849; 32737394; 23195952
Phenotypes for gene: ZNF407 were set to Global developmental delay; Intellectual disability
Penetrance for gene: ZNF407 were set to unknown
Review for gene: ZNF407 was set to AMBER
Added comment: You may consider inclusion of this gene probably with amber rating (or green if the evidence for biallelic variants is considered sufficient).

Biallelic variants:

- Kambouris et al. (2014 - PMID: 24907849) described 2 brothers with severe DD and ID, born to first cousin parents. Homozygosity mapping, following other non-diagnostic investigations (incl. aCGH), revealed 4 major homozygosity intervals. Exome sequencing in one identified 5 variants within these intervals, ZNF407 (c.5054C>G, p.Ser1685Trp) being the best candidate, supported also by segregation studies. The authors commented that zinc finger proteins act as transcriptional regulators, with mutations in genes encoding for other zinc finger proteins interfering with normal brain development.

- Zahra et al. (2020 - PMID: 32737394) report on 7 affected individuals (from 3 families) homozygous or compound heterozygous for ZNF407 variants. Features included hypotonia, DD and ID (in all) and variable occurrence of short stature (6/6), microcephaly (in at least 5), behavioural, visual problems and deafness. Linkage analysis in the first family revealed a 4.4 Mb shared homozygosity region and exome (30x) revealed a 3-bp duplication, confirmed by Sanger sequencing and segregating with the disease (NM_001146189:c.2814_2816dup, p.Val939dup). Affected subjects from the 2 other families were each found to be homozygous (c.2405G>T) or compound heterozygous (c.2884C>G, c.3642G>C) for other variants. Segregation was compatible in all families. Other studies were not performed. The authors comment than only the 3-bp duplication fulfilled ACMG criteria for classification as LP, the other variants being all formally classified as VUS (also due to in silico predictions predicting a LB effect). In addition, while several features such as DD/ID and short stature appeared to be frequent among all patients reported, Zahra et all comment that there was partial clinical overlap with the sibs described by Kambouris et al (additional variants?).


Monoallelic disruption of ZNF407:

- Ren et al (2013 - PMID: 23195952) described an 8 y.o. boy with ID and ASD. The boy was found to harbor a de novo translocation between chromosomes 3 and 18 [46,XY,t(3;18)(p13;q22.3)]. Array CGH did not reveal any P/LP CNV. Delineation of the breakpoints (FISH, long-range PCR) revealed that the chr18 breakpoint disrupted intron 3 of ZNF407 (isoform 1) with the other breakpoint within a gene-free region of exon 3. There was a loss of 4-8 nt in chr18 and 2-6 in chr3. Sequencing of ZNF407 did not reveal additional variants. RNA isolation in blood followed by RT-PCR studied expression of all 3 ZNF407 isoforms (the intronic region being shared by isoforms 1 and 2). Expression of isoform 1 was shown to be significantly reduced compared to controls. Isoform 2 was undetectable (in blood) while isoform 3 expression was similar to controls. Sequencing of 105 additional patients with similar clinical presentation (ID & ASD) revealed 2 further individuals with de novo missense variants.

- Based on the discussion by Kambouris et al (PMID: 24907849 - cited literature not here reviewed) ZNF407 may be deleted in patients with congenital aural atresia due to deletion of a critical region of 18q22.3 (though TSHZ1 is responsible for this phenotype) or 18q- although such deletions span several other genes (cited PMID: 16639285). In one case the breakpoint was shown to be disrupting ZNF407 (cited PMID: 24092497).

- The denovo db and Decipher (research variant tab) list few individuals with de novo ZNF407 SNVs although these do not seem to allow conclusions.

https://denovo-db.gs.washington.edu/denovo-db/QueryVariantServlet?searchBy=Gene&target=ZNF407
https://decipher.sanger.ac.uk/search/ddd-research-variants/results?q=znf407
Sources: Literature
Intellectual disability v3.219 MAPK1 Konstantinos Varvagiannis gene: MAPK1 was added
gene: MAPK1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: MAPK1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: MAPK1 were set to 32721402
Phenotypes for gene: MAPK1 were set to Global developmental delay; Intellectual disability; Behavioral abnormality; Growth delay; Abnormality of the face; Abnormality of the neck; Abnormality of the cardiovascular system; Abnormality of the skin
Penetrance for gene: MAPK1 were set to unknown
Mode of pathogenicity for gene: MAPK1 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: MAPK1 was set to GREEN
Added comment: Motta et al (2020 - PMID: 32721402) report on 7 unrelated individuals harboring de novo missense MAPK1 pathogenic variants.

The phenotype corresponded to a neurodevelopmental disorder and - as the authors comment - consistently included DD, ID , behavioral problems. Postnatal growth delay was observed in approximately half. Hypertelorism, ptosis, downslant of palpebral fissures, wide nasal bridge as low-set/posteriorly rotated ears were among the facial features observed (each in 3 or more subjects within this cohort). Together with short/webbed neck and abnormalities of skin (lentigines / CAL spots) and growth delay these led to clinical suspicion of Noonan s. or disorder of the same pathway in some. Congenital heart defects (ASD, mitral valve insufficiency, though not cardiomyopathy) occurred in 4/7. Bleeding diathesis and lymphedema were reported only once.

MAPK1 encodes the mitogen-activated protein kinase 1 (also known as ERK2) a serine/threonine kinase of the RAS-RAF-MEK-(MAPK/)ERK pathway.

MAPK1 de novo variants were identified in all individuals following trio exome sequencing (and extensive previous genetic investigations which were non-diagnostic).

The distribution of variants, as well as in silico/vitro/vivo studies suggest a GoF effect (boosted signal through the MAPK cascade. MAPK signaling also upregulated in Noonan syndrome).

The authors comment that screening of 267 additional individuals with suspected RASopathy (without mutations in previously implicated genes) did not reveal other MAPK1 variants.

Overall this gene can be considered for inclusion in the ID panel with green rating.
Sources: Literature
Intellectual disability v3.219 NCAPH Arina Puzriakova Added comment: Comment on list classification: Additional cases are required to substantiate causation but added to watchlist.
Intellectual disability v3.218 NCAPH Arina Puzriakova gene: NCAPH was added
gene: NCAPH was added to Intellectual disability. Sources: Literature
watchlist tags were added to gene: NCAPH.
Mode of inheritance for gene: NCAPH was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NCAPH were set to 27737959
Phenotypes for gene: NCAPH were set to Microcephaly 23, primary, autosomal recessive, 617985
Added comment: Associated with Microcephaly 23 in OMIM and a possible gene for microcephaly in G2P.

PMID: 27737959 (2016) - A homozygous missense variant in NCAPH (c.728C>T, p.Pro243Leu) was detected in a 42-year-old male with microcephaly (OFC -4.2 SD) and moderate ID. Functional studies indicated that although the variant did not affect cellular protein levels, it disrupted condensin-dependent mitotic chromosome integrity, providing supporting evidence for pathogenicity. Biallelic variants in other genes encoding subunits of the two condensin complexes result in a similar phenotype.
Sources: Literature
Intellectual disability v3.217 NCAPG2 Arina Puzriakova Added comment: Comment on list classification: Additional cases required to ascertain the contribution of NCAPG2 variants to an ID phenotype.
Intellectual disability v3.215 NCAPD2 Arina Puzriakova reviewed gene: NCAPD2: Rating: AMBER; Mode of pathogenicity: None; Publications: 27737959, 28097321, 31056748; Phenotypes: Microcephaly 21, primary, autosomal recessive, 617983; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.215 HADHB Arina Puzriakova Added comment: Comment on list classification: Rating Amber following consultation with the clinical team, in view of the borderline ID phenotype. Cases are more likely to be recognised on the basis of the metabolic phenotype, for which this gene is Green already.
Intellectual disability v3.213 VPS51 Arina Puzriakova Added comment: Comment on list classification: Additional cases are required before inclusion of VPS51 on a diagnostic panel; however, gene added to watchlist.
Intellectual disability v3.212 VPS51 Arina Puzriakova reviewed gene: VPS51: Rating: AMBER; Mode of pathogenicity: None; Publications: 30624672, 31207318; Phenotypes: Pontocerebellar hypoplasia, type 13, 618606; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.212 LRRC32 Arina Puzriakova changed review comment from: Not associated with phenotype in OMIM or G2P.

PMID: 30976112 (2019) - homozygous stop-gain variant in LRRC32 (c.1630C>T; p.Arg544Ter) in three affected individuals from two families with global developmental delay, cleft palate, and proliferative retinopathy. In one family developmental quotient (DQ) varied from borderline low in the female (DQ = 72 at 3 years-2 months) to severely delayed in the male (DQ = 57 at 2 years-11 months). The male in the second family was even more severely delayed (DQ = 23 at 3 years-3 months).

Haplotype analysis indicates a founder effect, and therefore further cases are required to substantiate causation.; to: Not associated with phenotype in OMIM or G2P.

PMID: 30976112 (2019) - homozygous stop-gain variant in LRRC32 (c.1630C>T; p.Arg544Ter) in three affected individuals from two families with global developmental delay, cleft palate, and proliferative retinopathy. In one family developmental quotient (DQ) varied from borderline low in the female (DQ = 72 at 3 years-2 months) to severely delayed in the male (DQ = 57 at 2 years-11 months). The male in the second family was even more severely delayed (DQ = 23 at 3 years-3 months).

Haplotype analysis indicates a founder effect, and therefore further cases are required to substantiate causation (added founder-effect tag).
Intellectual disability v3.212 LRRC32 Arina Puzriakova Added comment: Comment on list classification: Rated Red as there is not currently enough evidence that other variants in the LRRC32 gene are disease causing.
Intellectual disability v3.211 LMAN2L Arina Puzriakova Added comment: Comment on list classification: Two families with ID phenotype (one mild, one severe). Amber rating as additional cases and functional data are required to validate the causal association with the phenotype.
Intellectual disability v3.210 LAMB2 Arina Puzriakova Added comment: Comment on list classification: Given the incomplete penetrance of the ID phenotype, these patients are more likely to be recognised on the basis of the renal phenotype and ocular abnormalilites - LAMB2 has a Green rating on these panels, while an Amber classification might be most appropriate for the ID panel.
Intellectual disability v3.209 EEF1A2 Eleanor Williams changed review comment from: PMID: 32160274 - Davies et al 2020 - several reports of de novo missense mutations in EEF1A2 associated with neurodevelopmental disorders but no clear loss of function mutations. They created mice with a missense mutation in EEF1A2 (D252H) in both heterozygous and homozygous state and EEF1AS null mutant mice and analysed using behavioural and motor phenotyping alongside molecular modelling and analysis of binding partners. They found the D252H homozygous mice were more severely affected than null homozygotes on the same genetic background. The results suggest that the D252H mutation results in a gain of function.; to: PMID: 32160274 - Davies et al 2020 - several reports of de novo missense mutations in EEF1A2 associated with neurodevelopmental disorders but no clear loss of function mutations. They created mice with a missense mutation in EEF1A2 (D252H) in both heterozygous and homozygous state and EEF1A2 null mutant mice and analysed using behavioural and motor phenotyping alongside molecular modelling and analysis of binding partners. They found the D252H homozygous mice were more severely affected than null homozygotes on the same genetic background. The results suggest that the D252H mutation results in a gain of function.
Intellectual disability v3.209 EEF1A2 Eleanor Williams reviewed gene: EEF1A2: Rating: ; 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: 32160274; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.209 HERC2 Arina Puzriakova Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review - more than 3 distinct variants in unrelated cases presenting the relevant phenotype.
Intellectual disability v3.208 IFT27 Arina Puzriakova Added comment: Comment on list classification: Given the mild ID phenotype, IFT27 is classified Amber on this panel. Patients are more likely to be recognised in view of other features (e.g. Limb disorders panel), for which this gene is Green.
Intellectual disability v3.207 IFT27 Arina Puzriakova reviewed gene: IFT27: Rating: AMBER; Mode of pathogenicity: None; Publications: 24488770, 30761183, 29588463; Phenotypes: Bardet-Biedl syndrome 19, 615996; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.207 HNMT Arina Puzriakova Added comment: Comment on list classification: Amber rating as additional unrelated pedigrees are required before inclusion of HNMT on a diagnostic panel (added to watchlist).
Intellectual disability v3.206 HNMT Arina Puzriakova reviewed gene: HNMT: Rating: AMBER; Mode of pathogenicity: None; Publications: 26206890; Phenotypes: Intellectual disability, Mental retardation, 616739; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.205 EXOSC8 Arina Puzriakova Added comment: Comment on list classification: Three unrelated cases, but two share the same founder mutation - Rating Amber until further cases are reported (added to watchlist).
Intellectual disability v3.204 EXOSC8 Arina Puzriakova reviewed gene: EXOSC8: Rating: AMBER; Mode of pathogenicity: None; Publications: 24989451; Phenotypes: Pontocerebellar hypoplasia type 1C, 616081; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.204 DSCR3 Arina Puzriakova Added comment: Comment on list classification: Currently not associated with any phenotype in OMIM or G2P. Variants only found in one family - additional cases required to validate pathogenicity.
Intellectual disability v3.203 ATP6AP1 Arina Puzriakova Added comment: Comment on list classification: Unclear whether other ATP6AP1 variants are associated with a neurological phenotype. Amber rating in view of the mild ID phenotype, as a more significant, or consistent pattern, of DD/ID is required (added to watchlist).
Intellectual disability v3.202 PDE10A Arina Puzriakova Added comment: Comment on list classification: Only mild cognitive delay reported in one family. Additional cases with a more significant, or consistent pattern, of DD/ID required to ascertain the contribution of PDE10A variants to an ID phenotype.
Intellectual disability v3.201 LARS Konstantinos Varvagiannis gene: LARS was added
gene: LARS was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: LARS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LARS were set to 32699352
Phenotypes for gene: LARS were set to Infantile liver failure syndrome 1, MIM# 615438
Penetrance for gene: LARS were set to Complete
Review for gene: LARS was set to GREEN
Added comment: Please consider inclusion with amber/green rating in the current panel.

Biallelic pathogenic LARS1 variants cause Infantile liver failure syndrome 1, MIM# 615438.

Lenz et al (2020 - PMID: 32699352) review the phenotype of 25 affected individuals from 15 families.

Seizures occurred in 19/24 and were commonly associated with infections. Encephalopathic episodes (in 13 patients) accompanied by seizures up to status epilepticus occurred independently of hepatic decompensation.

In addition 22/24 presented with neurodevelopmental delay. The authors comment that cognitive impairment was present in 13/17 individuals (mild-severe) whereas most presented with learning disabilities.

These patients will be most likely investigated for their liver disease (although presentation was highly variable and/or very mild in few).

The gene encodes a cytoplasmic amino-acyl tRNA synthetase (ARS) with neurologic manifestations observed in almost all patients (and seizures / DD and ID common to other disorders due to mutations in other genes encoding for ARSs).

Please note that the HGNC approved symbol for this gene is LARS1.
Sources: Literature
Intellectual disability v3.201 SMARCA2 Konstantinos Varvagiannis reviewed gene: SMARCA2: Rating: GREEN; Mode of pathogenicity: None; Publications: 32694869; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.201 MORC2 Konstantinos Varvagiannis gene: MORC2 was added
gene: MORC2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: MORC2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: MORC2 were set to https://doi.org/10.1016/j.ajhg.2020.06.013
Phenotypes for gene: MORC2 were set to Charcot-Marie-Tooth disease, axonal, type 2Z, MIM #616688
Penetrance for gene: MORC2 were set to unknown
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
Added comment: The current review is based on a recent report by Sacoto et al (2020 - https://doi.org/10.1016/j.ajhg.2020.06.013).

While several previous studies focused on the phenotype of axonal motor and senory neuropathy in individuals with heterozygous MORC2 pathogenic variants (Charcot-Marie-Tooth disease, axonal, type 2Z, MIM #616688) some of them presented among others with hypotonia, muscle weakness, intellectual disability, microcephaly or hearing loss [refs provided by Sacoto et al - learning disabilities (in some patients) also listed in OMIM's clinical synopsis].

Sacoto et al present a cohort of 20 individuals having genetic testing for developmental delay or growth failure (with a single one for a diagnosis of sensorimotor neuropathy).

Overlapping features included DD, ID (18/20 - mild to severe), short stature (18/20), microcephaly (15/20) and variable craniofacial dysmorphisms. The authors comment that features suggestive of neuropathy (weakness, hyporeflexia, abnormal EMG/NCS) were frequent but not the predominant complaint. EMG/NCS abnormalities were abnormal in 6 out of 10 subjects investigated in this cohort. Other findings included brain MRI abnormalities (12/18 - in 5/18 Leigh-like lesions), hearing loss (11/19) and pigmentary retinopathy in few (5).

Affected subjects were found to harbor in all cases missense variants in the ATPase module of MORC2 [residues 1 to 494 - NM_001303256.1 - the module consists of an ATPase domain (aa 1-265), a transducer S5-like domain (266-494) and a coiled-coiled domain (CC1 - aa 282-361)].

Variants had occured mostly as de novo events although inheritance from a similarly affected parent was also reported.

Some of them were recurring within this cohort and/or the literature eg. c.79G>A/p.Glu27Lys (x5), c.260C>T/p.Ser87Leu (x2), c.394C>T/p.Arg132Cys (4x), c.1164C>G/p.Ser388Arg (x2), c.1181A>G/p.Tyr394Cys (x3).

MORC2 encodes an ATPase involved in chromatin remodeling, DNA repair and transcriptional regulation. Chromatin remodeling and epigenetic silencing by MORC2 is mediated by the HUSH (Human Silencing Hub) complex. Functional studies (MORC2-knockout HeLa cells harboring a HUSH-sensitive GFP reporter were transduced with wt or mt MORC2 followed by measurement of reporter repression) supported the deleterious effect of most variants known at the time (hyperactivation of HUSH-mediating silencing, in line with previous observations).

Overall this gene can be considered for inclusion in the ID panel with green rating. Also other gene panels (e.g. for short stature, microcephaly, hearing loss, pigmentary retinopathy, etc) if it meets the respective criteria for inclusion.
Sources: Literature
Intellectual disability v3.201 HIST1H4J Arina Puzriakova changed review comment from: This is a possible gene for intellectual disability with facial dysmorphism in G2P.

Tessadori et al. (2020) (PMID: 31804630) reported a 14-year old Hispanic male with profound intellectual disability, who was heterozygous for a de novo (c.274 A>G, p.K91E) variant in HIST1H4J. Clinical features were said to resemble those reported in patients with HIST1H4C variants, which encodes an identical H4 protein to that of HIST1H4J. Functional data obtained in zebrafish showed the missense variant caused developmental defects, specifically resulting in defective head structures and reduced body axis length.; to: Added new-gene-name tag, new approved HGNC gene symbol is H4C11.

This is a possible gene for intellectual disability with facial dysmorphism in G2P.

Tessadori et al. (2020) (PMID: 31804630) reported a 14-year old Hispanic male with profound intellectual disability, who was heterozygous for a de novo (c.274 A>G, p.K91E) variant in HIST1H4J. Clinical features were said to resemble those reported in patients with HIST1H4C variants, which encodes an identical H4 protein to that of HIST1H4J. Functional data obtained in zebrafish showed the missense variant caused developmental defects, specifically resulting in defective head structures and reduced body axis length.
Intellectual disability v3.201 HIST1H4J Arina Puzriakova Added comment: Comment on list classification: Amber rating as additional cases are required to validate pathogenicity, but added to watchlist.
Intellectual disability v3.200 ADAMTS10 Arina Puzriakova Added comment: Comment on list classification: While mild ID is reportedly a phenotypic feature associated with Weill–Marchesani syndrome, this is not evident in the literature cases. Therefore, a more consistent and/or significant pattern of ID is necessary for inclusion of ADAMTS10 on a diagnostic ID panel.
Intellectual disability v3.199 ADAMTS10 Arina Puzriakova reviewed gene: ADAMTS10: Rating: AMBER; Mode of pathogenicity: None; Publications: 15368195, 18567016, 19836009; Phenotypes: Weill-Marchesani syndrome, 277600; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.199 TOMM70 Eleanor Williams Added comment: Comment on list classification: After consultation with the Genomics England clinical team it was decided to rate this gene as Amber for now, until a clearer phenotype is established and the predominant mode of inheritance is determined.
Intellectual disability v3.197 LZTFL1 Arina Puzriakova changed review comment from: Associated with phenotype in OMIM and probable in G2P. Biallelic variants in the LZTFL1 gene are an established cause of BBS17, with supporting functional data. Cognitive impairment is a feature of the BBS17 associated phenotype in all cases reported to date. Two families have been reported in literature - PMID: 22510444 (2012) - cognitive impairment reported in a 10-year-old BBS17 patient, harbouring a homozygous 5 bp deletion leading to a premature stop codon (c.402-406del, p.Pro136ThrfsX5) in LZTFL1.; to: Associated with phenotype in OMIM and probable in G2P.

Biallelic variants in the LZTFL1 gene are an established cause of BBS17, with supporting functional data. Cognitive impairment is a feature of the BBS17 associated phenotype in all cases reported in literature to date:

PMID: 22510444 (2012) - cognitive impairment reported in a 10-year-old BBS17 patient, harbouring a homozygous 5 bp deletion leading to a premature stop codon (c.402-406del, p.Pro136ThrfsX5) in LZTFL1.

PMID: 23692385 (2014) - cognitive impairment reported in a pair of dizygotic twins with two compound heterozygous LZTFL1 variants ([c.260T>C, p.Leu87Pro];[c.778G>T, p.Glu260*]). One twin was said to have learning difficulties since childhood. She attended a specialised school, and at the age of 36, her educational level was equivalent to the elementary school level. The second twin was also reported to have scholastic difficulties and slowness with an educational level equivalent to primary school.
Intellectual disability v3.196 LYRM7 Arina Puzriakova changed review comment from: PMID: 24014394 (2013) - Homozygous variant (c.73G>A) in LYRM7 identified in a patient with normal initial development until the first 20 months of life, when she presented rapid deterioration which included severe psychomotor regression. Functional studies performed in yeast indicate functional impairment. PMID: 26912632 (2016) - Six distinct homozygous variants in the LYRM7 gene were identified in seven affected individuals (including 2 sibs). Initial cognitive development was delayed in three patients and borderline in one.; to: PMID: 24014394 (2013) - Homozygous variant (c.73G>A) in LYRM7 identified in a patient with normal initial development until the first 20 months of life, when she presented rapid deterioration which included severe psychomotor regression. Functional studies performed in yeast indicate functional impairment.

PMID: 26912632 (2016) - Six distinct homozygous variants in the LYRM7 gene were identified in seven affected individuals (including 2 sibs). Initial cognitive development was delayed in three patients and borderline in one. Continued development was delayed to variable degrees in five individuals, and all were said to have impaired intelligence at the time of the most recent assessment (aged 2.5-16 yrs).

PMID: 28694194 (2017) - Three affected family members with homozygosity for a splice site deletion (c.243_244+2delGAGT) in LYRM7. Development was normal for the first few months of life, however all experienced a rapidly progressive clinical course which included profound impairment of psychomotor and mental functions.
Intellectual disability v3.195 LIPT1 Arina Puzriakova changed review comment from: Associated with phenotype in OMIM and probable for Leigh syndrome with secondary deficiency for pyruvate and alpha-ketoglutarate dehydrogenase in G2P. LIPT1 deficiency, resulting from bi-allelic variants, is associated with developmental delay, epilepsy, and broad metabolic abnormalities. To date, five unrelated families have been reported with at least one affected child. PMID: 24341803 (2013) - In a boy with LIPT1 deficiency, exome sequencing revealed two heterozygous mutations (c.875C>G and c.535A>G). Psychomotor development was delayed from birth, but sudden further regression occurred at 18 months.; to: Associated with phenotype in OMIM and probable for Leigh syndrome with secondary deficiency for pyruvate and alpha-ketoglutarate dehydrogenase in G2P.

LIPT1 deficiency, resulting from biallelic variants, is associated with developmental delay, epilepsy, and broad metabolic abnormalities. To date, five unrelated families have been reported with at least one affected child.

PMID: 24341803 (2013) - In a boy with LIPT1 deficiency, exome sequencing revealed two compound heterozygous variants (c.875C>G and c.535A>G). Psychomotor development was delayed from birth, but sudden further regression occurred at 18 months. He could not speak but understood simple orders. He was otherwise fully conscious, alert, and he could smile, laugh and follow with eyes. Supporting functional data, including a yeast model.

PMID: 29681092 (2018) – Compound heterozygous variants (c.212C>T and c.539T>C) identified in a male with seizures, severe lactic acidosis, and failure to thrive. Initially he was reportedly developmentally normal; however, due to subsequent neurodevelopmental regression, he had global developmental delays by 21-months-of-age.

PMID 31042466 (2019) – In an 8-year-old female with developmental delay, seizures, and lactic acidosis, WES revealed two compound heterozygous variants (c.875C>G, c.131A>G). Two older sibs died of a similar condition at 7 months and 3 years. Sequencing was not possible in these individuals; however, a healthy sibling did not carry either variant. Functional analysis in patient-derived fibroblasts and mice confirmed LIPT1 deficiency.

In two unrelated families, the phenotype resulted in early infant death, and therefore ID could not be assessed:
PMID: 24256811 (2014) – compound heterozygous missense variants (c.212C>T and c.292C>G) were identified in a female that died on the ninth day of life.
PMID: 27247813 (2016) – compound heterozygous nonsense variants (c.806G>A and c.980T>G) detected in two sibs who both died on the first day of life. A third sibling, who did not harbour these variants, was healthy and thriving at 12 months of life.
Intellectual disability v3.193 KLF7 Arina Puzriakova changed review comment from: Not associated with phenotype in OMIM or G2P. Powis et al. (2018) PMID: 29251763 - Heterozygous de novo missense variants were reported in four unrelated individuals. The two females (aged 15 and 16) were both said to have ID; while the two males (aged 2 and 4) had cognitive delay - though ID had not been formally assessed, presumably due to age. Additional features also included motor and speech delay, hypotonia, and neuromuscular symptoms.; to: Not associated with phenotype in OMIM or G2P.

Powis et al. (2018) PMID: 29251763 - Heterozygous de novo missense variants were reported in four unrelated individuals. The two females (aged 15 and 16) were both said to have ID; while the two males (aged 2 and 4) had cognitive delay - though ID had not been formally assessed, presumably due to age. Additional features also included motor and speech delay, hypotonia, and neuromuscular symptoms.
Intellectual disability v3.193 KCNN3 Arina Puzriakova Added comment: Comment on mode of pathogenicity: Gain-of-function variants identified in all patients, reported to date.
Intellectual disability v3.193 KCNN3 Arina Puzriakova Mode of pathogenicity for gene: KCNN3 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
Intellectual disability v3.191 KCNN3 Arina Puzriakova changed review comment from: Associated with phenotype in OMIM, and probable gene-disease association in G2P. Bauer et al. (2019) PMID: 31155282 - De novo heterozygous gain-of-function variants identified in three unrelated individuals with ZimmermannLaband syndrome. Mild-moderate ID was reported in a 46-year-old man, while developmental delay was noted for the other two patients: a 4.5-year-old (first words at 2.5 y; attends nursery) and 5.5-year-old girl (limited spoken language; attends school with a personal aide). Additional features include coarse face, gingival hyperplasia, and/or nail hypo- or aplasia. ; to: Associated with phenotype in OMIM, and probable gene-disease association in G2P.

Bauer et al. (2019) PMID: 31155282 - De novo heterozygous gain-of-function variants identified in three unrelated individuals with ZimmermannLaband syndrome. Mild-moderate ID was reported in a 46-year-old man, while developmental delay was noted for the other two patients: a 4.5-year-old (first words at 2.5 y; attends nursery) and 5.5-year-old girl (limited spoken language; attends school with a personal aide). Additional features include coarse face, gingival hyperplasia, and/or nail hypo- or aplasia.
Intellectual disability v3.189 GPC4 Arina Puzriakova changed review comment from: Associated with phenotype in OMIM and a confirmed gene in G2P. Amor et al. (2019) (PMID: 30982611) reported ten affected males from six familes, each harbouring distinct GPC4 variants. All identified variants were truncating or resulted in a frameshift, suggesting loss of function as the likely disease mechanism. Variable degrees of ID (mild-moderate) were reported in 8/10 participants. Some supporting functional data. ; to: Associated with phenotype in OMIM and a confirmed gene for Keipert syndrome in G2P.

Amor et al. (2019) (PMID: 30982611) reported ten affected males from six familes, each harbouring distinct GPC4 variants. All identified variants were truncating or resulted in a frameshift, suggesting loss of function as the likely disease mechanism. Variable degrees of ID (mild-moderate) were reported in 8/10 participants. Some supporting functional data.
Intellectual disability v3.186 DNM1L Arina Puzriakova Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review - more than 3 unrelated cases with distinct variants, presenting with a relevant phenotype.
Intellectual disability v3.185 DNM1L Arina Puzriakova changed review comment from: Associated with related phenotype in OMIM and 'probable' gene in G2P. Variants in DNM1L cause a chronic neurological disorder, which is commonly associated with neonatal lethality. Global developmental delay or cognitive impairment (mild-profound) is reported in several surviving patients: PMID: 26931468 - Two unrelated cases: A male with global developmental delay, hypotonia and status epilepticus. WES revealed a c.1048G>A, p.G350R variant, for which low-level (68%) mosaicism was detected in the maternal sample.; to: Associated with related phenotype in OMIM and 'probable' gene in G2P.

Variants in DNM1L cause a chronic neurological disorder, which is commonly associated with neonatal lethality. Global developmental delay or cognitive impairment (mild-profound) is reported in several surviving patients:

PMID: 26931468 - Two unrelated cases: A male with global developmental delay, hypotonia and status epilepticus. WES revealed a c.1048G>A, p.G350R variant, for which low-level (6–8%) mosaicism was detected in the maternal sample. The second patient, with diffuse hypotonia, global developmental delay, poor growth, and persistent elevation of lactate, was found to harbour a de novo DNM1L variant (c.1135G>A, p.E379K). However, another de novo change in the PDHA1 gene (c.448G>A, p.G150R) was also found, and the definitive contribution of each variant to the patients phenotype could not be ascertained.

PMID: 27328748 - Compound heterozygous DNM1L variants (c.106A>G, p.Ser36Gly; c.346_347delGA, p.Glu116Lysfs*6) identified in two brothers (3 and 16-years-old) with psychomotor delay, ocular and cerebellar involvement, including mild cognitive impairment in the older brother. Some supporting functional evidence using patient fibroblasts and a yeast model.

PMID: 27301544 - De novo missense variant (c.1217T>C, p.Leu406Ser) identified in a child who presented severe hypotonia, infantile spasms with suppression‐burst and a high level of lactate in CSF. Development was profoundly delayed, and he attained no developmental milestones before his death at 18 months of age.

PMID: 26604000 - De novo missense substitution, (c.1085G>A; p.Gly362Asp) identified in a child with refractory epilepsy. Profound global developmental delay was reported, and at the last clinical assessment (age 7 years), he remained nonambulatory with the use of <10 monosyllabic words.

PMID: 26992161 - De novo heterozygous c.1084G>A (p.Gly362Ser) variant. Developmental delay was reported from 6-months of age, and at 2-years-old he was said to not be able to utter any intelligible words.

There are also reports of an identical de novo heterozygous missense variant (p.R403C) in four unrelated individuals who all experienced normal development until a sudden-onset episode of status epilepticus at the age of 4, 5, 10, and 11-years-old, respectively. Subsequently, all presented with rapid neurological regression, diffuse cerebral atrophy and substantial cognitive decline. Functional studies showed the variant confers a dominant negative effect (PMID: 27145208; 30767894; 30711678).
Intellectual disability v3.184 ATAD1 Arina Puzriakova changed review comment from: Not associated with any phenotype in G2P. Pathogenic variants have been described in seven affected individuals (three distinct consanguineous families) including a homozygous nonsense (c.826G>T; p.Glu276*), frameshift (c.1070_1071delAT; p.His357Argfs*15), and missense (c.162G>C; p.Gln54His) variant in the ATAD1 gene. Patients present with severe neurological features of essentially total absence of psychomotor development, encephalopathy, extreme hypertonia, non-responsiveness to stimuli, and death within the first few months of life. ; to: Not associated with any phenotype in G2P.

Pathogenic variants have been described in seven affected individuals (three distinct consanguineous families) including a homozygous nonsense (c.826G>T; p.Glu276*), frameshift (c.1070_1071delAT; p.His357Argfs*15), and missense (c.162G>C; p.Gln54His) variant in the ATAD1 gene. Patients present with severe neurological features of essentially total absence of psychomotor development, encephalopathy, extreme hypertonia, non-responsiveness to stimuli, and death within the first few months of life.

Knockout mouse model recapitulates phenotype. ATAD1 encodes Thorase, a mediator of AMPA receptor recycling; and therefore it was postulated that pathogenesis is a result of excessive AMPA receptor activity. Targeted therapy using perampanel, an AMPA receptor antagonist, ameliorated disease in both mice and humans, thus further supporting the role of ATAD1.
Intellectual disability v3.183 ADD3 Arina Puzriakova changed review comment from: Biallelic missense variants identified in four families (ten affected patients). Not associated with any phenotype in G2P. OMIM entry currently based on PMID:23836506. PMID: 23836506 (2013) - Homozygous missense variant c.1100G>A (p.G367D). ADD3 first identified in a consanguineous Jordanian family affecting four members. ID severe in two individuals and moderate/borderline in the others, some functional work from fibroblasts. The paper focused on the main phenotype of inheritable cerebral palsy. ; to: Biallelic missense variants identified in four families (ten affected patients). Not associated with any phenotype in G2P. OMIM entry currently based on PMID: 23836506.

PMID: 23836506 (2013) - Homozygous missense variant c.1100G>A (p.G367D). ADD3 first identified in a consanguineous Jordanian family affecting four members. ID severe in two individuals and moderate/borderline in the others, some functional work from fibroblasts. The paper focused on the main phenotype of inheritable cerebral palsy.

PMID: 29768408 (2018) - Two families with ADD3 biallelic variants and one family with ADD3 and KAT2B missense variants. Individuals with ADD3 variants have similar phenotypes and individuals with KAT2B variants have an extension to phenotype with impaired kidney and heart function, also demonstrated with functional evidence in flies. ID was reported in 5/6 participants.
Intellectual disability v3.183 LZTFL1 Arina Puzriakova reviewed gene: LZTFL1: Rating: GREEN; Mode of pathogenicity: ; Publications: 22510444, 23692385; Phenotypes: Bardet-Biedl syndrome 17, 615994; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.183 LYRM7 Arina Puzriakova reviewed gene: LYRM7: Rating: GREEN; Mode of pathogenicity: ; Publications: 24014394, 26912632, 28694194; Phenotypes: Mitochondrial complex III deficiency, nuclear type 8, 615838; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.183 KCNN3 Arina Puzriakova reviewed gene: KCNN3: 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: 31155282; Phenotypes: Zimmermann-Laband syndrome 3, 618658; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.183 EIF2AK1 Arina Puzriakova reviewed gene: EIF2AK1: Rating: RED; Mode of pathogenicity: ; Publications: 32197074; Phenotypes: Leukoencephalopathy, motor delay, spasticity, and dysarthria syndrome, 618878, ADHD; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.179 FEM1B Arina Puzriakova Added comment: Comment on list classification: Although phenotypic overlap is noted, it is not possible to ascertain whether the additional cases refer to different individuals. Also possible founder effect as all cases harbour the same variant. Additional cases/functional data are required to ascertain the contribution of FEM1B variants to an ID phenotype.
Intellectual disability v3.179 FEM1B Arina Puzriakova Added comment: Comment on list classification: Although phenotypic overlap is noted, it is not possible to ascertain whether the additional cases refer to different individuals. Also possible founder effect as all cases harbour the same variant. Additional cases/functional data are required to ascertain the contribution of FEM1B variants to an ID phenotype.
Intellectual disability v3.178 FEM1B Arina Puzriakova Added comment: Comment on list classification: Although phenotypic overlap is noted, it is not possible to ascertain whether the additional cases refer to different individuals. Also possible founder effect as all cases harbour the same variant. Additional cases/functional data are required to ascertain the contribution of FEM1B variants to an ID phenotype.
Intellectual disability v3.178 FEM1B Arina Puzriakova Added comment: Comment on list classification: Although phenotypic overlap is noted, it is not possible to ascertain whether the additional cases refer to different individuals. Also possible founder effect as all cases harbour the same variant. Additional cases/functional data are required to ascertain the contribution of FEM1B variants to an ID phenotype.
Intellectual disability v3.178 FEM1B Arina Puzriakova Added comment: Comment on list classification: Although phenotypic overlap is noted, it is not possible to ascertain whether the additional cases refer to different individuals. Also possible founder effect as all cases harbour the same variant. Additional cases/functional data are required to ascertain the contribution of FEM1B variants to an ID phenotype.
Intellectual disability v3.178 FEM1B Arina Puzriakova Added comment: Comment on list classification: Although phenotypic overlap is noted, it is not possible to ascertain whether the additional cases refer to different individuals. Also possible founder effect as all cases harbour the same variant. Additional cases/functional data are required to ascertain the contribution of FEM1B variants to an ID phenotype.
Intellectual disability v3.178 FEM1B Arina Puzriakova Added comment: Comment on list classification: Although phenotypic overlap is noted, it is not possible to ascertain whether the additional cases refer to different individuals. Also possible founder effect as all cases harbour the same variant. Additional cases/functional data are required to ascertain the contribution of FEM1B variants to an ID phenotype.
Intellectual disability v3.178 FEM1B Arina Puzriakova Added comment: Comment on list classification: Although phenotypic overlap is noted, it is not possible to ascertain whether the additional cases refer to different individuals. Also possible founder effect as all cases harbour the same variant. Additional cases/functional data are required to ascertain the contribution of FEM1B variants to an ID phenotype.
Intellectual disability v3.177 FEM1B Arina Puzriakova changed review comment from: Gene not associated with any phenotype on OMIM or G2P.

Lecoquierre et al. (2019) (PMID: 31036916) conducted a large candidate gene discovery study and identified a de novo missense variant (p.Arg126Gln) in a patient with syndromic global developmental delay. Recurrence of the same variant was highlighted in an individual from the DDD study, and the another from GeneMatcher. It is said that the three patients share a similar phenotype; however, any further details are limited and it is not possible to ascertain whether the additional cases refer to different individuals. No function analysis was undertaken to validate the implication of FEM1B.; to: Gene not associated with any phenotype on OMIM or G2P.

Lecoquierre et al. (2019) (PMID: 31036916) conducted a large candidate gene discovery study and identified a de novo missense variant (p.Arg126Gln) in a patient with syndromic global developmental delay. Recurrence of the same variant was highlighted in an individual from the DDD study, and the another from GeneMatcher, who were said to share a similar phenotype. No function analysis was undertaken to validate the implication of FEM1B.
Intellectual disability v3.176 CCDC32 Eleanor Williams gene: CCDC32 was added
gene: CCDC32 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: CCDC32 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CCDC32 were set to 32307552
Phenotypes for gene: CCDC32 were set to global developmental delay
Review for gene: CCDC32 was set to AMBER
Added comment: PMID: 32307552 - Harel et al 2020 - report 2 unrelated consanguineous families with probands with homozygous frameshift variants in CCDC32.  Parents are heterozygous. Phenotype is a congenital syndrome characterized by craniofacial, cardiac and neurodevelopmental anomalies.  In one family the child had global developmental delay, in the other the child had moderately delayed motor and language development and hyperactivity.

Functional studies in zebrafish show that ccdc32 depletion impairs cilia formation and demonstrate a contribution of ccdc32 in craniofacial, brain and left/right axis development.
Sources: Literature
Intellectual disability v3.175 ATL1 Zornitza Stark edited their review of gene: ATL1: Changed publications: 21336785, 28736820, 29180453, 29691679, 31236401; Changed phenotypes: Neuropathy, hereditary sensory, type ID, MIM# 613708, Spastic paraplegia 3A, autosomal dominant, MIM# 182600
Intellectual disability v3.175 ATL1 Zornitza Stark changed review comment from: Please note additional recent publications. Principal association is with HSP phenotype, often of later onset. Few reports of intellectual disability as part of this condition.; to: Please note additional recent publications. Principal association is with HSP/neuropathy phenotype, often of later onset. Few reports of intellectual disability as part of this condition (two families).
Intellectual disability v3.175 ATL1 Zornitza Stark changed review comment from: Please note additional recent publications; to: Please note additional recent publications. Principal association is with HSP phenotype, often of later onset. Few reports of intellectual disability as part of this condition.
Intellectual disability v3.175 ATL1 Sarah Leigh changed review comment from: Associated with phenotype in OMIM, not in G2P. Mild late onset mental retardation in 10 members of a three generation family with Spastic paraplegia 3A, autosomal dominant 182600; to: Associated with phenotype in OMIM, not in G2P. Mild to severe late onset mental retardation in 10 members of a three generation family with Spastic paraplegia 3A, autosomal dominant 182600
Intellectual disability v3.175 ATL1 Sarah Leigh commented on gene: ATL1: Associated with phenotype in OMIM, not in G2P. Mental retardation has been reported in a second family (PMID 31236401). In this publication, the 9 year old proband and his maternal grandfather had hereditary spastic paraplegia and intellectual disability, however, proband's mother had hereditary spastic paraplegia, but no intelectual disability.
Intellectual disability v3.174 FEM1B Arina Puzriakova changed review comment from: Lecoquierre et al. (2019) (PMID: 31036916) conducted a large candidate gene discovery studying and identified a de novo missense variant (p.Arg126Gln) in a patient with syndromic global developmental delay. Recurrence of the same variant was highlighted in an individual from the DDD study, and the another from GeneMatcher. It is said that the three patients share a similar phenotype; however, any further details are limited and it is not possible to ascertain whether the additional patients refer to different individuals. No function analysis was undertaken to validate the implication of FEM1B.

Gene not associated with any phenotype on OMIM or G2P.; to: Gene not associated with any phenotype on OMIM or G2P.

Lecoquierre et al. (2019) (PMID: 31036916) conducted a large candidate gene discovery study and identified a de novo missense variant (p.Arg126Gln) in a patient with syndromic global developmental delay. Recurrence of the same variant was highlighted in an individual from the DDD study, and the another from GeneMatcher. It is said that the three patients share a similar phenotype; however, any further details are limited and it is not possible to ascertain whether the additional cases refer to different individuals. No function analysis was undertaken to validate the implication of FEM1B.
Intellectual disability v3.171 CARS Eleanor Williams Phenotypes for gene: CARS were changed from Brittle hair; Fragile nails; Microcephaly; Neurodevelopmental delay to Brittle hair; Fragile nails; Microcephaly; Neurodevelopmental delay; Microcephaly, developmental delay, and brittle hair syndrome MIM#618891
Intellectual disability v3.170 ADARB1 Arina Puzriakova changed review comment from: Variants reported in four unrelated individuals with severe/profound intellectual disability, microcephaly, and seizures. Functional studies demonstrate variants result in reduction of ADARB1 product activity or changes in splicing (PMID: 32220291). Homozygous knockout mice presented with seizures and early death, supporting the role of ADARB1 in brain function (PMID: 10894545)

Gene is associated with phenotype in OMIM and G2P.; to: Gene is associated with phenotype in OMIM and G2P.

PMID: 32220291 - Bi-allelic variants reported in four unrelated individuals with severe/profound intellectual disability, microcephaly, and seizures. Functional studies demonstrate variants result in reduction in ADARB1 product activity or changes in splicing.
PMID: 10894545 - Homozygous knockout mice presented with siezures and early death, supporting the role of ADARB1 in brain function.

This gene has also been added to the Genetic Epilepsy and Severe Microcephaly panels with a suggested Green classification at the next major review.
Intellectual disability v3.170 CNPY3 Konstantinos Varvagiannis gene: CNPY3 was added
gene: CNPY3 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: CNPY3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CNPY3 were set to 29394991; 30237576
Phenotypes for gene: CNPY3 were set to Epileptic encephalopathy, early infantile, 60 (MIM 617929)
Penetrance for gene: CNPY3 were set to Complete
Review for gene: CNPY3 was set to GREEN
Added comment: Biallelic CNPY3 mutations cause Epileptic encephalopathy, early infantile, 60 (MIM 617929).

The phenotype including among others hypotonia, intractable seizures, DD and ID has been first reported by Mutoh et al (2018 - PMID: 29394991) in 3 subjects from 2 families. Evidence was provided for the role of the gene (incl. mouse model) and pathogenicity of the identified variants (resulting in LoF).

Another subject with similar features of hypotonia, DD, intractable epilepsy, feeding problems has been described briefly by Maddirevula et al (2019 - PMID: 30237576).
Sources: Literature
Intellectual disability v3.170 KIF21B Konstantinos Varvagiannis gene: KIF21B was added
gene: KIF21B was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: KIF21B was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: KIF21B were set to 32415109
Phenotypes for gene: KIF21B were set to Global developmental delay; Intellectual disability; Abnormality of brain morphology; Microcephaly
Penetrance for gene: KIF21B were set to unknown
Mode of pathogenicity for gene: KIF21B 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: KIF21B was set to GREEN
Added comment: Asselin et al (2020 - PMID: 32415109) report on 4 individuals with KIF21B pathogenic variants. DD/ID (borderline intellectual functioning to severe ID) was a feature in all. Variable other findings included brain malformations (CCA) and microcephaly. 3 missense variants and a 4-bp insertion were identified, in 3 cases as de novo events while in a single subject the variant was inherited from the father who was also affected. The authors provide evidence for a role of KIF21B in the regulation of processes involved in cortical development and deleterious effect of the missense variants impeding neuronal migration and kinesin autoinhibition. Phenotypes specific to variants (e.g. CCA or microcephaly) were recapitulated in animal models. Missense variants are thought to exert a gain-of-function effect. As commented on, the 4-bp duplication (/frameshift) variant might not be pathogenic. In blood sample from the respective individual, RT-qPCR analysis suggested that haploinsufficiency (NMD) applies. Although Kif21b haploinsufficiency in mice was shown to lead to impaired neuronal positioning, the gene might partially tolerate LoF variants as also suggested by 28 such variants in gnomAD. Homozygous Kif21b ko mice display severe morphological abnormalities, partial loss of commissural fibers, cognitive deficits and altered synaptic transmission (several refs to previous studies provided by the authors).
Sources: Literature
Intellectual disability v3.170 PAX1 Konstantinos Varvagiannis gene: PAX1 was added
gene: PAX1 was added to Intellectual disability. Sources: Literature,Radboud University Medical Center, Nijmegen
Mode of inheritance for gene: PAX1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PAX1 were set to 29681087; 23851939; 28657137
Phenotypes for gene: PAX1 were set to Otofaciocervical syndrome 2, 615560
Penetrance for gene: PAX1 were set to Complete
Review for gene: PAX1 was set to AMBER
Added comment: Biallelic PAX1 pathogenic variants cause Otofaciocervical syndrome 2 (OMIM 615560).

Brief review of the literature suggests 3 relevant publications to date (04-07-2020).

2 individuals with DD and ID have been reported (Patil et al, 2018 - PMID: 29681087 and Pohl et al, 2013 - PMID: 23851939). Other subjects reported were only evaluated as newborns(mostly)/infants [Paganini et al, 2017 - PMID: 28657137, Patil et al, 2018 - PMID: 29681087].

While the first report by Pohl et al identified a homozygous missense variant supported by functional studies [NM_006192.5:c.497G>T - p.(Gly166Val)] subsequent ones identified homozygosity for pLoF mutations [Patil et al: NM_006192.4:c.1173_1174insGCCCG / Paganini et al: NM_006192:c.1104C>A - p.(Cys368*)].

As discussed by Pohl et al:

PAX1 encodes a transcription factor with critical role in pattern formation during embryogenesis. Study of the mouse Gly157Val (equivalent to human Gly166Val) Pax1 variant suggested reduced binding affinity (reduced transactivation of a regulatory sequence of the Nkx3-2 promoter) and hypofunctional nature of this variant.

Mouse models seem to recapitulate features of the disorder (skeletal, immunodeficiency) while the role of Pax1 in hearing process was thought to be supported by early expression (P6) in mouse cochlea.

Overall this gene can be considered for inclusion in the ID panel with amber/green rating.
Sources: Literature, Radboud University Medical Center, Nijmegen
Intellectual disability v3.170 TMEM106B Konstantinos Varvagiannis gene: TMEM106B was added
gene: TMEM106B was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: TMEM106B was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: TMEM106B were set to 29186371; 29444210; 32595021
Phenotypes for gene: TMEM106B were set to Leukodystrophy, hypomyelinating, 16 (MIM #617964)
Penetrance for gene: TMEM106B were set to Complete
Mode of pathogenicity for gene: TMEM106B 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: TMEM106B was set to GREEN
Added comment: 6 unrelated individuals with Leukodystrophy, hypomyelinating, 16 (MIM #617964) due to a recurrent TMEM106B variant have been reported to date in the literature (Simons et al 2017 - PMID: 29186371, Yan et al 2018 - PMID: 29444210, Ikemoto et al 2020 - PMID: 32595021).

While a 3 y.o. female described by Yan et al had DD (eg sitting at 9m, walking at 25m) with normal cognitive functioning, and a 38 y.o. female had borderline intellectual functioning (IQ 76), 4 affected individuals had ID. Among them, a 19 y.o. male with severe ID was also found to harbor a second de novo possibly damaging USP7 variant. Seizures have been reported in 2 unrelated subjects. [Clinical features are also summarized in table 1 - Ikemoto et al].

All harbored NM_001134232.2(TMEM106B):c.754G>A (p.Asp252Asn) which in almost all cases occurred as a de novo event. In a single case this variant was inherited from a mosaic parent with mild DD in infancy but normal cognition (reported by Simons et al).

As discussed by Ito et al (2018 - PMID: 30643851) the encoded protein is a structural component of the lysosomal membrane, playing a role on lysosome acidification. Acidity of the lysosome mediates multiple aspects of lysosomal function. Ito et al, using patient-derived fibroblasts assessed mRNA and protein levels. These were unaltered compared with controls. While TMEM106B had been previously shown to affect lysosome number, morphology and acidification, Ito et al demonstrated increased number of lysosomes in patient cells as well as impaired acidification compared to controls. As commented lysosomes are required for generation of myelin.

Recurrence of this missense variant, the presence of pLoF TMEM106B variants in gnomAD as well as the phenotypically normal Tmem106b null mice suggest that this variant may have a gain-of-function or dominant negative effect.

Genes for other forms of hypomyelinating lipodystrophy (incl. PLP1) have green rating in the ID panel.

Overall TMEM106B can be considered for the ID panel with green rating and the epilepsy panel with amber rating.
Sources: Literature
Intellectual disability v3.170 TBC1D2B Konstantinos Varvagiannis gene: TBC1D2B was added
gene: TBC1D2B was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: TBC1D2B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TBC1D2B were set to 32623794
Phenotypes for gene: TBC1D2B were set to Global developmental delay; Intellectual disability; Seizures; Gingival overgrowth; Behavioral abnormality; Abnormality of the mandible; Abnormality of brain morphology; Abnormality of the eye; Hearing abnormality
Penetrance for gene: TBC1D2B were set to Complete
Review for gene: TBC1D2B was set to AMBER
Added comment: Harms et al (2020 - PMID: 32623794) report on 3 unrelated individuals with biallelic pLoF TBC1D2B variants.

Features included cognitive impairment (mild ID in one case, regression at the age of 12y in another, hypotonia and delayed milestones in a third aged 8m), seizures (3/3 - variable age of onset) and/or gingival overgrowth (2/3 - prior to initiation of AEDs). Other findings included behavioral abnormalities, mandibular anomalies, abnormal brain imaging and ophthalmologic or (rarely) audiometric evaluations.

All were born to non-consanguineous couples and additional investigations were performed in some.

Variants were identified by WES or trio WGS, with Sanger confirmation/compatible segregation analyses.

In line with the pLoF variants, mRNA studies in fibroblasts from 2 unrelated affected individuals demonstrated significantly reduced (~80-90%) TBC1C2D mRNA levels compared to controls, restored following cycloheximide treatment. Protein was absent in patient fibroblasts.

TBC-domain containing GTPase activating proteins are known as key regulators of RAB GTPase activity. TBC1D2B was shown to colocalize with RAB5-positive endocytic vesicles. CRISPR/Cas9-mediated ko of TBC1D2B in HeLa cells suggested a role in EGF receptor endocytosis and decreased cell viability of TBC1D2B-deficient HeLa cells upon serum deprivation.

Genes encoding other TBC domain-containg GTPase-activating proteins, e.g. TBC1D7 and TBC1D20, TBC1D24 are associated with recessive neurodevelopmental disorders (with ID and/or seizures) and the pathophysiological defect in TBC1D2B-related disorder (deficit in vesicle trafficking and/or cell survival) is proposed to be similar to that of TBC1D24.

Overall this gene can be considered for inclusion with amber/green rating in the ID panel and green in epilepsy panel.
Sources: Literature
Intellectual disability v3.170 EXOC2 Konstantinos Varvagiannis gene: EXOC2 was added
gene: EXOC2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: EXOC2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EXOC2 were set to 32639540
Phenotypes for gene: EXOC2 were set to Global developmental delay; Intellectual disability; Abnormality of the face; Abnormality of brain morphology
Penetrance for gene: EXOC2 were set to Complete
Review for gene: EXOC2 was set to AMBER
Added comment: Van Bergen et al (2020 - PMID: 32639540) report on 3 individuals from 2 families, harboring biallelic EXOC2 mutations.

Clinical presentation included DD, ID (severe in 2 subjects from fam1, borderline intellectual functioning in fam2), dysmorphic features and brain abnormalities. Cerebellar anomalies were common to all with a molar tooth sign observed in one (1/3). Other findings limited to subjects from one family included acquired microcephaly, congenital contractures, spastic quadriplegia (each observed 2/3).

Previous investigations were in all cases non-diagnostic. WES identified biallelic EXOC2 mutations in all affected individuals.

EXOC2 encodes an exocyst subunit. The latter is an octameric complex, component of the membrane transport machinery, required for tethering and fusion of vesicles at the plasma membrane. As discussed ,vesicle transport is important for the development of brain and the function of neurons and glia. Exocyst function is also important for delivery of Arl13b to the primary cilium (biallelic ARL13B mutations cause Joubert syndrome 8) and ciliogenesis.

Affected subjects from a broader consanguineous family (fam1) were homozygous for a truncating variant. Fibroblast studies revealed mRNA levels compatible with NMD (further restored in presence of CHX) as well as reduced protein levels. The female belonging to the second non-consanguineous family was found to harbor 2 missense variants in trans configuration.

An exocytosis defect was demonstrated in fibroblasts from individuals belonging to both families. Ciliogenesis appeared to be normal, however Arl13b localization/recruitment to the cilia was reduced compared with control cells with the defect rescued upon exogenous expression of wt EXOC2.

Mutations in other genes encoding components of the exocyst complex have been previously reported in individuals with relevant phenotypes (e.g. EXOC8 in a boy with features of Joubert s. or EXOC4 in nephrotic syndrome).

The authors discuss on the essential role of EXOC2 based on model organism studies (e.g. impaired neuronal membrane traffic, failure of neuronal polarization and neuromuscular junction expansion seen in Drosophila Sec5 (EXOC2) null mutants).
Sources: Literature
Intellectual disability v3.170 CEP120 Konstantinos Varvagiannis gene: CEP120 was added
gene: CEP120 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: CEP120 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CEP120 were set to 27208211
Phenotypes for gene: CEP120 were set to Joubert syndrome 31 (MIM 617761); Short-rib thoracic dysplasia 13 with or without polydactyly (MIM 616300)
Penetrance for gene: CEP120 were set to Complete
Review for gene: CEP120 was set to GREEN
Added comment: Pathogenic CEP120 variants have been reported in recessive ciliopathies, namely Short-rib thoracic dysplasia 13 with or without polydactyly (MIM 616300) and Joubert syndrome 31 (MIM 617761).

The former is associated with a severe/lethal outcome (4 unrelated infants described by Shaheen et al 2015 - PMID: 25361962, 2 fetuses reported by Roosing et al 2016 - PMID: 27208211).

Roosing et al however, also provided details on 4 unrelated subjects with Joubert syndrome diagnosis. All presented with a neurologic phenotype of hypotonia, DD, cognitive impairment and exhibited a molar tooth sign.

As a result, this gene can be considered for inclusion in the ID panel with green rating (>3 individuals/variants, consistent ciliopathy phenotype).
Sources: Literature
Intellectual disability v3.170 CCDC174 Konstantinos Varvagiannis gene: CCDC174 was added
gene: CCDC174 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: CCDC174 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CCDC174 were set to 26358778
Phenotypes for gene: CCDC174 were set to Hypotonia, infantile, with psychomotor retardation - IHPMR, 616816
Penetrance for gene: CCDC174 were set to Complete
Mode of pathogenicity for gene: CCDC174 was set to Other
Review for gene: CCDC174 was set to AMBER
Added comment: Biallelic pathogenic CCDC174 variants cause Hypotonia, infantile, with psychomotor retardation - IHPMR (MIM 616816).

Volodarsky et al [2015 - PMID: 26358778] describe 6 children from 2 unrelated families with - among others - severe hypotonia, psychomotor delay and abducens nerve palsy. All affected subjects were homozygous for a stoploss variant. Evidence from functional studies/animal model is provided supporting the role of the gene in this phenotype.

Overall this gene can be considered for inclusion in the ID panel with amber rating (2 families, single founder variant, consistent phenotype, supportive studies) pending further reports.
Sources: Literature
Intellectual disability v3.170 ACOX2 Konstantinos Varvagiannis gene: ACOX2 was added
gene: ACOX2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: ACOX2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ACOX2 were set to 27647924; 27884763; 29287774
Phenotypes for gene: ACOX2 were set to Bile acid synthesis defect, congenital, 6 - 617308
Penetrance for gene: ACOX2 were set to unknown
Review for gene: ACOX2 was set to RED
Added comment: Biallelic pathogenic ACOX2 variants cause Bile acid synthesis defect, congenital, 6 (MIM 617308). Overall the phenotype corresponds to an IEM/peroxisomal disorder.

As per 01-07-2020 there are 3 reports, briefly reviewed :

- Vilarinho et al [2016 - PMID: 27647924] provided details on an 8-year-old boy with ID.
- Monte et al [2017 - PMID: 27884763] described a 16 year old male with sustained elevation of transaminases *without* accompanying neurologic symptomatology (as they comment).
- Ferdinandusse et al [2018 - PMID: 29287774] reported on a girl deceased at the age of few months.

Please consider inclusion in the ID panel with amber/red rating pending further reports.
Sources: Literature
Intellectual disability v3.170 ABCA2 Konstantinos Varvagiannis gene: ABCA2 was added
gene: ABCA2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: ABCA2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ABCA2 were set to 30237576; 29302074; 31047799
Phenotypes for gene: ABCA2 were set to Intellectual developmental disorder with poor growth and with or without seizures or ataxia, 618808
Penetrance for gene: ABCA2 were set to Complete
Review for gene: ABCA2 was set to GREEN
Added comment: Biallelic pathogenic ABCA2 variants cause Intellectual developmental disorder with poor growth and with or without seizures or ataxia (MIM 618808).

There are 3 relevant publications (01-07-2020) :
- Maddirevula et al [2019 - PMID: 30237576] described briefly 2 unrelated subjects (16-2987, 16DG0071) both DD and seizures among other manifestations.
- Hu et al [2019 - PMID: 29302074] reported 3 sibs (M8600615 - III:1-3) born to consanguineous parents (M8600615 - III:1-3) with DD/ID (formal confirmation of moderate ID, in those (2) evaluated). One also presented with seizures.
- Aslam and Naz [2019 - PMID: 31047799] provided clinical details on 2 siblings born to consanguineous parents. ID was reported for the older sib but was absent in the younger one. Seizures were not part of the phenotype.

All subjects harbored biallelic pLoF variants.

N.B. : Steinberg et al [2015 - PMID: 25773295], within a cohort of patients with ALS, identified one with biallelic ABCA2 variants. As however Aslam and Naz comment, this person harbored a single pathogenic variant, with a second one rather unlikely to be pathogenic due to high allele frequency.

Overall this gene can be considered for inclusion with green rating in both ID and epilepsy panels (each in >=3 unrelated individuals).
Sources: Literature
Intellectual disability v3.170 HERC2 Konstantinos Varvagiannis edited their review of gene: HERC2: Added comment: Please consider upgrading this gene to green in the current panel based on the following updated review (13-07-2020):

Biallelic pathogenic HERC2 variants cause Mental retardation, autosomal recessive 38 (MIM 615516).

The current review is based mostly on the information provided by Elpidorou et al (2020 - PMID: 32571899) summarizing the findings in several affected individuals as published in the literature. ID was a universal feature among them (27/27) and seizures were reported in some (9/27):
- 22 subjects from Amish/Mennonite families were homozygous for p.Pro594Leu [NM_004667.5(HERC2):c.1781C>T] (Puffenberger et al 2012 - PMID: 23065719, Harlalka et al 2013 - PMID: 23243086, Abraham et al - PMID: 30902390)
- 2 additional patients were homozygous for another missense SNV [NM_004667.5(HERC2):c.4625G>A - p.Arg1542His] (Abraham et al 2019 - PMID: 30902390)
- 3 sibs born to consanguineous parents, homozygous for NM_004667.5:c.13767_13770delTGAA - p.(Asn4589LysTer4598)] as described by Elpidorou et al.
- 1 male homozygous 286 kb deletion spanning several 5' exons of HERC2 as well as the first exons of OCA2 was described by Morice-Picard et al (2016 - PMID: 27759030). Despite a neurological presentation (axial hypotonia, peripheral hypertonia, extrapyramidal symptoms and uncoordinated movements) further information was not available.

Apart from the cases summarized by Elpidorou et al, there have been few additional ones e.g. :
- Trujillano et al (2017 - PMID: 27848944) reported briefly on a patient, homozygous for NM_004667.5:c.4676-1G>A displaying seizures, hypotonia, global DD, "Encephalopathy" and abnormality of the liver.
- Yavarna et al (2015 - PMID: 26077850) provided few details with on an individual with primarily 'neurocognitive' phenotype but rather atypical presentation (MRI abnormalities, TGA, VSD, renal anomaly, growth retardation, hearing loss) due to p.Q3164X variant (recessive inheritance was specified).

Several lines of evidence support an important role for the protein encoded (an E3 ubiquitin protein ligase, interacting also with UBE3A, involved in several cellular processes incl. cell cycle regulation, spindle formation during mitosis, mitochondrial functions, DNA damage responses by targeting proteins such as XPA) as well as the effect of the reported variants (mRNA studies, Western blot, detection of a fusion transcript in the case of the deletion, etc).

Individuals from the Amish families displayed Angelman-like features (in line with HERC2-UBE3A interaction) with - among others - gait instability. Mouse models recapitulate some of these features (e.g. the movement disorder) as extensively discussed by Abraham et al.

Overall this gene can be included in the ID and epilepsy panels with green rating.

-----; Changed rating: GREEN; Changed publications: 23065719, 23243086, 30902390, 32571899, 27848944, 26077850, 27759030
Intellectual disability v3.170 SEC31A Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. One homozygous terminating variant reported in sibs of consanguineous Bedouin parents, together with a Drosophila model in which loss of sec31a was embryonically lethal and associated with defects in eye and brain development, consistent with abnormal neurodevelopment.
Intellectual disability v3.168 SBF1 Sarah Leigh changed review comment from: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 7 variants reported in at least 5 unrelated cases.; to: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 7 variants reported in at least 5 unrelated cases. The phenotypes vary, but early‐onset microcephaly and moderate‐severe developmental delay were reported in 3 cases (PMID 30039846, 21210780, 20658556).
Intellectual disability v3.168 SBF1 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 7 variants reported in at least 5 unrelated cases.
Intellectual disability v3.167 SBF1 Sarah Leigh Phenotypes for gene: SBF1 were changed from Charcot-Marie-Tooth disease, type 4B3, MIM# 615284 to Charcot-Marie-Tooth disease, type 4B3 615284
Intellectual disability v3.166 SARS2 Sarah Leigh edited their review of gene: SARS2: Added comment: There is enough evidence for this gene to be rated GREEN at the next major review.; Changed rating: GREEN
Intellectual disability v3.166 SARS2 Sarah Leigh Tag for-review tag was added to gene: SARS2.
Intellectual disability v3.166 SARS2 Sarah Leigh Classified gene: SARS2 as Amber List (moderate evidence)
Intellectual disability v3.166 SARS2 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 3 variants reported in at least 3 unrelated cases. Segregates with the disease.
Intellectual disability v3.166 SARS2 Sarah Leigh Gene: sars2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.165 SARS2 Sarah Leigh Publications for gene: SARS2 were set to 21255763; 24034276
Intellectual disability v3.164 SARS2 Sarah Leigh Phenotypes for gene: SARS2 were changed from Hyperuricemia, pulmonary hypertension, renal failure, and alkalosis, MIM#613845 to Hyperuricemia, pulmonary hypertension, renal failure, and alkalosis 613845
Intellectual disability v3.163 RUSC2 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 2 variants reported in at least 2 unrelated cases. No functional studies have been reported, although authors of PMID 27612186 suggest that p.R866* results in total loss of function as the sibs biallelic with this variant have a more severe phenotype than the case who is biallelic for p.R1318*, which they conclude results in partial loss of function.
Intellectual disability v3.162 RUSC2 Sarah Leigh Phenotypes for gene: RUSC2 were changed from Mental retardation, autosomal recessive 61, MIM# 617773 to Mental retardation, autosomal recessive 61 617773
Intellectual disability v3.161 SLC12A6 Sarah Leigh commented on gene: SLC12A6: For-review tag has been added as it maybe appropriate to change the MOI to BOTH monoallelic and biallelic, autosomal or pseudoautosomal at the next major review, to ensure that de novo heterozgous variants are identified.
Intellectual disability v3.159 GALNT2 Sarah Leigh gene: GALNT2 was added
gene: GALNT2 was added to Intellectual disability. Sources: Literature
for-review tags were added to gene: GALNT2.
Mode of inheritance for gene: GALNT2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GALNT2 were set to 27508872; 32293671
Phenotypes for gene: GALNT2 were set to Congenital disorder of glycosylation, type IIt 618885
Review for gene: GALNT2 was set to GREEN
Added comment: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 5 variants reported in at least 5 unrelated cases, together with mouse and rat models (PMID 27508872;32293671).
Sources: Literature
Intellectual disability v3.158 ADARB1 Sarah Leigh Classified gene: ADARB1 as Amber List (moderate evidence)
Intellectual disability v3.158 ADARB1 Sarah Leigh Gene: adarb1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.157 ADARB1 Sarah Leigh Tag for-review tag was added to gene: ADARB1.
Intellectual disability v3.157 ALG14 Sarah Leigh changed review comment from: Have added the "for review" tag, to address the phenotypic variability of published carriers of ALG14 variants.; to: Have added the "for review" tag, to address the phenotypic variability of published carriers of ALG14 variants. This will be reviewed as more cases are reported.
Intellectual disability v3.157 ADARB1 Arina Puzriakova reviewed gene: ADARB1: Rating: GREEN; Mode of pathogenicity: None; Publications: 32220291; Phenotypes: Neurodevelopmental disorder with hypotonia, microcephaly, and seizures, 618862; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.157 FEM1B Arina Puzriakova changed review comment from: Lecoquierre et al. (2019) (PMID: 31036916) conducted a large candidate gene discovery studying and identified a de novo missense variant (p.Arg126Gln) in a patient with syndromic global developmental delay. Recurrence of the same variant was highlighted in an individual from the DDD study, and the another from GeneMatcher. It is said that the three patients share a similar phenotype; however, any further details are limited and it is not possible to ascertain whether the additional patients refer to different individuals.

No function analysis was undertaken to validate the implication of FEM1B.

Gene not associated with any phenotype on OMIM or G2P.; to: Lecoquierre et al. (2019) (PMID: 31036916) conducted a large candidate gene discovery studying and identified a de novo missense variant (p.Arg126Gln) in a patient with syndromic global developmental delay. Recurrence of the same variant was highlighted in an individual from the DDD study, and the another from GeneMatcher. It is said that the three patients share a similar phenotype; however, any further details are limited and it is not possible to ascertain whether the additional patients refer to different individuals. No function analysis was undertaken to validate the implication of FEM1B.

Gene not associated with any phenotype on OMIM or G2P.
Intellectual disability v3.156 NRROS Sarah Leigh Phenotypes for gene: NRROS were changed from neurodegeneration; intracranial calcification; epilepsy to Seizures, early-onset, with neurodegeneration and brain calcification 618875
Intellectual disability v3.155 NRROS Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene for NRROS-related Infantile-Onset Neurodegeneration with Intracranial Calcification. At least 6 variants reported in at least 5 unrelated cases (PMIDs 32100099;32197075), together with supportive mouse model (PMID 28459434).
Intellectual disability v3.154 NRROS Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene for NRROS-related Infantile-Onset Neurodegeneration with Intracranial Calcification. At least 6 variants reported in at least 5 unrelated cases (PMIDs 32100099;32197075), together with supportive mouse model (PMID 28459434).
Intellectual disability v3.153 NOVA2 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least 6 terminating variants reported in unrelated cases, together supportive functional studies in a zebrafish knockdown of the NOVA2 ortholog (nova1a) (PMID 32197073).
Intellectual disability v3.152 NOVA2 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least 6 terminating variants reported in unrelated cases, together supportive functional studies in a zebrafish knockdown of the NOVA2 ortholog (nova1a) (PMID 32197073).
Intellectual disability v3.150 CDK19 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least 2 variants reported in 3 unrelated cases, together with supportive Drosophila, demonstating the effects of the variants (PMID 32330417).
Intellectual disability v3.149 CDK19 Sarah Leigh Phenotypes for gene: CDK19 were changed from microcephaly, congenital bilateral falciform retinal folds, nystagmus, and mental retardation to Epileptic encephalopathy, early infantile, 87 618916
Intellectual disability v3.147 WIPI2 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 1 homozygous variant was reported in 4 members of a consanguineous family.
Intellectual disability v3.146 WIPI2 Sarah Leigh Phenotypes for gene: WIPI2 were changed from Intellectual developmental disorder with short stature and variable skeletal anomalies 618453 to ?Intellectual developmental disorder with short stature and variable skeletal anomalies 618453
Intellectual disability v3.145 GSX2 Sarah Leigh changed review comment from: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 2 variants reported in at least 2 unrealated cases.; to: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 2 variants reported in at least 2 unrealated cases, together with supportive functional studies (PMID 31412107).
Intellectual disability v3.145 GSX2 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 2 variants reported in at least 2 unrealated cases.
Intellectual disability v3.144 YARS Sarah Leigh changed review comment from: Comment on list classification: Biallelic variants in three families with complex clinical conditions including developmental delay.; to: Comment on list classification: Biallelic variants in three families with complex clinical conditions including developmental delay. PMID 30304524 reports an extended family with microcephaly, expressive language delay, hearing loss, amongst other features. PMID 29232904 reports a proband whose phenotype included hearing loss, retnititis pigmentosa and hypotonia, but did not include intellectual disability. PMID 27633801 reports two sibblings with hypotionia, the older brother at 15 years of age has mild delays, he attends school on an individualized educational program and functions at a grade 3 level. He speaks and understands English and Polish.
Intellectual disability v3.144 YARS Sarah Leigh Classified gene: YARS as Amber List (moderate evidence)
Intellectual disability v3.144 YARS Sarah Leigh Added comment: Comment on list classification: Biallelic variants in three families with complex clinical conditions including developmental delay.
Intellectual disability v3.144 YARS Sarah Leigh Gene: yars has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.143 YARS Sarah Leigh Tag for-review was removed from gene: YARS.
Intellectual disability v3.143 YARS Sarah Leigh commented on gene: YARS
Intellectual disability v3.143 YARS Sarah Leigh Tag new-gene-name tag was added to gene: YARS.
Intellectual disability v3.143 YARS Sarah Leigh Tag for-review tag was added to gene: YARS.
Intellectual disability v3.139 RSRC1 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least 9 variants reported in unrelated families.
Intellectual disability v3.135 SLC12A2 Zornitza Stark gene: SLC12A2 was added
gene: SLC12A2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: SLC12A2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC12A2 were set to 30740830
Phenotypes for gene: SLC12A2 were set to Kilquist syndrome; deafness; intellectual disability; dysmorphic features; absent salivation; ectodermal dysplasia; constipation; intestinal malrotation; multiple congenital anomalies
Review for gene: SLC12A2 was set to GREEN
gene: SLC12A2 was marked as current diagnostic
Added comment: Two families reported and a mouse model. New report is not on PubMed yet: (https://doi.org/10.1212/NXG.0000000000000478)
Sources: Literature
Intellectual disability v3.135 RAP1GDS1 Zornitza Stark gene: RAP1GDS1 was added
gene: RAP1GDS1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: RAP1GDS1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RAP1GDS1 were set to 32431071
Phenotypes for gene: RAP1GDS1 were set to Intellectual disability; dysmorphic features
Review for gene: RAP1GDS1 was set to AMBER
Added comment: Four individuals from two consanguineous families, same homozygous splice site variant detected, borderline Red/Amber.
Sources: Literature
Intellectual disability v3.134 RIC1 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as possible Gen2Phen gene. At least one variant reported in numerous members of two families, who shared an autozygous interval, confirming Founder effect (PMID 27878435). Segregation was demonstrated, together with supportive functional and zebra fish model (PMID 31932796).
Intellectual disability v3.134 RIC1 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as possible Gen2Phen gene. At least one variant reported in numerous members of two families, who shared an autozygous interval, confirming Founder effect (PMID 27878435). Segregation was demonstrated, together with supportive functional and zebra fish model (PMID 31932796).
Intellectual disability v3.133 RIC1 Sarah Leigh Phenotypes for gene: RIC1 were changed from Cleft lip; cataract; tooth abnormality; intellectual disability; facial dysmorphism; ADHD to CATIFA syndrome 618761; Cleft lip; cataract; tooth abnormality; intellectual disability; facial dysmorphism; ADHD
Intellectual disability v3.132 OTUD7A Sarah Leigh Added comment: Comment on list classification: Not associated with phenotype in OMIM or in Gen2Phen, Although the region ISCA-46295-Loss, which encompasses the OTUD7A locus, is associated with seizures 20236110, mental retardation 22775350, dysmorphic features, developmental delay and severe epileptic encephalopathy. PMID 31997314 report a homozygous variant in a case of severe global developmental delay, language impairment and epileptic encephalopathy; segregation and functional studies support this gene disease association.
Intellectual disability v3.130 TOMM70 Eleanor Williams changed review comment from: Not associated with a disease phenotype in OMIM or Gene2Phenotype

PMID: 31907385 - Wei et al 2020 - report a patient with severe anemia, lactic acidosis, and developmental delay in which two compound heterozygous variants in TOMM70 [c.794C>T (p.T265M) and c.1745C>T (p.A582V)] were identified. Functional studies showed that patient-derived cells exhibited multi-oxidative phosphorylation system (OXPHOS) complex defects. Abstract only accessed.

PMID: 32356556 - Dutta et al 2020 - report 2 patients with de novo heterozygous missense variants in the C-terminal region of TOMM70. Both patients had shared symptoms including hypotonia, hyper-reflexia, ataxia, dystonia and significant white matter abnormalities. However, for patient 1 a neurodevelopmental disorder was noted in infancy, but patient 2 developed as normal until age 4 when neurological regression occurred. Some functional data from Drosophila show that the variants cause partial loss of function.

3 cases but different mode of inheritance and phenotypic presentation.
Sources: Literature; to: Not associated with a disease phenotype in OMIM or Gene2Phenotype

PMID: 31907385 - Wei et al 2020 - report a patient with severe anemia, lactic acidosis, and developmental delay in which two compound heterozygous variants in TOMM70 [c.794C>T (p.T265M) and c.1745C>T (p.A582V)] were identified. Functional studies showed that patient-derived cells exhibited multi-oxidative phosphorylation system (OXPHOS) complex defects. Abstract only accessed.

PMID: 32356556 - Dutta et al 2020 - report 2 patients with de novo heterozygous missense variants in the C-terminal region of TOMM70. Both patients had shared symptoms including hypotonia, hyper-reflexia, ataxia, dystonia and significant white matter abnormalities. Patient 1 showed severe global developmental delay. However, for patient 1 a neurodevelopmental disorder was noted in infancy, but patient 2 developed as normal until age 4 when neurological regression occurred. Some functional data from Drosophila show that the variants cause partial loss of function.

3 cases but different mode of inheritance and phenotypic presentation.
Sources: Literature
Intellectual disability v3.130 TOMM70 Eleanor Williams gene: TOMM70 was added
gene: TOMM70 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: TOMM70 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: TOMM70 were set to 31907385; 32356556
Phenotypes for gene: TOMM70 were set to Severe anaemia, lactic acidosis; developmental delay; white matter abnormalities
Review for gene: TOMM70 was set to AMBER
Added comment: Not associated with a disease phenotype in OMIM or Gene2Phenotype

PMID: 31907385 - Wei et al 2020 - report a patient with severe anemia, lactic acidosis, and developmental delay in which two compound heterozygous variants in TOMM70 [c.794C>T (p.T265M) and c.1745C>T (p.A582V)] were identified. Functional studies showed that patient-derived cells exhibited multi-oxidative phosphorylation system (OXPHOS) complex defects. Abstract only accessed.

PMID: 32356556 - Dutta et al 2020 - report 2 patients with de novo heterozygous missense variants in the C-terminal region of TOMM70. Both patients had shared symptoms including hypotonia, hyper-reflexia, ataxia, dystonia and significant white matter abnormalities. However, for patient 1 a neurodevelopmental disorder was noted in infancy, but patient 2 developed as normal until age 4 when neurological regression occurred. Some functional data from Drosophila show that the variants cause partial loss of function.

3 cases but different mode of inheritance and phenotypic presentation.
Sources: Literature
Intellectual disability v3.127 CAPZA2 Eleanor Williams gene: CAPZA2 was added
gene: CAPZA2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: CAPZA2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CAPZA2 were set to 32338762
Review for gene: CAPZA2 was set to AMBER
Added comment: Not associated with a disease phenotype in OMIM.

PMID: 32338762 - Huang et al 2020 - report 2 unrelated families (Chinese and European) in which a de novo heterozygous variant has been identified in CAPZA2 in paediatric probands that present with global motor development delay, speech delay, intellectual disability, hypotonia. One proband had seizures at 7 months but these were controlled with medication and did not repeat. The other proband at age one had an atypical febrile seizure that was controlled without medication. Functional studies in Drosophila suggest that these variants are mild loss of function mutations but that they can act as dominant negative variants in actin polymerization in bristles.
Sources: Literature
Intellectual disability v3.126 HARS Zornitza Stark changed review comment from: 3 cases from 2 unrelated families with biallelic variants and mild to severe intellectual disability as a feature of the condition.

Please note association with Usher syndrome (deafness/retinal phenotypes) has been assessed as 'refuted' by ClinGen, and this gene has a well-established association between heterozygous variants and CMT.
Sources: Literature; to: 3 cases from 2 unrelated families with biallelic variants and mild to severe intellectual disability as a feature of the condition. We have also added to paediatric ataxia panel as Amber.

Please note association with Usher syndrome (deafness/retinal phenotypes) has been assessed as 'refuted' by ClinGen, and this gene has a well-established association between heterozygous variants and CMT.
Sources: Literature
Intellectual disability v3.126 HARS Zornitza Stark gene: HARS was added
gene: HARS was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: HARS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HARS were set to 32296180
Phenotypes for gene: HARS were set to multisystem ataxic syndrome; mild-severe intellectual disability
Review for gene: HARS was set to AMBER
Added comment: 3 cases from 2 unrelated families with biallelic variants and mild to severe intellectual disability as a feature of the condition.

Please note association with Usher syndrome (deafness/retinal phenotypes) has been assessed as 'refuted' by ClinGen, and this gene has a well-established association between heterozygous variants and CMT.
Sources: Literature
Intellectual disability v3.126 EXOC7 Zornitza Stark gene: EXOC7 was added
gene: EXOC7 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: EXOC7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EXOC7 were set to 32103185
Phenotypes for gene: EXOC7 were set to brain atrophy; seizures; developmental delay; microcephaly
Review for gene: EXOC7 was set to GREEN
gene: EXOC7 was marked as current diagnostic
Added comment: 4 families with 8 affected individuals with brain atrophy, seizures, and developmental delay, and in more severe cases microcephaly and infantile death. Four novel homozygous or comp.heterozygous variants found in EXOC7, which segregated with disease in the families. They showed that EXOC7, a member of the mammalian exocyst complex, is highly expressed in developing human cortex. In addition, a zebrafish model of Exoc7 deficiency recapitulates the human disorder with increased apoptosis and decreased progenitor cells during telencephalon development, suggesting that the brain atrophy in human cases reflects neuronal degeneration. We have added to the Microcephaly and Genetic Epilepsies panels as well.
Sources: Literature
Intellectual disability v3.126 HNRNPH1 Zornitza Stark gene: HNRNPH1 was added
gene: HNRNPH1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: HNRNPH1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: HNRNPH1 were set to 32335897; 29938792
Phenotypes for gene: HNRNPH1 were set to HNRNPH1‐related syndromic intellectual disability
Review for gene: HNRNPH1 was set to GREEN
Added comment: 1st patient reported in 2018 with intellectual disability and dysmorphic features and HNRNPH1 heterozygous missense variant. 2020 paper reports additional 7 cases with ID, short stature, microcephaly, distinctive dysmorphic facial features, and congenital anomalies (cranial, brain, genitourinary, palate, ophthalmologic). They all had HNRNPH1 heterozygous pathogenic variants (missense, frameshift, in‐frame deletion, entire gene duplication) and were identified using clinical networks and GeneMatcher.
Sources: Literature
Intellectual disability v3.126 PDCD6IP Zornitza Stark gene: PDCD6IP was added
gene: PDCD6IP was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: PDCD6IP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PDCD6IP were set to 32286682
Phenotypes for gene: PDCD6IP were set to microcephaly; Intellectual disability
Review for gene: PDCD6IP was set to AMBER
Added comment: One consanguineous family with 2 affected sibs with primary microcephaly (-4SD), intellectual disability and short stature (-5/6SD), and homozygous frameshift variant in PDCD6IP. The homozygous variant was confirmed in both affected sibs, while the four healthy siblings and parents were heterozygous. The clinical features observed in the patients were similar to the phenotypes observed in mouse and zebrafish models of PDCD6IP mutations in previous studies.
Sources: Literature
Intellectual disability v3.123 RBL2 Sarah Leigh Added comment: Comment on list classification: Not associated with phenotype in OMIM or in Gen2Phen. Identified as a candidate gene in PMIDs 32105419; 9806916, with two variants in sibblings.
Intellectual disability v3.122 SOX6 Sarah Leigh Added comment: Comment on list classification: Not associated with relevant phenotype in OMIM and as probable Gen2Phen gene for SOX6-related neurodevelopmental syndrome. At least 17 unrelated cases, with 14 de novo heterozygous variants, a further 2 families where the variant appeared to inherited from the affected father and a single case where the variant was found to be mosaic in the unaffected father.
Intellectual disability v3.121 RBL2 Sarah Leigh Added comment: Comment on list classification: Not associated with phenotype in OMIM or in Gen2Phen. Identified as a candidate gene in PMIDs 32105419; 9806916, with two variants in sibblings.
Intellectual disability v3.120 TTC5 Sarah Leigh Added comment: Comment on list classification: Not associated with a relevant phenotype in OMIM and as probable Gen2Phen gene for TTC5-associated neurodevelopmental disorder. At least 7 cases with biallelic variants.
Intellectual disability v3.119 RBL2 Sarah Leigh Added comment: Comment on list classification: Not associated with phenotype in OMIM or in Gen2Phen. Identified as a candidate gene in PMIDs 32105419; 9806916, with two variants in sibblings.
Intellectual disability v3.110 SLC1A1 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 2 variants reported in 2 unrelated cases (PMID 21123949), a SLC1A1 null mouse model with age-dependent chronic neurodegeneration (PMID 16311588), together with historic reports of intellectual disability associated with the phenotype (PMID 894411).
Intellectual disability v3.109 SLC1A1 Sarah Leigh Phenotypes for gene: SLC1A1 were changed from Dicarboxylic aminoaciduria 222730 to Dicarboxylic aminoaciduria 222730
Intellectual disability v3.108 SLC1A1 Sarah Leigh Phenotypes for gene: SLC1A1 were changed from Dicarboxylic aminoaciduria 222730 to Dicarboxylic aminoaciduria 222730
Intellectual disability v3.106 SLC1A1 Sarah Leigh Publications for gene: SLC1A1 were set to Dicarboxylic aminoaciduria, MIM#222730
Intellectual disability v3.105 SLC1A1 Sarah Leigh Phenotypes for gene: SLC1A1 were changed from to Dicarboxylic aminoaciduria 222730
Intellectual disability v3.104 PIGS Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least 5 variants reported in at least 3 unrelated cases.
Intellectual disability v3.103 PIGS Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least 5 variants reported in at least 3 unrelated cases.
Intellectual disability v3.103 PIGS Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least 5 variants reported in at least 3 unrelated cases.
THIS GENE COULD BE RATED GREEN AT THE NEXT MAJOR REVIEW
Intellectual disability v3.101 ALG14 Sarah Leigh commented on gene: ALG14: Have added the "for review" tag, to address the phenotypic variability of published carriers of ALG14 variants.
Intellectual disability v3.101 ALG14 Sarah Leigh Added comment: Comment on list classification: Associated with Myasthenic syndrome, congenital, 15, without tubular aggregates 616227 in OMIM, but not associated with phenotype in Gen2Phen. At least 6 variants reported in at least 5 cases with varying phenotypes. PMID 23404334 reports compound heterozygous (p.P65L, P.R104*) sibs, who manifested with myasthenic syndromes, but did not have intellectural disability nor seizures and were 62 and 51 years old when reported. PMID 28733338 reports two compound heterozygous (p.D74N, pV141G), (p.D74N, p.R109Q) cases and a homozygous ((p.D74N), with early and lethal neurodegeneration with myasthenic and myopathic features, but the cases died before intellectual disability was manifiest. However, seizures were evident in two compound heterozygous families. PMID 30221345 reports a homozygous splicing variant in a case with intellectual disability and seizures. Functional studies were presented showing that this variant resulting in exon skipping, however, this was not completely prenetrant as wild type protein was detected at a low level in the patient.
Intellectual disability v3.100 ALG14 Sarah Leigh Phenotypes for gene: ALG14 were changed from Myasthenic syndrome, congenital, 15, without tubular aggregates, MIM#616227; Intellectual disability to Myasthenic syndrome, congenital, 15, without tubular aggregates 616227; Intellectual disability
Intellectual disability v3.99 PIGK Sarah Leigh Phenotypes for gene: PIGK were changed from Neurodevelopmental disorder with hypotonia and cerebellar atrophy, with or without seizures 618879 to Neurodevelopmental disorder with hypotonia and cerebellar atrophy, with or without seizures 618879
Intellectual disability v3.99 PIGK Sarah Leigh Phenotypes for gene: PIGK were changed from Neurodevelopmental disorder with hypotonia and cerebellar atrophy, with or without seizures 618879 to Neurodevelopmental disorder with hypotonia and cerebellar atrophy, with or without seizures 618879
Intellectual disability v3.98 PIGK Sarah Leigh Phenotypes for gene: PIGK were changed from Neurodevelopmental disorder with hypotonia and cerebellar atrophy, with or without seizures 618879 to Neurodevelopmental disorder with hypotonia and cerebellar atrophy, with or without seizures 618879
Intellectual disability v3.97 PIGK Sarah Leigh Phenotypes for gene: PIGK were changed from Neurodevelopmental disorder with hypotonia and cerebellar atrophy, with or without seizures 618879 to Neurodevelopmental disorder with hypotonia and cerebellar atrophy, with or without seizures 618879
Intellectual disability v3.96 PIGK Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene for PIGK-associated Neurodevelopmental Syndrome. At least 10 variants reported in at least 9 unrelated cases.
Intellectual disability v3.95 PIGK Sarah Leigh Phenotypes for gene: PIGK were changed from Neurodevelopmental disorder with hypotonia and cerebellar atrophy, with or without seizures 618879 to Neurodevelopmental disorder with hypotonia and cerebellar atrophy, with or without seizures 618879
Intellectual disability v3.95 PIGK Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene for PIGK-associated Neurodevelopmental Syndrome. At least 10 variants reported in at least 9 unrelated cases.
Intellectual disability v3.94 PIGK Sarah Leigh Phenotypes for gene: PIGK were changed from Neurodevelopmental disorder with hypotonia and cerebellar atrophy, with or without seizures 618879 to Neurodevelopmental disorder with hypotonia and cerebellar atrophy, with or without seizures 618879
Intellectual disability v3.93 PIGK Sarah Leigh Phenotypes for gene: PIGK were changed from Neurodevelopmental disorder with hypotonia and cerebellar atrophy, with or without seizures 618879 to Neurodevelopmental disorder with hypotonia and cerebellar atrophy, with or without seizures 618879
Intellectual disability v3.92 PIGK Sarah Leigh Phenotypes for gene: PIGK were changed from Intellectual disability; seizures; cerebellar atrophy to Neurodevelopmental disorder with hypotonia and cerebellar atrophy, with or without seizures 618879
Intellectual disability v3.91 WNT1 Catherine Snow Added comment: Comment on list classification: Identified by expert review from Zornitza Stark, sufficient number of unrelated patients for WNT1 to be classified as Green
Intellectual disability v3.90 SCAF4 Eleanor Williams changed review comment from: ESHG2020 - C02.1 - SCAF4 loss of function in humans and Drosophila implicates mRNA transcriptional termination in neurodevelopmental disorders - Fliedner et al - report 9 unrelated patients with likely pathogenic variants in SCAF4 and mild developmental delay and intellectual disability. 8 de novo. 1 inherited. Seizures, skeletal, renal and cardiac anomalies were also seen.
Sources: Literature; to: Conference talk/abstract from ESHG2020 - C02.1 - SCAF4 loss of function in humans and Drosophila implicates mRNA transcriptional termination in neurodevelopmental disorders - Fliedner et al - report 9 unrelated patients with likely pathogenic variants in SCAF4 and mild developmental delay and intellectual disability. 8 de novo. 1 inherited. Seizures, skeletal, renal and cardiac anomalies were also seen.
Sources: Literature
Intellectual disability v3.90 SCAF4 Eleanor Williams gene: SCAF4 was added
gene: SCAF4 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: SCAF4 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Added comment: ESHG2020 - C02.1 - SCAF4 loss of function in humans and Drosophila implicates mRNA transcriptional termination in neurodevelopmental disorders - Fliedner et al - report 9 unrelated patients with likely pathogenic variants in SCAF4 and mild developmental delay and intellectual disability. 8 de novo. 1 inherited. Seizures, skeletal, renal and cardiac anomalies were also seen.
Sources: Literature
Intellectual disability v3.88 CDC42BPB Sarah Leigh changed review comment from: Comment on list classification: Not associated with phenotype in OMIM and as possible Gen2Phen gene. At least 12 variants reported in 14 unrelated cases of CDC42BPB-related Neurodevelopmental Disorder. intellectual disability was apparent in 7/12 cases and at least 5 of these cases were de novo.; to: Comment on list classification: Not associated with phenotype in OMIM and as possible Gen2Phen gene. At least 12 variants reported in 14 unrelated cases of CDC42BPB-related Neurodevelopmental Disorder. Intellectual disability was apparent in 7/12 cases and at least 5 of these cases were de novo. However, only two of these cases did not have additional genetic changes reported.
Intellectual disability v3.88 CDC42BPB Sarah Leigh Added comment: Comment on list classification: Not associated with phenotype in OMIM and as possible Gen2Phen gene. At least 12 variants reported in 14 unrelated cases of CDC42BPB-related Neurodevelopmental Disorder. intellectual disability was apparent in 7/12 cases and at least 5 of these cases were de novo.
Intellectual disability v3.87 DSCR3 Zornitza Stark gene: DSCR3 was added
gene: DSCR3 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: DSCR3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DSCR3 were set to 31845315
Phenotypes for gene: DSCR3 were set to Intellectual disability, no OMIM # yet
Review for gene: DSCR3 was set to RED
Added comment: 1 family/2 cousins with cognitive impairment, growth failure, skeletal abnormalities, and distinctive facial features. Both shared the homozygous nonsense variant c.178G>T (p.Glu60*) in the VPS26C gene. This gene encodes VPS26C, a member of the retriever integral membrane protein recycling pathway. The nature of the variant which is predicted to result in loss‐of‐function, expression studies revealing significant reduction in the mutant transcript, and the co‐segregation of the homozygous variant with the phenotype in two affected individuals.
Sources: Literature
Intellectual disability v3.84 C16orf62 Sarah Leigh changed review comment from: Comment on list classification: Not associated with phenotype in OMIM or in Gen2Phen. Two variants have been reported as compound heterozygotes in two sibs with features of 3C/Ritscher-Schinzel syndrome. Functional studies show that loss of VPS35L function results in impared autophagy and VPS35L knockout mouse resulted in early embrionic lethality (PMID 25434475).; to: Comment on list classification: Not associated with phenotype in OMIM or in Gen2Phen. Two variants have been reported as compound heterozygotes in two sibs with features of 3C/Ritscher-Schinzel syndrome. Functional studies show that loss of VPS35L function results in impared autophagy and VPS35L knockout mouse resulted in early embrionic lethality (PMID 31712251).
Intellectual disability v3.83 SATB1 Eleanor Williams changed review comment from: Conference talk/abstract from ESHG 2020 - Mutation-specific pathophysiological mechanisms in a new SATB1-associated neurodevelopmental disorder - Den Hoed et al - report f26 individuals with SATB1 variants, 17 of which have missense variants and 9 have truncating variants. 21 of 26 variants (80%) were confirmed to be de novo in origin. Patients showed a broad phenotypic spectrum, including ID and/or neurodevelopmental delay, epilepsy, dental abnormalities and aspecific brain MRI findings. Additionally, patients with missense variants are more severely affected than those with truncating variants.
No peer reviewed publication was found in PubMed relating to these results so recommend Amber rating for now.
Sources: Other; to: Conference talk/abstract from ESHG 2020 - Mutation-specific pathophysiological mechanisms in a new SATB1-associated neurodevelopmental disorder - Den Hoed et al - report 26 individuals with SATB1 variants, 17 of which have missense variants and 9 have truncating variants. 21 of 26 variants (80%) were confirmed to be de novo in origin. Patients showed a broad phenotypic spectrum, including ID and/or neurodevelopmental delay, epilepsy, dental abnormalities and aspecific brain MRI findings. Additionally, patients with missense variants are more severely affected than those with truncating variants.
No peer reviewed publication was found in PubMed relating to these results so recommend Amber rating for now.
Sources: Other
Intellectual disability v3.83 SATB1 Eleanor Williams gene: SATB1 was added
gene: SATB1 was added to Intellectual disability. Sources: Other
Mode of inheritance for gene: SATB1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: SATB1 were set to intellectual disability
Review for gene: SATB1 was set to AMBER
Added comment: Conference talk/abstract from ESHG 2020 - Mutation-specific pathophysiological mechanisms in a new SATB1-associated neurodevelopmental disorder - Den Hoed et al - report f26 individuals with SATB1 variants, 17 of which have missense variants and 9 have truncating variants. 21 of 26 variants (80%) were confirmed to be de novo in origin. Patients showed a broad phenotypic spectrum, including ID and/or neurodevelopmental delay, epilepsy, dental abnormalities and aspecific brain MRI findings. Additionally, patients with missense variants are more severely affected than those with truncating variants.
No peer reviewed publication was found in PubMed relating to these results so recommend Amber rating for now.
Sources: Other
Intellectual disability v3.82 C16orf62 Sarah Leigh Added comment: Comment on list classification: Not associated with phenotype in OMIM or in Gen2Phen. Two variants have been reported as compound heterozygotes in two sibs with features of 3C/Ritscher-Schinzel syndrome. Functional studies show that loss of VPS35L function results in impared autophagy and VPS35L knockout mouse resulted in early embrionic lethality (PMID 25434475).
Intellectual disability v3.80 OTUD7A Zornitza Stark gene: OTUD7A was added
gene: OTUD7A was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: OTUD7A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: OTUD7A were set to 31997314; 29395075; 29395074
Phenotypes for gene: OTUD7A were set to Epileptic encephalopathy, intellectual disability, no OMIM# yet
Review for gene: OTUD7A was set to RED
Added comment: One patient with severe global developmental delay, language impairment and epileptic encephalopathy reported. Homozygous OTUD7A missense variant (c.697C>T, p.Leu233Phe), predicted to alter an ultraconserved amino acid, lying within the OTU catalytic domain. Its subsequent segregation analysis revealed that the parents, presenting with learning disability, and brother were heterozygous carriers. Biochemical assays demonstrated that proteasome complex formation and function were significantly reduced in patient‐derived fibroblasts and in OTUD7A knockout HAP1 cell line. Gene lies in the chromosome 15q13.3 region. Heterozygous microdeletions of chromosome 15q13.3 show incomplete penetrance and are associated with a highly variable phenotype that may include intellectual disability, epilepsy, facial dysmorphism and digit anomalies. Mouse model and other data support the role of this gene in neurodevelopmental phenotypes but nevertheless, single family to date.
Sources: Literature
Intellectual disability v3.80 TTC5 Zornitza Stark reviewed gene: TTC5: Rating: GREEN; Mode of pathogenicity: None; Publications: 29302074, 32439809; Phenotypes: Central hypotonia, Global developmental delay, Intellectual disability, Abnormality of nervous system morphology, Microcephaly, Abnormality of the face, Behavioral abnormality, Abnormality of the genitourinary system; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability v3.80 HIST1H4J Zornitza Stark gene: HIST1H4J was added
gene: HIST1H4J was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: HIST1H4J was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: HIST1H4J were set to 31804630
Phenotypes for gene: HIST1H4J were set to microcephaly; intellectual disability; dysmorphic features
Review for gene: HIST1H4J was set to AMBER
Added comment: Single case report but with functional evidence in zebrafish and phenotypic similarity to HIST1H4C phenotype
Sources: Literature
Intellectual disability v3.80 SNX27 Sarah Leigh Added comment: Comment on list classification: Not associated with phenotype in OMIM (lasted edited on 05/23/2012) or in Gen2Phen. However, five variants in three unrelated cases, together with supportive functional studies and mouse model.
Intellectual disability v3.79 SOX6 Zornitza Stark gene: SOX6 was added
gene: SOX6 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: SOX6 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SOX6 were set to 32442410
Phenotypes for gene: SOX6 were set to intellectual diability; ADHD; Craniosynostosis; Osteochondromas
Review for gene: SOX6 was set to GREEN
gene: SOX6 was marked as current diagnostic
Added comment: 19 individuals from 17 families with a neurodevelopmental syndrome reported. 6 LoF, 4 missense, and 6 intragenic deletion variants identified. ID ranged from mild to severe.
Sources: Literature
Intellectual disability v3.79 SLC5A6 Sarah Leigh Added comment: Comment on list classification: Not associated with phenotype in OMIM and as possible Gen2Phen gene for SLC5A6-related Neurodevelopmental Disorder. At least 5 variants published in three unrelated famililies (4 cases total) with SLC5A6-related Neurodevelopmental Disorder, together with supportive functional studies (PMID 29669219; 23104561). One of the cases had mixed semiology seizures including focal dyscognitive, absence, tonic spasms and generalised convulsive seizures with electrographic features of encephalopathy with generalised and independent multifocal spike-wave discharges (PMID 31754459), another case had brain, immune, bone and intestinal dysfunction (PMID 27904971) and the third had metabolic dysfunction mimicking biotinidase deficiency (PMID 31392107). This condition could be treated with biotin supplementation and introduction of pantothenic acid supplementation (PMID 31392107).
Intellectual disability v3.78 TTC5 Konstantinos Varvagiannis gene: TTC5 was added
gene: TTC5 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: TTC5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TTC5 were set to 29302074; 32439809
Phenotypes for gene: TTC5 were set to Central hypotonia; Global developmental delay; Intellectual disability; Abnormality of nervous system morphology; Microcephaly; Abnormality of the face; Behavioral abnormality; Abnormality of the genitourinary system
Penetrance for gene: TTC5 were set to Complete
Review for gene: TTC5 was set to GREEN
Added comment: Hu et al (2019 - PMID: 29302074) reported briefly on 3 individuals from 2 consanguineous families (from Turkey and Iran) with biallelic TTC5 variants. Features included DD (3/3), ID (severe in 2/2 with relevant age), microcephaly (3/3), brain abnormalities, etc. A nonsense and a variant affecting splice site were identified by WES/WGS.

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In a recent report, Rasheed et al (2020 - PMID: 32439809) report on the phenotype of 8 individuals - belonging to 5 consanguineous families - all 8 harboring homozygous TTC5 mutations.

Frequent features included hypotonia (6/8), motor and speech delay, moderate to severe ID (10/10 of relevant age - inclusion of less severely affected subjects was not considered by study design), brain MRI abnormalities (8/8). Other findings included microcephaly in some (6/11), behavioral abnormalities in few (autistic behavior in 2/8, aggression in 2/8), genitourinary anomalies (2/8), seizures (1/11). Facial phenotype incl. thin V-shaped upper lip, low-set ears (in most) and/or additional features.

TTC5 encodes a 440 aa protein, functioning as a scaffold to stabilise p300-JMY interactions. Apart from this role in nucleus, it has functions in the cytoplasm (inhibiting actin nucleataion, autophagosome formation, etc).

The gene has ubiquitous expression, highest in brain.

All variants were identified following WES - as the best candidates - in affected individuals with compatible Sanger studies in all affected family members and carrier parents.

2 missense and 2 nonsense variants were identified with the 2 missense SNVs localizing within TPR domains. qRT-PCR studies for a nonsense variant localizing 19 nt before the last exon, revealed fourfold decreased expression in affected individuals compared to carriers.

Families from Egypt shared a homozygous ~6.3 Mb haplotype block spanning TTC5, suggesting that p.(Arg263Ter) is likely a founder mutation.

The authors underscore some phenotypic (though not facial) similarities with Rubinstein-Taybi syndrome 2 due to EP300 mutations (in line with the role of TTC5).

Biallelic variants in genes encoding other members of the TTC family (containing a TPR motif), e.g. TTC8 or TTC15 cause disorders with neurologic manifestations (and DD/ID).
Sources: Literature
Intellectual disability v3.78 AGMO Rebecca Foulger changed review comment from: Comment on list classification: Gene was added to the panel and rated Green by Zornitza Stark. One family presented in PMID:27000257, and 2 compound het cases in PMID:31555905 (though there is one individual in gnomAD who is homozygous for the p.Gly144Arg variant). Functional data shows decreased enzyme activity of the variants. Although there are 3 cases, the phenotype is variable between patients (ID/DD vs regression). Therefore, rated as Amber awaiting further cases and clinical opinion.; to: Comment on list classification: Gene was added to the panel and rated Green by Zornitza Stark. One family presented in PMID:27000257, and 2 compound het cases in PMID:31555905 (though there is one individual in gnomAD who is homozygous for the p.Gly144Arg variant). Functional data shows decreased enzyme activity of the variants. Although there are 3 cases, the phenotype is variable between patients (ID/DD vs regression) and therefore this is borderline. Therefore, rated as Amber awaiting further cases and clinical opinion.
Intellectual disability v3.78 AGMO Rebecca Foulger changed review comment from: Comment on list classification: Gene was added to the panel and rated Green by Zornitza Stark. One homozygous case presented in PMID:27000257, and 2 compound het cases in PMID:31555905 (though there is one individual in gnomAD who is homozygous for the p.Gly144Arg variant). Functional data shows decreased enzyme activity of the variants. Although there are 3 cases, the phenotype is variable between patients (ID/DD vs regression). Therefore, rated as Amber awaiting further cases and clinical opinion.; to: Comment on list classification: Gene was added to the panel and rated Green by Zornitza Stark. One family presented in PMID:27000257, and 2 compound het cases in PMID:31555905 (though there is one individual in gnomAD who is homozygous for the p.Gly144Arg variant). Functional data shows decreased enzyme activity of the variants. Although there are 3 cases, the phenotype is variable between patients (ID/DD vs regression). Therefore, rated as Amber awaiting further cases and clinical opinion.
Intellectual disability v3.78 AGMO Rebecca Foulger Added comment: Comment on list classification: Gene was added to the panel and rated Green by Zornitza Stark. One homozygous case presented in PMID:27000257, and 2 compound het cases in PMID:31555905 (though there is one individual in gnomAD who is homozygous for the p.Gly144Arg variant). Functional data shows decreased enzyme activity of the variants. Although there are 3 cases, the phenotype is variable between patients (ID/DD vs regression). Therefore, rated as Amber awaiting further cases and clinical opinion.
Intellectual disability v3.77 AGMO Rebecca Foulger changed review comment from: PMID:27000257 (2016) Alrayes et al., 2016 enrolled a consanguineous family from Saudi Arabia presenting with primary microcephaly, developmental delay, short stature and intellectual disability. They identified a novel homozygous deletion mutation (c.967delA; p.Glu324Lysfs12*) in exon 10 of the alkylglycerol monooxygenase (AGMO) gene in 2 brothers. Population screening of 178 ethnically matched control chromosomes and consultation of the ExAC database confirmed that this variant was not present outside the family. Epilepsy is not mentioned amongst their phenotypes.; to: PMID:27000257 (2016) Alrayes et al., 2016 enrolled a consanguineous family from Saudi Arabia presenting with primary microcephaly, developmental delay, short stature and intellectual disability. They identified a novel homozygous deletion mutation (c.967delA; p.Glu324Lysfs12*) in exon 10 of the alkylglycerol monooxygenase (AGMO) gene in 2 brothers. Population screening of 178 ethnically matched control chromosomes and consultation of the ExAC database confirmed that this variant was not present outside the family.
Intellectual disability v3.77 AGMO Rebecca Foulger changed review comment from: PMID:31555905. Okur et al., report rare nonsense in-frame deletion and missense compound heterozygous variants in AGMO in 2 unrelated individuals (8 year old European girl, and 4-year old Ashkenazi Jewish boy). They demonstrated significantly diminished enzyme activity for all disease-associated variants. The girl harboured variants p.Trp130Ter & p.Gly238Cys. The boy harboured variants p.Gly144Arg and p.Tyr236del. Note that there is one individual in gnomAD who is homozygous for the p.Gly144Arg variant. Table 1 also mentions MTHFR C677T homozygous for the boy, but this is not referred to within the text. ID/DD (and seizures) was reported in the girl. The boy showed normal development to begin, but began to regress age 3.5 years.; to: PMID:31555905. Okur et al., report rare nonsense in-frame deletion and missense compound heterozygous variants in AGMO in 2 unrelated individuals (8 year old European girl, and 4-year old Ashkenazi Jewish boy). They demonstrated significantly diminished enzyme activity for all disease-associated variants. The girl harboured variants p.Trp130Ter & p.Gly238Cys. The boy harboured variants p.Gly144Arg and p.Tyr236del. Note that there is one individual in gnomAD who is homozygous for the p.Gly144Arg variant. Table 1 also mentions MTHFR C677T homozygous for the boy, but this is not referred to within the text. ID/DD (and seizures) were reported in the girl. The boy showed normal development to begin, but began to regress age 3.5 years.
Intellectual disability v3.76 AGMO Rebecca Foulger commented on gene: AGMO: PMID:31555905. Okur et al., report rare nonsense in-frame deletion and missense compound heterozygous variants in AGMO in 2 unrelated individuals (8 year old European girl, and 4-year old Ashkenazi Jewish boy). They demonstrated significantly diminished enzyme activity for all disease-associated variants. The girl harboured variants p.Trp130Ter & p.Gly238Cys. The boy harboured variants p.Gly144Arg and p.Tyr236del. Note that there is one individual in gnomAD who is homozygous for the p.Gly144Arg variant. Table 1 also mentions MTHFR C677T homozygous for the boy, but this is not referred to within the text. ID/DD (and seizures) was reported in the girl. The boy showed normal development to begin, but began to regress age 3.5 years.
Intellectual disability v3.76 KAT8 Rebecca Foulger commented on gene: KAT8: Added 'missense' tag because all de novo variants in PMID:31794431 are missense. Note that for the biallelic case in the same paper, one of the variants is nonsense.
Intellectual disability v3.75 KAT8 Rebecca Foulger Added comment: Comment on mode of inheritance: Individual T9 inherited biallelc variants from her asymptomatic parents. Her sister carried 1 variant and showed no obvious symptoms. This may be due to incomplete genetic penetrance, or the two variants act differently from the de novo heterozygous variants identified. This is the only example of biallelic inheritance, so have set MOI to 'monoallelic' until more cases are identified.
Intellectual disability v3.74 KAT8 Rebecca Foulger Added comment: Comment on list classification: Gene was added to the panel and rated Green by Konstantinos Varvagiannis, and subsequently reviewed Green by Zornitza Stark. Not yet associated with a disorder in OMIM or G2P. All cases come from PMID:31794431 (Li et al.2019) who report 8 unrelated individuals with heterozygous de novo pathogenic KAT8 variants (T1,T2,T3 had the same variant), plus one individual compound het for a nonsense and a missense variant (p.Lys175* and p.Arg325Cys). All individuals had DD and/or ID (Supplementary materials). Knockout mice failed to thrive, and showed early lethality and cerebral hypoplasia.
Intellectual disability v3.73 CXorf56 Rebecca Foulger changed review comment from: Comment on mode of inheritance: OMIM records XL inheritance for MIM:301013 with X-linked inactivation. In PMID:29374277 carrier females had skewed X-inactivation whereas the affected female did not. In PMID:31822863 X-linked skewing was seen in both affected females and the unaffected carrier.; to: Comment on mode of inheritance: OMIM records XL inheritance for MIM:301013 noting X-linked inactivation in the comments. In PMID:29374277 carrier females had skewed X-inactivation whereas the affected female did not. In PMID:31822863 X-linked skewing was seen in both affected females and the unaffected carrier. Have set MOI to XLD for now, to capture affected females and males.
Intellectual disability v3.73 CXorf56 Rebecca Foulger Added comment: Comment on list classification: Updated rating from Grey to Green. Gene was added to panel by Konstantinos Varvagiannis, with a subsequent Green review by Zornitza Stark. Sufficient cases in PMIDs:29374277 and 31822863. The reported pattern of X-inactivation differs between the papers, but sufficient cases and relevant phenotype for inclusion on the panel.
Intellectual disability v3.72 CXorf56 Rebecca Foulger Added comment: Comment on mode of inheritance: OMIM records XL inheritance for MIM:301013 with X-linked inactivation. In PMID:29374277 carrier females had skewed X-inactivation whereas the affected female did not. In PMID:31822863 X-linked skewing was seen in both affected females and the unaffected carrier.
Intellectual disability v3.71 CXorf56 Rebecca Foulger commented on gene: CXorf56: PMID:31822863. Rocha et al., 2019 report on 9 affected individuals (3 unrelated families) with mild to severe ID and variants in CXorf56. In comparison to PMID:29374277, X-linked skewing was seen in both affected females and the unaffected carrier had complete inactivation of the carrier X-chromosome.
Intellectual disability v3.71 UGP2 Rebecca Foulger Added comment: Comment on list classification: Gene added to panel and rated Green by Konstantinos Varvagiannis. Subsequently reviewed Green by Zornitza Stark. Sufficient evidence and appropriate phenotype (DD seen in all patients in PMID:31820119) for inclusion on panel: 20 patients from 13 unrelated families all with the same variant identified in PMID:31820119 (2019 publication). Therefore updated rating from Grey to Green.
Intellectual disability v3.70 UGP2 Rebecca Foulger Phenotypes for gene: UGP2 were changed from Seizures; Global developmental delay; Intellectual disability; Feeding difficulties; Abnormality of vision; Abnormality of the face to Epileptic encephalopathy, early infantile, 83, 618744; Global developmental delay; Intellectual disability; Feeding difficulties; Abnormality of vision; Abnormality of the face
Intellectual disability v3.69 TRAPPC4 Rebecca Foulger Added comment: Comment on list classification: Added to panel and rated Green by Konstantinos Varvagiannis. Subsequent Green review by Zornitza Stark. Updated rating from Grey to Green: 7 children from 3 unrelated families with MIM:618741 reported by, Van Bergen et al. (2020) with a recurring homozygous splice site variant in TRAPPC4 resulting in a splice site alteration, the skipping of exon 3, a frameshift, and premature termination (Leu120AspfsTer9). The variant segregated within the disorder within the families and was only found in heterozygous state in gnomAD. Appropriate phenotype and cases just reach threshold for inclusion.
Intellectual disability v3.68 TRAPPC4 Rebecca Foulger Phenotypes for gene: TRAPPC4 were changed from Feeding difficulties; Progressive microcephaly; Intellectual disability; Seizures; Spastic tetraparesis; Abnormality of the face; Scoliosis; Cortical visual impairment; Hearing impairment to Neurodevelopmental disorder with epilepsy, spasticity, and brain atrophy, 618741
Intellectual disability v3.67 WDR45B Rebecca Foulger Phenotypes for gene: WDR45B were changed from AUTOSOMAL RECESSIVE MENTAL RETARDATION to AUTOSOMAL RECESSIVE MENTAL RETARDATION; Neurodevelopmental disorder with spastic quadriplegia and brain abnormalities with or without seizures, 617977
Intellectual disability v3.66 ALKBH8 Rebecca Foulger Added comment: Comment on list classification: Demoted from Green to Amber based on advice from the Genomics England Clinical Team. In email correspondence, Helen Brittain notes that this is a borderline gene in terms of evidence (two families, 6/7 individuals with seizures and not particularly extensive functional / supportive information). Zornitza's review on the Genetic Epilepsy Syndromes panel focuses on the differing ratings of ALKBH8 on the ID (Green) and Epilepsy (Amber) panels. Based on borderline evidence, I have demoted ALKBH8 to Amber on the ID panel to be consistent with the GLH consensus on the Epilepsy panel (R59 #402).
Intellectual disability v3.65 PTRHD1 Helen Brittain Marked gene: PTRHD1 as ready
Intellectual disability v3.65 PTRHD1 Helen Brittain Added comment: Comment when marking as ready: Further case from personal correspondence. Considered sufficient for a green rating.
Intellectual disability v3.65 PTRHD1 Helen Brittain Phenotypes for gene: PTRHD1 were changed from Intellectual disability; Parkinsonism, Intellectual disability; Parkinsonism to Intellectual disability; Parkinsonism
Intellectual disability v3.61 SMARCD1 Eleanor Williams Phenotypes for gene: SMARCD1 were changed from Generalized hypotonia; Feeding difficulties; Global developmental delay; Intellectual disability; Abnormality of the hand; Abnormality of the foot to Generalized hypotonia; Feeding difficulties; Global developmental delay; Intellectual disability; Abnormality of the hand; Abnormality of the foot; Coffin-Siris syndrome 11, 618779
Intellectual disability v3.59 DLG4 Eleanor Williams Phenotypes for gene: DLG4 were changed from Intellectual disability; Marfanoid habitus to Intellectual disability; Marfanoid habitus; Intellectual developmental disorder 62 #618793
Intellectual disability v3.58 CDK8 Eleanor Williams Phenotypes for gene: CDK8 were changed from Generalized hypotonia; Feeding difficulties; Global developmental delay; Intellectual disability; Behavioral abnormality; Abnormality of cardiovascular system morphology; Hearing impairment; Abnormality of vision; Anorectal anomaly; Seizures to Generalized hypotonia; Feeding difficulties; Global developmental delay; Intellectual disability; Behavioral abnormality; Abnormality of cardiovascular system morphology; Hearing impairment; Abnormality of vision; Anorectal anomaly; Seizures; Intellectual developmental disorder with hypotonia and behavioral abnormalities #618748
Intellectual disability v3.57 PCYT2 Rebecca Foulger Phenotypes for gene: PCYT2 were changed from Global developmental delay; Developmental regression; Intellectual disability; Spastic paraparesis; Seizures; Spastic tetraparesis; Cerebral atrophy; Cerebellar atrophy to Spastic paraplegia 82, autosomal recessive, 618770; Global developmental delay; Developmental regression; Intellectual disability; Spastic paraparesis; Seizures; Spastic tetraparesis; Cerebral atrophy; Cerebellar atrophy
Intellectual disability v3.56 EXT2 Rebecca Foulger Added comment: Comment on list classification: Updated rating from Amber to Green. Sufficient cases to support causation of MIM:616682, of which ID is a prominent phenotype. Note that I have updated the Mode of Inheritance from AD to AR to match MIM:616682 (and the Genetic epilepsy syndromes panel, #402).
Intellectual disability v3.55 EXT2 Rebecca Foulger changed review comment from: PMID:30288735. In 2 siblings with MIM:616682, Gentile et al identified compound het missense variants in EXT2, which segregated with the disorder (D227N and Y608C). The D227N vairant contributes to exostosis (inherited from the mother who had a family history of exostosis).; to: PMID:30288735. In 2 siblings with MIM:616682, Gentile et al identified compound het missense variants in EXT2, which segregated with the disorder (D227N and Y608C). The D227N variant contributes to exostosis (inherited from the mother who had a family history of exostosis).
Intellectual disability v3.55 EXT2 Rebecca Foulger commented on gene: EXT2: PMID:30288735. In 2 siblings with MIM:616682, Gentile et al identified compound het missense variants in EXT2, which segregated with the disorder (D227N and Y608C). The D227N vairant contributes to exostosis (inherited from the mother who had a family history of exostosis).
Intellectual disability v3.55 EXT2 Rebecca Foulger commented on gene: EXT2: PMID:30997052. In a 14 year old girl, Gupta et al. (2019) identified compound het missense variants in the EXT2 gene (V373D and T672M), which segregated with the disorder in the family. The patient also carried a maternal heterozygous variant (R454C) in NDST1. She had developmental delay, autism and epilepsy amongst her phenotypes.
Intellectual disability v3.55 EXT2 Rebecca Foulger commented on gene: EXT2: PMID:30075207. In 2 brothers, born of consanguineous Syrian parents, with MIM:616682 El-Bazzal et al. (2019) identified a homozygous missense mutation in the EXT2 gene (p.Ser4Leu). Psychomotor delay was noted for both at the age of 3 months.
Intellectual disability v3.55 EXT2 Rebecca Foulger commented on gene: EXT2: PMID:26246518: In 4 siblings, born of consanguineous parents in the Old Order Mennonite community, with seizures, scoliosis, and macrocephaly/microcephaly syndrome (MIM:616682), Farhan et al. (2015) identified homozygosity for 2 missense mutations in EXT2 (M87R and R95C). All siblings had moderate ID and a seizure disorder.
Intellectual disability v3.54 EXT2 Rebecca Foulger Added comment: Comment on mode of inheritance: Updated MOI from MONOALLELIC to BIALLELIC. EXT2 is associated with 2 different disorders: Seizures, scoliosis, and macrocephaly syndrome, 616682 (AR) and Exostoses, multiple, type 2, 133701 (AD). MIM:616682 is relevant to this panel.
Intellectual disability v3.51 EXT2 Rebecca Foulger Added comment: Comment on mode of inheritance: Updated MOI from MONOALLELIC to BIALLELIC. EXT2 is associated with 2 different disorders: Seizures, scoliosis, and macrocephaly syndrome, 616682 (AR) and Exostoses, multiple, type 2, 133701 (AD). MIM:616682 is relevant to this panel.
Intellectual disability v3.48 WASF1 Rebecca Foulger Phenotypes for gene: WASF1 were changed from ID associated with autistic features, seizures, and developmental delay; intellectual disability to Neurodevelopmental disorder with absent language and variable seizures, 618707; ID associated with autistic features, seizures, and developmental delay; intellectual disability
Intellectual disability v3.46 POLR2A Rebecca Foulger Phenotypes for gene: POLR2A were changed from Global developmental delay; Generalized hypotonia; Feeding difficulties to Neurodevelopmental disorder with hypotonia and variable intellectual and behavioral abnormalities, 618603; Global developmental delay; Generalized hypotonia; Feeding difficulties
Intellectual disability v3.43 MSL3 Rebecca Foulger Phenotypes for gene: MSL3 were changed from Muscular hypotonia; Feeding difficulties; Neurodevelopmental delay; Intellectual disability; no OMIM number to Muscular hypotonia; Feeding difficulties; Neurodevelopmental delay; Intellectual disability; Basilicata-Akhtar syndrome, 301032
Intellectual disability v3.39 NR4A2 Konstantinos Varvagiannis edited their review of gene: NR4A2: Added comment: Singh et al (2020 - https://doi.org/10.1038/s41436-020-0815-4) provide details on the phenotype of 9 unrelated individuals with NR4A2 pathogenic variants (in almost all cases de novo).

Features included hypotonia (in 6/9), DD (9/9), varying levels of ID (mild to severe in 8/8 for whom this information was available), seizures (6/9 - variable epilepsy phenotypes), behavioral problems (5/9 - with autism reported for one). Less frequent features incl. hypermobility (in 3), ataxia/movement disorder (in 3).

8 total pLoF and missense variants were identified as de novo events following trio exome sequencing with Sanger validation (7/8 variants). For 1(/8) individual with a stopgain variant, a single parental sample was available. A 9th individual was found to harbor a ~3.7 Mb 2q deletion spanning also other genes (which might also contribute to his phenotype of epilepsy).

Only the effect of a variant affecting the splice-acceptor site was studied (c.865-1_865delGCinsAAAAAGGAGT - NM_006186.3) with RT-PCR demonstrating an out-of-frame skipping of exon 4. Another variant (NM_006186.3:c.325dup) found in a subject with DD, ID and epilepsy had also previously been reported in another individual with similar phenotype of epilepsy and ID (Ramos et al - PMID: 31428396 - the variant was de novo with other causes for his phenotype excluded).

As discussed by Singh et al, NR4A2 encodes a steroid-thyroid-retinoid receptor which acts as a nuclear receptor transcription factor. The authors summarize previous reports on NR4A2 haploinsufficiency (NR4A2 has a pLI of 1 and HI score of 1.28% - Z-score is 2.24).

The authors comment on mouse models suggesting a role of NR4A2 for dopaminergic neurons, and provide plausible explanations for the phenotype of ID/seizures.; Changed publications: https://doi.org/10.1038/s41436-020-0815-4, 31428396, 29770430, 30504930, 28544326, 27569545, 23554088, 28135719, 27479843, 25363768; Changed phenotypes: Generalized hypotonia, Global developmental delay, Intellectual disability, Seizures, Behavioral abnormality, Abnormality of movement, Joint hypermobility
Intellectual disability v3.39 CUL3 Konstantinos Varvagiannis reviewed gene: CUL3: Rating: GREEN; Mode of pathogenicity: None; Publications: 32341456; Phenotypes: Global developmental delay, Intellectual disability, Seizures, Abnormality of cardiovascular system morphology, Abnormality of the palate, Pseudohypoaldosteronism, type IIE - MIM #614496; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.38 ALG9 Rebecca Foulger Added comment: Comment on list classification: As highlighted by Zornitza Stark, since the last curation review, a number of papers have been published on the ALG9 phenotype, including PMID:26453364 and PMID:28932688 who review the literature and report additional cases. At least 6-7 (of 10/11) patients have developmental delay. Therefore sufficient cases to support causation and have updated rating from Red to Green.
Intellectual disability v3.36 ALG9 Rebecca Foulger commented on gene: ALG9: PMID:28932688. Davis et al., 2017 review the literature for ALG9:CDG cases. They summarise 10 patients from 6 different families with one of four ALG9 variants (including the 4 new patients reported by PMID:26453364). They also report an additional patient with ALG9-CDH with a milder phenotype. Prenatally, dysmorphic features, renal cysts and cardiac malformations were detected. She had seizures and developmental delay. She had a homozygous variant in ALG9: p.Tyr287Cys.
Intellectual disability v3.36 ALG9 Rebecca Foulger changed review comment from: PMID:26453364. AlSubhi et al., 2016 summarise 6 patients with ALG9-CDG from the literature and report 4 additional patients from a large consanguineous family. 6/10 patients had developmental disability including the index patient (IV:5), a6 year old girl with global DD, skeletal dysplasia, epilepsy, facial dysmorphisms amongst her phenotypes. The three affected cousins had similar phenotypes.; to: PMID:26453364. AlSubhi et al., 2016 summarise 6 patients with ALG9-CDG from the literature and report 4 additional patients from a large consanguineous family. 6/10 patients had developmental disability including the index patient (IV:5), a 6 year old girl with global DD, skeletal dysplasia, epilepsy, facial dysmorphisms amongst her phenotypes. The three affected cousins had similar phenotypes.
Intellectual disability v3.35 UGDH Konstantinos Varvagiannis gene: UGDH was added
gene: UGDH was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: UGDH was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: UGDH were set to 32001716
Phenotypes for gene: UGDH were set to Epileptic encephalopathy, early infantile, 84 - MIM #618792
Penetrance for gene: UGDH were set to Complete
Review for gene: UGDH was set to GREEN
Added comment: Hengel et al (2020 - PMID: 32001716) report on 36 individuals with biallelic UGDH pathogenic variants.

The phenotype corresponded overall to a developmental epileptic encephalopathy with hypotonia, feeding difficulties, severe global DD, moderate or commonly severe ID in all. Hypotonia and motor disorder (incl. spasticity, dystonia, ataxia, chorea, etc) often occurred prior to the onset of seizures. A single individual did not present seizures and 2 sibs had only seizures in the setting of fever.

Affected subjects were tested by exome sequencing and UGDH variants were the only/best candidates for the phenotype following also segregation studies. Many were compound heterozygous or homozygous (~6 families were consanguineous) for missense variants and few were compound heterozygous for missense and pLoF variants. There were no individuals with biallelic pLoF variants identified. Parental/sib studies were all compatible with AR inheritance mode.

UGDH encodes the enzyme UDP-glucose dehydrogenase which converts UDP-glucose to UDP-glucuronate, the latter being a critical component of the glycosaminoglycans, hyaluronan, chondroitin sulfate, and heparan sulfate [OMIM].

Patient fibroblast and biochemical assays suggested a LoF effect of variants leading to impairment of UGDH stability, oligomerization or enzymatic activity (decreased UGDH-catalyzed reduction of NAD+ to NADH / hyaluronic acid production which requires UDP-glucuronate).

Attempts to model the disorder using an already developped zebrafish model (for a hypomorphic LoF allele) were unsuccessful as fish did not exhibit seizures spontaneously or upon induction with PTZ.

Modelling of the disorder in vitro using patient-derived cerebral organoids demonstrated smaller organoids due to reduced number of proliferating neural progenitors.
Sources: Literature
Intellectual disability v3.35 YIF1B Konstantinos Varvagiannis gene: YIF1B was added
gene: YIF1B was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: YIF1B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: YIF1B were set to 32006098
Phenotypes for gene: YIF1B were set to Central hypotonia; Failure to thrive; Microcephaly; Global developmental delay; Intellectual disability; Seizures; Spasticity; Abnormality of movement
Penetrance for gene: YIF1B were set to Complete
Review for gene: YIF1B was set to GREEN
Added comment: AlMuhaizea et al (2020 - PMID: 32006098) report on the phenotype of 6 individuals (from 5 families) with biallelic YIF1B truncating variants.

Affected subjects presented hypotonia, failure to thrive, microcephaly (5/6), severe global DD and ID (as evident from best motor/language milestones achieved - Table S1) as well as features suggestive of a motor disorder (dystonia/spasticity/dyskinesia). Seizures were reported in 2 unrelated individuals (2/6). MRI abnormalities were observed in some with thin CC being a feature in 3.

Variable initial investigations were performed including SNP CMA, MECP2, microcephaly / neurotransmitter disorders gene panel testing did not reveal P/LP variants.

YIF1B variants were identified in 3 families within ROH. Following exome sequencing, affected individuals were found to be homozygous for truncating variants (4/5 families being consanguineous). The following 3 variants were identified (NM_001039672.2) : c.186dupT or p.Ala64fs / c.360_361insACAT or p.Gly121fs / c.598G>T or p.Glu200*.

YIF1B encodes an intracellular transmembrane protein.

It has been previously demonstrated that - similarly to other proteins of the Yip family being implicated in intracellular traffic between the Golgi - Yif1B is involved in the anterograde traffic pathway. Yif1B KO mice demonstrate a disorganized Golgi architecture in pyramidal hippocampal neurons (Alterio et al 2015 - PMID: 26077767). The rat ortholog interacts with serotonin receptor 1 (5-HT1AR) with colocalization of Yif1BB and 5-HT1AR in intermediate compartment vesicles and involvement of the former in intracellular trafficing/modulation of 5-HT1AR transport to dendrites (PMID cited: 18685031).

Available mRNA and protein expression data (Protein Atlas) suggest that the gene is widely expressed in all tissues incl. neuronal cells. Immunochemistry data from the Human Brain Atlas also suggest that YIF1B is found in vesicles and localized to the Golgi apparatus. Immunohistochemistry in normal human brain tissue (cerebral cortex) demonstrated labeling of neuronal cells (Human Protein Atlas).

Functional/network analysis of genes co-regulated with YIF1B based on available RNAseq data, suggest enrichement in in genes important for nervous system development and function.

Please consider inclusion in other panels that may be relevant (e.g. microcephaly, etc).
Sources: Literature
Intellectual disability v3.35 SPTBN4 Konstantinos Varvagiannis gene: SPTBN4 was added
gene: SPTBN4 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: SPTBN4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SPTBN4 were set to 28540413; 28940097; 29861105; 31230720; 31857255
Phenotypes for gene: SPTBN4 were set to Neurodevelopmental disorder with hypotonia, neuropathy, and deafness MIM#617519
Penetrance for gene: SPTBN4 were set to Complete
Review for gene: SPTBN4 was set to GREEN
Added comment: Biallelic pathogenic SPTBN4 variants cause Neurodevelopmental disorder with hypotonia, neuropathy, and deafness (MIM #617519).

There are several reports on the phenotype of relevant affected individuals with severe/profound DD/ID in at least 9 individuals :

- Knierim et al (2017 - PMID: 28540413) [1 affected individual]
- Anazi et al (2017 - PMID: 28940097) [1]
- Wang et al (2018 - PMID: 29861105) [6]
- Pehlivan et al (2019 - PMID: 31230720) [1]

A recent article by Häusler et al (2019 - PMID: 31857255) describes the phenotype of 2 sibs, both presenting with motor and speech delay, although the older one had reportedly 'normal' cognitive performance allowing attendance of regular school at the age of 6 years.

Features include congenital hypotonia, severe DD and ID (in most as outlined above, ID was the primary indication for testing on several occasions), poor or absent reflexes and weakness secondary to axonal motor neuropathy, feeding and respiratory difficulties, hearing and visual impairment. Seizures have been reported in at least 4 unrelated individuals (3 by Wang et al / 1 by Pehlivan et al).

Variants in most cases were nonsense/frameshift although biallelic missense variants have also been reported. Sibs in the report by Häusler et al harbored a homozygous splicing variant.

SPTBN4 encodes a member of the beta-spectrin protein family that is expressed in the brain, peripheral nervous system, pancreas, and skeletal muscle.

βIV spectrin links ankyrinG and clustered ion channels (at axon initial segments and nodes of Ranvier) to the axonal cytoskeleton. Pathogenic variants are proposed to disrupt the cytoskeletal machinery controlling proper localization of ion channels and function of axonal domains where ion channels are normally clustered in high density. Among the evidence provided : nerve biopsies from an affected individual displayed reduced nodal Na+ channels and no nodal KCNQ2 K+ channels / Loss of AnkyrinG and βIV spectrin in animal model resulted in loss of KCNQ2- and KCNQ3- subunit containing K+ channels.

Apart from the ID / epilepsy panels please consider inclusion in other relevant ones.
Sources: Literature
Intellectual disability v3.35 CDC42BPB Konstantinos Varvagiannis gene: CDC42BPB was added
gene: CDC42BPB was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: CDC42BPB was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CDC42BPB were set to 32031333
Phenotypes for gene: CDC42BPB were set to Central hypotonia; Global developmental delay; Intellectual disability; Seizures; Autistic behavior; Behavioral abnormality
Penetrance for gene: CDC42BPB were set to unknown
Review for gene: CDC42BPB was set to GREEN
Added comment: Chilton et al (2020 - PMID: 32031333) report on 14 individuals with missense and loss-of-function CDC42BPB variants.

Features included hypotonia (8/11), DD (12/13 - the 14th was a fetus), ID (7/13), ASD (8/12), clinical seizures (in 3 - a 4th had abnormal EEG without seizures), behavioral abnormalities. Variable non-specific dysmorphic features were reported in some (sparse hair being the most frequent - 4/8). Additional features were observed in few (=<4) incl. cryptorchidism, ophthalmological issues, constipation, kidney abnormalities, micropenis, etc.

All individuals had non-diagnostic prior genetic testing (incl. CMA, FMR1, MECP2, Angelman/Prader-Willi methylation studies, autism gene panel - suggesting relevance to the current panel) or metabolic testing.

Variants were identified following clinical exome sequencing with Sanger confirmation. Most occurred as de novo events (11/14) while inheritance was not available for few (3/14). Missense variants did not display (particular) clustering.

Almost all variants were absent from gnomAD and were predicted to be deleterious in silico (among others almost all had CADD scores >25).

As the authors comment, CDC42BPB encodes myotonic dystrophy-related Cdc42-binding kinase β (MRCKβ) a serine/threonine protein kinase playing a role in regulation of cytoskeletal reorganization and cell migration in nonmuscle cells (through phosporylation of MLC2).

Previous studies have demonstrated that it is ubiquitously expressed with prenatal brain expression.

The gene appears to be intolerant to pLoF (pLI of 1) as well as to missense variants (Z-score of 3.66).

CDC42BPB is a downstream effector of CDC42. Mutations of the latter cause Takenouchi-Kosaki syndrome with DD/ID and some further overlapping features (with CDC42BPB-associated phenotypes).

Homozygous Cdc42bpb KO in mouse appears to be nonviable (MGI:2136459). Loss of gek in the eyes of Drosophila results in disrupted growth cone targeting to the lamina (gek is the fly CDC42BPB ortholog).

Please consider inclusion with amber / green rating in the ID panel (>=4 relevant individuals / variants) and other panels (e.g. for epilepsy, ASD).
Sources: Literature
Intellectual disability v3.35 ADAM22 Rebecca Foulger Added comment: Comment on list classification: Set rating as Amber: 2 unrelated families with ID as part of the phenotype (PMID:27066583 and 30237576).
Intellectual disability v3.34 ADAM22 Rebecca Foulger commented on gene: ADAM22: PMID:27066583. Muona et al., 2016 report a Finnish proband-parent-trio with intractable seizures and ID. Compound het variants c.1202G>A, p.Cys401Tyr and c.2396delG, p.Ser799IlefsTer96 were found in ADAM22. Functional assays showed that mutant proteins failed to form the LGI1-ADAM22 ligand-receptor complex. The variants are unlikely to be full LOF.
Intellectual disability v3.34 ADAM22 Rebecca Foulger commented on gene: ADAM22: PMID:30237576 (Maddirevula et al., 2019) searched their database of clinical exomes for homozygous variants and report an 18 year old male with Arg860* variant and recurrent seizures (Supplementary Table). His development was normal until 5 months when he had a slower gain of milestones. He has ID with severely delayed speech. Family history revealed ID and epilepsy in his old brother and in wider family.
Intellectual disability v3.34 ADAM22 Rebecca Foulger gene: ADAM22 was added
gene: ADAM22 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: ADAM22 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ADAM22 were set to 27066583; 30237576
Added comment: Added ADAM22 to ID panel based on literature curation for Epilepsy phenotype. Patients in PMID:27066583 (Finnish trio with compound het ADAM22 variants in the proband) and PMID:30237576 (18 year old male with Arg860* variant) both report ID alongside epilepsy.
Sources: Literature
Intellectual disability v3.33 VPS51 Zornitza Stark gene: VPS51 was added
gene: VPS51 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: VPS51 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: VPS51 were set to 30624672; 31207318
Phenotypes for gene: VPS51 were set to Pontocerebellar hypoplasia, type 13, MIM# 618606
Review for gene: VPS51 was set to AMBER
Added comment: Two families reported with bi-allelic variants in this gene and global developmental delay, impaired intellectual development with absent speech, microcephaly, and progressive atrophy of the cerebellar vermis and brainstem. Additional features, including seizures and visual impairment, are variable.
Sources: Literature
Intellectual disability v3.33 LRRC32 Zornitza Stark gene: LRRC32 was added
gene: LRRC32 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: LRRC32 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LRRC32 were set to 30976112
Phenotypes for gene: LRRC32 were set to Intellectual disability; cleft palate; proliferative retinopathy
Review for gene: LRRC32 was set to AMBER
Added comment: Three individuals from two consanguineous families segregated the same homozygous bi-allelic variant, c.1630C>T; p.(Arg544Ter), shared haplotype indicative of founder effect. Mouse model has cleft palate and neonatal death.
Sources: Literature
Intellectual disability v3.33 CTU2 Rebecca Foulger Added comment: Comment on list classification: Gene was added to panel and rated Green by Zornitza Stark. Sufficient cases of global DD in PMID:31301155 in patients that survived infancy to support causation. Therefore updated rating from Grey to Green.
Intellectual disability v3.31 FEM1B Zornitza Stark gene: FEM1B was added
gene: FEM1B was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: FEM1B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FEM1B were set to 31036916
Phenotypes for gene: FEM1B were set to Syndromic intellectual disability
Review for gene: FEM1B was set to AMBER
Added comment: PMID: 31036916 - a single individual with de novo variant reported in a neurodevelopmental disorder cohort. Authors note another de novo case with the exact same variant (p.Arg126Gln) from the DDD study, and a 3rd patient from GeneMatcher with the same de novo missense again. The variant is in a highly constrained region of the protein. Cannot be certain the DDD and GeneMatcher individuals are unrelated, therefore I have treated as two reports for now.
Sources: Literature
Intellectual disability v3.31 WIPI2 Zornitza Stark gene: WIPI2 was added
gene: WIPI2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: WIPI2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: WIPI2 were set to 30968111
Phenotypes for gene: WIPI2 were set to Intellectual developmental disorder with short stature and variable skeletal anomalies 618453
Review for gene: WIPI2 was set to RED
Added comment: Four homozygous individuals from one consanguineous family with intellectual disability, short stature and variable skeletal anomalies. Functional studies in patient cells showed impaired protein function. One to watch.
Sources: Literature
Intellectual disability v3.31 GSX2 Zornitza Stark gene: GSX2 was added
gene: GSX2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: GSX2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GSX2 were set to 31412107
Phenotypes for gene: GSX2 were set to Diencephalic-mesencephalic junction dysplasia syndrome 2 618646; Intellectual disability; Dystonia; Spastic tetra paresis
Review for gene: GSX2 was set to AMBER
Added comment: Two unrelated families, some functional data.
Sources: Literature
Intellectual disability v3.31 YARS Zornitza Stark gene: YARS was added
gene: YARS was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: YARS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: YARS were set to 30304524; 29232904; 27633801
Phenotypes for gene: YARS were set to Intellectual disability; deafness; nystagmus; liver dysfunction
Review for gene: YARS was set to GREEN
gene: YARS was marked as current diagnostic
Added comment: Mono-allelic variants are associated with CMT. However, 10 individuals from three unrelated families reported with bi-allelic variants and a severe phenotype, comprising ID, nystagmus, deafness, liver dysfunction and a range of other features.
Sources: Literature
Intellectual disability v3.31 CEP55 Rebecca Foulger Added comment: Comment on list classification: Rated CEP55 as Green: >3 unrelated cases in PMID:32100459 with DD/ID (2 of which are severe).
Intellectual disability v3.30 CEP55 Rebecca Foulger changed review comment from: PMID:32100459 (Barrie et al., 2020) describe 7 living individuals (5 families) with biallelic variants (compound het and homozygous splice site variant) in CEP55. Global/severe DD was seen in patient 2, and the 3 siblings (patients 5,6,7). Mild/delayed motor/speech development was seen in unrelated patients 3 and 4.; to: PMID:32100459 (Barrie et al., 2020) describe 7 living individuals (5 families) with biallelic variants (compound het and homozygous splice site variant) in CEP55. Global/severe DD was seen in patient 2, and the 3 siblings (patients 5,6,7). Mild/delayed motor & speech development was seen in unrelated patients 3 and 4.
Intellectual disability v3.30 CEP55 Rebecca Foulger changed review comment from: PMID:32100459 (Barrie et al., 2020) describe 7 living individuals (5 families) with biallelic variants (compound het and homozygous splice site variant) in CEP55. Global/severe DD wax seen in patient 2, and the 3 siblings (patients 5,6,7). Mild/delayed motor/speech development was seen in unrelated patients 3 and 4.; to: PMID:32100459 (Barrie et al., 2020) describe 7 living individuals (5 families) with biallelic variants (compound het and homozygous splice site variant) in CEP55. Global/severe DD was seen in patient 2, and the 3 siblings (patients 5,6,7). Mild/delayed motor/speech development was seen in unrelated patients 3 and 4.
Intellectual disability v3.30 CEP55 Rebecca Foulger commented on gene: CEP55: PMID:32100459 (Barrie et al., 2020) describe 7 living individuals (5 families) with biallelic variants (compound het and homozygous splice site variant) in CEP55. Global/severe DD wax seen in patient 2, and the 3 siblings (patients 5,6,7). Mild/delayed motor/speech development was seen in unrelated patients 3 and 4.
Intellectual disability v3.30 CEP55 Rebecca Foulger gene: CEP55 was added
gene: CEP55 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: CEP55 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CEP55 were set to 32100459
Phenotypes for gene: CEP55 were set to microcephaly, delayed development, and bilateral toe syndactyly
Added comment: Added to ID panel on advice from Helen Brittain, Genomics England Clinical Team. Phenotype of living individuals in PMID:32100459 (Barrie et al., 2020) includes developmental delay.
Sources: Literature
Intellectual disability v3.29 EIF2AK2 Zornitza Stark gene: EIF2AK2 was added
gene: EIF2AK2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: EIF2AK2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: EIF2AK2 were set to 32197074
Phenotypes for gene: EIF2AK2 were set to Intellectual disability; white matter abnormalities; ataxia; regression with febrile illness
Review for gene: EIF2AK2 was set to GREEN
gene: EIF2AK2 was marked as current diagnostic
Added comment: Eight individuals with de novo variants and complex neurodevelopmental phenotype.
Sources: Literature
Intellectual disability v3.29 EIF2AK1 Zornitza Stark gene: EIF2AK1 was added
gene: EIF2AK1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: EIF2AK1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: EIF2AK1 were set to 32197074
Phenotypes for gene: EIF2AK1 were set to Intellectual disability; white matter abnormalities
Review for gene: EIF2AK1 was set to RED
Added comment: Single individual reported with de novo variant in this gene, one to watch.
Sources: Literature
Intellectual disability v3.29 NRROS Zornitza Stark gene: NRROS was added
gene: NRROS was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: NRROS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NRROS were set to 32100099; 32197075
Phenotypes for gene: NRROS were set to neurodegeneration; intracranial calcification; epilepsy
Review for gene: NRROS was set to GREEN
Added comment: Normal development or mild developmental delay until onset of regression around age of 1 concurrent with epilepsy
Biallelic LOF mutations with functional evidence of pathogenicity reported in 6 unrelated families. Suggest also add to Epilepsy panel, possibly others.
Sources: Literature
Intellectual disability v3.29 NOVA2 Zornitza Stark gene: NOVA2 was added
gene: NOVA2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: NOVA2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: NOVA2 were set to 32197073
Phenotypes for gene: NOVA2 were set to Intellectual disability; autism; hypotonia; spasticity; ataxia
Review for gene: NOVA2 was set to GREEN
gene: NOVA2 was marked as current diagnostic
Added comment: Six individuals with de novo frameshift variants resulting in C-terminal extension suggesting partial LoF as mechanism.
Sources: Literature
Intellectual disability v3.28 GAD1 Sarah Leigh Publications for gene: GAD1 were set to 26503795; 24896178; 26350204; https://doi-org.ezproxy.library.qmul.ac.uk/10.1093/brain/awaa085
Intellectual disability v3.27 GAD1 Sarah Leigh Added comment: Comment on publications: https://doi-org.ezproxy.library.qmul.ac.uk/10.1093/brain/awaa085 new publication, without a PMID
Intellectual disability v3.27 GAD1 Sarah Leigh Publications for gene: GAD1 were set to 26503795; 24896178; 26350204; https://doi-org.ezproxy.library.qmul.ac.uk/10.1093/brain/awaa085
Intellectual disability v3.27 GAD1 Sarah Leigh Added comment: Comment on publications: https://doi-org.ezproxy.library.qmul.ac.uk/10.1093/brain/awaa085 new publication, without a PMID
Intellectual disability v3.25 GAD1 Sarah Leigh Added comment: Comment on list classification: Five biallelic loss of function variants reported in 11 cases in 6 unrelated families. All cases had epilepsy syndrome, 10 profound intellectual disabilty (1 case died at day 9 of life) and other nuerological and developement features. Supportive functional studies were also presented
Intellectual disability v3.24 NUP188 Zornitza Stark reviewed gene: NUP188: Rating: GREEN; Mode of pathogenicity: None; Publications: 32021605, 28726809, 32275884; Phenotypes: microcephaly, ID, cataract, structural brain abnormalities, hypoventilation; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability v3.24 PIGK Zornitza Stark gene: PIGK was added
gene: PIGK was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: PIGK was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PIGK were set to 32220290
Phenotypes for gene: PIGK were set to Intellectual disability; seizures; cerebellar atrophy
Review for gene: PIGK was set to GREEN
gene: PIGK was marked as current diagnostic
Added comment: 12 individuals from 9 unrelated families reported.
Sources: Expert list
Intellectual disability v3.24 ADARB1 Zornitza Stark changed review comment from: Four unrelated individuals with bi-allelic variants in this gene.
Sources: Literature; to: Four unrelated individuals with bi-allelic variants in this gene. Suggest also adding to Genetic Epilepsy and Microcephaly panels.
Sources: Literature
Intellectual disability v3.24 ADARB1 Zornitza Stark gene: ADARB1 was added
gene: ADARB1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: ADARB1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ADARB1 were set to 32220291
Phenotypes for gene: ADARB1 were set to Intellectual disability; microcephaly; seizures
Review for gene: ADARB1 was set to GREEN
gene: ADARB1 was marked as current diagnostic
Added comment: Four unrelated individuals with bi-allelic variants in this gene.
Sources: Literature
Intellectual disability v3.23 RNF13 Sarah Leigh changed review comment from: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least 2 variants reported in 3 unrelated cases, together with supportive functional studies.; to: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least 2 variants reported in 3 unrelated cases, together with supportive functional studies.

Gain-of-function mechanism has been reported, therefore the mutational spectrum may be limited and is still to be determined through further cases or further functional studies (view of Helen Britain, GeL Clincial Fellow).
Intellectual disability v3.23 SCAMP5 Sarah Leigh changed review comment from: Comment on list classification: Not associated with phenotype in OMIM (last edited on 10/06/2014) or in Gen2Phen. Two variants have been identified in three unrelated cases (one monoallelic, one biallelic). Supportive functional studies have been reported.
It would appear that the two variants reported so far in this gene result in differing mode of pathogenicity and phenotypic features. With heterozygous c.538G>T, p.Gly180Trp seeming to have a dominant-negative effect resulting in autistic spectrum disorder, intellectual disability and seizures. While homozygous c.271C>T, p.R91W seems to have a loss of function effect resulting in early onset epilepsy and Parkinson’s disease. This may be due to different functional domains of the mature protein being altered.; to: Comment on list classification: Not associated with phenotype in OMIM (last edited on 10/06/2014) or in Gen2Phen. Two variants have been identified in three unrelated cases (one monoallelic, one biallelic). Supportive functional studies have been reported.
It would appear that the two variants reported so far in this gene result in differing mode of pathogenicity and phenotypic features. With heterozygous c.538G>T, p.Gly180Trp seeming to have a dominant-negative effect resulting in autistic spectrum disorder, intellectual disability and seizures. While homozygous c.271C>T, p.R91W seems to have a loss of function effect resulting in early onset epilepsy and Parkinson’s disease. This may be due to different functional domains of the mature protein being altered.
Based on this evidence, SCAMP5 is rated as Amber, with a Watchlist tag. This status may change if further cases are reported.
Intellectual disability v3.23 SCN8A Sarah Leigh Added comment: Comment on mode of pathogenicity: Based on report in PMID 31625145, reporting biallelic loss of function SCN8A variants in three cases in two families with severe developmental and epileptic encephalopathy. This differs from the previosly reported gain of function monoallelic variants (PMID 24194747;22365152).
Intellectual disability v3.22 SCN8A Sarah Leigh Added comment: Comment on mode of inheritance: Based on report in PMID 31625145, reporting biallelic loss of function SCN8A variants in three cases in two families with severe developmental and epileptic encephalopathy.
Intellectual disability v3.21 SCN8A Sarah Leigh Phenotypes for gene: SCN8A were changed from Cognitive impairment with or without cerebellar ataxia, 614306Epileptic encephalopathy, early infantile, 13, 614558; COGNITIVE IMPAIRMENT WITH OR WITHOUT CEREBELLAR ATAXIA to ?Cognitive impairment with or without cerebellar ataxia,614306; Epileptic encephalopathy, early infantile,614558; Seizures, benign familial infantile,617080
Intellectual disability v3.19 SCAMP5 Sarah Leigh Added comment: Comment on mode of pathogenicity: Heterozygous c.538G>T, p.Gly180Trp seeming to have a dominant-negative effect resulting in autistic spectrum disorder, intellectual disability and seizures. While homozygous c.271C>T, p.R91W seems to have a loss of function effect resulting in early onset epilepsy and Parkinson’s disease.
Intellectual disability v3.19 SCAMP5 Sarah Leigh Mode of pathogenicity for gene: SCAMP5 was changed from Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments to Other
Intellectual disability v3.18 SCAMP5 Sarah Leigh Added comment: Comment on list classification: Not associated with phenotype in OMIM (last edited on 10/06/2014) or in Gen2Phen. Two variants have been identified in three unrelated cases (one monoallelic, one biallelic). Supportive functional studies have been reported.
It would appear that the two variants reported so far in this gene result in differing mode of pathogenicity and phenotypic features. With heterozygous c.538G>T, p.Gly180Trp seeming to have a dominant-negative effect resulting in autistic spectrum disorder, intellectual disability and seizures. While homozygous c.271C>T, p.R91W seems to have a loss of function effect resulting in early onset epilepsy and Parkinson’s disease. This may be due to different functional domains of the mature protein being altered.
Intellectual disability v3.17 SCAMP5 Sarah Leigh Added comment: Comment on mode of inheritance: Based on the reporting of a de novo heterozygous varaiant (NM_001178111.1:c.538G>T) in two unrelated cases (PMID: 31439720) and a homozygous variant (NM_001178111:c.271C>T, rs747966691) in two members of a Chinese consanguienious family (PMID: 32020363).
Intellectual disability v3.15 RNF13 Sarah Leigh reviewed gene: RNF13: 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: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.15 RNF113A Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as possible Gen2Phen gene for X-linked trichothiodystrophy. At least 3 terminating variants reported in unrelated cases. Supportive functional studies also reported.
Intellectual disability v3.13 RARS Sarah Leigh Classified gene: RARS as Green List (high evidence)
Intellectual disability v3.13 RARS Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least 19 variants reported in at least 13 cases of Hypomyelinating Leukodystrophy exhibinting intellectual disability to varying degrees. Supportive functional studies were also reported.
Intellectual disability v3.13 RARS Sarah Leigh Gene: rars has been classified as Green List (High Evidence).
Intellectual disability v3.12 RARS Sarah Leigh commented on gene: RARS
Intellectual disability v3.12 RARS Sarah Leigh Tag new-gene-name tag was added to gene: RARS.
Intellectual disability v3.12 RALGAPA1 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene for RALGAPA1-related neurodevelopmental disorder. At least 5 variants reported in at least 4 unrelated cases.
Intellectual disability v3.9 PUM1 Sarah Leigh Phenotypes for gene: PUM1 were changed from Global developmental delay; Intellectual disability; Seizures; Abnormality of the face; Ataxia; Cryptorchidism to Spinocerebellar ataxia 47 617931
Intellectual disability v3.7 PIGP Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 2 variants reported (rs768633670, rs778481061). rs768633670 were reported as a compound heterozygotes in one case and was present in at least two geographically separated consanguineous European families; suggesting a founder effect in the European population (PMID 32042915).
Supportive functional studies are also presented.
Intellectual disability v3.5 PIGP Sarah Leigh Phenotypes for gene: PIGP were changed from ?Epileptic encephalopathy, early infantile, 55, 617599; Generalized hypotonia; Global developmental delay; Seizures; Intellectual disability; Feeding difficulties; Cortical visual impairment to Epileptic encephalopathy, early infantile, 55, 617599; Generalized hypotonia; Global developmental delay; Seizures; Intellectual disability; Feeding difficulties; Cortical visual impairment
Intellectual disability v3.3 RARS Zornitza Stark reviewed gene: RARS: Rating: GREEN; Mode of pathogenicity: None; Publications: 31814314; Phenotypes: Leukodystrophy, hypomyelinating, 9 (# 616140); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.3 CXorf56 Zornitza Stark reviewed gene: CXorf56: Rating: GREEN; Mode of pathogenicity: None; Publications: 29374277, 31822863; Phenotypes: Mental retardation, X-linked 107, MIM# 301013; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females; Current diagnostic: yes
Intellectual disability v3.3 TNR Zornitza Stark gene: TNR was added
gene: TNR was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: TNR was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TNR were set to 32099069
Phenotypes for gene: TNR were set to Spastic para- or tetraparesis; Axial muscular hypotonia; Intellectual disability; Transient opisthotonus
Review for gene: TNR was set to GREEN
gene: TNR was marked as current diagnostic
Added comment: 13 individuals from 8 unrelated families reported.
Sources: Expert list
Intellectual disability v3.3 RUSC2 Zornitza Stark gene: RUSC2 was added
gene: RUSC2 was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: RUSC2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RUSC2 were set to 27612186
Phenotypes for gene: RUSC2 were set to Mental retardation, autosomal recessive 61, MIM# 617773
Review for gene: RUSC2 was set to AMBER
Added comment: Two unrelated families reported.
Sources: Expert list
Intellectual disability v3.3 RSPH3 Zornitza Stark reviewed gene: RSPH3: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Ciliary dyskinesia, primary, 32, MIM# 616481; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.3 RSPH1 Zornitza Stark reviewed gene: RSPH1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Ciliary dyskinesia, primary, 24, MIM# 615481; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.3 RNF13 Zornitza Stark reviewed gene: RNF13: Rating: GREEN; Mode of pathogenicity: None; Publications: 30595371; Phenotypes: Epileptic encephalopathy, early infantile, 73, MIM# 618379; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Intellectual disability v3.3 RIC1 Zornitza Stark gene: RIC1 was added
gene: RIC1 was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: RIC1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RIC1 were set to 31932796
Phenotypes for gene: RIC1 were set to Cleft lip; cataract; tooth abnormality; intellectual disability; facial dysmorphism; ADHD
Review for gene: RIC1 was set to AMBER
Added comment: Zebrafish model and consanguineous families but homozygous-by-descent. One to watch.
Sources: Expert list
Intellectual disability v3.3 RETREG1 Zornitza Stark reviewed gene: RETREG1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Neuropathy, hereditary sensory and autonomic, type IIB, MIM# 613115; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.3 MYH9 Zornitza Stark reviewed gene: MYH9: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss, MIM# 155100; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.3 MYH6 Zornitza Stark reviewed gene: MYH6: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: {Sick sinus syndrome 3} 614090 3 Atrial septal defect 3, MIM# 614089, Cardiomyopathy, dilated, 1EE, MIM# 613252, Cardiomyopathy, hypertrophic, 14, MIM# 613251; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.3 MSX2 Zornitza Stark reviewed gene: MSX2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Craniosynostosis 2, MIM# 604757, Parietal foramina 1, MIM# 168500, Parietal foramina with cleidocranial dysplasia, MIM# 168550; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.3 MNX1 Zornitza Stark reviewed gene: MNX1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Currarino syndrome, OMIM #176450; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.3 MFSD2A Zornitza Stark reviewed gene: MFSD2A: Rating: GREEN; Mode of pathogenicity: None; Publications: 26005865, 26005868, 24828044; Phenotypes: Microcephaly 15, primary, autosomal recessive, MIM# 616486; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.3 MATN3 Zornitza Stark reviewed gene: MATN3: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Spondyloepimetaphyseal dysplasia 608728, {Osteoarthritis susceptibility 2} 140600, Epiphyseal dysplasia, multiple, 5 607078; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.3 NUP214 Zornitza Stark gene: NUP214 was added
gene: NUP214 was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: NUP214 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NUP214 were set to 31178128
Phenotypes for gene: NUP214 were set to developmental delay; intellectual disability; epileptic encephalopathy; developmental regression; microcephaly
Review for gene: NUP214 was set to GREEN
gene: NUP214 was marked as current diagnostic
Added comment: Three unrelated families reported, regression on background of pre-existing neurodisability.
Sources: Expert list
Intellectual disability v3.3 NRXN2 Zornitza Stark edited their review of gene: NRXN2: Added comment: One individual reported with autism and a paternally inherited variant in this gene, father had a language disorder. Another infant reported with severe EE and a maternally inherited variants in NRXN1 and a paternally inherited variant in NRXN2. Some animal data.; Changed publications: 21424692, 30709877, 25745399; Changed phenotypes: Autism
Intellectual disability v3.3 NR5A1 Zornitza Stark reviewed gene: NR5A1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: 46XY sex reversal 3, 612965, Premature ovarian failure 7, 612964, Adrenocortical insufficiency, Spermatogenic failure 8, 613957; Mode of inheritance: None
Intellectual disability v3.3 NR2F2 Zornitza Stark reviewed gene: NR2F2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Congenital heart defects, multiple types, 4, MIM# 615779; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.3 NPR2 Zornitza Stark reviewed gene: NPR2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Acromesomelic dysplasia, Maroteaux type, MIM# 602875, Epiphyseal chondrodysplasia, Miura type MIM#615923, Short stature with nonspecific skeletal abnormalities 616255; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.3 NOG Zornitza Stark reviewed gene: NOG: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Brachydactyly, type B2, MIM# 611377, Multiple synostoses syndrome 1, MIM# 186500, Stapes ankylosis with broad thumbs and toes, MIM# 184460, Symphalangism, proximal, 1A, MIM# 185800, Tarsal-carpal coalition syndrome, MIM# 186570; Mode of inheritance: None
Intellectual disability v3.3 NHP2 Zornitza Stark reviewed gene: NHP2: Rating: AMBER; Mode of pathogenicity: None; Publications: 18523010, 31985013; Phenotypes: Dyskeratosis congenita, autosomal recessive 2, MIM# 613987, Høyeraal-Hreidarsson syndrome; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.3 NHEJ1 Zornitza Stark reviewed gene: NHEJ1: Rating: RED; Mode of pathogenicity: None; Publications: 16439204; Phenotypes: Severe combined immunodeficiency with microcephaly, growth retardation, and sensitivity to ionizing radiation; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.3 NGF Zornitza Stark reviewed gene: NGF: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Neuropathy, hereditary sensory and autonomic, type V, MIM# 608654; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.3 NEDD4L Zornitza Stark reviewed gene: NEDD4L: Rating: GREEN; Mode of pathogenicity: None; Publications: 27694961; Phenotypes: Periventricular nodular heterotopia 7, MIM#617201; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Intellectual disability v3.3 NDUFAF1 Zornitza Stark gene: NDUFAF1 was added
gene: NDUFAF1 was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: NDUFAF1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NDUFAF1 were set to 17557076; 21931170; 24963768
Phenotypes for gene: NDUFAF1 were set to Mitochondrial complex I deficiency, nuclear type 11, MIM#618234
Review for gene: NDUFAF1 was set to GREEN
gene: NDUFAF1 was marked as current diagnostic
Added comment: Three unrelated families described, DD/ID part of the phenotype, specifically mentioned in two families, child in third family died in infancy from HOCM.
Sources: Expert list
Intellectual disability v3.3 NDUFA2 Zornitza Stark gene: NDUFA2 was added
gene: NDUFA2 was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: NDUFA2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NDUFA2 were set to 18513682; 28857146
Phenotypes for gene: NDUFA2 were set to Mitochondrial complex I deficiency, nuclear type 13, MIM#618235
Review for gene: NDUFA2 was set to GREEN
gene: NDUFA2 was marked as current diagnostic
Added comment: Three unrelated families reported, DD/IDD in all.
Sources: Expert list
Intellectual disability v3.3 NCAPG2 Zornitza Stark gene: NCAPG2 was added
gene: NCAPG2 was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: NCAPG2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NCAPG2 were set to 30609410
Phenotypes for gene: NCAPG2 were set to Khan-Khan-Katsanis syndrome, MIM# 618460
Review for gene: NCAPG2 was set to GREEN
gene: NCAPG2 was marked as current diagnostic
Added comment: Two unrelated families and an animal model (zebrafish).
Sources: Expert list
Intellectual disability v3.3 NCAPD2 Zornitza Stark gene: NCAPD2 was added
gene: NCAPD2 was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: NCAPD2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NCAPD2 were set to 31056748; 27737959; 28097321
Phenotypes for gene: NCAPD2 were set to Microcephaly 21, primary, autosomal recessive, OMIM #617983
Review for gene: NCAPD2 was set to GREEN
gene: NCAPD2 was marked as current diagnostic
Added comment: 5 individuals from three unrelated families reported, some functional evidence.
Sources: Expert list
Intellectual disability v3.3 ZNF335 Zornitza Stark reviewed gene: ZNF335: Rating: GREEN; Mode of pathogenicity: None; Publications: 23178126, 27540107, 29652087; Phenotypes: Microcephaly 10, primary, autosomal recessive, OMIM #615095; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.3 ZIC3 Zornitza Stark reviewed gene: ZIC3: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Heterotaxy, visceral, 1, X-linked 306955, Congenital heart defects, nonsyndromic, 1, X-linked, 306955, VACTERL association, X-linked, 314390; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability v3.3 WDFY3 Zornitza Stark edited their review of gene: WDFY3: Added comment: >10 individuals with heterozygous variants in this gene and mild/moderate intellectual disability now described in the literature. Some evidence for opposing effects on brain size depending on variant location.; Changed rating: GREEN; Changed publications: 31327001, 27008544; Set current diagnostic: yes
Intellectual disability v3.3 VARS2 Zornitza Stark gene: VARS2 was added
gene: VARS2 was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: VARS2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: VARS2 were set to 24827421; 25058219; 29137650; 29314548; 31064326
Phenotypes for gene: VARS2 were set to Combined oxidative phosphorylation deficiency 20, OMIM #615917
Review for gene: VARS2 was set to GREEN
gene: VARS2 was marked as current diagnostic
Added comment: ID is part of the phenotype of this metabolic disorder.
Sources: Expert list
Intellectual disability v3.3 UGT1A1 Zornitza Stark reviewed gene: UGT1A1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Crigler-Najjar syndrome, type I, OMIM #218800, Crigler-Najjar syndrome, type II, OMIM #606785; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.3 TUBGCP2 Zornitza Stark gene: TUBGCP2 was added
gene: TUBGCP2 was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: TUBGCP2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TUBGCP2 were set to 31630790
Phenotypes for gene: TUBGCP2 were set to Lissencephaly; pachygyria; subcortical band heterotopia; microcephaly; intellectual disability
Review for gene: TUBGCP2 was set to GREEN
gene: TUBGCP2 was marked as current diagnostic
Added comment: Four unrelated families reported.
Sources: Expert list
Intellectual disability v3.3 TRPM1 Zornitza Stark reviewed gene: TRPM1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Night blindness, congenital stationary (complete), 1C, autosomal recessive, MIM# 613216; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.3 TRNT1 Zornitza Stark gene: TRNT1 was added
gene: TRNT1 was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: TRNT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TRNT1 were set to 25193871; 23553769; 29170023; 27389523
Phenotypes for gene: TRNT1 were set to Sideroblastic anemia with B-cell immunodeficiency, periodic fevers, and developmental delay, OMIM #616084
Review for gene: TRNT1 was set to GREEN
gene: TRNT1 was marked as current diagnostic
Added comment: > 10 families reported with congenital sideroblastic anemia, B-cell deficiency, periodic fevers, and variable degrees of delayed psychomotor development.
Sources: Expert list
Intellectual disability v3.3 TRIM32 Zornitza Stark reviewed gene: TRIM32: Rating: RED; Mode of pathogenicity: None; Publications: 16606853; Phenotypes: Bardet-Biedl syndrome 11, MIM# 615988; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.3 TRAPPC2 Zornitza Stark reviewed gene: TRAPPC2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Spondyloepiphyseal dysplasia tarda, MIM# 313400; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability v3.3 TRAK1 Zornitza Stark reviewed gene: TRAK1: Rating: GREEN; Mode of pathogenicity: None; Publications: 28940097, 28364549, 29846532; Phenotypes: Epileptic encephalopathy, early infantile, 68, MIM# 618201; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.3 TP63 Zornitza Stark reviewed gene: TP63: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ADULT syndrome, OMIM #103285, Ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome 3, OMIM #604292, Hay-Wells syndrome, OMIM #106260, Limb-mammary syndrome, OMIM #603543, Orofacial cleft 8, OMIM #618149, Rapp-Hodgkin syndrome, OMIM #129400, Split-hand/foot malformation 4, OMIM #605289; Mode of inheritance: None
Intellectual disability v3.3 SPOP Zornitza Stark gene: SPOP was added
gene: SPOP was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: SPOP was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SPOP were set to 32109420
Phenotypes for gene: SPOP were set to Intellectual disability; dysmorphism; microcephaly; macrocephaly
Mode of pathogenicity for gene: SPOP was set to Other
Review for gene: SPOP was set to GREEN
gene: SPOP was marked as current diagnostic
Added comment: Seven individuals reported with de novo missense variants in this gene. Gain-of-function variants associated with microcephaly whereas dominant-negative variants associated with macrocephaly.
Sources: Literature
Intellectual disability v3.3 TMEM126B Zornitza Stark reviewed gene: TMEM126B: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Mitochondrial complex I deficiency, nuclear type 29, MIM# 618250; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.3 TGFB3 Zornitza Stark reviewed gene: TGFB3: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Arrhythmogenic right ventricular dysplasia 1, MIM# 107970, Loeys-Dietz syndrome 5, MIM# 615582; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.3 TENM3 Zornitza Stark gene: TENM3 was added
gene: TENM3 was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: TENM3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TENM3 were set to 30513139; 22766609; 27103084; 29753094
Phenotypes for gene: TENM3 were set to Microphthalmia, syndromic 15, MIM#615145; coloboma
Review for gene: TENM3 was set to GREEN
gene: TENM3 was marked as current diagnostic
Added comment: At least four unrelated families described with syndromic microphthalmia and bi-allelic variants in this gene, ID is part of the phenotype.
Sources: Expert list
Intellectual disability v3.3 TEK Zornitza Stark reviewed gene: TEK: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Glaucoma 3, primary congenital, E , MIM#617272, Venous malformations, multiple cutaneous and mucosal, MIM# 600195; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.3 TBX4 Zornitza Stark reviewed gene: TBX4: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Amelia, posterior, with pelvic and pulmonary hypoplasia syndrome, MIM# 601360, Ischiocoxopodopatellar syndrome with or without pulmonary arterial hypertension, MIM# 147891; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.3 TBX3 Zornitza Stark reviewed gene: TBX3: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Ulnar-mammary syndrome, MIM# 181450; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.3 TASP1 Zornitza Stark gene: TASP1 was added
gene: TASP1 was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: TASP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TASP1 were set to 31209944; 31350873
Phenotypes for gene: TASP1 were set to Developmental delay; microcephaly; dysmorphic features; congenital abnormalities
Review for gene: TASP1 was set to GREEN
gene: TASP1 was marked as current diagnostic
Added comment: Four unrelated families reported; two with founder mutation. Protein interacts with KMT2A and KMT2D. Another de novo missense variant reported in a single infant with multiple congenital abnormalities, insufficient evidence for mono allelic disease at present.
Sources: Expert list
Intellectual disability v3.3 TAB2 Zornitza Stark reviewed gene: TAB2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Congenital heart defects, nonsyndromic, 2, MIM# 614980; Mode of inheritance: None
Intellectual disability v3.3 SUCLA2 Zornitza Stark gene: SUCLA2 was added
gene: SUCLA2 was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: SUCLA2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SUCLA2 were set to 27913098; 15877282; 23759946; 17287286; 17301081
Phenotypes for gene: SUCLA2 were set to Mitochondrial DNA depletion syndrome 5 (encephalomyopathic with or without methylmalonic aciduria); OMIM #612073
Review for gene: SUCLA2 was set to GREEN
Added comment: ID is part of the phenotype of this mitochondrial disorder.
Sources: Expert list
Intellectual disability v3.3 STAR Zornitza Stark reviewed gene: STAR: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Lipoid adrenal hyperplasia, MIM# 201710; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.3 SPEG Zornitza Stark reviewed gene: SPEG: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Centronuclear myopathy 5, OMIM #615959; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.3 SPAG1 Zornitza Stark reviewed gene: SPAG1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Ciliary dyskinesia, primary, 28, MIM# 615505; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.3 RASA1 Zornitza Stark reviewed gene: RASA1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Capillary malformation-arteriovenous malformation 1, MIM# 608354; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.3 SMCHD1 Zornitza Stark reviewed gene: SMCHD1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Bosma arhinia microphthalmia syndrome, OMIM #603457, Fascioscapulohumeral muscular dystrophy 2, digenic, OMIM #158901; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.3 DDC Lothar Schlueter reviewed gene: DDC: Rating: GREEN; Mode of pathogenicity: None; Publications: 28100251, 30952622, 30689738, 25597765, 24788355; Phenotypes: Aromatic L-amino acid decarboxylase deficiency 608643, floppy child, dystonia, hypotonia, developmental delay, oculogyric crisis; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.3 SLC9A7 Zornitza Stark gene: SLC9A7 was added
gene: SLC9A7 was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: SLC9A7 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: SLC9A7 were set to 30335141
Phenotypes for gene: SLC9A7 were set to Intellectual developmental disorder, X-linked 108; OMIM #301024
Review for gene: SLC9A7 was set to AMBER
Added comment: 6 males from 2 unrelated families with hemizygous missense mutation in the SLC9A7 gene. The mutation segregated with the disorder in the family. In vitro functional expression studies in CHO cells (AP-1 cells) showed that the mutation caused decreased levels of protein expression and reduced oligosaccharide maturation/glycosylation compared to wildtype, indicating impaired posttranslational processing. Subcellular localization studies indicated that protein trafficking was unaffected by the mutation. However, examination of the trans-Golgi compartment suggested a gain-of-function effect and a perturbation of glycosylation of secretory cargo. Serum transferrin studies in 1 patient suggested a glycosylation defect. One to watch.
Sources: Expert list
Intellectual disability v3.3 SLC1A1 Zornitza Stark gene: SLC1A1 was added
gene: SLC1A1 was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: SLC1A1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC1A1 were set to Dicarboxylic aminoaciduria, MIM#222730
Review for gene: SLC1A1 was set to GREEN
gene: SLC1A1 was marked as current diagnostic
Added comment: ID is part of the phenotype of this metabolic disorder.
Sources: Expert list
Intellectual disability v3.3 SH3PXD2B Zornitza Stark reviewed gene: SH3PXD2B: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Frank-ter Haar syndrome, MIM# 249420; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.3 SFXN4 Zornitza Stark gene: SFXN4 was added
gene: SFXN4 was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: SFXN4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SFXN4 were set to 31059822; 24119684
Phenotypes for gene: SFXN4 were set to Combined oxidative phosphorylation deficiency 18, MIM#615578
Review for gene: SFXN4 was set to GREEN
gene: SFXN4 was marked as current diagnostic
Added comment: Three unrelated families reported, mild ID as well as other neurological features are part of the phenotype.
Sources: Expert list
Intellectual disability v3.3 SCN1B Zornitza Stark reviewed gene: SCN1B: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Epileptic encephalopathy, early infantile, 52, MIM#617350; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability v3.3 SCN11A Zornitza Stark reviewed gene: SCN11A: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Neuropathy, hereditary sensory and autonomic, type VII, MIM#615548; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.3 SCARF2 Zornitza Stark reviewed gene: SCARF2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Van den Ende-Gupta syndrome, MIM# 600920; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.3 SBF1 Zornitza Stark gene: SBF1 was added
gene: SBF1 was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: SBF1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SBF1 were set to 24799518; 23749797; 30039846; 28902413
Phenotypes for gene: SBF1 were set to Charcot-Marie-Tooth disease, type 4B3, MIM# 615284
Review for gene: SBF1 was set to GREEN
Added comment: At least 4 families with multiple affected individuals described. Some have had central features including microcephaly and DD/ID, it is likely this gene causes a mixed picture.
Sources: Expert list
Intellectual disability v3.3 SARS2 Zornitza Stark gene: SARS2 was added
gene: SARS2 was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: SARS2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SARS2 were set to 21255763; 24034276
Phenotypes for gene: SARS2 were set to Hyperuricemia, pulmonary hypertension, renal failure, and alkalosis, MIM#613845
Review for gene: SARS2 was set to GREEN
gene: SARS2 was marked as current diagnostic
Added comment: DD/ID is part of the phenotype. Two unrelated families reported, highly specific phenotype.
Sources: Expert list
Intellectual disability v3.3 SOX3 Zornitza Stark reviewed gene: SOX3: Rating: AMBER; Mode of pathogenicity: None; Publications: 29175558, 30125608, 12428212, 15800844; Phenotypes: Mental retardation, X-linked, with isolated growth hormone deficiency, MIM#300123, Panhypopituitarism, X-linked, MIM#312000; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability v3.3 PUM1 Zornitza Stark reviewed gene: PUM1: Rating: GREEN; Mode of pathogenicity: None; Publications: 29474920, 25768905; Phenotypes: Spinocerebellar ataxia 47, MIM#617931; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.3 PROP1 Zornitza Stark reviewed gene: PROP1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Pituitary hormone deficiency, combined, 2, MIM# 262600; Mode of inheritance: None
Intellectual disability v3.3 PRKAR1A Zornitza Stark reviewed gene: PRKAR1A: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Acrodysostosis 1, with or without hormone resistance, MIM# 101800; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.3 PRDM12 Zornitza Stark reviewed gene: PRDM12: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Neuropathy, hereditary sensory and autonomic, type VIII, MIM# 616488; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.3 PPP1R12A Zornitza Stark gene: PPP1R12A was added
gene: PPP1R12A was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: PPP1R12A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PPP1R12A were set to 31883643
Phenotypes for gene: PPP1R12A were set to Intellectual disability; holoprosencephaly; disorder of sex development
Review for gene: PPP1R12A was set to GREEN
gene: PPP1R12A was marked as current diagnostic
Added comment: 12 individuals reported.
Sources: Expert list
Intellectual disability v3.3 PPA2 Zornitza Stark reviewed gene: PPA2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Sudden cardiac failure, infantile, MIM# 617222; Mode of inheritance: None
Intellectual disability v3.1 POMK Zornitza Stark gene: POMK was added
gene: POMK was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: POMK was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: POMK were set to Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 12, MIM# 615249
Review for gene: POMK was set to GREEN
gene: POMK was marked as current diagnostic
Added comment: ID is part of the phenotype.
Sources: Expert list
Intellectual disability v3.1 POLD1 Zornitza Stark reviewed gene: POLD1: Rating: RED; Mode of pathogenicity: None; Publications: 31449058; Phenotypes: Intellectual disability, immunodeficiency, Mandibular hypoplasia, deafness, progeroid features, and lipodystrophy syndrome, MIM#615381; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.0 PITX3 Zornitza Stark reviewed gene: PITX3: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Anterior segment dysgenesis 1, multiple subtypes, MIM# 107250, cataract; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.0 PISD Zornitza Stark gene: PISD was added
gene: PISD was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: PISD was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PISD were set to 31263216; 30858161
Phenotypes for gene: PISD were set to intellectual disability; cataract; microcephaly; deafness; skeletal dysplasia
Review for gene: PISD was set to GREEN
Added comment: Three unrelated families reported.
Sources: Expert list
Intellectual disability v3.0 PIGS Zornitza Stark gene: PIGS was added
gene: PIGS was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: PIGS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PIGS were set to 30269814
Phenotypes for gene: PIGS were set to Glycosylphosphatidylinositol biosynthesis defect 18, MIM# 618143
Review for gene: PIGS was set to GREEN
gene: PIGS was marked as current diagnostic
Added comment: Three unrelated families reported. Severe neurological phenotype ranging from fetal akinesia to ID/EE.
Sources: Expert list
Intellectual disability v3.0 PIGH Zornitza Stark edited their review of gene: PIGH: Added comment: I note this gene is Green on the epilepsy panel, and I agree this family of genes cause similar phenotypes, there is some functional data to support the gene-disease relationship, so we have rated it Green on both panels.; Changed rating: GREEN; Changed publications: 29573052, 29603516
Intellectual disability v3.0 PIBF1 Zornitza Stark gene: PIBF1 was added
gene: PIBF1 was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: PIBF1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PIBF1 were set to 26167768; 30858804; 29695797
Phenotypes for gene: PIBF1 were set to Joubert syndrome 33; OMIM #617767
Review for gene: PIBF1 was set to GREEN
gene: PIBF1 was marked as current diagnostic
Added comment: 7 families altogether: 3 of these are Hutterite and share the same founder variant.
Sources: Expert list
Intellectual disability v3.0 PDP1 Zornitza Stark gene: PDP1 was added
gene: PDP1 was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: PDP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PDP1 were set to 19184109; 15855260; 31392110
Phenotypes for gene: PDP1 were set to Pyruvate dehydrogenase phosphatase deficiency, MIM#608782
Review for gene: PDP1 was set to GREEN
gene: PDP1 was marked as current diagnostic
Added comment: DD/ID is part of the phenotype of this metabolic condition.
Sources: Expert list
Intellectual disability v3.0 PDHB Zornitza Stark gene: PDHB was added
gene: PDHB was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: PDHB was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PDHB were set to 15138885; 26014431
Phenotypes for gene: PDHB were set to Pyruvate dehydrogenase E1-beta deficiency, MIM#614111
Review for gene: PDHB was set to GREEN
gene: PDHB was marked as current diagnostic
Added comment: DD/ID is a feature of this metabolic disorder.
Sources: Expert list
Intellectual disability v3.0 PDE10A Zornitza Stark gene: PDE10A was added
gene: PDE10A was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: PDE10A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PDE10A were set to 27058446
Phenotypes for gene: PDE10A were set to Dyskinesia, limb and orofacial, infantile-onset, MIM#616921
Review for gene: PDE10A was set to GREEN
gene: PDE10A was marked as current diagnostic
Added comment: Two unrelated families and functional data (animal model). Note that allelic disorder, Striatal degeneration, autosomal dominant, MIM#616922, is caused by heterozygous variants and ID is not part of the phenotype.
Sources: Expert list
Intellectual disability v3.0 PAX3 Zornitza Stark reviewed gene: PAX3: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Craniofacial-deafness-hand syndrome, MIM#122880, Waardenburg syndrome, type 1, MIM#193500, Waardenburg syndrome, type 3, MIM#148820; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.0 PAM16 Zornitza Stark gene: PAM16 was added
gene: PAM16 was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: PAM16 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PAM16 were set to 24786642; 27354339
Phenotypes for gene: PAM16 were set to Spondylometaphyseal dysplasia, Megarbane-Dagher-Melike type, MIM#613320
Review for gene: PAM16 was set to GREEN
gene: PAM16 was marked as current diagnostic
Added comment: DD/ID is part of the phenotype of this skeletal dysplasia.
Sources: Expert list
Intellectual disability v3.0 OXR1 Zornitza Stark reviewed gene: OXR1: Rating: GREEN; Mode of pathogenicity: None; Publications: 31785787; Phenotypes: Intellectual disability, seizures, cerebellar atrophy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability v3.0 LZTFL1 Zornitza Stark gene: LZTFL1 was added
gene: LZTFL1 was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: LZTFL1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LZTFL1 were set to 22510444; 23692385; 27312011
Phenotypes for gene: LZTFL1 were set to Bardet-Biedl syndrome 17, MIM#615994
Review for gene: LZTFL1 was set to GREEN
gene: LZTFL1 was marked as current diagnostic
Added comment: Two unrelated families and functional evidence.
Sources: Expert list
Intellectual disability v3.0 LYRM7 Zornitza Stark gene: LYRM7 was added
gene: LYRM7 was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: LYRM7 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: LYRM7 were set to Mitochondrial complex III deficiency, nuclear type 8, MIM#615838
Review for gene: LYRM7 was set to GREEN
gene: LYRM7 was marked as current diagnostic
Added comment: Condition is characterised by progressive deterioration but some individuals described as developmentally delayed from birth.
Sources: Expert list
Intellectual disability v3.0 LTBP2 Zornitza Stark reviewed gene: LTBP2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Weill-Marchesani syndrome 3, recessive, MIM# 614819, Glaucoma 3, primary congenital, MIM# 613086, Microspherophakia and/or megalocornea, with ectopia lentis and with or without secondary glaucoma, MIM# 251750; Mode of inheritance: None
Intellectual disability v3.0 LRRC6 Zornitza Stark reviewed gene: LRRC6: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Ciliary dyskinesia, primary, 19, MIM# 614935; Mode of inheritance: None
Intellectual disability v3.0 LMAN2L Zornitza Stark gene: LMAN2L was added
gene: LMAN2L was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: LMAN2L was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: LMAN2L were set to 31020005; 26566883
Phenotypes for gene: LMAN2L were set to Intellectual disability; epilepsy
Review for gene: LMAN2L was set to AMBER
Added comment: 1 consanguineous family with 7 individuals with ID and epilepsy, with homozygous LMAN2L missense mutation. Segregated with disease in family, and unaffected family members were heterozygous variant carriers. No functional studies.

1 non-consanguineous family with 4 affected with heterozygous frameshift LMAN2L mutation. Segregates in family. Mutation eliminates LMAN2L's endoplasmic reticulum retention signal and mislocalizes the protein from that compartment to the plasma membrane.

Amber or Red.
Sources: Expert list
Intellectual disability v3.0 LIPT1 Zornitza Stark gene: LIPT1 was added
gene: LIPT1 was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: LIPT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LIPT1 were set to 24341803; 24256811; 29681092
Phenotypes for gene: LIPT1 were set to Lipoyltransferase 1 deficiency, MIM#616299
Review for gene: LIPT1 was set to GREEN
gene: LIPT1 was marked as current diagnostic
Added comment: Cognitive development is affected in this metabolic condition.
Sources: Expert list
Intellectual disability v3.0 LHX3 Zornitza Stark reviewed gene: LHX3: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Pituitary hormone deficiency, combined, 3, MIM# 221750; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.0 LGI4 Zornitza Stark reviewed gene: LGI4: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Arthrogryposis multiplex congenita, neurogenic, with myelin defect, MIM#617468; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.0 LAMB2 Zornitza Stark gene: LAMB2 was added
gene: LAMB2 was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: LAMB2 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: LAMB2 were set to Pierson syndrome, MIM#609049
gene: LAMB2 was marked as current diagnostic
Added comment: Cognitive impairment described in survivors.
Sources: Expert list
Intellectual disability v3.0 KLF7 Zornitza Stark gene: KLF7 was added
gene: KLF7 was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: KLF7 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KLF7 were set to 29251763
Phenotypes for gene: KLF7 were set to Intellectual disability
Review for gene: KLF7 was set to GREEN
gene: KLF7 was marked as current diagnostic
Added comment: Four unrelated individuals with de novo missense variants; animal model data supportive.
Sources: Expert list
Intellectual disability v3.0 KCNN3 Zornitza Stark gene: KCNN3 was added
gene: KCNN3 was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: KCNN3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KCNN3 were set to 31155282
Phenotypes for gene: KCNN3 were set to Zimmermann-Laband syndrome 3; OMIM# 618658
Review for gene: KCNN3 was set to GREEN
gene: KCNN3 was marked as current diagnostic
Added comment: Three unrelated individuals reported.
Sources: Expert list
Intellectual disability v3.0 KCNMA1 Zornitza Stark reviewed gene: KCNMA1: Rating: GREEN; Mode of pathogenicity: Other; Publications: 27567911, 29545233, 26195193, 31427379; Phenotypes: Cerebellar atrophy, developmental delay, and seizures, MIM# 617643, Paroxysmal nonkinesigenic dyskinesia, 3, with or without generalized epilepsy, MIM#609446; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.0 KCND3 Zornitza Stark reviewed gene: KCND3: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Spinocerebellar ataxia 19, MIM#607346; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.0 KCNC3 Zornitza Stark reviewed gene: KCNC3: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Spinocerebellar ataxia 13, MIM#605259; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.0 IREB2 Zornitza Stark gene: IREB2 was added
gene: IREB2 was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: IREB2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: IREB2 were set to 30915432; 31243445; 11175792
Phenotypes for gene: IREB2 were set to Neurodegeneration, early-onset, with choreoathetoid movements and microcytic anemia, MIM#618451
Review for gene: IREB2 was set to GREEN
gene: IREB2 was marked as current diagnostic
Added comment: Two affected individuals from unrelated families with functional evidence including highly specific, concordant phenotype in mice.
Sources: Expert list
Intellectual disability v3.0 SCN4A Zornitza Stark reviewed gene: SCN4A: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Hyperkalemic periodic paralysis, type 2, MIM# 170500, Hypokalemic periodic paralysis, type 2, MIM# 613345, Myasthenic syndrome, congenital, 16, MIM# 614198, Myotonia congenita, atypical, acetazolamide-responsive 608390, Paramyotonia congenita 168300; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.0 IFT27 Zornitza Stark gene: IFT27 was added
gene: IFT27 was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: IFT27 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: IFT27 were set to 24488770; 30761183
Phenotypes for gene: IFT27 were set to Bardet-Biedl syndrome 19, MIM#615996
Review for gene: IFT27 was set to AMBER
Added comment: Two families with functional evidence.
Sources: Expert list
Intellectual disability v3.0 HSPG2 Zornitza Stark reviewed gene: HSPG2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Schwartz-Jampel syndrome, type 1, MIM#255800; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.0 HNMT Zornitza Stark gene: HNMT was added
gene: HNMT was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: HNMT was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HNMT were set to 26206890; 30744146
Phenotypes for gene: HNMT were set to Mental retardation, autosomal recessive 51, MIM#616739
Review for gene: HNMT was set to GREEN
Added comment: 7 individuals from two unrelated families, some functional evidence and other circumstantial evidence linking this gene to brain function. Borderline Amber/Green.
Sources: Expert list
Intellectual disability v3.0 HADHB Zornitza Stark gene: HADHB was added
gene: HADHB was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: HADHB was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: HADHB were set to Trifunctional protein deficiency, MIM#609015
Review for gene: HADHB was set to GREEN
gene: HADHB was marked as current diagnostic
Added comment: ID is part of the phenotype.
Sources: Expert list
Intellectual disability v3.0 GPC4 Zornitza Stark gene: GPC4 was added
gene: GPC4 was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: GPC4 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: GPC4 were set to 30982611
Phenotypes for gene: GPC4 were set to Keipert syndrome OMIM# 301026
Review for gene: GPC4 was set to GREEN
gene: GPC4 was marked as current diagnostic
Added comment: 10 individuals from 6 families reported, functional studies in mice. Mild to moderate ID part of the phenotype.
Sources: Expert list
Intellectual disability v3.0 GOT2 Zornitza Stark reviewed gene: GOT2: Rating: GREEN; Mode of pathogenicity: None; Publications: 31422819; Phenotypes: Epileptic encephalopathy, early infantile, 82, MIM# 618721; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability v3.0 GNE Zornitza Stark gene: GNE was added
gene: GNE was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: GNE was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: GNE were set to Sialuria, MIM#269921
Review for gene: GNE was set to GREEN
gene: GNE was marked as current diagnostic
Added comment: Metabolic disorder with varying degrees of ID being a feature.
Bi-allelic variants cause Nonaka myopathy, MIM#605820
Sources: Expert list
Intellectual disability v3.0 HDAC4 Zornitza Stark reviewed gene: HDAC4: Rating: AMBER; Mode of pathogenicity: None; Publications: 24715439, 20691407, 31209962; Phenotypes: Brachydactyly mental retardation syndrome, Brachydactyly without intellectual disability; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.0 GLS Zornitza Stark gene: GLS was added
gene: GLS was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: GLS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GLS were set to 30970188
Phenotypes for gene: GLS were set to Global developmental delay, progressive ataxia, and elevated glutamine, MIM# 618412
Review for gene: GLS was set to GREEN
Added comment: Three unrelated individuals described with compound het variants, however, note one of these is a triplet expansion in the 5' UTR.
Sources: Expert list
Intellectual disability v3.0 GJB1 Zornitza Stark reviewed gene: GJB1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Charcot-Marie-Tooth neuropathy, X-linked dominant, 1, MIM#302800; Mode of inheritance: None
Intellectual disability v3.0 GJA1 Zornitza Stark reviewed gene: GJA1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Atrioventricular septal defect 3, MIM#600309, Craniometaphyseal dysplasia, autosomal recessive, MIM#218400, Erythrokeratodermia variabilis et progressiva 3, MIM#617525, Hypoplastic left heart syndrome 1, MIM#241550, Oculodentodigital dysplasia, MIM#164200, Oculodentodigital dysplasia, autosomal recessive, MIM#257850, Palmoplantar keratoderma with congenital alopecia, MIM#104100, Syndactyly, type III, MIM# 186100; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.0 GHR Zornitza Stark reviewed gene: GHR: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Growth hormone insensitivity, partial, MIM#604271, Laron dwarfism, MIM#262500; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.0 GBA2 Zornitza Stark reviewed gene: GBA2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Spastic paraplegia 46, autosomal recessive, MIM#614409; Mode of inheritance: None
Intellectual disability v3.0 GATA6 Zornitza Stark reviewed gene: GATA6: Rating: GREEN; Mode of pathogenicity: None; Publications: 22158542; Phenotypes: Pancreatic agenesis and congenital heart defects, MIM#600001; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.0 FTL Zornitza Stark reviewed gene: FTL: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodegeneration with brain iron accumulation 3, MIM#606159, Hyperferritinemia-cataract syndrome, MIM#600886, L-ferritin deficiency, dominant and recessive, MIM#615604; Mode of inheritance: None
Intellectual disability v3.0 FGFR1 Zornitza Stark edited their review of gene: FGFR1: Added comment: Gene causes several phenotypes but this specific phenotype caused by germline variants is associated with significant ID.; Changed publications: 23812909; Changed phenotypes: Hartsfield syndrome, MIM# 615465
Intellectual disability v3.0 TKFC Zornitza Stark gene: TKFC was added
gene: TKFC was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: TKFC was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TKFC were set to 32004446
Phenotypes for gene: TKFC were set to Developmental delay; cataracts; liver dysfunction
Review for gene: TKFC was set to AMBER
Added comment: Two unrelated individuals reported.
Sources: Expert list
Intellectual disability v3.0 RALGAPA1 Zornitza Stark gene: RALGAPA1 was added
gene: RALGAPA1 was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: RALGAPA1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RALGAPA1 were set to 32004447
Phenotypes for gene: RALGAPA1 were set to Intellectual disability; hypotonia; infantile spasms.
Review for gene: RALGAPA1 was set to GREEN
gene: RALGAPA1 was marked as current diagnostic
Added comment: Four unrelated individuals reported.
Sources: Expert list
Intellectual disability v3.0 FGF3 Zornitza Stark reviewed gene: FGF3: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Deafness, congenital with inner ear agenesis, microtia, and microdontia, MIM#610706; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.0 FGF14 Zornitza Stark reviewed gene: FGF14: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Spinocerebellar ataxia 27, MIM# 609307; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Intellectual disability v3.0 FARSB Zornitza Stark gene: FARSB was added
gene: FARSB was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: FARSB was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FARSB were set to 29573043; 1916114; 29979980; 30014610
Phenotypes for gene: FARSB were set to Rajab syndrome, MIM#613658; interstitial lung disease; brain calcifications; microcephaly; intellectual disability
Review for gene: FARSB was set to GREEN
gene: FARSB was marked as current diagnostic
Added comment: 7 unrelated families reported.
Sources: Expert list
Intellectual disability v3.0 FAR1 Zornitza Stark reviewed gene: FAR1: Rating: AMBER; Mode of pathogenicity: None; Publications: 25439727; Phenotypes: Peroxisomal fatty acyl-CoA reductase 1 disorder, MIM#616154; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.0 EXOSC8 Zornitza Stark gene: EXOSC8 was added
gene: EXOSC8 was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: EXOSC8 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EXOSC8 were set to 24989451; 29656927
Phenotypes for gene: EXOSC8 were set to Pontocerebellar hypoplasia, type 1C, MIM#616081
Review for gene: EXOSC8 was set to GREEN
gene: EXOSC8 was marked as current diagnostic
Added comment: Complex neurological phenotype includes ID.
Sources: Expert list
Intellectual disability v3.0 ERMARD Zornitza Stark reviewed gene: ERMARD: Rating: RED; Mode of pathogenicity: None; Publications: 24056535, 27087860; Phenotypes: Periventricular nodular heterotopia 6, MIM#615544; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.0 ELN Zornitza Stark reviewed gene: ELN: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Supravalvar aortic stenosis; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.0 ATAD3A Zornitza Stark reviewed gene: ATAD3A: Rating: GREEN; Mode of pathogenicity: None; Publications: 32004445; Phenotypes: Harel-Yoon syndrome 617183; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Intellectual disability v3.0 EARS2 Zornitza Stark gene: EARS2 was added
gene: EARS2 was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: EARS2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EARS2 were set to 22492562
Phenotypes for gene: EARS2 were set to Combined oxidative phosphorylation deficiency 12, MIM#614924
Review for gene: EARS2 was set to GREEN
gene: EARS2 was marked as current diagnostic
Added comment: ID is part of the phenotype, particularly in those severely affected.
Sources: Expert list
Intellectual disability v3.0 DPM3 Zornitza Stark reviewed gene: DPM3: Rating: RED; Mode of pathogenicity: None; Publications: 19576565, 28803818, 30931530, 31469168; Phenotypes: Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 15 612937; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.0 DNM1L Zornitza Stark gene: DNM1L was added
gene: DNM1L was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: DNM1L was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Phenotypes for gene: DNM1L were set to Encephalopathy, lethal, due to defective mitochondrial peroxisomal fission 1, MIM#614388
Mode of pathogenicity for gene: DNM1L was set to Other
Review for gene: DNM1L was set to GREEN
gene: DNM1L was marked as current diagnostic
Added comment: Dominant and recessive disease described depending on domain affected; dominant negative effect of heterozygous missense variants. LoF/LoF or LoF/missense for AR variants.
Sources: Expert list
Intellectual disability v3.0 DLL1 Zornitza Stark reviewed gene: DLL1: Rating: GREEN; Mode of pathogenicity: None; Publications: 31353024; Phenotypes: Intellectual disability, autism, seizures, variable brain abnormalities, scoliosis; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Intellectual disability v3.0 DENND5A Zornitza Stark reviewed gene: DENND5A: Rating: GREEN; Mode of pathogenicity: None; Publications: 27431290, 27866705; Phenotypes: Epileptic encephalopathy, early infantile, 49 617281; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.0 CYP7B1 Zornitza Stark reviewed gene: CYP7B1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Spastic paraplegia 5A, autosomal recessive, MIM# 270800; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.0 CYP2U1 Zornitza Stark reviewed gene: CYP2U1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Spastic paraplegia 56, autosomal recessive, MIM#615030; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.0 CTU2 Zornitza Stark gene: CTU2 was added
gene: CTU2 was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: CTU2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CTU2 were set to 27480277; 26633546
Phenotypes for gene: CTU2 were set to Microcephaly, facial dysmorphism, renal agenesis, and ambiguous genitalia syndrome, MIM#618142
Review for gene: CTU2 was set to GREEN
Added comment: Multiple Saudi families reported with same homozygous variant; founder effect. Severe disorder of infancy.
Sources: Expert list
Intellectual disability v3.0 CRYGD Zornitza Stark commented on gene: CRYGD: ID is not part of the phenotype.
Intellectual disability v3.0 CNTNAP1 Zornitza Stark gene: CNTNAP1 was added
gene: CNTNAP1 was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: CNTNAP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CNTNAP1 were set to 28374019; 29511323; 27668699
Phenotypes for gene: CNTNAP1 were set to Hypomyelinating neuropathy, congenital, 3, MIM#618186; Lethal congenital contracture syndrome 7, MIM# 616286
Review for gene: CNTNAP1 was set to GREEN
gene: CNTNAP1 was marked as current diagnostic
Added comment: Multiple affected individuals reported; ID is part of the phenotype.
Sources: Expert list
Intellectual disability v3.0 CLDN19 Zornitza Stark reviewed gene: CLDN19: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Hypomagnesemia 5, renal, with ocular involvement, MIM# 248190; Mode of inheritance: None
Intellectual disability v3.0 CHRNG Zornitza Stark reviewed gene: CHRNG: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Escobar syndrome, MIM# 265000, Multiple pterygium syndrome, lethal type, MIM# 253290; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.0 CHD1 Zornitza Stark gene: CHD1 was added
gene: CHD1 was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: CHD1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CHD1 were set to 28866611
Phenotypes for gene: CHD1 were set to Pilarowski-Bjornsson syndrome, MIM#617682
Mode of pathogenicity for gene: CHD1 was set to Other
Review for gene: CHD1 was set to GREEN
gene: CHD1 was marked as current diagnostic
Added comment: Six unrelated individuals with heterozygous variants reported. Possible dominant negative mechanism: reported variants are missense, and an individual with a deletion did not have a neurological phenotype.
Sources: Expert list
Intellectual disability v3.0 CDH3 Zornitza Stark reviewed gene: CDH3: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Ectodermal dysplasia, ectrodactyly, and macular dystrophy 225280, Hypotrichosis, congenital, with juvenile macular dystrophy 601553; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.0 CCT5 Zornitza Stark reviewed gene: CCT5: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Neuropathy, hereditary sensory, with spastic paraplegia, MIM# 256840; Mode of inheritance: None
Intellectual disability v3.0 CCNO Zornitza Stark reviewed gene: CCNO: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Ciliary dyskinesia, primary, 29, MIM# 615872; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.0 CCDC65 Zornitza Stark reviewed gene: CCDC65: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Ciliary dyskinesia, primary, 27, MIM# 615504; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.0 CCDC40 Zornitza Stark reviewed gene: CCDC40: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Ciliary dyskinesia, primary, 15, MIM# 613808; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.0 CCDC114 Zornitza Stark reviewed gene: CCDC114: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Ciliary dyskinesia, primary, 20, MIM# 615067; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.0 CCDC103 Zornitza Stark reviewed gene: CCDC103: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Ciliary dyskinesia, primary, 17, MIM# 614679; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.0 CARS2 Zornitza Stark reviewed gene: CARS2: Rating: GREEN; Mode of pathogenicity: None; Publications: 30139652; Phenotypes: Combined oxidative phosphorylation deficiency 27, MIM#616672; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.0 CACNA2D2 Zornitza Stark reviewed gene: CACNA2D2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Cerebellar atrophy with seizures and variable developmental delay, MIM#618501; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability v3.0 CA5A Zornitza Stark reviewed gene: CA5A: Rating: RED; Mode of pathogenicity: None; Publications: 26913920; Phenotypes: Hyperammonemia due to carbonic anhydrase VA deficiency, MIM# 615751; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.0 C8orf37 Zornitza Stark reviewed gene: C8orf37: Rating: ; Mode of pathogenicity: None; Publications: 26854863, 27008867; Phenotypes: Bardet-Biedl syndrome 21, MIM#617406; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.0 BICD2 Zornitza Stark reviewed gene: BICD2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Spinal muscular atrophy, lower extremity-predominant, 2A, autosomal dominant, MIM#615290; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.0 BFSP2 Zornitza Stark reviewed gene: BFSP2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Cataract 12, multiple types, MIM# 611597; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.0 B9D2 Zornitza Stark gene: B9D2 was added
gene: B9D2 was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: B9D2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: B9D2 were set to 26092869; 21763481
Phenotypes for gene: B9D2 were set to Joubert syndrome 34, MIM#614175; Meckel syndrome 10, MIM#614175
Review for gene: B9D2 was set to GREEN
gene: B9D2 was marked as current diagnostic
Added comment: Two unrelated individuals with Joubert syndrome and bi-allelic variants reported; single family with two affected individuals also reported with homozygous variant in this gene and more severe Meckel phenotype, overall supporting gene-disease association for a ciliopathy with CNS involvement. ID is part of the phenotype of these conditions.
Sources: Expert list
Intellectual disability v3.0 ATP6V1B1 Zornitza Stark reviewed gene: ATP6V1B1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Renal tubular acidosis with deafness 267300; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.0 ATP6AP1 Zornitza Stark gene: ATP6AP1 was added
gene: ATP6AP1 was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: ATP6AP1 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: ATP6AP1 were set to 27231034
Phenotypes for gene: ATP6AP1 were set to Immunodeficiency 47, MIM#300972
Review for gene: ATP6AP1 was set to GREEN
gene: ATP6AP1 was marked as current diagnostic
Added comment: 11 males from 6 unrelated families with primarily an immunodeficiency disorder; six patients from 3 families who carried the same variant (E346K) had neurologic features, including seizures, mild intellectual disability, and behavioral abnormalities
Sources: Expert list
Intellectual disability v3.0 ASTN1 Zornitza Stark gene: ASTN1 was added
gene: ASTN1 was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: ASTN1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ASTN1 were set to 29706646; 27431290; 26539891
Phenotypes for gene: ASTN1 were set to Intellectual disability
Review for gene: ASTN1 was set to GREEN
gene: ASTN1 was marked as current diagnostic
Added comment: Three families reported as part of large cohorts albeit proposing multiple novel candidate genes with minimal detail and no functional validation.
Sources: Expert list
Intellectual disability v3.0 ARHGEF6 Zornitza Stark reviewed gene: ARHGEF6: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: MENTAL RETARDATION X-LINKED TYPE 46; Mode of inheritance: None
Intellectual disability v3.0 ALG14 Zornitza Stark gene: ALG14 was added
gene: ALG14 was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: ALG14 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ALG14 were set to 30221345; 23404334; 28733338
Phenotypes for gene: ALG14 were set to Myasthenic syndrome, congenital, 15, without tubular aggregates, MIM#616227; Intellectual disability
Review for gene: ALG14 was set to GREEN
gene: ALG14 was marked as current diagnostic
Added comment: 5 individuals from unrelated families described in the literature: one with myasthenic syndrome, no report of ID; second with predominantly ID phenotype; and three more with a neurodegenerative phenotype.
Sources: Expert list
Intellectual disability v3.0 ALDOB Zornitza Stark reviewed gene: ALDOB: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Fructose intolerance, hereditary, MIM# 229600; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.0 AGMO Zornitza Stark gene: AGMO was added
gene: AGMO was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: AGMO was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AGMO were set to 31555905
Phenotypes for gene: AGMO were set to microcephaly; intellectual disability; epilepsy
Review for gene: AGMO was set to GREEN
gene: AGMO was marked as current diagnostic
Added comment: Three unrelated families and functional data.
Sources: Expert list
Intellectual disability v3.0 ADD3 Zornitza Stark gene: ADD3 was added
gene: ADD3 was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: ADD3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ADD3 were set to 29768408; 23836506
Phenotypes for gene: ADD3 were set to Cerebral palsy, spastic quadriplegic, 3, MIM#617008
Review for gene: ADD3 was set to GREEN
gene: ADD3 was marked as current diagnostic
Added comment: Four families reported in the literature with bi-allelic variants in this gene causing intellectual disability.
Sources: Expert list
Intellectual disability v3.0 ADAMTS10 Zornitza Stark gene: ADAMTS10 was added
gene: ADAMTS10 was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: ADAMTS10 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: ADAMTS10 were set to Weill-Marchesani syndrome 1, recessive, MIM#277600
Review for gene: ADAMTS10 was set to AMBER
Added comment: Mild intellectual disability is described in around 10% of affected individuals.
Sources: Expert list
Intellectual disability v3.0 ABCC6 Zornitza Stark reviewed gene: ABCC6: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Arterial calcification, generalized, of infancy, 2, MIM#614473, Pseudoxanthoma elasticum, MIM#264800; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.0 SUPT16H Konstantinos Varvagiannis gene: SUPT16H was added
gene: SUPT16H was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: SUPT16H was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SUPT16H were set to http://dx.doi.org/10.1136/jmedgenet-2019-106193
Phenotypes for gene: SUPT16H were set to Global developmental delay; Intellectual disability; Abnormality of the corpus callosum
Penetrance for gene: SUPT16H were set to Complete
Review for gene: SUPT16H was set to AMBER
Added comment: Bina et al (2020 - http://dx.doi.org/10.1136/jmedgenet-2019-106193) report on 4 unrelated individuals with heterozygous SNVs affecting SUPT16H as well as 1 further with microdeletion spanning this gene.

The phenotype consisted of DD with subsequent ID in a subset of them (ages of the cohort: 2y-14y), autistic features in few, abnormalities of the corpus callosum (for 3 with available MRI images), variable gastrointestinal problems in some, and possibly minor dysmorphic features.

SUPT16H encodes a subunit of the FACT (facilitates chromatin transcription) complex, a chromatin-specific factor required for transcription elongation as well as for DNA replication and repair (OMIM citing Belotserkovskaya et al. 2003 - PMID: 12934006). The 2 subunits of the complex [Spt16 (encoded by SUPT16H) and SSRP1] are essential for histone regulation. As the authors note, Spt16 interacts with the histone dimer H2A-H2B during transcription to allow RNA polymerase access to previously coiled DNA [cited PMIDs : 9489704, 10421373 / A recent study by Liu et al 2019 (PMID: 31775157) appears highly relevant].

SUPT16H has a Z-score of 5.1 in gnomAD and a pLI of 1 (%HI of 22.56 in Decipher).

SNVs :
4 de novo missense SNVs were identified following exome sequencing (NM_007192.3:c.484A>G or I162V / L432P / N571S / R734W), all absent from gnomAD and mostly predicted to be deleterious (I162V predicted benign, tolerated, disease-causing by PolyPhen2, SIFT, MutationTaster respectively and had a CADD score of 13.61). Prior work-up for these individuals (incl. CMA in some / MS-MLPA for Angelman s. in 1 / metabolic investigations) had (probably) not revealed an apparent cause, with small CNVs inherited from healthy parents (a 4q13.3 dup / 20q13.2 del - coordinates not provided).

There were no studies performed for the identified variants.

CNVs :
A 5th individual reported by Bina et al was found to harbor a 2.05 Mb 14q11.2 deletion spanning SUPT16H. The specific deletion also spanned CHD8 while the same individual harbored also a 30.17 Mb duplication of 18p11.32q12.1.

CNVs spanning SUPT16H reported to date, also span the (very) proximal CHD8. [Genomic coordinates (GRCh38) for SUPT16H and CHD8 as provided by OMIM : 14:21,351,471-21,384,018 / 14:21,385,198-21,456,122]. Haploinsufficiency of CHD8 is associated with a distinctive syndrome with overgrowth and ID (Douzgou et al 2019 - PMID: 31001818). The phenotype of SUPT16H-CHD8 duplications is discussed in other studies/reviews. [Smol et al 2020 - PMID: 31823155 / Smyk et al 2016 - PMID: 26834018].

Animal models were not commented on by Bina et al (possibly not available for mouse : http://www.informatics.jax.org/marker/MGI:1890948 / https://www.mousephenotype.org/data/genes/MGI:1890948 ).
Sources: Literature
Intellectual disability v3.0 TET3 Konstantinos Varvagiannis gene: TET3 was added
gene: TET3 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: TET3 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: TET3 were set to https://doi.org/10.1016/j.ajhg.2019.12.007
Phenotypes for gene: TET3 were set to Global developmental delay; Intellectual disability; Macrocephaly; Growth abnormality; Seizures; Autistic behavior; Abnormality of movement; Abnormality of the face
Penetrance for gene: TET3 were set to Complete
Review for gene: TET3 was set to GREEN
Added comment: Beck et al (2020 - DOI: https://doi.org/10.1016/j.ajhg.2019.12.007) report on individuals with monoallelic de novo or biallelic pathogenic TET3 variants.

For both inheritance modes (AR/AD) DD/ID were among the observed features (mild-severe - individuals from families 2, 4 and 6 for whom presence of ID was not commented, relevance to the current panel is suggested from the developmental milestones in the supplement. One individual presented DD without ID). Other features included hypotonia (in 8), ASD/autistic features (in 5), seizures (2 unrelated subjects for each inheritance mode). Postnatal growth abnormalities were observed in many, in most cases involving head size (with/without abnormal stature) and few presented abnormal prenatal growth. Variable movement disorders were observed in some. Some facial features appeared to be more common (eg. long face, tall forehead, etc).

Most were referred for their DD. Extensive prior genetic investigations had (mostly) come out normal (with possible contribution of a 16p11.2 dup in an individual with monoallelic variant or a 16q22 dup in another with biallelic TET3 variants). Monoallelic / biallelic variants in all subjects were identified following exome sequencing.

TET3 encodes a methylcytosine dioxygenase (the TET family consisting of 3 enzymes, TET1, TET2, TET3). These enzymes are involved in DNA demethylation through a series of reactions beginning with the conversion of 5-methyl cytosine [5mc] to 5-hydromethylcytosine [5hmC].

5 individuals from 3 families (1/3 consanguineous) harbored biallelic missense variants. 5 different missense variants were observed. Heterozygous parents appeared to be mildly affected (eg. having learning difficulties, etc).

6 individuals from 5 families harbored monoallelic variants [3 truncating (of which 2 localizing in the last exon), 2 missense SNVs]. In one family the variant was inherited from a similarly affected parent. In all other cases the variant had occured de novo. No additional TET3 variants were identified, with the limitations of WES.

All missense mutations, whether observed in individuals with biallelic or monoallelic variants, were located within the catalytic domain or - for a single variant (NM_001287491.1:c.2254C>T / p.Arg752Cys) - adjacent to it.

Functional studies were carried out only for (all) missense variants observed in individuals with biallelic variants. Conversion of 5mC to 5hmC is the first step in DNA demethylation. In HEK293 cells overexpressing either wt or variants, production of 5hmc was measured. 4/5 missense variants evaluated demonstrated a defect in converting 5mC to 5hmC, Arg752Cys being an exception (as also predicted by its localization).

DD/ID and abnormal growth are also features of disorders of the epigenetic machinery (DNA methylation machinery, histone machinery, chromatin remodelers, other chromatin-associated proteins). Similarly to TET3, both monoallelic and biallelic variants in KDM5B, encoding for another component of the epigenetic machinery, have been identified in individuals with ID.

Mouse models discussed by the authors [several Refs provided though not here reviewed] : The gene has been shown to be highly expressed in oocytes, zygotes and neurons and to play a role in demethylation of the paternal genome after fertilization. (From the MGI: 'mice inheriting a null allele from a germ cell conditional null mother display impaired reprogramming of the paternal genome resulting in reduced embryo viability'). Beck et al also note that Tet3 inhibition or depletion in differentiated neurons can impact synaptic function [PMIDs cited: 25915473, 24757058, 26711116].
Sources: Literature
Intellectual disability v3.0 PIGP Konstantinos Varvagiannis changed review comment from: Please consider upgrading this gene to Green.

A recent study Vetro et al. (2020 - https://doi.org/10.1212/NXG.0000000000000387) identified 4 additional affected individuals with severe EIEE, belonging to a large inbred family. Following extensive genetic investigations (all of which were non-diagnostic) these subjects were found to harbor in homozygosity the frameshift variant also reported in the 2 previous studies (NM_153681.2:c.456delA / p.Glu153AsnfsTer34 or NM_153682.2:c.384delA / p.Glu129AsnfsTer34). Reduced expression of the GPI-anchor protein CD16 was demonstrated in granulocytes of affected individuals.; to: Please consider upgrading this gene to Green.

In a recent study, Vetro et al. (2020 - https://doi.org/10.1212/NXG.0000000000000387) identified 4 additional affected individuals with severe EIEE, belonging to a large inbred family. Following extensive genetic investigations (all of which were non-diagnostic) these subjects were found to harbor in homozygosity the frameshift variant also reported in the 2 previous studies (NM_153681.2:c.456delA / p.Glu153AsnfsTer34 or NM_153682.2:c.384delA / p.Glu129AsnfsTer34). Reduced expression of the GPI-anchor protein CD16 was demonstrated in granulocytes of affected individuals.
Intellectual disability v3.0 PIGP Konstantinos Varvagiannis edited their review of gene: PIGP: Added comment: Please consider upgrading this gene to Green.

A recent study Vetro et al. (2020 - https://doi.org/10.1212/NXG.0000000000000387) identified 4 additional affected individuals with severe EIEE, belonging to a large inbred family. Following extensive genetic investigations (all of which were non-diagnostic) these subjects were found to harbor in homozygosity the frameshift variant also reported in the 2 previous studies (NM_153681.2:c.456delA / p.Glu153AsnfsTer34 or NM_153682.2:c.384delA / p.Glu129AsnfsTer34). Reduced expression of the GPI-anchor protein CD16 was demonstrated in granulocytes of affected individuals.; Changed publications: 28334793, 31139695, https://doi.org/10.1212/NXG.0000000000000387
Intellectual disability v3.0 ZNF292 Konstantinos Varvagiannis commented on gene: ZNF292: Correction to the phrase "Manual review of some relevant LoF variants in gnomAD suggested that they represent false positive calls":

Irrespective of the variants identified in their cohort, Mirzaa et al. reviewed many pLoF variants which are listed in gnomAD. The authors suggested that some of these variants may not represent true LoF variants.

Eg. NM_015021.3:c.2690C>A ( https://gnomad.broadinstitute.org/variant/6-87966037-C-A ) which appears to be a stopgain variant (Ser[TCA]>Ter[TAA]) is probably not a true LoF variant. It always occurred in cis (/the same reads) with NM_015021.3:c.2689T>C (Ser[TCA] to Pro[CCA]). This is visible in the IGV graph of gnomAD (url above).

Thus, gnomAD lists 2 single-nucleotide variants affecting the same codon, one next to the other. However, as the 2 SNVs always occurred in cis, this represents a single missense multi-nucleotide variant (Ser[TCA]>Gln[CAA]) [ NM_015021.3(ZNF292_v001):c.2689_2690delinsCA ].

Similar observations were made for other variants seen in gnomAD.
Intellectual disability v3.0 NUS1 Konstantinos Varvagiannis edited their review of gene: NUS1: Added comment: Please consider upgrading this gene (NUS1 is also rated Green in the epilepsy panel).

Den et al (2019 - PMID: 31656175) reported on 2 additional unrelated individuals (aged 17 and 59y) both presenting intellectual disability, epilepsy , involuntary movements, ataxia and scoliosis. Both were found to harbor the same splicing variant in NUS1 (NM_138459.4:c.691+1C>A) following exome sequencing. Using lymphoblastoid cell lines from both individuals it was demonstrated that the variant creates a new splice donor site in exon 3 further creating a new reading frame and producing a premature termination codon [c.601_691del or p.(Arg202Glnfs*9)]. Using cyclohexamide, it was further shown that the mutant mRNA is partially subjected to NMD. [Additional variants identified by exome for the 2 subjects were non diagnostic (/VUS). An SPTAN1 nonsense variant identified in one was inherited from an unaffected parent (dominant-negative mechanism listed in G2P for this gene / in ClinVar all pLoF variants are submitted as VUS)].
-----; Changed rating: GREEN; Changed publications: 25066056, 29100083, 24824130, 30348779, 31656175