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Intellectual disability v9.370 MPDU1 Arina Puzriakova Phenotypes for gene: MPDU1 were changed from Congenital disorder of glycosylation, type If, 609180; CONGENITAL DISORDERS OF GLYCOSYLATION to Congenital disorder of glycosylation, type If, OMIM:609180
Intellectual disability v9.369 MYCBP2 Arina Puzriakova Publications for gene: MYCBP2 were set to 36200388; 41200582; 41543631
Intellectual disability v9.368 MYCBP2 Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: MYCBP2.
Intellectual disability v9.368 MYCBP2 Ida Ertmanska edited their review of gene: MYCBP2: Changed publications to: 33875846, 36200388, 41200582, 41543631
Intellectual disability v9.368 MYCBP2 Ida Ertmanska Publications for gene: MYCBP2 were set to 36200388; 41543631; 41200582
Intellectual disability v9.367 MYCBP2 Ida Ertmanska Publications for gene: MYCBP2 were set to 41200582; 36200388; 41543631
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 v9.366 MYCBP2 Ida Ertmanska edited their review of gene: MYCBP2: Changed publications to: 36200388, 41200582, 41543631
Intellectual disability v9.366 MYCBP2 Ida Ertmanska Phenotypes for gene: MYCBP2 were changed from to neurodevelopmental disorder, MONDO:0700092
Intellectual disability v9.365 MYCBP2 Ida Ertmanska Classified gene: MYCBP2 as Amber List (moderate evidence)
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 v9.365 MYCBP2 Ida Ertmanska Gene: mycbp2 has been classified as Amber List (Moderate Evidence).
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 v9.364 MYCBP2 Ida Ertmanska reviewed gene: MYCBP2: Rating: GREEN; Mode of pathogenicity: None; Publications: 36200388; Phenotypes: neurodevelopmental disorder, MONDO:0700092; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v9.364 COQ5 Ida Ertmanska Publications for gene: COQ5 were set to 19377476; 26350204; 21937992; 29044765
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 Classified gene: COQ5 as Amber List (moderate evidence)
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 v9.362 COQ5 Ida Ertmanska Gene: coq5 has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.361 COQ5 Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: COQ5.
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 Classified gene: RDH11 as Amber List (moderate evidence)
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 v9.361 RDH11 Ida Ertmanska Gene: rdh11 has been classified as Amber List (Moderate Evidence).
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 Classified gene: ATG12 as Amber List (moderate evidence)
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 v9.359 ATG12 Ida Ertmanska Gene: atg12 has been classified as Amber List (Moderate Evidence).
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 Tag Q1_26_promote_green was removed from gene: OLA1.
Tag Q2_26_promote_green tag was added to gene: OLA1.
Intellectual disability v9.357 OLA1 Ida Ertmanska Classified gene: OLA1 as Amber List (moderate evidence)
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 v9.357 OLA1 Ida Ertmanska Gene: ola1 has been classified as Amber List (Moderate Evidence).
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 Classified gene: BRF2 as Amber List (moderate evidence)
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 v9.355 BRF2 Ida Ertmanska Gene: brf2 has been classified as Amber List (Moderate Evidence).
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 v9.353 RHOBTB2 Ida Ertmanska Publications for gene: RHOBTB2 were set to 29276004; 29768694; 26740508
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 Tag Q1_26_MOI tag was added to gene: 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 RHOBTB2 Ida Ertmanska reviewed gene: RHOBTB2: Rating: GREEN; Mode of pathogenicity: None; Publications: 37165955; Phenotypes: Developmental and epileptic encephalopathy 64, OMIM:618004, developmental and epileptic encephalopathy, 64, MONDO:0033373; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v9.351 PTPN1 Ida Ertmanska Tag Q1_26_expert_review tag was added to gene: PTPN1.
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 Tag Q1_26_promote_green tag was added to gene: PTPN1.
Intellectual disability v9.351 PTPN1 Ida Ertmanska edited their review of gene: PTPN1: Changed rating: GREEN
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 v9.350 PTPN1 Ida Ertmanska edited their review of gene: PTPN1: Changed publications to: 10066179, 39986310; Changed phenotypes to: Encephalopathy, HP:0001298
Intellectual disability v9.350 PTPN1 Ida Ertmanska Phenotypes for gene: PTPN1 were changed from to Encephalopathy, HP:0001298
Intellectual disability v9.349 PTPN1 Ida Ertmanska Publications for gene: PTPN1 were set to 39986310
Intellectual disability v9.348 PTPN1 Ida Ertmanska Classified gene: PTPN1 as Amber List (moderate evidence)
Intellectual disability v9.348 PTPN1 Ida Ertmanska Gene: ptpn1 has been classified as Amber List (Moderate Evidence).
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 SOD1 Ida Ertmanska Tag treatable tag was added to gene: SOD1.
Intellectual disability v9.346 SOD1 Ida Ertmanska commented on gene: SOD1
Intellectual disability v9.346 UNC13A Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated 23 Mar 2026.
Intellectual disability v9.346 UNC13A Ida Ertmanska Phenotypes for gene: UNC13A were changed from developmental and epileptic encephalopathy, MONDO:0100620 to Neurodevelopmental disorder with speech delay, movement abnormalities, and seizures, OMIM:621456; Neurodevelopmental disorder with hypotonia, epilepsy, and absent speech, OMIM:621455; ?Intellectual development disorder with seizures and dysmorphic facies , OMIM:621457
Intellectual disability v9.345 UNC13A Arina Puzriakova Mode of inheritance for gene: UNC13A was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v9.344 UNC13A Arina Puzriakova Tag Q1_26_MOI was removed from gene: UNC13A.
Intellectual disability v9.344 UNC13A Arina Puzriakova changed review comment from: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.; to: The rating of this gene has been updated to green and the mode of inheritance set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.
Intellectual disability v9.344 PPP2R2B Arina Puzriakova Added comment: Comment on mode of inheritance: Set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to allow detection of SNVs.
Intellectual disability v9.344 PPP2R2B Arina Puzriakova Mode of inheritance for gene: PPP2R2B was changed from Other to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v9.343 CXorf56 Ida Ertmanska Tag gene-checked was removed from gene: CXorf56.
Intellectual disability v9.343 PDE1B Ida Ertmanska Tag gene-checked tag was added to gene: PDE1B.
Intellectual disability v9.343 NTNG2 Ida Ertmanska Tag gene-checked was removed from gene: NTNG2.
Intellectual disability v9.343 NHLRC2 Ida Ertmanska Tag gene-checked was removed from gene: NHLRC2.
Intellectual disability v9.343 METTL5 Ida Ertmanska Tag gene-checked was removed from gene: METTL5.
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 v9.342 LRRC7 Ida Ertmanska Phenotypes for gene: LRRC7 were changed from neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071 to Intellectual developmental disorder, autosomal dominant 77, OMIM:621415; intellectual developmental disorder, autosomal dominant 77, MONDO:0980748
Intellectual disability v9.341 LRRC7 Ida Ertmanska Tag gene-checked was removed from gene: LRRC7.
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 LMBRD2 Ida Ertmanska Tag gene-checked was removed from gene: LMBRD2.
Intellectual disability v9.340 ZNFX1 Arina Puzriakova Tag gene-checked was removed from gene: ZNFX1.
Intellectual disability v9.340 ZFHX4 Arina Puzriakova Tag gene-checked tag was added to gene: ZFHX4.
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 v9.339 KLHL20 Ida Ertmanska Tag gene-checked was removed from gene: KLHL20.
Intellectual disability v9.339 ZBTB11 Arina Puzriakova Tag gene-checked was removed from gene: ZBTB11.
Intellectual disability v9.339 YIF1B Arina Puzriakova Tag gene-checked was removed from gene: YIF1B.
Intellectual disability v9.339 WSB2 Arina Puzriakova Tag gene-checked tag was added to gene: WSB2.
Intellectual disability v9.339 KDM2B Ida Ertmanska Publications for gene: KDM2B were set to 36322151
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 KDM2B Ida Ertmanska Tag gene-checked was removed from gene: KDM2B.
Intellectual disability v9.337 HPDL Ida Ertmanska Tag gene-checked was removed from gene: HPDL.
Intellectual disability v9.337 WDR83OS Arina Puzriakova Tag gene-checked was removed from gene: WDR83OS.
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 v9.336 WDR37 Arina Puzriakova Tag gene-checked was removed from gene: WDR37.
Intellectual disability v9.336 UPF1 Arina Puzriakova Tag gene-checked tag was added to gene: UPF1.
Intellectual disability v9.336 HECTD4 Ida Ertmanska Tag gene-checked was removed from gene: HECTD4.
Intellectual disability v9.336 TUBGCP2 Arina Puzriakova Tag gene-checked was removed from gene: TUBGCP2.
Intellectual disability v9.336 TTC5 Arina Puzriakova Tag gene-checked was removed from gene: TTC5.
Intellectual disability v9.336 HEATR5B Ida Ertmanska Tag gene-checked tag was added to gene: HEATR5B.
Intellectual disability v9.336 TRIT1 Arina Puzriakova Tag gene-checked was removed from gene: TRIT1.
Intellectual disability v9.336 TRA2B Achchuthan Shanmugasundram Deleted their comment
Intellectual disability v9.336 TRA2B Achchuthan Shanmugasundram Deleted their comment
Intellectual disability v9.336 TRA2B Achchuthan Shanmugasundram Deleted their comment
Intellectual disability v9.336 TRA2B Arina Puzriakova Added comment: Comment on phenotypes: OMIM phenotype accessed on 20-03-2026
Intellectual disability v9.336 TRA2B Arina Puzriakova Phenotypes for gene: TRA2B were changed from neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071 to Ramond-Elliott neurodevelopmental syndrome, OMIM:621421
Intellectual disability v9.335 TRA2B Arina Puzriakova Tag gene-checked was removed from gene: TRA2B.
Intellectual disability v9.335 TMEM94 Arina Puzriakova Tag gene-checked was removed from gene: TMEM94.
Intellectual disability v9.335 GPATCH11 Ida Ertmanska Tag gene-checked tag was added to gene: GPATCH11.
Intellectual disability v9.335 TMEM63C Arina Puzriakova Added comment: Comment on phenotypes: OMIM phenotype accessed on 20-03-2026
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 v9.334 TMEM63C Arina Puzriakova Tag gene-checked was removed from gene: TMEM63C.
Intellectual disability v9.334 TMEM63B Arina Puzriakova Added comment: Comment on phenotypes: OMIM phenotype accessed on 20-03-2026
Intellectual disability v9.334 TMEM63B Arina Puzriakova Phenotypes for gene: TMEM63B were changed from developmental and epileptic encephalopathy, MONDO:0100062 to Developmental and epileptic encephalopathy 118, OMIM:621250
Intellectual disability v9.333 TMEM63B Arina Puzriakova Tag gene-checked was removed from gene: TMEM63B.
Intellectual disability v9.333 FRYL Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype added 20 Mar 2026.
Intellectual disability v9.333 FRYL Ida Ertmanska Phenotypes for gene: FRYL were changed from Neurodevelopmental disorder, MONDO:0700092 to Pan-Chung-Bellen syndrome, OMIM:621049; Pan-Chung-Bellen syndrome, MONDO:0975953
Intellectual disability v9.332 FRYL Ida Ertmanska Tag gene-checked was removed from gene: FRYL.
Intellectual disability v9.332 TMEM222 Arina Puzriakova Added comment: Comment on phenotypes: OMIM phenotype accessed on 20-03-2026
Intellectual disability v9.332 TMEM222 Arina Puzriakova Phenotypes for gene: TMEM222 were changed from Motor delay; Delayed speech and language development; Intellectual disability; Generalized hypotonia; Broad-based gait; Abnormality of nervous system morphology; Seizures; Microcephaly; Behavioral abnormality to Neurodevelopmental disorder with motor and speech delay and behavioral abnormalities, OMIM:619470
Intellectual disability v9.331 TMEM222 Arina Puzriakova Tag gene-checked was removed from gene: TMEM222.
Intellectual disability v9.331 TBC1D8B Arina Puzriakova Tag gene-checked was removed from gene: TBC1D8B.
Intellectual disability v9.331 TBC1D2B Arina Puzriakova Tag gene-checked was removed from gene: TBC1D2B.
Intellectual disability v9.331 SVBP Arina Puzriakova Tag gene-checked was removed from gene: SVBP.
Intellectual disability v9.331 SPATA5L1 Arina Puzriakova Tag gene-checked was removed from gene: SPATA5L1.
Intellectual disability v9.331 SEPHS1 Arina Puzriakova Tag gene-checked was removed from gene: SEPHS1.
Intellectual disability v9.331 RNU7-1 Arina Puzriakova Added comment: Comment on phenotypes: OMIM phenotype accessed on 20-03-2026
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 RNU7-1 Arina Puzriakova Tag gene-checked was removed from gene: RNU7-1.
Intellectual disability v9.330 RNU5B-1 Arina Puzriakova Tag gene-checked was removed from gene: RNU5B-1.
Intellectual disability v9.330 RNU4-2 Arina Puzriakova Tag gene-checked was removed from gene: RNU4-2.
Intellectual disability v9.330 RNPC3 Arina Puzriakova Tag gene-checked was removed from gene: RNPC3.
Intellectual disability v9.330 PITRM1 Arina Puzriakova Tag gene-checked was removed from gene: PITRM1.
Intellectual disability v9.330 FRYL Ida Ertmanska Tag gene-checked tag was added to gene: FRYL.
Intellectual disability v9.330 FICD Ida Ertmanska Tag gene-checked was removed from gene: FICD.
Intellectual disability v9.330 FICD Ida Ertmanska Tag gene-checked tag was added to gene: FICD.
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 v9.329 FEM1B Ida Ertmanska Tag gene-checked was removed from gene: FEM1B.
Intellectual disability v9.329 EPB41L3 Ida Ertmanska Tag gene-checked tag was added to gene: EPB41L3.
Intellectual disability v9.329 DDX39B Ida Ertmanska Tag gene-checked tag was added to gene: DDX39B.
Intellectual disability v9.329 CFAP47 Ida Ertmanska Tag gene-checked tag was added to gene: CFAP47.
Intellectual disability v9.329 CELF4 Ida Ertmanska Tag gene-checked tag was added to gene: CELF4.
Intellectual disability v9.329 TAOK2 Arina Puzriakova Publications for gene: TAOK2 were set to 39737487
Intellectual disability v9.328 TAOK2 Arina Puzriakova Tag gene-checked tag was added to gene: TAOK2.
Intellectual disability v9.328 SUPV3L1 Arina Puzriakova Tag gene-checked tag was added to gene: SUPV3L1.
Intellectual disability v9.328 SMARCA1 Arina Puzriakova Tag gene-checked tag was added to gene: SMARCA1.
Intellectual disability v9.328 BRSK1 Ida Ertmanska Tag gene-checked tag was added to gene: BRSK1.
Intellectual disability v9.328 SF1 Arina Puzriakova Tag gene-checked tag was added to gene: SF1.
Intellectual disability v9.328 SEPHS1 Arina Puzriakova Phenotypes for gene: SEPHS1 were changed from Neurodevelopmental disorder, MONDO:0700092 to Ververi-Brady syndrome 2, OMIM:621325; Neurodevelopmental disorder, MONDO:0700092
Intellectual disability v9.327 WARS Ida Ertmanska commented on gene: WARS
Intellectual disability v9.327 ABI2 Ida Ertmanska Tag gene-checked tag was added to gene: ABI2.
Intellectual disability v9.327 RREB1 Arina Puzriakova Tag gene-checked tag was added to gene: RREB1.
Intellectual disability v9.327 RNU2-2P Arina Puzriakova Phenotypes for gene: RNU2-2P were changed from neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071 to Developmental and epileptic encephalopathy 119, OMIM:621304
Intellectual disability v9.326 PPP1R21 Arina Puzriakova Tag gene-checked was removed from gene: PPP1R21.
Intellectual disability v9.326 WARS Ida Ertmanska Tag new-gene-name tag was added to gene: WARS.
Intellectual disability v9.326 PHF5A Arina Puzriakova Phenotypes for gene: PHF5A were changed from PHF5A-related neurodevelopmental disorder with congenital malformations to PHF5A-related neurodevelopmental disorder with congenital malformations; neurodevelopmental disorder, MONDO:0700092
Intellectual disability v9.325 PHF5A Arina Puzriakova Tag gene-checked tag was added to gene: PHF5A.
Intellectual disability v9.325 PHF12 Arina Puzriakova Tag gene-checked tag was added to gene: PHF12.
Intellectual disability v9.325 TANC2 Eleanor Williams Phenotypes for gene: TANC2 were changed from Intellectual developmental disorder with autistic features and language delay, with or without seizures, 618906 to Intellectual developmental disorder with autistic features and language delay, with or without seizures, OMIM:618906; intellectual developmental disorder with autistic features and language delay, with or without seizures, MONDO:0030051
Intellectual disability v9.324 TYW1 Eleanor Williams Phenotypes for gene: TYW1 were changed from cerebral palsy, MONDO:0006497 to cerebral palsy, MONDO:0006497; intellectual disability, MONDO:0001071
Intellectual disability v9.323 GABRA3 Arina Puzriakova Publications for gene: GABRA3 were set to 41289009
Intellectual disability v9.322 CDC42BPB Arina Puzriakova Mode of inheritance for gene: CDC42BPB was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v9.321 CDC42BPB Arina Puzriakova Publications for gene: CDC42BPB were set to 32031333
Intellectual disability v9.320 CDC42BPB Arina Puzriakova Tag Q1_26_promote_green tag was added to gene: CDC42BPB.
Intellectual disability v9.320 KCNT2 Arina Puzriakova Publications for gene: KCNT2 were set to 29069600; 29740868
Intellectual disability v9.319 KCNT2 Arina Puzriakova Phenotypes for gene: KCNT2 were changed from Developmental and epileptic encephalopathy 57, OMIM:617771 developmental and epileptic encephalopathy, 57, MONDO:0033366 to Developmental and epileptic encephalopathy 57, OMIM:617771; developmental and epileptic encephalopathy, 57, MONDO:0033366
Intellectual disability v9.318 ISCA-37448-Loss Ida Ertmanska Variant type for ISCA-37448-Loss was changed from small to cnv_loss.
Intellectual disability v9.317 ISCA-37433-Loss Arina Puzriakova Classified Region: ISCA-37433-Loss as No list
Intellectual disability v9.317 ISCA-37433-Loss Arina Puzriakova Region: isca-37433-loss has been removed from the panel.
Intellectual disability v9.316 ISCA-37433-Loss Arina Puzriakova Tag Q3_25_demote_red was removed from Region: ISCA-37433-Loss.
Tag curated_removed tag was added to Region: ISCA-37433-Loss.
Intellectual disability v9.316 ISCA-37433-Loss Arina Puzriakova commented on Region: ISCA-37433-Loss: The rating of this gene has been updated to Grey (removed) following NHS Genomic Medicine Service approval.
Intellectual disability v9.316 ISCA-37433-Gain Arina Puzriakova Classified Region: ISCA-37433-Gain as No list
Intellectual disability v9.316 ISCA-37433-Gain Arina Puzriakova Region: isca-37433-gain has been removed from the panel.
Intellectual disability v9.315 ISCA-37433-Gain Arina Puzriakova Tag Q3_25_demote_red was removed from Region: ISCA-37433-Gain.
Tag curated_removed tag was added to Region: ISCA-37433-Gain.
Intellectual disability v9.315 ISCA-37433-Gain Arina Puzriakova commented on Region: ISCA-37433-Gain: The rating of this gene has been updated to Grey (removed) following NHS Genomic Medicine Service approval.
Intellectual disability v9.315 ISCA-37404-Loss Arina Puzriakova Tag curated_removed tag was added to Region: ISCA-37404-Loss.
Intellectual disability v9.315 ISCA-37404-Loss Arina Puzriakova Classified Region: ISCA-37404-Loss as No list
Intellectual disability v9.315 ISCA-37404-Loss Arina Puzriakova Region: isca-37404-loss has been removed from the panel.
Intellectual disability v9.314 ISCA-37404-Loss Arina Puzriakova Tag Q3_25_demote_red was removed from Region: ISCA-37404-Loss.
Intellectual disability v9.314 ISCA-37404-Loss Arina Puzriakova commented on Region: ISCA-37404-Loss: The rating of this gene has been updated to Grey (removed) following NHS Genomic Medicine Service approval.
Intellectual disability v9.314 ISCA-37404-Gain Arina Puzriakova Classified Region: ISCA-37404-Gain as No list
Intellectual disability v9.314 ISCA-37404-Gain Arina Puzriakova Region: isca-37404-gain has been removed from the panel.
Intellectual disability v9.313 ISCA-37404-Gain Arina Puzriakova Tag curated_removed tag was added to Region: ISCA-37404-Gain.
Intellectual disability v9.313 ISCA-37404-Gain Arina Puzriakova Tag Q3_25_demote_red was removed from Region: ISCA-37404-Gain.
Intellectual disability v9.313 ISCA-37404-Gain Arina Puzriakova commented on Region: ISCA-37404-Gain: The rating of this gene has been updated to Grey (removed) following NHS Genomic Medicine Service approval.
Intellectual disability v9.313 ISCA-37448-Loss Arina Puzriakova Classified Region: ISCA-37448-Loss as Green List (high evidence)
Intellectual disability v9.313 ISCA-37448-Loss Arina Puzriakova Region: isca-37448-loss has been classified as Green List (High Evidence).
Intellectual disability v9.312 ISCA-37448-Loss Arina Puzriakova Tag Q3_25_promote_green was removed from Region: ISCA-37448-Loss.
Intellectual disability v9.312 ISCA-37448-Loss Arina Puzriakova commented on Region: ISCA-37448-Loss: The rating of this region has been updated to Green following NHS Genomic Medicine Service approval.
Intellectual disability v9.312 ISCA-46300-Loss Arina Puzriakova Classified Region: ISCA-46300-Loss as Green List (high evidence)
Intellectual disability v9.312 ISCA-46300-Loss Arina Puzriakova Region: isca-46300-loss has been classified as Green List (High Evidence).
Intellectual disability v9.311 ISCA-46300-Loss Arina Puzriakova Tag Q3_25_promote_green was removed from Region: ISCA-46300-Loss.
Intellectual disability v9.311 ISCA-46300-Loss Arina Puzriakova commented on Region: ISCA-46300-Loss: The rating of this region has been updated to Green following NHS Genomic Medicine Service approval.
Intellectual disability v9.311 ISCA-46296-Loss Arina Puzriakova Classified Region: ISCA-46296-Loss as Green List (high evidence)
Intellectual disability v9.311 ISCA-46296-Loss Arina Puzriakova Region: isca-46296-loss has been classified as Green List (High Evidence).
Intellectual disability v9.310 ISCA-46296-Loss Arina Puzriakova Tag Q3_25_promote_green was removed from Region: ISCA-46296-Loss.
Intellectual disability v9.310 ISCA-46296-Loss Arina Puzriakova commented on Region: ISCA-46296-Loss: The rating of this region has been updated to Green following NHS Genomic Medicine Service approval.
Intellectual disability v9.310 ISCA-37498-Loss Arina Puzriakova Classified Region: ISCA-37498-Loss as Green List (high evidence)
Intellectual disability v9.310 ISCA-37498-Loss Arina Puzriakova Region: isca-37498-loss has been classified as Green List (High Evidence).
Intellectual disability v9.309 ISCA-37498-Loss Arina Puzriakova Tag Q3_25_promote_green was removed from Region: ISCA-37498-Loss.
Intellectual disability v9.309 ISCA-37498-Loss Arina Puzriakova commented on Region: ISCA-37498-Loss: The rating of this region has been updated to Green following NHS Genomic Medicine Service approval.
Intellectual disability v9.309 WDR83 Ida Ertmanska edited their review of gene: WDR83: Changed publications to: 19726548, 28332277, 37509073, 41381792
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 v9.309 WDR83 Ida Ertmanska Publications for gene: WDR83 were set to 28332277; 41381792
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 Classified gene: WDR83 as Amber List (moderate evidence)
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 v9.308 WDR83 Ida Ertmanska Gene: wdr83 has been classified as Amber List (Moderate Evidence).
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 Classified gene: TYW1 as Amber List (moderate evidence)
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 v9.306 TYW1 Ida Ertmanska Gene: tyw1 has been classified as Amber List (Moderate Evidence).
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 IKBKG Achchuthan Shanmugasundram Tag currently-ngs-unreportable tag was added to gene: IKBKG.
Intellectual disability v9.304 PPP2R2B Achchuthan Shanmugasundram Tag Q1_25_ promote_green was removed from gene: PPP2R2B.
Intellectual disability v9.304 FBXO31 Ida Ertmanska Tag Q1_26_MOI was removed from gene: FBXO31.
Intellectual disability v9.304 FBXO31 Ida Ertmanska Tag Q1_26_MOI tag was added to gene: FBXO31.
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 FBXO31 Ida Ertmanska reviewed gene: FBXO31: Rating: GREEN; Mode of pathogenicity: None; Publications: 32989326, 33675180; Phenotypes: neurodevelopmental disorder, MONDO:0700092; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
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 v9.304 PPP2R1A Ida Ertmanska Phenotypes for gene: PPP2R1A were changed from INTELLECTUAL DISABILITY to Houge-Janssens syndrome 2, OMIM:616362; Houge-Janssens syndrome 2, MONDO:0014605
Intellectual disability v9.304 PPP2R1A Ida Ertmanska Publications for gene: PPP2R1A were set to 25533962
Intellectual disability v9.303 PPP2R1A Ida Ertmanska edited their review of gene: PPP2R1A: Changed phenotypes to: Houge-Janssens syndrome 2, OMIM:616362, Houge-Janssens syndrome 2, MONDO:0014605
Intellectual disability v9.303 PPP2R1A Ida Ertmanska reviewed gene: PPP2R1A: Rating: GREEN; Mode of pathogenicity: None; Publications: 33106617; Phenotypes: Houge-Janssens syndrome 2, OMIM:616362; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
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 edited their review of gene: CDC42BPB: Changed publications to: 28263302, 31785789, 35586607, 36344539
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 XPA Arina Puzriakova Tag Q1_25_ promote_green was removed from gene: XPA.
Intellectual disability v9.303 WDR47 Arina Puzriakova Tag Q1_25_ promote_green was removed from gene: WDR47.
Intellectual disability v9.303 WBP4 Arina Puzriakova Tag Q4_24_NHS_review was removed from gene: WBP4.
Tag Q4_24_promote_green was removed from gene: WBP4.
Intellectual disability v9.303 WARS Arina Puzriakova Tag Q3_25_promote_green was removed from gene: WARS.
Intellectual disability v9.303 VPS33A Arina Puzriakova Tag Q1_25_ promote_green was removed from gene: VPS33A.
Intellectual disability v9.303 UPF1 Arina Puzriakova Tag Q3_25_promote_green was removed from gene: UPF1.
Tag Q3_25_NHS_review was removed from gene: UPF1.
Intellectual disability v9.303 UNC13A Arina Puzriakova Tag Q3_25_promote_green was removed from gene: UNC13A.
Tag Q3_25_NHS_review was removed from gene: UNC13A.
Intellectual disability v9.303 POLRMT Achchuthan Shanmugasundram Added comment: Comment on phenotypes: OMIM phenotype was last accessed on 12 March 2026.
Intellectual disability v9.303 POLRMT Achchuthan Shanmugasundram Phenotypes for gene: POLRMT were changed from Combined oxidative phosphorylation deficiency 55, OMIM:619743 to Combined oxidative phosphorylation deficiency 55, OMIM:619743; combined oxidative phosphorylation deficiency 55, MONDO:0859228
Intellectual disability v9.302 UGGT1 Arina Puzriakova Tag Q3_25_promote_green was removed from gene: UGGT1.
Tag Q3_25_NHS_review was removed from gene: UGGT1.
Intellectual disability v9.302 UBR5 Arina Puzriakova Tag dd_review was removed from gene: UBR5.
Tag Q3_25_promote_green was removed from gene: UBR5.
Intellectual disability v9.302 TUBGCP2 Arina Puzriakova Tag Q1_25_ promote_green was removed from gene: TUBGCP2.
Intellectual disability v9.302 POLRMT Achchuthan Shanmugasundram Publications for gene: POLRMT were set to 24386581; 33602924
Intellectual disability v9.301 TSPAN7 Arina Puzriakova Tag Q3_25_expert_review was removed from gene: TSPAN7.
Tag Q3_25_demote_amber was removed from gene: TSPAN7.
Intellectual disability v9.301 TNR Arina Puzriakova Tag Q3_25_promote_green was removed from gene: TNR.
Intellectual disability v9.301 POLRMT Achchuthan Shanmugasundram reviewed gene: POLRMT: Rating: GREEN; Mode of pathogenicity: None; Publications: 33602924, 40583167; Phenotypes: Combined oxidative phosphorylation deficiency 55, OMIM:619743, combined oxidative phosphorylation deficiency 55, MONDO:0859228; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v9.301 TFG Arina Puzriakova Tag Q1_25_ promote_green was removed from gene: TFG.
Intellectual disability v9.301 TARS2 Arina Puzriakova Tag Q1_25_ promote_green was removed from gene: TARS2.
Intellectual disability v9.301 TAOK2 Arina Puzriakova Tag Q1_25_ NHS_review was removed from gene: TAOK2.
Tag Q1_25_ promote_green was removed from gene: TAOK2.
Intellectual disability v9.301 SUPV3L1 Arina Puzriakova Tag Q1_25_ promote_green was removed from gene: SUPV3L1.
Intellectual disability v9.301 SPOUT1 Arina Puzriakova Tag Q1_25_ promote_green was removed from gene: SPOUT1.
Intellectual disability v9.301 SPAST Arina Puzriakova Tag Q1_25_ promote_green was removed from gene: SPAST.
Intellectual disability v9.301 SOD1 Arina Puzriakova Tag Q3_25_promote_green was removed from gene: SOD1.
Intellectual disability v9.301 SMARCA1 Arina Puzriakova Tag Q2_25_ promote_green was removed from gene: SMARCA1.
Intellectual disability v9.301 SLC5A7 Arina Puzriakova Tag Q1_25_ promote_green was removed from gene: SLC5A7.
Intellectual disability v9.301 SF1 Arina Puzriakova Tag Q3_25_promote_green was removed from gene: SF1.
Tag Q3_25_NHS_review was removed from gene: SF1.
Intellectual disability v9.301 SEL1L Arina Puzriakova Tag Q2_25_ promote_green was removed from gene: SEL1L.
Tag Q2_25_ NHS_review was removed from gene: SEL1L.
Intellectual disability v9.301 RSPRY1 Arina Puzriakova Tag Q1_25_ promote_green was removed from gene: RSPRY1.
Intellectual disability v9.301 RREB1 Arina Puzriakova Tag Q3_25_promote_green was removed from gene: RREB1.
Tag Q3_25_NHS_review was removed from gene: RREB1.
Intellectual disability v9.301 RNU5B-1 Arina Puzriakova Tag dd_review was removed from gene: RNU5B-1.
Tag Q3_25_promote_green was removed from gene: RNU5B-1.
Intellectual disability v9.301 RNU2-2P Arina Puzriakova Tag dd_review was removed from gene: RNU2-2P.
Tag Q2_25_ promote_green was removed from gene: RNU2-2P.
Intellectual disability v9.301 PTRH2 Arina Puzriakova Tag watchlist was removed from gene: PTRH2.
Tag Q1_25_ promote_green was removed from gene: PTRH2.
Intellectual disability v9.301 PTBP1 Arina Puzriakova Tag Q3_25_promote_green was removed from gene: PTBP1.
Intellectual disability v9.301 PPP2R5C Arina Puzriakova Tag Q1_25_ promote_green was removed from gene: PPP2R5C.
Intellectual disability v9.301 PPOX Arina Puzriakova Tag Q3_25_promote_green was removed from gene: PPOX.
Intellectual disability v9.301 PNPLA8 Arina Puzriakova Tag Q1_25_ promote_green was removed from gene: PNPLA8.
Intellectual disability v9.301 PABPC1 Arina Puzriakova Tag dd_review was removed from gene: PABPC1.
Tag Q4_24_MOI was removed from gene: PABPC1.
Intellectual disability v9.301 OPA1 Arina Puzriakova Tag Q1_25_ promote_green was removed from gene: OPA1.
Intellectual disability v9.301 NOTCH3 Arina Puzriakova Tag dd_review was removed from gene: NOTCH3.
Tag Q3_25_promote_green was removed from gene: NOTCH3.
Intellectual disability v9.301 NHLRC2 Arina Puzriakova Tag Q1_25_ promote_green was removed from gene: NHLRC2.
Intellectual disability v9.301 NAV3 Arina Puzriakova Tag Q1_25_ promote_green was removed from gene: NAV3.
Intellectual disability v9.301 NAA20 Arina Puzriakova Tag Q1_25_ promote_green was removed from gene: NAA20.
Intellectual disability v9.301 HCN2 Ida Ertmanska Classified gene: HCN2 as Amber List (moderate evidence)
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 v9.301 HCN2 Ida Ertmanska Gene: hcn2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.300 MRPL49 Arina Puzriakova Tag Q2_25_ promote_green was removed from gene: MRPL49.
Intellectual disability v9.300 MED16 Arina Puzriakova Tag Q3_25_promote_green was removed from gene: MED16.
Tag Q3_25_NHS_review was removed from gene: MED16.
Intellectual disability v9.300 MED12L Arina Puzriakova Tag Q3_25_promote_green was removed from gene: MED12L.
Intellectual disability v9.300 MAP4K4 Arina Puzriakova Tag Q2_25_ promote_green was removed from gene: MAP4K4.
Intellectual disability v9.300 MAG Arina Puzriakova Tag Q1_25_ promote_green was removed from gene: MAG.
Intellectual disability v9.300 LAMC3 Arina Puzriakova Tag Q3_25_MOI was removed from gene: LAMC3.
Tag Q3_25_expert_review was removed from gene: LAMC3.
Tag Q3_25_demote_red was removed from gene: LAMC3.
Intellectual disability v9.300 KIRREL3 Arina Puzriakova Tag Q3_25_expert_review was removed from gene: KIRREL3.
Tag Q3_25_demote_red was removed from gene: KIRREL3.
Intellectual disability v9.300 KIAA0556 Arina Puzriakova Tag Q3_25_promote_green was removed from gene: KIAA0556.
Intellectual disability v9.300 KDM5B Arina Puzriakova Tag Q2_25_ MOI was removed from gene: KDM5B.
Tag Q2_25_expert_review was removed from gene: KDM5B.
Tag Q2_25_ NHS_review was removed from gene: KDM5B.
Intellectual disability v9.300 INPP4A Arina Puzriakova Tag Q1_25_ promote_green was removed from gene: INPP4A.
Intellectual disability v9.300 HNRNPC Arina Puzriakova Tag Q1_25_ promote_green was removed from gene: HNRNPC.
Intellectual disability v9.300 GTF3C3 Arina Puzriakova Tag Q1_25_ promote_green was removed from gene: GTF3C3.
Intellectual disability v9.300 GPATCH11 Arina Puzriakova Tag Q1_25_ promote_green was removed from gene: GPATCH11.
Intellectual disability v9.300 FLVCR1 Arina Puzriakova Tag Q3_25_promote_green was removed from gene: FLVCR1.
Intellectual disability v9.300 FBXO22 Arina Puzriakova Tag Q2_25_ promote_green was removed from gene: FBXO22.
Tag Q2_25_ NHS_review was removed from gene: FBXO22.
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 EXOSC8 Arina Puzriakova Tag Q3_25_promote_green was removed from gene: EXOSC8.
Intellectual disability v9.299 EPB41L3 Arina Puzriakova Tag Q2_25_ promote_green was removed from gene: EPB41L3.
Tag Q2_25_ NHS_review was removed from gene: EPB41L3.
Intellectual disability v9.299 EMX2 Arina Puzriakova Tag Q3_25_expert_review was removed from gene: EMX2.
Tag Q3_25_NHS_review was removed from gene: EMX2.
Tag Q3_25_demote_amber was removed from gene: EMX2.
Intellectual disability v9.299 ELFN1 Arina Puzriakova Tag Q3_25_promote_green was removed from gene: ELFN1.
Intellectual disability v9.299 EEFSEC Arina Puzriakova Tag Q1_25_ promote_green was removed from gene: EEFSEC.
Intellectual disability v9.299 EEF1D Arina Puzriakova Tag Q2_25_ promote_green was removed from gene: EEF1D.
Tag Q2_25_ NHS_review was removed from gene: EEF1D.
Intellectual disability v9.299 DDX39B Arina Puzriakova Tag Q2_25_ promote_green was removed from gene: DDX39B.
Tag Q2_25_ NHS_review was removed from gene: DDX39B.
Intellectual disability v9.299 CRNKL1 Arina Puzriakova Tag dd_review was removed from gene: CRNKL1.
Tag Q3_25_promote_green was removed from gene: CRNKL1.
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 CELF4 Arina Puzriakova Tag dd_review was removed from gene: CELF4.
Tag Q2_25_ promote_green was removed from gene: CELF4.
Intellectual disability v9.299 CDK9 Arina Puzriakova Tag watchlist was removed from gene: CDK9.
Tag Q3_25_promote_green was removed from gene: CDK9.
Intellectual disability v9.299 CCT6A Arina Puzriakova Tag Q3_25_promote_green was removed from gene: CCT6A.
Intellectual disability v9.299 C12orf66 Arina Puzriakova Tag Q1_25_ promote_green was removed from gene: C12orf66.
Intellectual disability v9.299 ATM Arina Puzriakova Tag Q2_25_ demote_red was removed from gene: ATM.
Tag Q2_25_expert_review was removed from gene: ATM.
Intellectual disability v9.299 ASCC3 Arina Puzriakova Tag Q1_25_ promote_green was removed from gene: ASCC3.
Intellectual disability v9.299 AP1B1 Arina Puzriakova Tag Q3_25_promote_green was removed from gene: AP1B1.
Intellectual disability v9.299 XPA Arina Puzriakova reviewed gene: XPA: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Intellectual disability v9.299 WDR47 Arina Puzriakova reviewed gene: WDR47: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Intellectual disability v9.299 WBP4 Arina Puzriakova reviewed gene: WBP4: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Intellectual disability v9.299 WARS Arina Puzriakova reviewed gene: WARS: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Intellectual disability v9.299 VPS33A Arina Puzriakova reviewed gene: VPS33A: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Intellectual disability v9.299 UPF1 Arina Puzriakova reviewed gene: UPF1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Intellectual disability v9.299 UNC13A Arina Puzriakova reviewed gene: UNC13A: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Intellectual disability v9.299 UGGT1 Arina Puzriakova reviewed gene: UGGT1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Intellectual disability v9.299 UBR5 Arina Puzriakova reviewed gene: UBR5: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Intellectual disability v9.299 TUBGCP2 Arina Puzriakova commented on gene: TUBGCP2: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.
Intellectual disability v9.299 TSPAN7 Arina Puzriakova reviewed gene: TSPAN7: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Intellectual disability v9.299 TNR Arina Puzriakova commented on gene: TNR: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.
Intellectual disability v9.299 TFG Arina Puzriakova reviewed gene: TFG: 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 TAOK2 Arina Puzriakova reviewed gene: TAOK2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Intellectual disability v9.299 SUPV3L1 Arina Puzriakova reviewed gene: SUPV3L1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Intellectual disability v9.299 SPOUT1 Arina Puzriakova reviewed gene: SPOUT1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Intellectual disability v9.299 SPAST Arina Puzriakova edited their review of gene: SPAST: Added comment: The rating of this gene has been updated to green and the mode of inheritance updated to BOTH monoallelic and biallelic, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.; Changed rating: GREEN
Intellectual disability v9.299 SOD1 Arina Puzriakova commented on gene: SOD1: The rating of this gene has been updated to green and the mode of inheritance set to BIALLELIC, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.
Intellectual disability v9.299 SMARCA1 Arina Puzriakova reviewed gene: SMARCA1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Intellectual disability v9.299 SLC5A7 Arina Puzriakova commented on gene: SLC5A7: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.
Intellectual disability v9.299 SF1 Arina Puzriakova reviewed gene: SF1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Intellectual disability v9.299 SEL1L Arina Puzriakova reviewed gene: SEL1L: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Intellectual disability v9.299 RSPRY1 Arina Puzriakova commented on gene: RSPRY1: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.
Intellectual disability v9.299 RREB1 Arina Puzriakova reviewed gene: RREB1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Intellectual disability v9.299 RNU5B-1 Arina Puzriakova commented on gene: RNU5B-1: The rating of this gene has been updated to green and the mode of inheritance set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown following NHS Genomic Medicine Service approval.
Intellectual disability v9.299 RNU2-2P Arina Puzriakova reviewed gene: RNU2-2P: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Intellectual disability v9.299 PTRH2 Arina Puzriakova reviewed gene: PTRH2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Intellectual disability v9.299 PTBP1 Arina Puzriakova commented on gene: PTBP1: The rating of this gene has been updated to green and the mode of inheritance set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted following NHS Genomic Medicine Service approval.
Intellectual disability v9.299 PPP2R5C Arina Puzriakova reviewed gene: PPP2R5C: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Intellectual disability v9.299 PPP2R2B Arina Puzriakova edited their review of gene: PPP2R2B: Added comment: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.; Changed rating: GREEN
Intellectual disability v9.299 PPOX Arina Puzriakova reviewed gene: PPOX: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Intellectual disability v9.299 PNPLA8 Arina Puzriakova reviewed gene: PNPLA8: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Intellectual disability v9.299 PABPC1 Arina Puzriakova commented on gene: PABPC1
Intellectual disability v9.299 OPA1 Arina Puzriakova reviewed gene: OPA1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Intellectual disability v9.299 NOTCH3 Arina Puzriakova reviewed gene: NOTCH3: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Intellectual disability v9.299 NHLRC2 Arina Puzriakova reviewed gene: NHLRC2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Intellectual disability v9.299 NAV3 Arina Puzriakova reviewed gene: NAV3: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Intellectual disability v9.299 NAA20 Arina Puzriakova reviewed gene: NAA20: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Intellectual disability v9.299 MRPL49 Arina Puzriakova reviewed gene: MRPL49: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Intellectual disability v9.299 MED16 Arina Puzriakova reviewed gene: MED16: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Intellectual disability v9.299 MED12L Arina Puzriakova reviewed gene: MED12L: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Intellectual disability v9.299 MAP4K4 Arina Puzriakova edited their review of gene: MAP4K4: Added comment: The rating of this gene has been updated to green and the mode of inheritance set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown following NHS Genomic Medicine Service approval.; Changed rating: GREEN
Intellectual disability v9.299 MAG Arina Puzriakova reviewed gene: MAG: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Intellectual disability v9.299 LAMC3 Arina Puzriakova reviewed gene: LAMC3: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Intellectual disability v9.299 KIRREL3 Arina Puzriakova edited their review of gene: KIRREL3: Added comment: The rating of this gene has been updated to red following NHS Genomic Medicine Service approval.; Changed rating: RED
Intellectual disability v9.299 KIAA0556 Arina Puzriakova commented on gene: KIAA0556: The rating of this gene has been updated to green and the mode of inheritance set to BIALLELIC, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.
Intellectual disability v9.299 KDM5B Arina Puzriakova commented on gene: KDM5B: The mode of inheritance of this gene has been updated to BIALLELIC, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.
Intellectual disability v9.299 INPP4A Arina Puzriakova edited their review of gene: INPP4A: Added comment: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.; Changed rating: GREEN
Intellectual disability v9.299 HNRNPC Arina Puzriakova reviewed gene: HNRNPC: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Intellectual disability v9.299 GTF3C3 Arina Puzriakova commented on gene: GTF3C3: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.
Intellectual disability v9.299 GPATCH11 Arina Puzriakova reviewed gene: GPATCH11: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Intellectual disability v9.299 FLVCR1 Arina Puzriakova reviewed gene: FLVCR1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Intellectual disability v9.299 FBXO22 Arina Puzriakova reviewed gene: FBXO22: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Intellectual disability v9.299 EXOSC8 Arina Puzriakova commented on gene: EXOSC8: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.
Intellectual disability v9.299 EPB41L3 Arina Puzriakova commented on gene: EPB41L3: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.
Intellectual disability v9.299 EMX2 Arina Puzriakova reviewed gene: EMX2: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Intellectual disability v9.299 ELFN1 Arina Puzriakova commented on gene: ELFN1: The rating of this gene has been updated to green and the mode of inheritance set to BIALLELIC, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.
Intellectual disability v9.299 EEFSEC Arina Puzriakova reviewed gene: EEFSEC: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Intellectual disability v9.299 EEF1D Arina Puzriakova commented on gene: EEF1D: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.
Intellectual disability v9.299 DDX39B Arina Puzriakova reviewed gene: DDX39B: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Intellectual disability v9.299 CRNKL1 Arina Puzriakova reviewed gene: CRNKL1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Intellectual disability v9.299 CELF4 Arina Puzriakova reviewed gene: CELF4: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Intellectual disability v9.299 CDK9 Arina Puzriakova reviewed gene: CDK9: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Intellectual disability v9.299 CCT6A Arina Puzriakova commented on gene: CCT6A: The rating of this gene has been updated to green and the mode of inheritance set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown following NHS Genomic Medicine Service approval.
Intellectual disability v9.299 C12orf66 Arina Puzriakova commented on gene: C12orf66: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.
Intellectual disability v9.299 ATM Arina Puzriakova edited their review of gene: ATM: Added comment: The rating of this gene has been updated to red following NHS Genomic Medicine Service approval.; Changed rating: RED
Intellectual disability v9.299 ASCC3 Arina Puzriakova edited their review of gene: ASCC3: Added comment: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.; Changed rating: GREEN
Intellectual disability v9.299 AP1B1 Arina Puzriakova reviewed gene: AP1B1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Intellectual disability v9.298 WDR47 Arina Puzriakova Source NHS GMS was added to WDR47.
Source Expert Review Green was added to WDR47.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v9.298 WBP4 Arina Puzriakova Source NHS GMS was added to WBP4.
Source Expert Review Green was added to WBP4.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
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 VPS33A Arina Puzriakova Source NHS GMS was added to VPS33A.
Source Expert Review Green was added to VPS33A.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v9.298 UPF1 Arina Puzriakova Source NHS GMS was added to UPF1.
Source Expert Review Green was added to UPF1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v9.298 UNC13A Arina Puzriakova Source NHS GMS was added to UNC13A.
Source Expert Review Green was added to UNC13A.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v9.298 UGGT1 Arina Puzriakova Source NHS GMS was added to UGGT1.
Source Expert Review Green was added to UGGT1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v9.298 UBR5 Arina Puzriakova Source NHS GMS was added to UBR5.
Source Expert Review Green was added to UBR5.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v9.298 TUBGCP2 Arina Puzriakova Source NHS GMS was added to TUBGCP2.
Source Expert Review Green was added to TUBGCP2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v9.298 TSPAN7 Arina Puzriakova Source NHS GMS was added to TSPAN7.
Source Expert Review Amber was added to TSPAN7.
Rating Changed from Green List (high evidence) to Amber List (moderate evidence)
Intellectual disability v9.298 TNR Arina Puzriakova Source NHS GMS was added to TNR.
Source Expert Review Green was added to TNR.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v9.298 TFG Arina Puzriakova Source NHS GMS was added to TFG.
Source Expert Review Green was added to TFG.
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 TAOK2 Arina Puzriakova Source NHS GMS was added to TAOK2.
Source Expert Review Green was added to TAOK2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v9.298 SUPV3L1 Arina Puzriakova Source NHS GMS was added to SUPV3L1.
Source Expert Review Green was added to SUPV3L1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v9.298 SPOUT1 Arina Puzriakova Source NHS GMS was added to SPOUT1.
Source Expert Review Green was added to SPOUT1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v9.298 SPAST Arina Puzriakova Source NHS GMS was added to SPAST.
Source Expert Review Green was added to SPAST.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v9.298 SOD1 Arina Puzriakova Source NHS GMS was added to SOD1.
Source Expert Review Green was added to SOD1.
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 v9.298 SLC5A7 Arina Puzriakova Source NHS GMS was added to SLC5A7.
Source Expert Review Green was added to SLC5A7.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v9.298 SF1 Arina Puzriakova Source NHS GMS was added to SF1.
Source Expert Review Green was added to SF1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v9.298 SEL1L Arina Puzriakova Source NHS GMS was added to SEL1L.
Source Expert Review Green was added to SEL1L.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v9.298 RSPRY1 Arina Puzriakova Source NHS GMS was added to RSPRY1.
Source Expert Review Green was added to RSPRY1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v9.298 RREB1 Arina Puzriakova Source NHS GMS was added to RREB1.
Source Expert Review Green was added to RREB1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v9.298 RNU5B-1 Arina Puzriakova Source NHS GMS was added to RNU5B-1.
Source Expert Review Green was added to RNU5B-1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v9.298 RNU2-2P Arina Puzriakova Source NHS GMS was added to RNU2-2P.
Source Expert Review Green was added to RNU2-2P.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v9.298 PTRH2 Arina Puzriakova Source NHS GMS was added to PTRH2.
Source Expert Review Green was added to PTRH2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v9.298 PTBP1 Arina Puzriakova Source Expert Review Green was added to PTBP1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v9.298 PPP2R5C Arina Puzriakova Source NHS GMS was added to PPP2R5C.
Source Expert Review Green was added to PPP2R5C.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v9.298 PPP2R2B Arina Puzriakova Source NHS GMS was added to PPP2R2B.
Source Expert Review Green was added to PPP2R2B.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v9.298 PPOX Arina Puzriakova Source NHS GMS was added to PPOX.
Source Expert Review Green was added to PPOX.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v9.298 PNPLA8 Arina Puzriakova Source NHS GMS was added to PNPLA8.
Source Expert Review Green was added to PNPLA8.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v9.298 PABPC1 Arina Puzriakova Mode of inheritance for gene PABPC1 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v9.298 OPA1 Arina Puzriakova Source NHS GMS was added to OPA1.
Source Expert Review Green was added to OPA1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v9.298 NOTCH3 Arina Puzriakova Source NHS GMS was added to NOTCH3.
Source Expert Review Green was added to NOTCH3.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v9.298 NHLRC2 Arina Puzriakova Source NHS GMS was added to NHLRC2.
Source Expert Review Green was added to NHLRC2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v9.298 NAV3 Arina Puzriakova Source NHS GMS was added to NAV3.
Source Expert Review Green was added to NAV3.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v9.298 NAA20 Arina Puzriakova Source NHS GMS was added to NAA20.
Source Expert Review Green was added to NAA20.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v9.298 MRPL49 Arina Puzriakova Source NHS GMS was added to MRPL49.
Source Expert Review Green was added to MRPL49.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v9.298 MED16 Arina Puzriakova Source Expert Review Green was added to MED16.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v9.298 MED12L Arina Puzriakova Source NHS GMS was added to MED12L.
Source Expert Review Green was added to MED12L.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v9.298 MAP4K4 Arina Puzriakova Source NHS GMS was added to MAP4K4.
Source Expert Review Green was added to MAP4K4.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v9.298 MAG Arina Puzriakova Source NHS GMS was added to MAG.
Source Expert Review Green was added to MAG.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v9.298 LAMC3 Arina Puzriakova Source NHS GMS was added to LAMC3.
Source Expert Review Red was added to LAMC3.
Mode of inheritance for gene LAMC3 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Rating Changed from Green List (high evidence) to Red List (low evidence)
Intellectual disability v9.298 KIRREL3 Arina Puzriakova Source Expert Review Red was added to KIRREL3.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Intellectual disability v9.298 KIAA0556 Arina Puzriakova Source NHS GMS was added to KIAA0556.
Source Expert Review Green was added to KIAA0556.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v9.298 KDM5B Arina Puzriakova Source NHS GMS was added to KDM5B.
Mode of inheritance for gene KDM5B was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v9.298 INPP4A Arina Puzriakova Source NHS GMS was added to INPP4A.
Source Expert Review Green was added to INPP4A.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v9.298 HNRNPC Arina Puzriakova Source NHS GMS was added to HNRNPC.
Source Expert Review Green was added to HNRNPC.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v9.298 GTF3C3 Arina Puzriakova Source NHS GMS was added to GTF3C3.
Source Expert Review Green was added to GTF3C3.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v9.298 GPATCH11 Arina Puzriakova Source NHS GMS was added to GPATCH11.
Source Expert Review Green was added to GPATCH11.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v9.298 FLVCR1 Arina Puzriakova Source NHS GMS was added to FLVCR1.
Source Expert Review Green was added to FLVCR1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v9.298 FBXO22 Arina Puzriakova Source NHS GMS was added to FBXO22.
Source Expert Review Green was added to FBXO22.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v9.298 EXOSC8 Arina Puzriakova Source NHS GMS was added to EXOSC8.
Source Expert Review Green was added to EXOSC8.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v9.298 EPB41L3 Arina Puzriakova Source NHS GMS was added to EPB41L3.
Source Expert Review Green was added to EPB41L3.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v9.298 EMX2 Arina Puzriakova Source NHS GMS was added to EMX2.
Source Expert Review Amber was added to EMX2.
Rating Changed from Green List (high evidence) to Amber List (moderate evidence)
Intellectual disability v9.298 ELFN1 Arina Puzriakova Source NHS GMS was added to ELFN1.
Source Expert Review Green was added to ELFN1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v9.298 EEFSEC Arina Puzriakova Source NHS GMS was added to EEFSEC.
Source Expert Review Green was added to EEFSEC.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v9.298 EEF1D Arina Puzriakova Source NHS GMS was added to EEF1D.
Source Expert Review Green was added to EEF1D.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v9.298 DDX39B Arina Puzriakova Source NHS GMS was added to DDX39B.
Source Expert Review Green was added to DDX39B.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v9.298 CRNKL1 Arina Puzriakova Source NHS GMS was added to CRNKL1.
Source Expert Review Green was added to CRNKL1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v9.298 CDK9 Arina Puzriakova Source NHS GMS was added to CDK9.
Source Expert Review Green was added to CDK9.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v9.298 CCT6A Arina Puzriakova Source NHS GMS was added to CCT6A.
Source Expert Review Green was added to CCT6A.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v9.298 C12orf66 Arina Puzriakova Source NHS GMS was added to C12orf66.
Source Expert Review Green was added to C12orf66.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v9.298 ATM Arina Puzriakova Source NHS GMS was added to ATM.
Source Expert Review Red was added to ATM.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Intellectual disability v9.298 ASCC3 Arina Puzriakova Source NHS GMS was added to ASCC3.
Source Expert Review Green was added to ASCC3.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v9.297 GTF3C3 Arina Puzriakova Added comment: Comment on phenotypes: OMIM phenotype accessed on 11-03-2026
Intellectual disability v9.297 GTF3C3 Arina Puzriakova Phenotypes for gene: GTF3C3 were changed from Global developmental delay; Intellectual disability; Seizures to Neurodevelopmental disorder with dysmorphic facies, brain anomalies, and seizures, OMIM:621201
Intellectual disability v9.296 GABRA3 Ida Ertmanska Classified gene: GABRA3 as Amber List (moderate 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 v9.296 GABRA3 Ida Ertmanska Gene: gabra3 has been classified as Amber List (Moderate Evidence).
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 v9.294 ZNF865 Ida Ertmanska Mode of inheritance for gene: ZNF865 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v9.293 ZNF865 Ida Ertmanska edited their review of gene: ZNF865: Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
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 v9.293 NRDC Ida Ertmanska Phenotypes for gene: NRDC were changed from to neurodevelopmental disorder, MONDO:0700092
Intellectual disability v9.292 NRDC Ida Ertmanska Classified gene: NRDC as Amber List (moderate evidence)
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 v9.292 NRDC Ida Ertmanska Gene: nrdc has been classified as Amber List (Moderate Evidence).
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 Classified gene: FSD1L as Amber List (moderate evidence)
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 v9.290 FSD1L Ida Ertmanska Gene: fsd1l has been classified as Amber List (Moderate Evidence).
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 v9.288 ALPL Arina Puzriakova Phenotypes for gene: ALPL were changed from Hypophosphatasia, infantile, 241500; Hypophosphatasia, childhood, 241510; Odontohypophosphatasia, 146300; Hypophosphatasia, adult, 146300 to Hypophosphatasia, adult, OMIM:146300; Hypophosphatasia, childhood, OMIM:241510; Hypophosphatasia, infantile, OMIM:241500; Odontohypophosphatasia, OMIM:146300
Intellectual disability v9.287 PHF5A Arina Puzriakova Classified gene: PHF5A as Amber List (moderate evidence)
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 v9.287 PHF5A Arina Puzriakova Gene: phf5a has been classified as Amber List (Moderate Evidence).
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 v9.285 PPFIA3 Arina Puzriakova Tag watchlist_moi tag was added to gene: PPFIA3.
Intellectual disability v9.285 ABI2 Ida Ertmanska Publications for gene: ABI2 were set to 28397838; 39774290
Intellectual disability v9.284 ABI2 Ida Ertmanska Phenotypes for gene: ABI2 were changed from intellectual disability, MONDO:0001071 to intellectual disability, MONDO:0001071; neurodevelopmental disorder, MONDO:0700092
Intellectual disability v9.283 ABI2 Ida Ertmanska Mode of inheritance for gene: ABI2 was changed from BIALLELIC, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v9.282 ABI2 Ida Ertmanska Classified gene: ABI2 as Amber List (moderate evidence)
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 v9.282 ABI2 Ida Ertmanska Gene: abi2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.281 ABI2 Ida Ertmanska edited their review of gene: ABI2: Changed rating: GREEN
Intellectual disability v9.281 ABI2 Ida Ertmanska reviewed gene: ABI2: Rating: AMBER; Mode of pathogenicity: None; Publications: 40475134; Phenotypes: neurodevelopmental disorder, MONDO:0700092; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v9.281 PTPMT1 Arina Puzriakova Classified gene: PTPMT1 as Amber List (moderate evidence)
Intellectual disability v9.281 PTPMT1 Arina Puzriakova Gene: ptpmt1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.280 KCNT2 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated 27th Feb 2026.
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 v9.279 CDC42BPB Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype accessed 24th Feb 2026.
Intellectual disability v9.279 CDC42BPB Ida Ertmanska Phenotypes for gene: CDC42BPB were changed from CDC42BPB-related Neurodevelopmental Disorder; Central hypotonia; Global developmental delay; Intellectual disability; Seizures; Autistic behavior; Behavioral abnormality to Chilton-Okur-Chung neurodevelopmental syndrome, OMIM:619841; Chilton-Okur-Chung neurodevelopmental syndrome, MONDO:0859239
Intellectual disability v9.278 CDC42BPB Ida Ertmanska reviewed gene: CDC42BPB: Rating: AMBER; Mode of pathogenicity: None; Publications: 31785789, 35586607; Phenotypes: Chilton-Okur-Chung neurodevelopmental syndrome, OMIM:619841; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
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 Classified gene: ATOH1 as Amber List (moderate evidence)
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 v9.278 ATOH1 Ida Ertmanska Gene: atoh1 has been classified as Amber List (Moderate Evidence).
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 v9.276 BORCS5 Ida Ertmanska Classified gene: BORCS5 as Amber List (moderate evidence)
Intellectual disability v9.276 BORCS5 Ida Ertmanska Added comment: Comment on list classification: Gene will not be tagged for promotion to Green until PMID: 40385417 pre-print is published.
Intellectual disability v9.276 BORCS5 Ida Ertmanska Gene: borcs5 has been classified as Amber List (Moderate Evidence).
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 v9.274 CCT8 Ida Ertmanska Classified gene: CCT8 as Amber List (moderate evidence)
Intellectual disability v9.274 CCT8 Ida Ertmanska Gene: cct8 has been classified as Amber List (Moderate Evidence).
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 v9.271 CCT5 Ida Ertmanska Publications for gene: CCT5 were set to 16399879; 25124038
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 Classified gene: CCT3 as Amber List (moderate evidence)
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 v9.270 CCT3 Ida Ertmanska Gene: cct3 has been classified as Amber List (Moderate Evidence).
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 v9.268 TCP1 Ida Ertmanska Phenotypes for gene: TCP1 were changed from Intellectual developmental disorder with polymicrogyria and seizures, OMIM:621021 to Intellectual developmental disorder with polymicrogyria and seizures, OMIM:621021; intellectual developmental disorder with polymicrogyria and seizures, MONDO:0976124
Intellectual disability v9.267 TCP1 Ida Ertmanska Classified gene: TCP1 as Amber List (moderate evidence)
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 v9.267 TCP1 Ida Ertmanska Gene: tcp1 has been classified as Amber List (Moderate Evidence).
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 Classified gene: SLC12A9 as Amber List (moderate evidence)
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 v9.265 SLC12A9 Ida Ertmanska Gene: slc12a9 has been classified as Amber List (Moderate Evidence).
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 Classified gene: PPFIA3 as Amber List (moderate evidence)
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 v9.263 PPFIA3 Ida Ertmanska Gene: ppfia3 has been classified as Amber List (Moderate Evidence).
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 Added comment: Comment on phenotypes: OMIM phenotypes accessed on 16-02-2026
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 v9.260 PKHD1 Arina Puzriakova Phenotypes for gene: PKHD1 were changed from Polycystic kidney and hepatic disease, 263200 to Polycystic kidney disease 4 with or without hepatic disease, OMIM:263200
Intellectual disability v9.259 SLITRK2 Ida Ertmanska Phenotypes for gene: SLITRK2 were changed from to Intellectual developmental disorder, X-linked 111, OMIM:301107; intellectual developmental disorder, X-linked 111, MONDO:0957203
Intellectual disability v9.258 SLITRK2 Ida Ertmanska Publications for gene: SLITRK2 were set to PMID: 35840571
Intellectual disability v9.257 SLITRK2 Ida Ertmanska Classified gene: SLITRK2 as Amber List (moderate evidence)
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 v9.257 SLITRK2 Ida Ertmanska Gene: slitrk2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.256 SLITRK2 Ida Ertmanska Tag Q1_26_promote_green tag was added to gene: SLITRK2.
Tag Q1_26_NHS_review tag was added to gene: SLITRK2.
Intellectual disability v9.256 SLITRK2 Ida Ertmanska edited their review of gene: SLITRK2: Changed publications to: 35840571, 38283150
Intellectual disability v9.256 SLITRK2 Ida Ertmanska reviewed gene: SLITRK2: Rating: GREEN; Mode of pathogenicity: None; Publications: 35840571; Phenotypes: Intellectual developmental disorder, X-linked 111, OMIM:301107, intellectual developmental disorder, X-linked 111, MONDO:0957203; 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 v9.256 PHF12 Ida Ertmanska Phenotypes for gene: PHF12 were changed from to complex neurodevelopmental disorder, MONDO:0100038
Intellectual disability v9.255 PHF12 Ida Ertmanska Publications for gene: PHF12 were set to
Intellectual disability v9.254 PHF12 Ida Ertmanska Classified gene: PHF12 as Amber List (moderate evidence)
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 v9.254 PHF12 Ida Ertmanska Gene: phf12 has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.253 PHF12 Ida Ertmanska Tag Q1_26_NHS_review tag was added to gene: PHF12.
Intellectual disability v9.253 PHF12 Ida Ertmanska Tag Q1_26_promote_green tag was added to gene: PHF12.
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 v9.253 PHF12 Ida Ertmanska reviewed gene: PHF12: Rating: GREEN; Mode of pathogenicity: None; Publications: 27479843, 28135719, 28263302, 33057194; Phenotypes: complex neurodevelopmental disorder, MONDO:0100038; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v9.253 RSF1 Ida Ertmanska Phenotypes for gene: RSF1 were changed from Neurodevelopmental disorder with dysmorphic facies and behavioral abnormalities, OMIM:620489 to neurodevelopmental disorder, MONDO:0700092
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 edited their review of gene: RSF1: Changed phenotypes to: neurodevelopmental disorder, MONDO:0700092
Intellectual disability v9.252 RSF1 Ida Ertmanska Classified gene: RSF1 as Amber List (moderate evidence)
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 v9.252 RSF1 Ida Ertmanska Gene: rsf1 has been classified as Amber List (Moderate Evidence).
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 v9.250 ASTN1 Ida Ertmanska Phenotypes for gene: ASTN1 were changed from neurodevelopmental disorder, MONDO:0700092 to neurodevelopmental disorder, MONDO:0700092
Intellectual disability v9.249 ASTN1 Ida Ertmanska Phenotypes for gene: ASTN1 were changed from Intellectual disability to neurodevelopmental disorder, MONDO:0700092
Intellectual disability v9.249 ASTN1 Ida Ertmanska Publications for gene: ASTN1 were set to 29706646; 27431290; 26539891
Intellectual disability v9.248 ASTN1 Ida Ertmanska Tag watchlist was removed from gene: ASTN1.
Tag Q1_26_promote_green tag was added to gene: ASTN1.
Intellectual disability v9.248 ASTN1 Ida Ertmanska reviewed gene: ASTN1: Rating: GREEN; Mode of pathogenicity: None; Publications: 41544630; Phenotypes: neurodevelopmental disorder, MONDO:0700092; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v9.248 JKAMP Ida Ertmanska Classified gene: JKAMP as Amber List (moderate evidence)
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 v9.248 JKAMP Ida Ertmanska Gene: jkamp has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.247 JKAMP Ida Ertmanska Tag Q1_26_promote_green tag was added to gene: JKAMP.
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 Added comment: Comment on phenotypes: OMIM phenotype accessed on 03-02-2026
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 v9.245 ATP2B1 Arina Puzriakova Publications for gene: ATP2B1 were set to 35358416; 35358416
Intellectual disability v9.244 ATP2B1 Arina Puzriakova Tag watchlist_moi tag was added to gene: ATP2B1.
Intellectual disability v9.244 ATP2B1 Arina Puzriakova Phenotypes for gene: ATP2B1 were changed from Intellectual developmental disorder, autosomal dominant 66, 619910 to Intellectual developmental disorder, autosomal dominant 66, OMIM:619910
Intellectual disability v9.243 CRNKL1 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype added 26th Jan 2026.
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 v9.242 CRNKL1 Ida Ertmanska Publications for gene: CRNKL1 were set to https://doi.org/10.1016/j.ajhg.2025.05.013
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 ATP2B1 Ida Ertmanska reviewed gene: ATP2B1: Rating: GREEN; Mode of pathogenicity: None; Publications: 37926713; Phenotypes: Intellectual developmental disorder, autosomal dominant 66, OMIM:619910; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
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 v9.239 AIMP2 Eleanor Williams Publications for gene: AIMP2 were set to 29215095
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 SLITRK2 Mike Spiller gene: SLITRK2 was added
gene: SLITRK2 was added to Intellectual disability. Sources: NHS GMS,Literature
Mode of inheritance for gene: SLITRK2 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: SLITRK2 were set to PMID: 35840571
Review for gene: SLITRK2 was set to GREEN
Added comment: Gene is associated with Intellectual developmental disorder, X-linked 111 (OMIM 301107).
Association based on PMID: 35840571 - 7 probands, 6 male one female. Female de novo, males mix of de novo and maternally inherited. ID levels range from borderline-severe, 5 patients moderate-severe.
One LOF, others missenses distributed through the gene. Missenses well supported by mouse data including inability to rescue KO phenotypes, as well as HEK293 transcfection studies..

Also 2 hemizygous LOF on CVA with consistent phenotypes (NHS GMS).
Sources: NHS GMS, Literature
Intellectual disability v9.236 AIMP2 Ida Ertmanska Tag Q1_26_promote_green tag was added to gene: AIMP2.
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 AIMP2 Ida Ertmanska commented on gene: AIMP2
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 v9.236 CELSR3 Achchuthan Shanmugasundram Classified gene: CELSR3 as Amber List (moderate evidence)
Intellectual disability v9.236 CELSR3 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (eight patients with ID/DD) for the promotion of this gene to green rating in the next GMS update.
Intellectual disability v9.236 CELSR3 Achchuthan Shanmugasundram Gene: celsr3 has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.235 CELSR3 Achchuthan Shanmugasundram Tag Q1_26_promote_green tag was added to gene: CELSR3.
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 edited their review of gene: WASHC5: Changed publications to: 24065355, 36130690, 39988189
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 v9.232 WASHC4 Ida Ertmanska Tag Q1_26_promote_green tag was added to gene: WASHC4.
Intellectual disability v9.232 WASHC5 Ida Ertmanska Publications for gene: WASHC5 were set to 24065355; 24916641
Intellectual disability v9.231 WASHC5 Ida Ertmanska Tag Q1_26_promote_green tag was added to gene: WASHC5.
Intellectual disability v9.231 WASHC5 Ida Ertmanska edited their review of gene: WASHC5: Changed publications to: 24065355, 36130690; Changed phenotypes to: Ritscher-Schinzel syndrome, OMIM:220210, Ritscher-Schinzel syndrome, MONDO:0019078
Intellectual disability v9.231 WASHC5 Ida Ertmanska reviewed gene: WASHC5: Rating: GREEN; Mode of pathogenicity: None; Publications: 36130690; Phenotypes: Ritscher-Schinzel syndrome, OMIM:220210; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v9.231 WASHC4 Ida Ertmanska reviewed gene: WASHC4: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Intellectual developmental disorder, autosomal recessive 43, OMIM:615817; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
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 v9.231 KDM2A Achchuthan Shanmugasundram Classified gene: KDM2A as Amber List (moderate evidence)
Intellectual disability v9.231 KDM2A Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (17 unrelated patients) for the association of KDM2A gene with syndromic intellectual disability. Hence, this gene can be promoted to green rating in the next GMS update.
Intellectual disability v9.231 KDM2A Achchuthan Shanmugasundram Gene: kdm2a has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.230 KDM2A Achchuthan Shanmugasundram Tag Q1_26_promote_green tag was added to gene: KDM2A.
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 v9.229 PRMT9 Achchuthan Shanmugasundram Classified gene: PRMT9 as Amber List (moderate evidence)
Intellectual disability v9.229 PRMT9 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the association of PRMT9 with syndromic intellectual disability (>20 unrelated families). Hence, this gene can be promoted to green rating in the next GMS update.
Intellectual disability v9.229 PRMT9 Achchuthan Shanmugasundram Gene: prmt9 has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.228 PRMT9 Achchuthan Shanmugasundram Publications for gene: PRMT9 were set to 21937992; 38561334
Intellectual disability v9.227 PRMT9 Achchuthan Shanmugasundram Tag Q1_26_promote_green tag was added to gene: PRMT9.
Intellectual disability v9.227 PRMT9 Achchuthan Shanmugasundram edited their review of gene: PRMT9: Changed rating: GREEN
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 v9.227 GLUL Achchuthan Shanmugasundram Mode of inheritance for gene: GLUL was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v9.226 GLUL Achchuthan Shanmugasundram Phenotypes for gene: GLUL were changed from CONGENITAL SYSTEMIC GLUTAMINE DEFICIENCY (CSGD) to Glutamine deficiency, congenital, OMIM:610015; Developmental and epileptic encephalopathy 116, OMIM:620806; congenital brain dysgenesis due to glutamine synthetase deficiency, MONDO:0012393; developmental and epileptic encephalopathy 116, MONDO:0970945
Intellectual disability v9.225 GLUL Achchuthan Shanmugasundram Publications for gene: GLUL were set to 21353613; 16267323
Intellectual disability v9.224 GLUL Achchuthan Shanmugasundram Tag Q1_26_MOI tag was added to gene: GLUL.
Intellectual disability v9.224 GLUL Achchuthan Shanmugasundram reviewed gene: GLUL: Rating: GREEN; Mode of pathogenicity: None; Publications: 38579670, 39985170, 41083803; Phenotypes: Glutamine deficiency, congenital, OMIM:610015, Developmental and epileptic encephalopathy 116, OMIM:620806, congenital brain dysgenesis due to glutamine synthetase deficiency, MONDO:0012393, developmental and epileptic encephalopathy 116, MONDO:0970945; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
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 Classified gene: LSM1 as Amber List (moderate evidence)
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 v9.224 LSM1 Achchuthan Shanmugasundram Gene: lsm1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.223 LSM1 Achchuthan Shanmugasundram Tag Q1_26_promote_green tag was added to gene: LSM1.
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 v9.222 GTF2I Achchuthan Shanmugasundram Mode of inheritance for gene: GTF2I was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v9.221 GTF2I Achchuthan Shanmugasundram edited their review of gene: GTF2I: Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v9.221 GTF2I Achchuthan Shanmugasundram Classified gene: GTF2I as Amber List (moderate evidence)
Intellectual disability v9.221 GTF2I Achchuthan Shanmugasundram Added comment: Comment on list classification: Although five of seven patients presented with mild global developmental delay/ intellectual disability (moderate and severe in one each), they all displayed syndromic phenotype including dysmorphic features. Hence, this gene can be promoted to green rating in the next GMS update.
Intellectual disability v9.221 GTF2I Achchuthan Shanmugasundram Gene: gtf2i has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.220 GTF2I Achchuthan Shanmugasundram Tag Q1_26_promote_green tag was added to gene: GTF2I.
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 v9.219 EIPR1 Achchuthan Shanmugasundram Classified gene: EIPR1 as Amber List (moderate evidence)
Intellectual disability v9.219 EIPR1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (six unrelated families) for the association of this gene with global developmental delay/ intellectual disability. Hence, this gene can be promoted to green rating in the next GMS update.
Intellectual disability v9.219 EIPR1 Achchuthan Shanmugasundram Gene: eipr1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.218 EIPR1 Achchuthan Shanmugasundram Tag Q1_26_promote_green tag was added to gene: EIPR1.
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 v9.217 RPS6KC1 Achchuthan Shanmugasundram Classified gene: RPS6KC1 as Amber List (moderate evidence)
Intellectual disability v9.217 RPS6KC1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the promotion of this gene to green rating in the next GMS update.
Intellectual disability v9.217 RPS6KC1 Achchuthan Shanmugasundram Gene: rps6kc1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.216 RPS6KC1 Achchuthan Shanmugasundram Tag Q1_26_promote_green tag was added to gene: RPS6KC1.
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 v9.215 UNC13A Achchuthan Shanmugasundram Mode of inheritance for gene: UNC13A was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v9.214 UNC13A Achchuthan Shanmugasundram Publications for gene: UNC13A were set to 28192369; 39634123
Intellectual disability v9.213 UNC13A Achchuthan Shanmugasundram Tag Q1_26_MOI tag was added to gene: UNC13A.
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 Classified gene: TM2D3 as Amber List (moderate evidence)
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 v9.213 TM2D3 Achchuthan Shanmugasundram Gene: tm2d3 has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.212 TM2D3 Achchuthan Shanmugasundram Tag Q1_26_promote_green tag was added to gene: TM2D3.
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 v9.211 WSB2 Achchuthan Shanmugasundram Classified gene: WSB2 as Amber List (moderate evidence)
Intellectual disability v9.211 WSB2 Achchuthan Shanmugasundram Added comment: Comment on list classification: Although intellectual disability has only been noted in one of four families (family with two patients where ID is moderate in one and severity not given in other), the phenotype is syndromic and GDD is present in all four families. Hence, this gene can be promoted to green rating in the next GMS update.
Intellectual disability v9.211 WSB2 Achchuthan Shanmugasundram Gene: wsb2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.210 WSB2 Achchuthan Shanmugasundram Tag Q1_26_promote_green tag was added to gene: WSB2.
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 v9.209 BHLHE22 Arina Puzriakova Tag Q3_25_promote_green was removed from gene: BHLHE22.
Tag watchlist tag was added to gene: BHLHE22.
Intellectual disability v9.209 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 - 6/7 individuals available for examination exhibited significant GDD and ID.; to: Comment on list classification: There is sufficient evidence to support classification of this gene as Green (6/7 individuals available for examination exhibited significant GDD and ID). However, PMID:39502664 is currently still in pre-print and therefore this gene-disease association should be considered provisional pending peer-reviewed publication.
Intellectual disability v9.209 ZNF865 Ida Ertmanska Classified gene: ZNF865 as Amber List (moderate evidence)
Intellectual disability v9.209 ZNF865 Ida Ertmanska Gene: znf865 has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.208 ZNF865 Ida Ertmanska Tag Q4_25_promote_green tag was added to gene: ZNF865.
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 v9.207 TK2 Arina Puzriakova Phenotypes for gene: TK2 were changed from Mitochondrial DNA depletion syndrome 2 (myopathic type), 609560 to Mitochondrial DNA depletion syndrome 2 (myopathic type), OMIM:609560
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 BHLHE22 Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: BHLHE22.
Intellectual disability v9.206 WDR47 Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: WDR47.
Intellectual disability v9.206 LDB1 Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: LDB1.
Intellectual disability v9.206 KIF5B Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: KIF5B.
Intellectual disability v9.206 OGDHL Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: OGDHL.
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 v9.205 SOX3 Ida Ertmanska Publications for gene: SOX3 were set to
Intellectual disability v9.204 SOX3 Ida Ertmanska Mode of inheritance for gene: SOX3 was changed from X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability 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 v9.203 SOX3 Ida Ertmanska reviewed gene: SOX3: Rating: ; Mode of pathogenicity: None; Publications: 29175558, 35114986, 35295983; Phenotypes: Intellectual developmental disorder, X-linked, with isolated growth hormone deficiency, OMIM:300123; Mode of inheritance: None
Intellectual disability v9.203 RNU5B-1 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #621302) and the OMIM record was last accessed on 18 December 2025.
Intellectual disability v9.203 RNU5B-1 Achchuthan Shanmugasundram Phenotypes for gene: RNU5B-1 were changed from Neurodevelopmental disorder, MONDO:0700092 to Neurodevelopmental disorder with seizures and joint laxity, OMIM:621302; RNU5B-1 related neurodevelopmental disorder with seizures and joint laxity, MONDO:1060179
Intellectual disability v9.202 RNU5B-1 Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: RNU5B-1.
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 Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #621384) and the OMIM record was last accessed on 18 December 2025.
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 v9.200 PAN2 Achchuthan Shanmugasundram Tag gene-checked was removed from gene: PAN2.
Intellectual disability v9.200 GON4L Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #621212) and the OMIM record was last accessed on 18 December 2025.
Intellectual disability v9.200 GON4L Achchuthan Shanmugasundram Phenotypes for gene: GON4L were changed from prenatal-onset growth impairment and developmental delay to Li-Takada-Miyake syndrome, OMIM:621212; Li-Takada-Miyake syndrome, MONDO:0978303
Intellectual disability v9.199 PPP2R5C Arina Puzriakova Phenotypes for gene: PPP2R5C were changed from neurodevelopmental disorder to Houge-Janssens syndrome 4, OMIM:621185
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 v9.197 TSEN34 Ida Ertmanska Publications for gene: TSEN34 were set to 0
Intellectual disability v9.196 TSEN34 Ida Ertmanska Tag Q4_25_demote_amber tag was added to gene: TSEN34.
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 edited their review of gene: TSEN34: Changed rating: AMBER
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 v9.196 ANKS1B Ida Ertmanska Phenotypes for gene: ANKS1B were changed from complex neurodevelopmental disorder, MONDO:0100038 to complex neurodevelopmental disorder, MONDO:0100038
Intellectual disability v9.195 ANKS1B Ida Ertmanska Phenotypes for gene: ANKS1B were changed from Developmental delay; Intellectual disability; Autism; Speech and language delay to complex neurodevelopmental disorder, MONDO:0100038
Intellectual disability v9.195 ANKS1B Ida Ertmanska Classified gene: ANKS1B as Amber List (moderate evidence)
Intellectual disability v9.195 ANKS1B Ida Ertmanska Gene: anks1b has been classified as Amber List (Moderate Evidence).
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: Comment on list classification: Affected individuals had normal intellect or slightly below average, which does not meet the eligibility criteria of moderate/severe/profound global developmental delay/intellectual disability. Hence, ANKS1B should remain Amber for Intellectual disability until more evidence emerges.; to: Comment on list classification: Individuals with monogenic heterozygous microdeletions in ANSK1B had normal intellect or slightly below average, which does not meet the eligibility criteria of moderate/severe/profound global developmental delay/intellectual disability. Hence, ANKS1B should remain Amber for Intellectual disability until more evidence emerges.
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 ANKS1B Ida Ertmanska edited their review of gene: ANKS1B: Added comment: Comment on list classification: Affected individuals had normal intellect or slightly below average, which does not meet the eligibility criteria of moderate/severe/profound global developmental delay/intellectual disability. Hence, ANKS1B should remain Amber for Intellectual disability until more evidence emerges.; Changed rating: AMBER; Changed publications to: 31388001, 38129387; Changed phenotypes to: complex neurodevelopmental disorder, MONDO:0100038; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v9.194 ANKS1B Ida Ertmanska commented on gene: ANKS1B
Intellectual disability v9.194 LDB1 Arina Puzriakova Classified gene: LDB1 as Amber List (moderate evidence)
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 v9.194 LDB1 Arina Puzriakova Gene: ldb1 has been classified as Amber List (Moderate Evidence).
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 v9.191 CYP27A1 Ida Ertmanska Mode of inheritance for gene: CYP27A1 was changed from Other - please specify in evaluation comments to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v9.190 SOX3 Sahana Chatakondu reviewed gene: SOX3: Rating: AMBER; Mode of pathogenicity: Other; Publications: 25402377; Phenotypes: Dyspraxia, Growth Hormone Deficiency, Intellectual Disability, Short stature,; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
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 Deleted their comment
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 v9.190 CCNK Ida Ertmanska edited their review of gene: CCNK: Changed phenotypes to: ?Intellectual developmental disorder with hypertelorism and distinctive facies, OMIM:618147, intellectual developmental disorder with hypertelorism and distinctive facies, MONDO:0029143
Intellectual disability v9.190 CCNK Ida Ertmanska Phenotypes for gene: CCNK were changed from ?Intellectual developmental disorder with hypertelorism and distinctive facies, OMIM:618147 to ?Intellectual developmental disorder with hypertelorism and distinctive facies, OMIM:618147; intellectual developmental disorder with hypertelorism and distinctive facies, MONDO:0029143
Intellectual disability v9.189 CCNK Ida Ertmanska Classified gene: CCNK as Amber List (moderate evidence)
Intellectual disability v9.189 CCNK Ida Ertmanska Gene: ccnk has been classified as Amber List (Moderate Evidence).
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 v9.187 SPAST Arina Puzriakova Publications for gene: SPAST were set to 39731306
Intellectual disability v9.186 SPAST Arina Puzriakova reviewed gene: SPAST: Rating: ; Mode of pathogenicity: None; Publications: 39457434; Phenotypes: ; Mode of inheritance: None
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 v9.186 BSN Ida Ertmanska Classified gene: BSN as Amber List (moderate evidence)
Intellectual disability v9.186 BSN Ida Ertmanska Gene: bsn has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.185 BSN Ida Ertmanska Tag Q4_25_promote_green tag was added to gene: BSN.
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 Classified gene: BAIAP2 as Amber List (moderate evidence)
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 v9.184 BAIAP2 Ida Ertmanska Gene: baiap2 has been classified as Amber List (Moderate Evidence).
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 v9.182 UROC1 Ida Ertmanska Phenotypes for gene: UROC1 were changed from UROCANASE DEFICIENCY (UROD) to ?Urocanase deficiency , OMIM:276880; urocanic aciduria, MONDO:0010167
Intellectual disability v9.181 UROC1 Ida Ertmanska Publications for gene: UROC1 were set to 19304569
Intellectual disability v9.180 UROC1 Ida Ertmanska Tag Q4_25_demote_red tag was added to gene: UROC1.
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 v9.180 UROC1 Ida Ertmanska reviewed gene: UROC1: Rating: RED; Mode of pathogenicity: None; Publications: 19304569, 27391121, 30619714, 32439973; Phenotypes: ?Urocanase deficiency , OMIM:276880, urocanic aciduria, MONDO:0010167; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v9.180 SPRTN Ida Ertmanska Classified gene: SPRTN as Red List (low evidence)
Intellectual disability v9.180 SPRTN Ida Ertmanska Gene: sprtn has been classified as Red List (Low Evidence).
Intellectual disability v9.179 SPRTN Ida Ertmanska Classified gene: SPRTN as No list
Intellectual disability v9.179 SPRTN Ida Ertmanska Gene: sprtn has been removed from the panel.
Intellectual disability v9.178 ISCA-37433-Loss Arina Puzriakova Classified Region: ISCA-37433-Loss as Green List (high evidence)
Intellectual disability v9.178 ISCA-37433-Loss Arina Puzriakova Added comment: Comment on list classification: This region has been deprecated by ClinGen and therefore should be removed from the panel.

This region has been subsumed into ISCA-37446 which is green on multiple GMS panels including this panel (https://panelapp.genomicsengland.co.uk/panels/entities/ISCA-37446-Loss)

Checked and approved by the Genomics England Clinical team.
Intellectual disability v9.178 ISCA-37433-Loss Arina Puzriakova Region: isca-37433-loss has been classified as Green List (High Evidence).
Intellectual disability v9.177 ISCA-37433-Loss Arina Puzriakova Tag Q3_25_demote_red tag was added to Region: ISCA-37433-Loss.
Intellectual disability v9.177 ISCA-37433-Gain Arina Puzriakova Classified Region: ISCA-37433-Gain as Green List (high evidence)
Intellectual disability v9.177 ISCA-37433-Gain Arina Puzriakova Added comment: Comment on list classification: This region has been deprecated by ClinGen and therefore should be removed from the panel.

This region has been subsumed into ISCA-37446 which is green on multiple GMS panels including this panel (https://panelapp.genomicsengland.co.uk/panels/entities/ISCA-37446-Gain)

Checked and approved by the Genomics England Clinical team.
Intellectual disability v9.177 ISCA-37433-Gain Arina Puzriakova Region: isca-37433-gain has been classified as Green List (High Evidence).
Intellectual disability v9.176 ISCA-37433-Gain Arina Puzriakova Tag Q3_25_demote_red tag was added to Region: ISCA-37433-Gain.
Intellectual disability v9.176 ISCA-37404-Loss Arina Puzriakova Classified Region: ISCA-37404-Loss as Green List (high evidence)
Intellectual disability v9.176 ISCA-37404-Loss Arina Puzriakova Added comment: Comment on list classification: This region has been deprecated by ClinGen and therefore should be removed from the panel.

This region has been subsumed into ISCA-37478 which is green on multiple GMS panels including this panel (https://panelapp.genomicsengland.co.uk/panels/entities/ISCA-37478-Loss)

Checked and approved by the Genomics England Clinical team.
Intellectual disability v9.176 ISCA-37404-Loss Arina Puzriakova Region: isca-37404-loss has been classified as Green List (High Evidence).
Intellectual disability v9.175 ISCA-37404-Loss Arina Puzriakova Tag Q3_25_demote_red tag was added to Region: ISCA-37404-Loss.
Intellectual disability v9.175 ISCA-37404-Gain Arina Puzriakova Classified Region: ISCA-37404-Gain as Green List (high evidence)
Intellectual disability v9.175 ISCA-37404-Gain Arina Puzriakova Added comment: Comment on list classification: This region has been deprecated by ClinGen and therefore should be removed from the panel.

This region has been subsumed into ISCA-37478 which is green on multiple GMS panels including this panel (https://panelapp.genomicsengland.co.uk/panels/entities/ISCA-37478-Gain).

Checked and approved by the Genomics England Clinical team.
Intellectual disability v9.175 ISCA-37404-Gain Arina Puzriakova Region: isca-37404-gain has been classified as Green List (High Evidence).
Intellectual disability v9.174 ISCA-37404-Gain Arina Puzriakova Tag Q3_25_demote_red tag was added to Region: ISCA-37404-Gain.
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 v9.173 ISCA-37448-Loss Arina Puzriakova Classified Region: ISCA-37448-Loss as Amber List (moderate evidence)
Intellectual disability v9.173 ISCA-37448-Loss Arina Puzriakova Added comment: Comment on list classification: This region has Sufficient Evidence for Haploinsufficiency in ClinGen and should be promoted to Green at the next GMS panel update.

Panel inclusion has been reviewed and approved by the Genomics England Clinical team.
Intellectual disability v9.173 ISCA-37448-Loss Arina Puzriakova Region: isca-37448-loss has been classified as Amber List (Moderate Evidence).
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 v9.171 ISCA-46296-Loss Arina Puzriakova Classified Region: ISCA-46296-Loss as Amber List (moderate evidence)
Intellectual disability v9.171 ISCA-46296-Loss Arina Puzriakova Added comment: Comment on list classification: This region has Sufficient Evidence for Haploinsufficiency in ClinGen and should be promoted to Green at the next GMS panel update.

Panel inclusion has been reviewed and approved by the Genomics England Clinical team.
Intellectual disability v9.171 ISCA-46296-Loss Arina Puzriakova Region: isca-46296-loss has been classified as Amber List (Moderate Evidence).
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 v9.169 ISCA-46300-Loss Arina Puzriakova Classified Region: ISCA-46300-Loss as Amber List (moderate evidence)
Intellectual disability v9.169 ISCA-46300-Loss Arina Puzriakova Added comment: Comment on list classification: This region has Sufficient Evidence for Haploinsufficiency in ClinGen and should be promoted to Green at the next GMS panel update.

Panel inclusion has been reviewed and approved by the Genomics England Clinical team.
Intellectual disability v9.169 ISCA-46300-Loss Arina Puzriakova Region: isca-46300-loss has been classified as Amber List (Moderate Evidence).
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 v9.167 ISCA-37498-Loss Arina Puzriakova Classified Region: ISCA-37498-Loss as Amber List (moderate evidence)
Intellectual disability v9.167 ISCA-37498-Loss Arina Puzriakova Added comment: Comment on list classification: This region has Sufficient Evidence for Haploinsufficiency in ClinGen and should be promoted to Green at the next GMS panel update.

Panel inclusion has been reviewed and approved by the Genomics England Clinical team.
Intellectual disability v9.167 ISCA-37498-Loss Arina Puzriakova Region: isca-37498-loss has been classified as Amber List (Moderate Evidence).
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 Tag Q4_25_promote_green tag was added to gene: LRRC45.
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 v9.165 LRRC45 Ida Ertmanska Classified gene: LRRC45 as Amber List (moderate evidence)
Intellectual disability v9.165 LRRC45 Ida Ertmanska Gene: lrrc45 has been classified as Amber List (Moderate Evidence).
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 v9.163 AIRE Ida Ertmanska Publications for gene: AIRE were set to
Intellectual disability v9.162 AIRE Ida Ertmanska Phenotypes for gene: AIRE were changed from Autoimmune polyendocrinopathy syndrome , type I, with or without,reversible metaphyseal dysplasia, 240300 to Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, OMIM:240300; autoimmune polyendocrine syndrome type 1, MONDO:0009411
Intellectual disability v9.161 KIF26A Ida Ertmanska Classified gene: KIF26A as Amber List (moderate evidence)
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 v9.161 KIF26A Ida Ertmanska Gene: kif26a has been classified as Amber List (Moderate Evidence).
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 v9.159 ASXL1 Ida Ertmanska Publications for gene: ASXL1 were set to
Intellectual disability v9.158 ASXL1 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype accessed 3rd Nov 2025.
Intellectual disability v9.158 ASXL1 Ida Ertmanska Phenotypes for gene: ASXL1 were changed from Bohring-Opitz syndrome, 605039Myelodysplastic syndrome, somatic, 614286; BOHRING-OPITZ SYNDROME to Bohring-Opitz syndrome, OMIM:605039; Bohring-Opitz syndrome, MONDO:0011510
Intellectual disability v9.157 NAV3 Arina Puzriakova Tag Q1_25_ expert_review was removed from gene: NAV3.
Intellectual disability v9.157 EMX2 Arina Puzriakova Tag Q3_25_expert_review tag was added to gene: EMX2.
Intellectual disability v9.157 TSPAN7 Arina Puzriakova Tag Q3_25_expert_review tag was added to gene: TSPAN7.
Intellectual disability v9.157 SPAST Arina Puzriakova Mode of inheritance for gene: SPAST was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v9.156 SPAST Arina Puzriakova Tag Q1_25_ MOI was removed from gene: SPAST.
Intellectual disability v9.156 KIAA0556 Arina Puzriakova Classified gene: KIAA0556 as Amber List (moderate evidence)
Intellectual disability v9.156 KIAA0556 Arina Puzriakova Gene: kiaa0556 has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.155 KIAA0556 Arina Puzriakova Publications for gene: KIAA0556 were set to
Intellectual disability v9.155 KIAA0556 Arina Puzriakova Classified gene: KIAA0556 as Amber List (moderate evidence)
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 v9.155 KIAA0556 Arina Puzriakova Gene: kiaa0556 has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.154 KIAA0556 Arina Puzriakova edited their review of gene: KIAA0556: Changed publications to: 26714646, 27245168, 31197031, 31197031, 36580738, 40725402, 40428346, 32164589, 30982090
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 v9.153 SETBP1 Ida Ertmanska Phenotypes for gene: SETBP1 were changed from Schinzel-Giedion midface retraction syndrome, 269150; SCHINZEL-GIEDION MIDFACE RETRACTION SYNDROME (SGMFS) to Intellectual developmental disorder, autosomal dominant 29, OMIM: 616078; Schinzel-Giedion midface retraction syndrome, OMIM: 269150; Schinzel-Giedion syndrome, MONDO:0010010
Intellectual disability v9.152 SETBP1 Ida Ertmanska Publications for gene: SETBP1 were set to 20436468
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 v9.151 SETBP1 Ida Ertmanska reviewed gene: SETBP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 20436468, 21037274, 22473152, 23020937, 25217958, 25356899, 25028416, 25082129, 25663181, 26096993, 26188272, 28346496, 29463886, 32445275, 32460883; Phenotypes: Intellectual developmental disorder, autosomal dominant 29, OMIM: 616078, Schinzel-Giedion midface retraction syndrome, OMIM: 269150, Schinzel-Giedion syndrome, MONDO:0010010; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v9.151 RAP1B Arina Puzriakova Phenotypes for gene: RAP1B were changed from Syndromic intellectual disability to Thrombocytopenia 11 with multiple congenital anomalies and dysmorphic facies, OMIM:620654; Syndromic intellectual disability
Intellectual disability v9.150 PTRH2 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: OMIM phenotype accessed on 24 October 2025.
Intellectual disability v9.150 PTRH2 Achchuthan Shanmugasundram Phenotypes for gene: PTRH2 were changed from Infantile-onset multisystem neurologic, endocrine, and pancreatic disease, OMIM:616263 to Infantile-onset multisystem neurologic, endocrine, and pancreatic disease, OMIM:616263; neurologic, endocrine, and pancreatic disease, multisystem, infantile-onset 1, MONDO:8000012
Intellectual disability v9.149 PTRH2 Achchuthan Shanmugasundram edited their review of gene: PTRH2: Changed phenotypes to: Infantile-onset multisystem neurologic, endocrine, and pancreatic disease, OMIM:616263, neurologic, endocrine, and pancreatic disease, multisystem, infantile-onset 1, MONDO:8000012
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 Classified gene: BRSK1 as Amber List (moderate evidence)
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 v9.149 BRSK1 Arina Puzriakova Gene: brsk1 has been classified as Amber List (Moderate Evidence).
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 v9.147 SIX5 Arina Puzriakova Phenotypes for gene: SIX5 were changed from Branchiootorenal syndrome 2, 610896 to Branchiootorenal syndrome 2, OMIM:610896
Intellectual disability v9.146 LAMC3 Achchuthan Shanmugasundram Classified gene: LAMC3 as Green List (high evidence)
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 v9.146 LAMC3 Achchuthan Shanmugasundram Gene: lamc3 has been classified as Green List (High Evidence).
Intellectual disability v9.145 LAMC3 Achchuthan Shanmugasundram Tag Q3_25_MOI tag was added to gene: LAMC3.
Tag Q3_25_expert_review tag was added to gene: LAMC3.
Tag Q3_25_demote_red tag was added to gene: LAMC3.
Intellectual disability v9.145 LAMC3 Achchuthan Shanmugasundram edited their review of gene: LAMC3: Changed rating: RED; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v9.145 LAMC3 Achchuthan Shanmugasundram edited their review of gene: LAMC3: Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v9.145 LAMC3 Achchuthan Shanmugasundram Publications for gene: LAMC3 were set to 21572413; 25529582; 24896178
Intellectual disability v9.144 LAMC3 Achchuthan Shanmugasundram reviewed gene: LAMC3: Rating: AMBER; Mode of pathogenicity: None; Publications: 21572413, 26802095, 29247375, 33639934, 34354730, 38758065; Phenotypes: Cortical malformations, occipital, OMIM:614115, occipital pachygyria and polymicrogyria, MONDO:0013583; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
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 v9.144 MED12L Eleanor Williams Classified gene: MED12L as Amber List (moderate evidence)
Intellectual disability v9.144 MED12L Eleanor Williams Added comment: Comment on list classification: There is now sufficient evidence for this gene to be promoted to green following GMS review.
Intellectual disability v9.144 MED12L Eleanor Williams Gene: med12l has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.143 MED12L Eleanor Williams Tag Q3_25_promote_green tag was added to gene: MED12L.
Intellectual disability v9.143 MED12L Eleanor Williams Phenotypes for gene: MED12L were changed from Motor delay; Delayed speech and language development; Intellectual disability; Behavioral abnormality; Abnormality of the abdomen; Seizures; Abnormality of the corpus callosum to Nizon-Isidor syndrome, OMIM:618872; Nizon-Isidor syndrome, MONDO:0030030
Intellectual disability v9.142 MED12L Eleanor Williams Publications for gene: MED12L were set to 31155615
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 v9.141 LAMC3 Eleanor Williams Publications for gene: LAMC3 were set to
Intellectual disability v9.140 LAMC3 Eleanor Williams Added comment: Comment on phenotypes: OMIM phenotype accessed on 21st October 2025
Intellectual disability v9.140 LAMC3 Eleanor Williams Phenotypes for gene: LAMC3 were changed from Cortical malformations, occipital, 614115; OCCIPITAL CORTICAL MALFORMATIONS to Cortical malformations, occipital, OMIM:614115; occipital pachygyria and polymicrogyria, MONDO:0013583
Intellectual disability v9.139 PTBP1 Arina Puzriakova edited their review of gene: PTBP1: Changed publications to: 40965981; Changed phenotypes to: Neurodevelopmental disorder, MONDO:0700092; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v9.139 PTBP1 Arina Puzriakova edited their review of gene: PTBP1: Changed rating: GREEN
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 v9.139 PTBP1 Arina Puzriakova Tag Q3_25_NHS_review was removed from gene: PTBP1.
Intellectual disability v9.139 PTBP1 Arina Puzriakova Entity copied from Skeletal dysplasia v8.20
Intellectual disability v9.139 PTBP1 Arina Puzriakova gene: PTBP1 was added
gene: PTBP1 was added to Intellectual disability. Sources: Literature,Expert Review Amber,NHS GMS
Q3_25_promote_green, Q3_25_NHS_review tags were added to gene: PTBP1.
Mode of inheritance for gene: PTBP1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PTBP1 were set to 40965981
Phenotypes for gene: PTBP1 were set to Neurodevelopmental disorder, MONDO:0700092
Penetrance for gene: PTBP1 were set to unknown
Intellectual disability v9.138 AP1B1 Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: AP1B1.
Intellectual disability v9.138 AP1B1 Achchuthan Shanmugasundram Publications for gene: AP1B1 were set to 31630788; 31630791
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 edited their review of gene: AP1B1: Changed phenotypes to: Keratitis-ichthyosis-deafness syndrome, autosomal recessive, OMIM:242150, KID syndrome, MONDO:0018781
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 AP1B1 Ida Ertmanska commented on gene: AP1B1
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 v9.136 SOD1 Arina Puzriakova Classified gene: SOD1 as Amber List (moderate evidence)
Intellectual disability v9.136 SOD1 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update. Inclusion on this panel would also ensure inclusion on the Hypotonic Infant super panel which is a significant feature observed in affected individuals.
Intellectual disability v9.136 SOD1 Arina Puzriakova Gene: sod1 has been classified as Amber List (Moderate Evidence).
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 v9.134 KIRREL3 Achchuthan Shanmugasundram Classified gene: KIRREL3 as Green List (high evidence)
Intellectual disability v9.134 KIRREL3 Achchuthan Shanmugasundram Added comment: Comment on list classification: As the evidence for the association of KIRREL3 gene with neurodevelopmental disorder is disputed, this gene should be considered for demotion to red rating in the next GMS update.
Intellectual disability v9.134 KIRREL3 Achchuthan Shanmugasundram Gene: kirrel3 has been classified as Green List (High Evidence).
Intellectual disability v9.133 KIRREL3 Achchuthan Shanmugasundram Tag Q3_25_expert_review tag was added to gene: KIRREL3.
Tag disputed tag was added to gene: KIRREL3.
Tag Q3_25_demote_red tag was added to gene: KIRREL3.
Intellectual disability v9.133 KIRREL3 Achchuthan Shanmugasundram Phenotypes for gene: KIRREL3 were changed from Intellectual developmental disorder, autosomal dominant 4, OMIM:612581; intellectual disability, autosomal dominant 4, MONDO:0012947 to complex neurodevelopmental disorder, MONDO:0100038
Intellectual disability v9.132 KIRREL3 Achchuthan Shanmugasundram Publications for gene: KIRREL3 were set to 22965935; 19012874; 29271092; 37605258; 33853164
Intellectual disability v9.131 NAA60 Arina Puzriakova Phenotypes for gene: NAA60 were changed from Basal ganglia calcification, idiopathic, 9, autosomal recessive, 620786; basal ganglia calcification, idiopathic, 9, autosomal recessive, MONDO:0968977 to Basal ganglia calcification, idiopathic, 9, autosomal recessive, OMIM:620786; basal ganglia calcification, idiopathic, 9, autosomal recessive, MONDO:0968977
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 v9.130 NAA60 Arina Puzriakova Classified gene: NAA60 as Red List (low evidence)
Intellectual disability v9.130 NAA60 Arina Puzriakova Gene: naa60 has been classified as Red List (Low Evidence).
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 Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: CDK9.
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 v9.128 CDK9 Ida Ertmanska reviewed gene: CDK9: Rating: GREEN; Mode of pathogenicity: None; Publications: 26633546, 29302074, 30237576, 33640901; Phenotypes: Global developmental delay HP:0001263, syndromic intellectual disability MONDO:0000508; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v9.128 PPOX Arina Puzriakova Publications for gene: PPOX were set to 8290408; 9811936; 2004012; 35164799; 37879139; 40114189
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 v9.127 FICD Arina Puzriakova commented on gene: FICD
Intellectual disability v9.127 FICD Arina Puzriakova Publications for gene: FICD were set to
Intellectual disability v9.126 PPOX Arina Puzriakova Mode of inheritance for gene: PPOX was changed from to BIALLELIC, autosomal or pseudoautosomal
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 v9.124 PPOX Arina Puzriakova Publications for gene: PPOX were set to
Intellectual disability v9.123 PPOX Arina Puzriakova Classified gene: PPOX as Amber List (moderate evidence)
Intellectual disability v9.123 PPOX Arina Puzriakova Gene: ppox has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.122 PPOX Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: PPOX.
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 Classified gene: SF1 as Amber List (moderate evidence)
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 v9.121 SF1 Achchuthan Shanmugasundram Gene: sf1 has been classified as Amber List (Moderate Evidence).
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 v9.120 SF1 Achchuthan Shanmugasundram Phenotypes for gene: SF1 were changed from to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Intellectual disability v9.119 SF1 Achchuthan Shanmugasundram Publications for gene: SF1 were set to PMID: 40987292
Intellectual disability v9.118 SF1 Achchuthan Shanmugasundram Tag Q3_25_NHS_review tag was added to gene: SF1.
Intellectual disability v9.118 SF1 Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: SF1.
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 v9.118 SF1 Achchuthan Shanmugasundram reviewed gene: SF1: Rating: GREEN; Mode of pathogenicity: None; Publications: 40987292; Phenotypes: neurodevelopmental disorder, MONDO:0700092, intellectual disability, MONDO:0001071; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v9.118 DLD Arina Puzriakova Phenotypes for gene: DLD were changed from Dihydrolipoamide dehydrogenase deficiency, 246900; DIHYDROLIPOAMIDE DEHYDROGENASE (E3) DEFICIENCY to Dihydrolipoamide dehydrogenase deficiency, OMIM:246900
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 PPOX Ida Ertmanska edited their review of gene: PPOX: Changed mode of inheritance: 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 v9.117 LGI1 Ida Ertmanska edited their review of gene: LGI1: Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v9.117 LGI1 Arina Puzriakova Mode of inheritance for gene: LGI1 was changed from BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal 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 edited their review of gene: PPOX: Changed publications to: 8290408, 9811936, 2004012, 35164799, 37879139, 40114189
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 v9.115 LGI1 Arina Puzriakova Publications for gene: LGI1 were set to 0
Intellectual disability v9.114 LGI1 Arina Puzriakova Mode of inheritance for gene: LGI1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
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 LGI1 Ida Ertmanska reviewed gene: LGI1: Rating: RED; Mode of pathogenicity: None; Publications: 26773249, 40455867, 41000458; Phenotypes: developmental and epileptic encephalopathy MONDO:0100620; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
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 Classified gene: ADCY5 as Amber List (moderate evidence)
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 v9.113 ADCY5 Achchuthan Shanmugasundram Gene: adcy5 has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.112 ADCY5 Achchuthan Shanmugasundram Mode of inheritance for gene: ADCY5 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v9.111 ADCY5 Achchuthan Shanmugasundram Mode of pathogenicity for gene: ADCY5 was changed from Other - please provide details in the comments to None
Intellectual disability v9.110 ADCY5 Achchuthan Shanmugasundram Publications for gene: ADCY5 were set to 28511835
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 v9.109 ADCY5 Achchuthan Shanmugasundram Phenotypes for gene: ADCY5 were changed from Dyskinesia, familial, with facial myokymia, 606703 to Neurodevelopmental disorder with hyperkinetic movements and dyskinesia, OMIM:619651; neurodevelopmental disorder with hyperkinetic movements and dyskinesia, MONDO:0859211
Intellectual disability v9.108 ADCY5 Achchuthan Shanmugasundram reviewed gene: ADCY5: Rating: AMBER; Mode of pathogenicity: None; Publications: 33704598, 34631954; Phenotypes: Neurodevelopmental disorder with hyperkinetic movements and dyskinesia, OMIM:619651, neurodevelopmental disorder with hyperkinetic movements and dyskinesia, MONDO:0859211; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v9.108 KCND3 Eleanor Williams Added comment: Comment on phenotypes: OMIM phenotype accessed on 5th 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 v9.107 KCND3 Eleanor Williams Publications for gene: KCND3 were set to
Intellectual disability v9.106 KCND3 Eleanor Williams Classified gene: KCND3 as Amber List (moderate evidence)
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 v9.106 KCND3 Eleanor Williams Gene: kcnd3 has been classified as Amber List (Moderate Evidence).
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 edited their review of gene: KCND3: Changed publications to: 26189493, 28895081, 32823520, 31293010, 32921676, 39562497
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 edited their review of gene: KCND3: Changed publications to: 26189493, 28895081, 32823520, 31293010, 32921676
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: Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
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 v9.105 ERCC1 Arina Puzriakova Phenotypes for gene: ERCC1 were changed from FANCONI ANEMIA to Cerebrooculofacioskeletal syndrome 4, OMIM:610758
Intellectual disability v9.104 EMX2 Eleanor Williams Tag Q3_25_NHS_review tag was added to gene: EMX2.
Intellectual disability v9.104 EMX2 Eleanor Williams Added comment: Comment on phenotypes: OMIM phenotype accessed on 29th September 2025
Intellectual disability v9.104 EMX2 Eleanor Williams Phenotypes for gene: EMX2 were changed from Schizencephaly 269160 to Schizencephaly, OMIM:269160; schizencephaly, MONDO:0010011
Intellectual disability v9.103 EMX2 Eleanor Williams Publications for gene: EMX2 were set to 9359037; 24975717; 27125467; 9153481
Intellectual disability v9.102 EMX2 Eleanor Williams Tag Q3_25_demote_amber tag was added to gene: EMX2.
Intellectual disability v9.102 UGGT1 Achchuthan Shanmugasundram Classified gene: UGGT1 as Amber List (moderate evidence)
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 v9.102 UGGT1 Achchuthan Shanmugasundram Gene: uggt1 has been classified as Amber List (Moderate Evidence).
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 v9.100 UGGT1 Achchuthan Shanmugasundram Publications for gene: UGGT1 were set to PMID: 40267907
Intellectual disability v9.99 UGGT1 Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: UGGT1.
Tag Q3_25_NHS_review tag was added to gene: UGGT1.
Intellectual disability v9.99 UGGT1 Achchuthan Shanmugasundram reviewed gene: UGGT1: Rating: GREEN; Mode of pathogenicity: None; Publications: 40267907; Phenotypes: congenital disorder of glycosylation, MONDO:0015286; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
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 EMX2 Ida Ertmanska edited their review of gene: EMX2: Changed publications to: 8528262, 9153481, 9359037, 17506092, 18409201, 20157829
Intellectual disability v9.99 EMX2 Ida Ertmanska reviewed gene: EMX2: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Schizencephaly, OMIM:269160, schizencephaly, MONDO:0010011; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v9.99 KCND3 Nour Elkhateeb reviewed gene: KCND3: Rating: GREEN; Mode of pathogenicity: None; Publications: 32823520, 32921676, 26189493, 28895081, 40140957; Phenotypes: Developmental delay, intellectual disability, ataxia, Seizures; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
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 OGDHL Ida Ertmanska reviewed gene: OGDHL: Rating: GREEN; Mode of pathogenicity: None; Publications: 28017472, 34800363, 38031187; Phenotypes: Yoon-Bellen neurodevelopmental syndrome, MONDO:0859221; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v9.99 CCT6A Arina Puzriakova Tag gene-checked tag was added to gene: CCT6A.
Intellectual disability v9.99 CCT6A Arina Puzriakova Classified gene: CCT6A as Amber List (moderate evidence)
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 v9.99 CCT6A Arina Puzriakova Gene: cct6a has been classified as Amber List (Moderate Evidence).
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 v9.97 TSPAN7 Eleanor Williams Phenotypes for gene: TSPAN7 were changed from ntellectual developmental disorder, X-linked 58, OMIM:300210; intellectual disability, MONDO:0010266 X-linked 58, to ntellectual developmental disorder, X-linked 58, OMIM:300210; intellectual disability, X-linked 58, MONDO:0010266
Intellectual disability v9.96 TSPAN7 Eleanor Williams Added comment: Comment on phenotypes: OMIM phenotype term accessed on 22nd September 2025
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 v9.95 TSPAN7 Eleanor Williams Publications for gene: TSPAN7 were set to
Intellectual disability v9.94 TSPAN7 Eleanor Williams Tag Q3_25_demote_amber tag was added to gene: TSPAN7.
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 edited their review of gene: TSPAN7: Changed rating: AMBER
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 TSPAN7 Ida Ertmanska reviewed gene: TSPAN7: Rating: GREEN; Mode of pathogenicity: None; Publications: 10655063, 12376945, 14735593, 12070254, 22511893, 26290131; Phenotypes: Intellectual developmental disorder, X-linked 58, OMIM:300210, intellectual disability, MONDO:0001071; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
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 Classified gene: BHLHE22 as Amber List (moderate evidence)
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 v9.94 BHLHE22 Arina Puzriakova Gene: bhlhe22 has been classified as Amber List (Moderate Evidence).
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 Tag Q3_25_promote_green tag was added to gene: TNR.
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 v9.92 TNR Arina Puzriakova Tag Q3_25_promote_green was removed from gene: TNR.
Intellectual disability v9.92 TNR Arina Puzriakova Publications for gene: TNR were updated from 22730557; 32099069 to 28334938; 32099069
Intellectual disability v9.91 TNR Arina Puzriakova Publications for gene: TNR were set to 32099069
Intellectual disability v9.91 TNR Arina Puzriakova Phenotypes for gene: TNR were changed from Neurodevelopmental disorder, nonprogressive, with spasticity and transient opisthotonus, OMIM:619653 to Neurodevelopmental disorder, nonprogressive, with spasticity and transient opisthotonus, OMIM:619653
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 TNR Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: TNR.
Intellectual disability v9.89 UPF1 Achchuthan Shanmugasundram Deleted their comment
Intellectual disability v9.89 UPF1 Achchuthan Shanmugasundram Classified gene: UPF1 as Amber List (moderate evidence)
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 v9.89 UPF1 Achchuthan Shanmugasundram Gene: upf1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.88 UPF1 Achchuthan Shanmugasundram Classified gene: UPF1 as Amber List (moderate evidence)
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 v9.88 UPF1 Achchuthan Shanmugasundram Gene: upf1 has been classified as Amber List (Moderate Evidence).
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 v9.87 UPF1 Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: UPF1.
Tag Q3_25_NHS_review tag was added to gene: UPF1.
Intellectual disability v9.87 UPF1 Achchuthan Shanmugasundram Phenotypes for gene: UPF1 were changed from Developmental disorders to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Intellectual disability v9.86 UPF1 Achchuthan Shanmugasundram Publications for gene: UPF1 were set to 33057194; 28539120
Intellectual disability v9.85 UPF1 Achchuthan Shanmugasundram edited their review of gene: UPF1: Changed phenotypes to: neurodevelopmental disorder, MONDO:0700092, intellectual disability, MONDO:0001071
Intellectual disability v9.85 UPF1 Achchuthan Shanmugasundram reviewed gene: UPF1: Rating: GREEN; Mode of pathogenicity: None; Publications: 28135719, 28539120, 39571789, 39993774; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v9.85 SPOUT1 Arina Puzriakova Phenotypes for gene: SPOUT1 were changed from SPOUT1 Associated Development delay Microcephaly Seizures Short stature to Neurodevelopmental disorder with poor growth, seizures, and brain abnormalities, OMIM:621154
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 v9.81 ODC1 Arina Puzriakova Phenotypes for gene: ODC1 were changed from Global developmental delay; Intellectual disability; Macrocephaly; Alopecia; Ectodermal dysplasia to Bachmann-Bupp syndrome, OMIM:619075
Intellectual disability v9.80 NR2F1 Arina Puzriakova Phenotypes for gene: NR2F1 were changed from BOSCH-BOONSTRA OPTIC ATROPHY SYNDROME to Bosch-Boonstra-Schaaf optic atrophy syndrome, OMIM:615722
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 v9.76 GALT Arina Puzriakova Phenotypes for gene: GALT were changed from Galactosemia, 230400; GALACTOSEMIA (GALCT) to Galactosemia, OMIM:230400
Intellectual disability v9.75 EXOSC8 Arina Puzriakova Publications for gene: EXOSC8 were set to 24989451; 38017281; 34210538
Intellectual disability v9.74 EXOSC8 Arina Puzriakova Publications for gene: EXOSC8 were set to 24989451; 29656927
Intellectual disability v9.73 EXOSC8 Arina Puzriakova Classified gene: EXOSC8 as Amber List (moderate evidence)
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 v9.73 EXOSC8 Arina Puzriakova Gene: exosc8 has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.72 EXOSC8 Arina Puzriakova Tag founder-effect tag was added to gene: EXOSC8.
Intellectual disability v9.72 EXOSC8 Arina Puzriakova Tag watchlist was removed from gene: EXOSC8.
Tag founder-effect was removed from gene: EXOSC8.
Tag Q3_25_promote_green tag was added to gene: EXOSC8.
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 PPOX Sharon Whatley reviewed gene: PPOX: Rating: GREEN; Mode of pathogenicity: None; Publications: 37879139,40114189, 33159949, 35164799, 9811936, 8290408, 2004012, 6143163; Phenotypes: 620483; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
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 v9.69 EEFSEC Arina Puzriakova Phenotypes for gene: EEFSEC were changed from neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071 to Neurodevelopmental disorder with progressive spasticity and brain abnormalities, OMIM:621102
Intellectual disability v9.68 ELFN1 Arina Puzriakova Classified gene: ELFN1 as Amber List (moderate evidence)
Intellectual disability v9.68 ELFN1 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update.
Intellectual disability v9.68 ELFN1 Arina Puzriakova Gene: elfn1 has been classified as Amber List (Moderate Evidence).
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 UPF1 Karen Stals reviewed gene: UPF1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 39993774, PMID: 39571789, PMID: 28539120; Phenotypes: Developmental delay, autism, intellectual disability, speech delay; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
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 edited their review of gene: UNC13A: Changed rating: GREEN
Intellectual disability v9.64 UNC13A Achchuthan Shanmugasundram Classified gene: UNC13A as Amber List (moderate evidence)
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 v9.64 UNC13A Achchuthan Shanmugasundram Gene: unc13a has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.63 UNC13A Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: UNC13A.
Tag Q3_25_NHS_review tag was added to gene: UNC13A.
Intellectual disability v9.63 UNC13A Achchuthan Shanmugasundram Phenotypes for gene: UNC13A were changed from to developmental and epileptic encephalopathy, MONDO:0100620
Intellectual disability v9.62 UNC13A Achchuthan Shanmugasundram Publications for gene: UNC13A were set to 28192369
Intellectual disability v9.61 UNC13A Achchuthan Shanmugasundram reviewed gene: UNC13A: Rating: ; Mode of pathogenicity: None; Publications: 28192369, 39634123; Phenotypes: developmental and epileptic encephalopathy, MONDO:0100620; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v9.61 INPP4A Achchuthan Shanmugasundram Classified gene: INPP4A as Amber List (moderate evidence)
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 v9.61 INPP4A Achchuthan Shanmugasundram Gene: inpp4a has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.60 INPP4A Achchuthan Shanmugasundram edited their review of gene: INPP4A: Changed publications to: 39315527, 40748307, 40772914
Intellectual disability v9.60 INPP4A Achchuthan Shanmugasundram Phenotypes for gene: INPP4A were changed from Intellectual disability; Seizures to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Intellectual disability v9.59 INPP4A Achchuthan Shanmugasundram Publications for gene: INPP4A were set to 21937992; 31978615; 31938306; 25338135; 20011524; 36653678; 39315527; 4074830740772914
Intellectual disability v9.58 INPP4A Achchuthan Shanmugasundram Publications for gene: INPP4A were set to 21937992; 31978615; 31938306; 25338135; 20011524; 36653678
Intellectual disability v9.57 INPP4A Achchuthan Shanmugasundram reviewed gene: INPP4A: Rating: GREEN; Mode of pathogenicity: None; Publications: 39315527, 4074830740772914; Phenotypes: neurodevelopmental disorder, MONDO:0700092, intellectual disability, MONDO:0001071; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v9.57 MED16 Achchuthan Shanmugasundram Classified gene: MED16 as Amber List (moderate evidence)
Intellectual disability v9.57 MED16 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence (10 unrelated families) available for the promotion of this gene to green rating in the next GMS update.
Intellectual disability v9.57 MED16 Achchuthan Shanmugasundram Gene: med16 has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.56 MED16 Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: MED16.
Tag Q3_25_NHS_review tag was added to gene: MED16.
Intellectual disability v9.56 MED16 Achchuthan Shanmugasundram Phenotypes for gene: MED16 were changed from developmental delay; multiple congenital abnormalities; Medopathy to Guillouet-Gordon syndrome, OMIM:621220
Intellectual disability v9.56 MED16 Achchuthan Shanmugasundram Publications for gene: MED16 were set to PMID: 40081376
Intellectual disability v9.55 MED16 Achchuthan Shanmugasundram reviewed gene: MED16: Rating: GREEN; Mode of pathogenicity: None; Publications: 40081376; Phenotypes: Guillouet-Gordon syndrome, OMIM:621220; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
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 Tag Q3_25_promote_green tag was added to gene: RREB1.
Tag Q3_25_NHS_review tag was added to gene: RREB1.
Intellectual disability v9.55 RREB1 Achchuthan Shanmugasundram Classified gene: RREB1 as Amber List (moderate evidence)
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 v9.55 RREB1 Achchuthan Shanmugasundram Gene: rreb1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.54 RREB1 Achchuthan Shanmugasundram Publications for gene: RREB1 were set to 38332451; 40418122
Intellectual disability v9.53 RREB1 Achchuthan Shanmugasundram Phenotypes for gene: RREB1 were changed from Rasopathy; Noonan-like; developmental disorder to RASopathy, MONDO:0021060
Intellectual disability v9.53 RREB1 Achchuthan Shanmugasundram Publications for gene: RREB1 were set to PMID: 40418122
Intellectual disability v9.52 RREB1 Achchuthan Shanmugasundram reviewed gene: RREB1: Rating: GREEN; Mode of pathogenicity: None; Publications: 38332451, 40418122; Phenotypes: RASopathy, MONDO:0021060; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v9.52 MYH3 Arina Puzriakova Mode of inheritance for gene: MYH3 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
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 Classified gene: RNU5A-1 as Red List (low evidence)
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 v9.51 RNU5A-1 Arina Puzriakova Gene: rnu5a-1 has been classified as Red List (Low Evidence).
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 v9.49 RNU2-2P Arina Puzriakova Publications for gene: RNU2-2P were set to 40210679; 40442284
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 v9.48 RNU2-2P Arina Puzriakova Publications for gene: RNU2-2P were set to 40210679
Intellectual disability v9.47 RNU5B-1 Arina Puzriakova Classified gene: RNU5B-1 as Amber List (moderate evidence)
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 v9.47 RNU5B-1 Arina Puzriakova Gene: rnu5b-1 has been classified as Amber List (Moderate Evidence).
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 v9.45 UNC13A Tom Hodgkinson reviewed gene: UNC13A: Rating: AMBER; Mode of pathogenicity: Other; Publications: PMID: 8192369, 39634123; Phenotypes: ASD, dyskinetic movement disorder, febrile seizures, developmental delay, intellectual disability, ataxia; Mode of inheritance: None
Intellectual disability v9.45 PRMT9 Achchuthan Shanmugasundram Phenotypes for gene: PRMT9 were changed from to neurodevelopmental disorder, MONDO:0700092
Intellectual disability v9.44 PRMT9 Achchuthan Shanmugasundram Publications for gene: PRMT9 were set to 21937992
Intellectual disability v9.43 PRMT9 Achchuthan Shanmugasundram reviewed gene: PRMT9: Rating: RED; Mode of pathogenicity: None; Publications: 21937992, 38561334; Phenotypes: neurodevelopmental disorder, MONDO:0700092; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v9.43 UBR5 Achchuthan Shanmugasundram Classified gene: UBR5 as Amber List (moderate evidence)
Intellectual disability v9.43 UBR5 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the promotion of this gene to green rating in the next GMS update.
Intellectual disability v9.43 UBR5 Achchuthan Shanmugasundram Gene: ubr5 has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.42 UBR5 Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: UBR5.
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 v9.41 CRNKL1 Achchuthan Shanmugasundram Tag dd_review tag was added to gene: CRNKL1.
Intellectual disability v9.41 PDE1B Achchuthan Shanmugasundram Classified gene: PDE1B as Amber List (moderate evidence)
Intellectual disability v9.41 PDE1B Achchuthan Shanmugasundram Added comment: Comment on list classification: Intellectual disability was reported with the severity of moderate or above in only one patient and was either mild or severity not reported in others. Hence, this gene can only be rated amber with the current evidence.
Intellectual disability v9.41 PDE1B Achchuthan Shanmugasundram Gene: pde1b has been classified as Amber List (Moderate Evidence).
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 v9.40 PDE1B Achchuthan Shanmugasundram Classified gene: PDE1B as Amber List (moderate evidence)
Intellectual disability v9.40 PDE1B Achchuthan Shanmugasundram Gene: pde1b has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.39 PDE1B Achchuthan Shanmugasundram Phenotypes for gene: PDE1B were changed from hypotonia; ataxia; dystonia; developmental delay; intellectual disability to movement disorder, MONDO:0005395; intellectual disability, MONDO:0001071
Intellectual disability v9.38 PDE1B Achchuthan Shanmugasundram edited their review of gene: PDE1B: Changed phenotypes to: movement disorder, MONDO:0005395, intellectual disability, MONDO:0001071
Intellectual disability v9.38 PDE1B Achchuthan Shanmugasundram Publications for gene: PDE1B were set to PMID: 40492975
Intellectual disability v9.37 PDE1B Achchuthan Shanmugasundram reviewed gene: PDE1B: Rating: AMBER; Mode of pathogenicity: None; Publications: 40492975; Phenotypes: movement disorder, MONDO:0005395; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v9.37 FLVCR1 Eleanor Williams Phenotypes for gene: FLVCR1 were changed from Neurodevelopmental disorder with microcephaly, absent speech, and hypotonia, OMIM:621060; neurodevelopmental disorder with microcephaly, absent speech, and hypotonia, MONDO:0976126 to Neurodevelopmental disorder with microcephaly, absent speech, and hypotonia, OMIM:621060; neurodevelopmental disorder with microcephaly, absent speech, and hypotonia, MONDO:0976126
Intellectual disability v9.36 FLVCR1 Eleanor Williams Publications for gene: FLVCR1 were set to 30656474; 22279524; 21267618; 21070897; 9409377; 30444160; 39306721
Intellectual disability v9.36 FLVCR1 Eleanor Williams Phenotypes for gene: FLVCR1 were changed from ATAXIA, POSTERIOR COLUMN, WITH RETINITIS PIGMENTOSA to Neurodevelopmental disorder with microcephaly, absent speech, and hypotonia, OMIM:621060; neurodevelopmental disorder with microcephaly, absent speech, and hypotonia, MONDO:0976126
Intellectual disability v9.35 FLVCR1 Eleanor Williams Publications for gene: FLVCR1 were set to 21267618; 9409377; 21070897
Intellectual disability v9.35 FLVCR1 Eleanor Williams Classified gene: FLVCR1 as Amber List (moderate evidence)
Intellectual disability v9.35 FLVCR1 Eleanor Williams Added comment: Comment on list classification: Promoting this gene to amber with a recommendation for green rating following GMS review.
Intellectual disability v9.35 FLVCR1 Eleanor Williams Gene: flvcr1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.34 FLVCR1 Eleanor Williams Tag Q3_25_promote_green tag was added to gene: FLVCR1.
Intellectual disability v9.34 FLVCR1 Eleanor Williams edited their review of gene: FLVCR1: Changed rating: GREEN
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 v9.32 CRNKL1 Achchuthan Shanmugasundram Classified gene: CRNKL1 as Amber List (moderate evidence)
Intellectual disability v9.32 CRNKL1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the promotion of this gene to green rating in the next GMS update.
Intellectual disability v9.32 CRNKL1 Achchuthan Shanmugasundram Gene: crnkl1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.31 CRNKL1 Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: CRNKL1.
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 Classified gene: NOTCH3 as Amber List (moderate evidence)
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 v9.30 NOTCH3 Achchuthan Shanmugasundram Gene: notch3 has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.29 NOTCH3 Achchuthan Shanmugasundram Tag dd_review tag was added to gene: NOTCH3.
Tag Q3_25_promote_green tag was added to gene: NOTCH3.
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 v9.28 KDM5B Arina Puzriakova commented on gene: KDM5B
Intellectual disability v9.28 KDM5B Arina Puzriakova Tag Q2_25_ demote_red was removed from gene: KDM5B.
Tag Q2_25_ MOI tag was added to gene: KDM5B.
Intellectual disability v9.28 KDM5B Arina Puzriakova Tag Q2_25_ demote_amber was removed from gene: KDM5B.
Tag Q2_25_ demote_red tag was added to gene: KDM5B.
Intellectual disability v9.28 KDM5B Arina Puzriakova Tag Q2_25_expert_review tag was added to gene: KDM5B.
Tag Q2_25_ demote_amber tag was added to gene: KDM5B.
Tag Q2_25_ NHS_review tag was added to gene: KDM5B.
Intellectual disability v9.28 CELF4 Achchuthan Shanmugasundram Classified gene: CELF4 as Amber List (moderate evidence)
Intellectual disability v9.28 CELF4 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (12 unrelated cases with GDD/ ID) for the promotion of this gene to green rating in the next GMS update.
Intellectual disability v9.28 CELF4 Achchuthan Shanmugasundram Gene: celf4 has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.27 CELF4 Achchuthan Shanmugasundram Tag dd_review tag was added to gene: CELF4.
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 v9.26 SRPK3 Arina Puzriakova Phenotypes for gene: SRPK3 were changed from neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071 to Intellectual developmental disorder, X-linked 114, OMIM:301134
Intellectual disability v9.25 ABCD1 Arina Puzriakova Phenotypes for gene: ABCD1 were changed from Adrenoleukodystrophy, 300100; Adrenomyeloneuropathy, adult, 300100; ADRENOLEUKODYSTROPHY, X-LINKED to Adrenoleukodystrophy, OMIM:300100; Adrenoleukodystrophy, adult, OMIM:300100
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 v9.24 CLCN5 Arina Puzriakova Mode of inheritance for gene: CLCN5 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Intellectual disability v9.23 MRPL49 Sarah Leigh Classified gene: MRPL49 as Amber List (moderate evidence)
Intellectual disability v9.23 MRPL49 Sarah Leigh Gene: mrpl49 has been classified as Amber List (Moderate Evidence).
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 has been classified as Red List (Low Evidence).
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 edited their review of gene: RAB3A: Changed rating: AMBER
Intellectual disability v9.21 RAB3A Sarah Leigh Tag Q2_25_ promote_green was removed from gene: RAB3A.
Tag Q2_25_ NHS_review was removed from gene: RAB3A.
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 v9.20 FBXO22 Achchuthan Shanmugasundram Classified gene: FBXO22 as Amber List (moderate evidence)
Intellectual disability v9.20 FBXO22 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the promotion of this gene to green rating in the next GMS update.
Intellectual disability v9.20 FBXO22 Achchuthan Shanmugasundram Gene: fbxo22 has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.19 FBXO22 Achchuthan Shanmugasundram Phenotypes for gene: FBXO22 were changed from neurodevelopmental delay; malformations; OMIM# 621184 to Tayoun-Maawali syndrome, OMIM:621184
Intellectual disability v9.18 FBXO22 Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: FBXO22.
Tag Q2_25_ NHS_review tag was added to gene: FBXO22.
Intellectual disability v9.18 FBXO22 Achchuthan Shanmugasundram reviewed gene: FBXO22: Rating: GREEN; Mode of pathogenicity: None; Publications: 40215970; Phenotypes: Tayoun-Maawali syndrome, OMIM:621184; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
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 Classified gene: ATM as Green List (high evidence)
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 v9.15 ATM Arina Puzriakova Gene: atm has been classified as Green List (High Evidence).
Intellectual disability v9.14 ATM Arina Puzriakova Tag Q2_25_ demote_red tag was added to gene: ATM.
Tag Q2_25_expert_review tag was added to gene: ATM.
Intellectual disability v9.14 MAP4K4 Arina Puzriakova Tag Q2_25_ promote_green tag was added to gene: MAP4K4.
Intellectual disability v9.14 MAP4K4 Arina Puzriakova Classified gene: MAP4K4 as Amber List (moderate evidence)
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 v9.14 MAP4K4 Arina Puzriakova Gene: map4k4 has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.13 MAP4K4 Arina Puzriakova Entity copied from DDG2P v6.1
Intellectual disability v9.13 MAP4K4 Arina Puzriakova gene: MAP4K4 was added
gene: MAP4K4 was added to Intellectual disability. Sources: Literature,Expert Review Green,DD-Gene2Phenotype
gene-checked tags were added to gene: MAP4K4.
Mode of inheritance for gene: MAP4K4 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: MAP4K4 were set to 36469137; 28518170; 37126546; 37126546
Phenotypes for gene: MAP4K4 were set to MAP4K4-related neurodevelopmental disorder with/without congenital anomalies; multiple congenital anomalies; neurodevelopmental differences
Mode of pathogenicity for gene: MAP4K4 was set to Other
Intellectual disability v9.12 SEL1L Achchuthan Shanmugasundram Classified gene: SEL1L as Amber List (moderate evidence)
Intellectual disability v9.12 SEL1L Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Julia Baptista, there is sufficient evidence available (three unrelated families) for the association of this gene with intellectual disability. Hence, this gene can be promoted to green rating in the next GMS update.
Intellectual disability v9.12 SEL1L Achchuthan Shanmugasundram Gene: sel1l has been classified as Amber List (Moderate Evidence).
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 v9.11 SEL1L Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: SEL1L.
Tag Q2_25_ NHS_review tag was added to gene: SEL1L.
Intellectual disability v9.11 SEL1L Achchuthan Shanmugasundram Phenotypes for gene: SEL1L were changed from Neurodevelopmental disorder to Neurodevelopmental disorder with hypotonia, poor growth, dysmorphic facies, and agammaglobulinemia, OMIM:621068; ?Neurodevelopmental disorder with poor growth, absent speech, progressive ataxia, and dysmorphic facies, OMIM:621067
Intellectual disability v9.10 SEL1L Achchuthan Shanmugasundram Publications for gene: SEL1L were set to 37943610, 37943617
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 SEL1L Achchuthan Shanmugasundram reviewed gene: SEL1L: Rating: GREEN; Mode of pathogenicity: None; Publications: 37943610, 37943617; Phenotypes: Neurodevelopmental disorder with hypotonia, poor growth, dysmorphic facies, and agammaglobulinemia, OMIM:621068, ?Neurodevelopmental disorder with poor growth, absent speech, progressive ataxia, and dysmorphic facies, OMIM:621067; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
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 v9.6 EPB41L3 Arina Puzriakova Classified gene: EPB41L3 as Amber List (moderate evidence)
Intellectual disability v9.6 EPB41L3 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update.
Intellectual disability v9.6 EPB41L3 Arina Puzriakova Gene: epb41l3 has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.5 EPB41L3 Arina Puzriakova Tag Q2_25_ promote_green tag was added to gene: EPB41L3.
Tag Q2_25_ NHS_review tag was added to gene: EPB41L3.
Intellectual disability v9.5 EPB41L3 Arina Puzriakova reviewed gene: EPB41L3: Rating: GREEN; Mode of pathogenicity: None; Publications: 39292993; Phenotypes: Developmental disorder with seizures and myelination defects; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v9.5 EPB41L3 Arina Puzriakova Phenotypes for gene: EPB41L3 were changed from developmental delay; intellectual disability; seizures; hypotonia; neuroregression to Developmental disorder with seizures and myelination defects
Intellectual disability v9.4 EEF1D Arina Puzriakova Phenotypes for gene: EEF1D were changed from Neurodevelopmental disorder; OMIM#621150 to Neurodevelopmental disorder with thin corpus callosum, hypotonia, and absent language, OMIM:621150
Intellectual disability v9.3 EEF1D Arina Puzriakova Classified gene: EEF1D as Amber List (moderate evidence)
Intellectual disability v9.3 EEF1D Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update.
Intellectual disability v9.3 EEF1D Arina Puzriakova Gene: eef1d has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.2 EEF1D Arina Puzriakova Tag Q2_25_ promote_green tag was added to gene: EEF1D.
Tag Q2_25_ NHS_review tag was added to gene: EEF1D.
Intellectual disability v9.2 EEF1D Arina Puzriakova reviewed gene: EEF1D: Rating: GREEN; Mode of pathogenicity: None; Publications: 28097321, 30787422, 36576126, 38083972; Phenotypes: Neurodevelopmental disorder with thin corpus callosum, hypotonia, and absent language, OMIM:621150; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v9.2 NEU1 Arina Puzriakova Phenotypes for gene: NEU1 were changed from Sialidosis, type I, 256550Sialidosis, type II, 256550; SIALIDOSIS (SIALIDOSIS) to Sialidosis, type I, OMIM:256550; Sialidosis, type II, OMIM:256550
Intellectual disability v9.1 Sarah Leigh Panel version 9.0 has been signed off on 2025-04-30
Intellectual disability v9.0 Sarah Leigh promoted panel to version 9.0
Intellectual disability v8.243 PRMT9 Shahryar Alavi reviewed gene: PRMT9: Rating: AMBER; Mode of pathogenicity: Other; Publications: PMID: 38561334; Phenotypes: intellectual disability, failure to thrive; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability v8.243 GAS8 Achchuthan Shanmugasundram Tag new-gene-name tag was added to gene: GAS8.
Intellectual disability v8.243 CCDC65 Achchuthan Shanmugasundram Tag new-gene-name tag was added to gene: CCDC65.
Intellectual disability v8.243 CCDC65 Achchuthan Shanmugasundram commented on gene: CCDC65
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 v8.243 ATXN10_ATTCT Sarah Leigh Classified STR: ATXN10_ATTCT as Amber List (moderate evidence)
Intellectual disability v8.243 ATXN10_ATTCT Sarah Leigh Str: atxn10_attct has been classified as Amber List (Moderate Evidence).
Intellectual disability v8.242 ATXN10_ATTCT Sarah Leigh reviewed STR: ATXN10_ATTCT: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v8.242 ATXN10_ATTCT Sarah Leigh Tag curated_removed was removed from STR: ATXN10_ATTCT.
Intellectual disability v8.242 RNU4-2 Hayley Lees reviewed gene: RNU4-2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v8.242 RNU2-2P Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There is sufficient evidence available for the association of this gene with ID and GDD. Hence, this gene can be promoted to green rating on this panel.; to: Comment on list classification: There is sufficient evidence available for the association of this gene with ID and GDD. Hence, this gene can be promoted to green rating on the next GMS update.
Intellectual disability v8.242 RNU2-2P Achchuthan Shanmugasundram Classified gene: RNU2-2P as Amber List (moderate evidence)
Intellectual disability v8.242 RNU2-2P Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the association of this gene with ID and GDD. Hence, this gene can be promoted to green rating on this panel.
Intellectual disability v8.242 RNU2-2P Achchuthan Shanmugasundram Gene: rnu2-2p has been classified as Amber List (Moderate Evidence).
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 v8.241 RNU2-2P Achchuthan Shanmugasundram Tag dd_review tag was added to gene: RNU2-2P.
Tag Q2_25_ promote_green tag was added to gene: RNU2-2P.
Intellectual disability v8.241 RNU2-2P Achchuthan Shanmugasundram Mode of inheritance for gene: RNU2-2P was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v8.240 RNU2-2P Achchuthan Shanmugasundram Publications for gene: RNU2-2P were set to
Intellectual disability v8.239 RNU2-2P Achchuthan Shanmugasundram Phenotypes for gene: RNU2-2P were changed from to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
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 RNU2-2P Achchuthan Shanmugasundram reviewed gene: RNU2-2P: Rating: GREEN; Mode of pathogenicity: None; Publications: 40210679; Phenotypes: neurodevelopmental disorder, MONDO:0700092, intellectual disability, MONDO:0001071; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v8.238 DDX39B Achchuthan Shanmugasundram Classified gene: DDX39B as Amber List (moderate evidence)
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 v8.238 DDX39B Achchuthan Shanmugasundram Gene: ddx39b has been classified as Amber List (Moderate Evidence).
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 v8.237 DDX39B Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: DDX39B.
Tag Q2_25_ NHS_review tag was added to gene: DDX39B.
Intellectual disability v8.237 DDX39B Achchuthan Shanmugasundram Phenotypes for gene: DDX39B were changed from neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071 to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Intellectual disability v8.236 DDX39B Achchuthan Shanmugasundram Phenotypes for gene: DDX39B were changed from to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Intellectual disability v8.236 DDX39B Achchuthan Shanmugasundram Publications for gene: DDX39B were set to PMID: 39918047
Intellectual disability v8.235 DDX39B Achchuthan Shanmugasundram reviewed gene: DDX39B: Rating: GREEN; Mode of pathogenicity: None; Publications: 39918047; Phenotypes: neurodevelopmental disorder, MONDO:0700092, intellectual disability, MONDO:0001071; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v8.235 KDM5B Tracy Lester reviewed gene: KDM5B: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Intellectual disability, developmental delay; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
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 v8.235 CLCN7 Arina Puzriakova Publications for gene: CLCN7 were set to
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 Classified gene: TMLHE as Amber List (moderate evidence)
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 v8.234 TMLHE Arina Puzriakova Gene: tmlhe has been classified as Amber List (Moderate Evidence).
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 v8.233 TMLHE Arina Puzriakova Publications for gene: TMLHE were set to 39845198; 23092983
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 v8.232 TRMT1L Arina Puzriakova Publications for gene: TRMT1L were set to 39786990
Intellectual disability v8.231 TMLHE Arina Puzriakova Publications for gene: TMLHE were set to
Intellectual disability v8.230 TMLHE Arina Puzriakova reviewed gene: TMLHE: Rating: ; Mode of pathogenicity: None; Publications: 39845198, 23092983; Phenotypes: {Autism, susceptibility to, X-linked 6}, OMIM:300872; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
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 v8.229 KCNJ2 Arina Puzriakova Publications for gene: KCNJ2 were set to 22155372
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 v8.227 VIPAS39 Arina Puzriakova Publications for gene: VIPAS39 were set to
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 v8.225 WT1 Arina Puzriakova Publications for gene: WT1 were set to
Intellectual disability v8.224 WT1 Arina Puzriakova reviewed gene: WT1: Rating: ; Mode of pathogenicity: None; Publications: 39625990; Phenotypes: Denys-Drash syndrome, OMIM:194080; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
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 v8.224 FUT2 Arina Puzriakova Publications for gene: FUT2 were set to 39350204
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 v8.222 EPM2A Arina Puzriakova Phenotypes for gene: EPM2A were changed from Epilepsy, progressive myoclonic 2A (Lafora) 254780 to Myoclonic epilepsy of Lafora 1, OMIM:254780
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 v8.221 EPM2A Arina Puzriakova Publications for gene: EPM2A were set to 21376300
Intellectual disability v8.220 EPM2A Arina Puzriakova reviewed gene: EPM2A: Rating: ; Mode of pathogenicity: None; Publications: 39385815; Phenotypes: ; Mode of inheritance: None
Intellectual disability v8.220 TFG Sarah Leigh Classified gene: TFG as Amber List (moderate evidence)
Intellectual disability v8.220 TFG Sarah Leigh Gene: tfg has been classified as Amber List (Moderate Evidence).
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 v8.219 TFG Sarah Leigh Tag Q1_25_ promote_green tag was added to gene: TFG.
Intellectual disability v8.219 TFG Sarah Leigh Publications for gene: TFG were set to 23479643; 33767317
Intellectual disability v8.218 TFG Sarah Leigh Publications for gene: TFG were set to 33767317
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 v8.217 TFG Sarah Leigh Publications for gene: TFG were set to 33767317
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 v8.216 YBX3 Arina Puzriakova Publications for gene: YBX3 were set to 39423228
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 v8.214 ABI2 Achchuthan Shanmugasundram Publications for gene: ABI2 were set to 28397838; 39774290
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 v8.212 CYFIP1 Achchuthan Shanmugasundram Publications for gene: CYFIP1 were set to 37704042; 39774290
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 v8.210 C1QC Achchuthan Shanmugasundram Publications for gene: C1QC were set to 39196411
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 v8.208 C1QA Achchuthan Shanmugasundram Publications for gene: C1QA were set to 39196411
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 v8.206 TFG Sarah Leigh Publications for gene: TFG were set to
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 Tag Q1_25_ promote_green tag was added to gene: ASCC3.
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 v8.204 ASCC3 Arina Puzriakova Publications for gene: ASCC3 were set to 21937992; 26350204; https://doi.org/10.1016/j.xhgg.2021.100024
Intellectual disability v8.203 SUPV3L1 Sarah Leigh Classified gene: SUPV3L1 as Amber List (moderate evidence)
Intellectual disability v8.203 SUPV3L1 Sarah Leigh Gene: supv3l1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v8.202 SUPV3L1 Sarah Leigh edited their review of gene: SUPV3L1: Changed rating: GREEN
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 v8.202 SUPV3L1 Sarah Leigh Publications for gene: SUPV3L1 were set to 35023579; 39596606
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 v8.199 HNRNPC Achchuthan Shanmugasundram Classified gene: HNRNPC as Amber List (moderate evidence)
Intellectual disability v8.199 HNRNPC Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (14 unrelated cases) for the promotion of this gene to green rating in the next GMS update.
Intellectual disability v8.199 HNRNPC Achchuthan Shanmugasundram Gene: hnrnpc has been classified as Amber List (Moderate Evidence).
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 v8.198 HNRNPC Achchuthan Shanmugasundram Publications for gene: HNRNPC were set to 37541189; 40004505
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 v8.196 VPS33A Sarah Leigh Publications for gene: VPS33A were set to 27547915; 28013294; 31070736; 39273517
Intellectual disability v8.195 VPS33A Sarah Leigh Classified gene: VPS33A as Amber List (moderate evidence)
Intellectual disability v8.195 VPS33A Sarah Leigh Gene: vps33a has been classified as Amber List (Moderate Evidence).
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 Classified gene: CRMP1 as Amber List (moderate evidence)
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 v8.193 CRMP1 Achchuthan Shanmugasundram Gene: crmp1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v8.192 CRMP1 Achchuthan Shanmugasundram Tag watchlist tag was added to gene: CRMP1.
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 v8.192 CRMP1 Achchuthan Shanmugasundram Publications for gene: CRMP1 were set to 36511780; 39758889
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 v8.190 GAP43 Achchuthan Shanmugasundram Publications for gene: GAP43 were set to 39738362
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 v8.189 ERCC4 Sarah Leigh Publications for gene: ERCC4 were set to 39769235
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 v8.187 HINT1 Sarah Leigh Publications for gene: HINT1 were set to 22961002; 34694653; 39596683
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 v8.186 LRRC8C Achchuthan Shanmugasundram Publications for gene: LRRC8C were set to 39623139
Intellectual disability v8.185 LRRC8C Achchuthan Shanmugasundram Classified gene: LRRC8C as Amber List (moderate evidence)
Intellectual disability v8.185 LRRC8C Achchuthan Shanmugasundram Gene: lrrc8c has been classified as Amber List (Moderate Evidence).
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 edited their review of gene: WFS1: Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v8.183 WFS1 Achchuthan Shanmugasundram edited their review of gene: WFS1: Changed rating: RED
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 v8.183 WFS1 Achchuthan Shanmugasundram Publications for gene: WFS1 were set to
Intellectual disability v8.182 WFS1 Achchuthan Shanmugasundram reviewed gene: WFS1: Rating: AMBER; Mode of pathogenicity: None; Publications: 39767643; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
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 v8.182 LMNA Achchuthan Shanmugasundram Publications for gene: LMNA were set to 25529582; 39767643
Intellectual disability v8.181 LMNA Achchuthan Shanmugasundram Classified gene: LMNA as Amber List (moderate evidence)
Intellectual disability v8.181 LMNA Achchuthan Shanmugasundram Gene: lmna has been classified as Amber List (Moderate Evidence).
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 v8.180 LMNA Achchuthan Shanmugasundram Publications for gene: LMNA were set to
Intellectual disability v8.179 LMNA Achchuthan Shanmugasundram Mode of inheritance for gene: LMNA was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v8.178 LMNA Achchuthan Shanmugasundram Deleted their comment
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 v8.178 LMNA Achchuthan Shanmugasundram reviewed gene: LMNA: Rating: AMBER; Mode of pathogenicity: None; Publications: 25529582, 39767643; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v8.178 ERCC4 Sarah Leigh reviewed gene: ERCC4: Rating: RED; Mode of pathogenicity: None; Publications: 39769235; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v8.178 ERCC4 Sarah Leigh Publications for gene: ERCC4 were set to
Intellectual disability v8.178 ERCC4 Sarah Leigh Phenotypes for gene: ERCC4 were changed from Xeroderma pigmentosum, group F, 278760; XFE progeroid syndrome, 610965; Fanconi anemia, complementation group Q, 615272; Xeroderma pigmentosum, type F/Cockayne syndrome, 278760 to Xeroderma pigmentosum, group F 278760; XFE progeroid syndrome, OMIM: 610965
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 v8.177 HINT1 Sarah Leigh Publications for gene: HINT1 were set to 22961002; 34694653; 39596683
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 v8.175 HINT1 Sarah Leigh Publications for gene: HINT1 were set to
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 v8.174 DAP3 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: This gene is currently rated amber as there is only case identified with severe ID, while two other cases had only mild ID.; to: Comment on list classification: This gene is currently rated amber as there is only one case identified with severe ID, while two other cases had only mild ID.
Intellectual disability v8.174 PLAT Achchuthan Shanmugasundram Classified gene: PLAT as Amber List (moderate evidence)
Intellectual disability v8.174 PLAT Achchuthan Shanmugasundram Added comment: Comment on list classification: This gene should be rated amber with current evidence as there is one case reported with GDD and two cases reported with only mild ID.
Intellectual disability v8.174 PLAT Achchuthan Shanmugasundram Gene: plat has been classified as Amber List (Moderate Evidence).
Intellectual disability v8.173 DAP3 Achchuthan Shanmugasundram Classified gene: DAP3 as Amber List (moderate evidence)
Intellectual disability v8.173 DAP3 Achchuthan Shanmugasundram Gene: dap3 has been classified as Amber List (Moderate Evidence).
Intellectual disability v8.172 DAP3 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: This gene is currently rated amber as there is only case identified with severe ID, while two other cases had only mild ID.; to: Comment on list classification: This gene is currently rated amber as there is only case identified with severe ID, while two other cases had only mild ID.
Intellectual disability v8.172 DAP3 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: This gene is currently rated red as there is only case identified with severe ID, while two other cases had only mild ID.; to: Comment on list classification: This gene is currently rated amber as there is only case identified with severe ID, while two other cases had only mild ID.
Intellectual disability v8.172 DAP3 Achchuthan Shanmugasundram edited their review of gene: DAP3: Changed rating: AMBER
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 v8.169 NHLRC2 Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: NHLRC2.
Intellectual disability v8.169 DAP3 Achchuthan Shanmugasundram Classified gene: DAP3 as Red List (low evidence)
Intellectual disability v8.169 DAP3 Achchuthan Shanmugasundram Added comment: Comment on list classification: This gene is currently rated red as there is only case identified with severe ID, while two other cases had only mild ID.
Intellectual disability v8.169 DAP3 Achchuthan Shanmugasundram Gene: dap3 has been classified as Red List (Low Evidence).
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 v8.168 DAP3 Achchuthan Shanmugasundram Publications for gene: DAP3 were set to 39701103
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 v8.166 NHLRC2 Achchuthan Shanmugasundram Classified gene: NHLRC2 as Amber List (moderate evidence)
Intellectual disability v8.166 NHLRC2 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (>15 unrelated cases with moderate/ severe GDD/ ID) for the promotion of this gene to green rating in the next GMS update.
Intellectual disability v8.166 NHLRC2 Achchuthan Shanmugasundram Gene: nhlrc2 has been classified as Amber List (Moderate Evidence).
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 v8.165 NHLRC2 Achchuthan Shanmugasundram Publications for gene: NHLRC2 were set to 37188825; 39328589
Intellectual disability v8.164 NHLRC2 Achchuthan Shanmugasundram Tag Q1_25_ promote_green tag was added to gene: NHLRC2.
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 v8.162 THAP11_CAG Sarah Leigh commented on STR: THAP11_CAG: PMID: 37148549 - 2 Chinese cases but one case had unaffected father with same number of repeats, PMID: 38113319 - 1 European case but inconclusive due to additional STR.

Also PMID: 38757579 and PMID: 39441143 report no cases with this repeat.
Intellectual disability v8.162 THAP11_CAG Sarah Leigh Classified STR: THAP11_CAG as Red List (low evidence)
Intellectual disability v8.162 THAP11_CAG Sarah Leigh Added comment: Comment on list classification: This STR has not been approved by NHS STR working group and is not NGS Not Validated
Intellectual disability v8.162 THAP11_CAG Sarah Leigh Str: thap11_cag has been classified as Red List (Low Evidence).
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 v8.159 PPP2R2B Sarah Leigh Classified gene: PPP2R2B as Amber List (moderate evidence)
Intellectual disability v8.159 PPP2R2B Sarah Leigh Gene: ppp2r2b has been classified as Amber List (Moderate Evidence).
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 v8.157 PPP2R2B Sarah Leigh Publications for gene: PPP2R2B were set to 25356899
Intellectual disability v8.156 PPP2R2B Sarah Leigh edited their review of gene: PPP2R2B: Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v8.156 PPP2R2B Sarah Leigh Tag nucleotide-repeat-expansion was removed from gene: PPP2R2B.
Tag currently-ngs-unreportable was removed from gene: PPP2R2B.
Tag Q1_25_ promote_green tag was added to gene: PPP2R2B.
Intellectual disability v8.156 PPP2R2B Sarah Leigh reviewed gene: PPP2R2B: Rating: GREEN; Mode of pathogenicity: None; Publications: 39565297, 25356899; Phenotypes: neurodevelopmental syndrome; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v8.156 PPP2R2B_CAG Sarah Leigh reviewed STR: PPP2R2B_CAG: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
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 v8.155 NAV3 Sarah Leigh Publications for gene: NAV3 were set to 38977784; 39038237; 39708122
Intellectual disability v8.154 NAV3 Sarah Leigh Classified gene: NAV3 as Amber List (moderate evidence)
Intellectual disability v8.154 NAV3 Sarah Leigh Gene: nav3 has been classified as Amber List (Moderate Evidence).
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 Tag watchlist was removed from gene: TUBGCP2.
Tag Q1_25_ promote_green tag was added to gene: TUBGCP2.
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 v8.152 TUBGCP2 Arina Puzriakova Publications for gene: TUBGCP2 were set to 31630790
Intellectual disability v8.151 GTF3C3 Arina Puzriakova Classified gene: GTF3C3 as Amber List (moderate evidence)
Intellectual disability v8.151 GTF3C3 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update.
Intellectual disability v8.151 GTF3C3 Arina Puzriakova Gene: gtf3c3 has been classified as Amber List (Moderate Evidence).
Intellectual disability v8.150 GTF3C3 Arina Puzriakova Tag watchlist was removed from gene: GTF3C3.
Tag Q1_25_ promote_green tag was added to gene: GTF3C3.
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 v8.150 GTF3C3 Arina Puzriakova Publications for gene: GTF3C3 were set to 28940097, 28097321; 30552426
Intellectual disability v8.149 C12orf66 Arina Puzriakova Classified gene: C12orf66 as Amber List (moderate evidence)
Intellectual disability v8.149 C12orf66 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green the next GMS panel update.
Intellectual disability v8.149 C12orf66 Arina Puzriakova Gene: c12orf66 has been classified as Amber List (Moderate Evidence).
Intellectual disability v8.148 C12orf66 Arina Puzriakova commented on gene: C12orf66: Added new-gene-name tag, new approved HGNC gene symbol for C12orf66 is KICS2
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 v8.148 C12orf66 Arina Puzriakova Deleted their comment
Intellectual disability v8.148 C12orf66 Arina Puzriakova Classified gene: C12orf66 as Amber List (moderate evidence)
Intellectual disability v8.148 C12orf66 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update.
Intellectual disability v8.148 C12orf66 Arina Puzriakova Gene: c12orf66 has been classified as Amber List (Moderate Evidence).
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 v8.146 SPOUT1 Sarah Leigh Publications for gene: SPOUT1 were set to 39962046
Intellectual disability v8.145 SPOUT1 Sarah Leigh Classified gene: SPOUT1 as Amber List (moderate evidence)
Intellectual disability v8.145 SPOUT1 Sarah Leigh Gene: spout1 has been classified as Amber List (Moderate Evidence).
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 Tag watchlist was removed from gene: RSPRY1.
Tag Q1_25_ promote_green tag was added to gene: RSPRY1.
Intellectual disability v8.142 RSPRY1 Arina Puzriakova Classified gene: RSPRY1 as Amber List (moderate evidence)
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 v8.142 RSPRY1 Arina Puzriakova Gene: rspry1 has been classified as Amber List (Moderate Evidence).
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 v8.141 RSPRY1 Arina Puzriakova Publications for gene: RSPRY1 were set to 26365341; 30063090; 38562122; 39940902
Intellectual disability v8.140 RSPRY1 Arina Puzriakova Phenotypes for gene: RSPRY1 were changed from Spondyloepimetaphyseal dysplasia, Faden-Alkuraya type, 616585 to Spondyloepimetaphyseal dysplasia, Faden-Alkuraya type, OMIM:616723
Intellectual disability v8.139 RSPRY1 Arina Puzriakova Publications for gene: RSPRY1 were set to 26365341; 30914295
Intellectual disability v8.138 RSPRY1 Arina Puzriakova reviewed gene: RSPRY1: Rating: GREEN; Mode of pathogenicity: None; Publications: 26365341, 30063090, 38562122, 39940902; Phenotypes: Spondyloepimetaphyseal dysplasia, Faden-Alkuraya type, OMIM:616723; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v8.138 DALRD3 Arina Puzriakova Classified gene: DALRD3 as Amber List (moderate evidence)
Intellectual disability v8.138 DALRD3 Arina Puzriakova Added comment: Comment on list classification: Maintaining Amber rating as only 2 families have been reported to date.
Intellectual disability v8.138 DALRD3 Arina Puzriakova Gene: dalrd3 has been classified as Amber List (Moderate Evidence).
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 v8.137 DALRD3 Arina Puzriakova Publications for gene: DALRD3 were set to 32427860
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 v8.136 SPR Arina Puzriakova Phenotypes for gene: SPR were changed from DOPA-RESPONSIVE DYSTONIA DUE TO SEPIAPTERIN REDUCTASE DEFICIENCY to Dystonia, dopa-responsive, due to sepiapterin reductase deficiency, OMIM:612716
Intellectual disability v8.135 SPAST Sarah Leigh Tag Q1_25_ MOI tag was added to gene: SPAST.
Tag Q1_25_ promote_green tag was added to gene: SPAST.
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 v8.133 SPAST Sarah Leigh Publications for gene: SPAST were set to
Intellectual disability v8.132 SPAST Sarah Leigh Classified gene: SPAST as Amber List (moderate evidence)
Intellectual disability v8.132 SPAST Sarah Leigh Gene: spast has been classified as Amber List (Moderate Evidence).
Intellectual disability v8.131 LSM7 Arina Puzriakova Entity copied from White matter disorders and cerebral calcification - narrow panel v6.9
Intellectual disability v8.131 LSM7 Arina Puzriakova gene: LSM7 was added
gene: LSM7 was added to Intellectual disability. Sources: Literature,Expert Review Amber
watchlist tags were added to gene: LSM7.
Mode of inheritance for gene: LSM7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LSM7 were set to 35047835; 39420558
Phenotypes for gene: LSM7 were set to Leukodystrophy, MONDO:0019046
Intellectual disability v8.130 CCDC115 Eleanor Williams commented on gene: CCDC115
Intellectual disability v8.130 CCDC115 Eleanor Williams Tag new-gene-name tag was added to gene: CCDC115.
Intellectual disability v8.130 ZNRF3 Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: ZNRF3.
Intellectual disability v8.130 RBBP5 Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: RBBP5.
Intellectual disability v8.130 PSMC5 Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: PSMC5.
Intellectual disability v8.130 MARK2 Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: MARK2.
Intellectual disability v8.130 LRRC7 Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: LRRC7.
Intellectual disability v8.130 HDAC3 Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: HDAC3.
Intellectual disability v8.130 DDX17 Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: DDX17.
Intellectual disability v8.130 WDR83OS Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has now been associated with relevant phenotypes in OMIM (MIM #621016).
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 v8.129 WDR83OS Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: WDR83OS.
Intellectual disability v8.129 RNU4-2 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has now been associated with relevant phenotypes in OMIM (MIM #620851).
Intellectual disability v8.129 RNU4-2 Achchuthan Shanmugasundram Phenotypes for gene: RNU4-2 were changed from Neurodevelopmental disorder, MONDO:0700092, RNU4-2 related to ReNU syndrome, OMIM:620851
Intellectual disability v8.128 LINC01578 Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: LINC01578.
Intellectual disability v8.128 DHRSX Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has now been associated with relevant phenotypes in OMIM (MIM #301133).
Intellectual disability v8.128 DHRSX Achchuthan Shanmugasundram Phenotypes for gene: DHRSX were changed from congenital disorder of glycosylation, MONDO:0015286; intellectual disability, MONDO:0001071 to Congenital disorder of glycosylation, type 1DD, OMIM:301133
Intellectual disability v8.127 DHRSX Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: DHRSX.
Intellectual disability v8.127 ATXN7L3 Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: ATXN7L3.
Intellectual disability v8.127 DHX9 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has now been associated with relevant phenotypes in OMIM (MIM #620988).
Intellectual disability v8.127 DHX9 Achchuthan Shanmugasundram Phenotypes for gene: DHX9 were changed from neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071 to Intellectual developmental disorder, autosomal dominant 75, OMIM:620988
Intellectual disability v8.126 DHX9 Achchuthan Shanmugasundram Tag gene-checked was removed from gene: DHX9.
Intellectual disability v8.126 XPA Sarah Leigh Tag Q1_25_ promote_green tag was added to gene: XPA.
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 v8.126 XPA Sarah Leigh Publications for gene: XPA were set to 26302748; 25566891; 24135642
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 XPA Sarah Leigh reviewed gene: XPA: Rating: GREEN; Mode of pathogenicity: None; Publications: 39621777; Phenotypes: Xeroderma pigmentosum, group A, OMIM: 278700; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
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 v8.124 MAG Sarah Leigh Publications for gene: MAG were set to 39336794
Intellectual disability v8.123 MAG Sarah Leigh Classified gene: MAG as Amber List (moderate evidence)
Intellectual disability v8.123 MAG Sarah Leigh Gene: mag has been classified as Amber List (Moderate Evidence).
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 v8.121 CCDC88A Arina Puzriakova Publications for gene: CCDC88A were set to 26917597; 30392057; 37798908; 39334473
Intellectual disability v8.120 AFF3_GGC Sarah Leigh AFF3_GCC was changed to AFF3_GGC
Repeated Sequence for AFF3_GGC was changed from GCC to GGC.
Intellectual disability v8.119 LINC01578 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has now been associated with relevant phenotype in OMIM (MIM #621012), but not yet in Gene2Phenotype.
Intellectual disability v8.119 LINC01578 Achchuthan Shanmugasundram Phenotypes for gene: LINC01578 were changed from Neurodevelopmental disorder, MONDO:0700092, CHASERR-related to Neurodevelopmental disorder with dysmorphic facies, absent speech and ambulation, and brain abnormalities, OMIM:621012
Intellectual disability v8.118 LINC01578 Achchuthan Shanmugasundram Tag locus-type-rna-long-non-coding tag was added to gene: LINC01578.
Intellectual disability v8.118 TDP1 Sarah Leigh Classified gene: TDP1 as Amber List (moderate evidence)
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 v8.118 TDP1 Sarah Leigh Gene: tdp1 has been classified as Amber List (Moderate Evidence).
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 v8.117 TDP1 Sarah Leigh Publications for gene: TDP1 were set to 12244316; 31182267; 39576382
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 v8.115 PPP2R5C Sarah Leigh Publications for gene: PPP2R5C were set to 25972378; 39500882; 39978342
Intellectual disability v8.114 PPP2R5C Sarah Leigh edited their review of gene: PPP2R5C: Changed publications to: 25972378, 39696819, 39978342
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 v8.114 PPP2R5C Sarah Leigh Publications for gene: PPP2R5C were set to 25972378; 39500882; 39978342
Intellectual disability v8.113 PPP2R5C Sarah Leigh Classified gene: PPP2R5C as Amber List (moderate evidence)
Intellectual disability v8.113 PPP2R5C Sarah Leigh Gene: ppp2r5c has been classified as Amber List (Moderate Evidence).
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 v8.111 GON4L Sarah Leigh Publications for gene: GON4L were set to 21937992; 26350204; 24896178; 39500882
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 Classified gene: GON4L as Amber List (moderate evidence)
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 v8.110 GON4L Sarah Leigh Gene: gon4l has been classified as Amber List (Moderate Evidence).
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 v8.109 GON4L Sarah Leigh Publications for gene: GON4L were set to 21937992
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 v8.108 PNPLA8 Sarah Leigh Publications for gene: PNPLA8 were set to 39082157
Intellectual disability v8.107 PNPLA8 Sarah Leigh Classified gene: PNPLA8 as Amber List (moderate evidence)
Intellectual disability v8.107 PNPLA8 Sarah Leigh Gene: pnpla8 has been classified as Amber List (Moderate Evidence).
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 v8.105 PLEKHG1 Sarah Leigh Publications for gene: PLEKHG1 were set to 39202455; 30659137
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 v8.103 ISCA-37447-Loss Arina Puzriakova Classified Region: ISCA-37447-Loss as Green List (high evidence)
Intellectual disability v8.103 ISCA-37447-Loss Arina Puzriakova Region: isca-37447-loss has been classified as Green List (High Evidence).
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 v8.102 ISCA-37447-Loss Arina Puzriakova Mode of inheritance for Region: ISCA-37447-Loss was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
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 v8.100 ATP11A Sarah Leigh Publications for gene: ATP11A were set to 34403372; 39432785
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 v8.99 ATP11A Sarah Leigh Publications for gene: ATP11A were set to 34403372; 39432785
Intellectual disability v8.98 ATP11A Sarah Leigh reviewed gene: ATP11A: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v8.98 ATP11A Sarah Leigh Publications for gene: ATP11A were set to 34403372
Intellectual disability v8.97 RBBP5 Sarah Leigh Tag Q3_24_promote_green was removed from gene: RBBP5.
Intellectual disability v8.97 SLC4A10 Sarah Leigh Tag Q3_24_promote_green was removed from gene: SLC4A10.
Intellectual disability v8.97 SRPK3 Sarah Leigh Tag Q3_24_promote_green was removed from gene: SRPK3.
Intellectual disability v8.97 TBC1D7 Sarah Leigh Tag Q3_24_promote_green was removed from gene: TBC1D7.
Tag Q3_24_NHS_review was removed from gene: TBC1D7.
Intellectual disability v8.97 TRMT5 Sarah Leigh Tag Q3_24_promote_green was removed from gene: TRMT5.
Intellectual disability v8.97 WDR83OS Sarah Leigh Tag Q3_24_promote_green was removed from gene: WDR83OS.
Intellectual disability v8.97 GEMIN4 Sarah Leigh Tag Q3_24_promote_green was removed from gene: GEMIN4.
Intellectual disability v8.97 GNAI2 Sarah Leigh Tag Q3_24_promote_green was removed from gene: GNAI2.
Intellectual disability v8.97 HDAC3 Sarah Leigh Tag Q3_24_promote_green was removed from gene: HDAC3.
Intellectual disability v8.97 IREB2 Sarah Leigh Tag watchlist was removed from gene: IREB2.
Tag Q3_24_promote_green was removed from gene: IREB2.
Intellectual disability v8.97 LINC01578 Sarah Leigh Tag Q3_24_promote_green was removed from gene: LINC01578.
Tag Q3_24_NHS_review was removed from gene: LINC01578.
Intellectual disability v8.97 LRRC7 Sarah Leigh Tag Q3_24_promote_green was removed from gene: LRRC7.
Tag Q3_24_NHS_review was removed from gene: LRRC7.
Intellectual disability v8.97 MAPKAPK5 Sarah Leigh Tag watchlist was removed from gene: MAPKAPK5.
Tag Q3_24_promote_green was removed from gene: MAPKAPK5.
Intellectual disability v8.97 MARK2 Sarah Leigh Tag Q3_24_promote_green was removed from gene: MARK2.
Intellectual disability v8.97 MSL2 Sarah Leigh Tag Q3_24_promote_green was removed from gene: MSL2.
Tag Q3_24_NHS_review was removed from gene: MSL2.
Intellectual disability v8.97 PI4K2A Sarah Leigh Tag Q3_24_promote_green was removed from gene: PI4K2A.
Tag Q3_24_NHS_review was removed from gene: PI4K2A.
Intellectual disability v8.97 PLEKHG2 Sarah Leigh Tag Q3_24_promote_green was removed from gene: PLEKHG2.
Intellectual disability v8.97 PSMC5 Sarah Leigh Tag Q3_24_promote_green was removed from gene: PSMC5.
Intellectual disability v8.97 ATXN7L3 Sarah Leigh Tag Q3_24_promote_green was removed from gene: ATXN7L3.
Intellectual disability v8.97 B9D1 Sarah Leigh Tag Q3_24_promote_green was removed from gene: B9D1.
Intellectual disability v8.97 BORCS8 Sarah Leigh Tag Q3_24_promote_green was removed from gene: BORCS8.
Intellectual disability v8.97 CCDC88A Sarah Leigh Tag Q3_24_promote_green was removed from gene: CCDC88A.
Intellectual disability v8.97 CIAO1 Sarah Leigh Tag Q3_24_promote_green was removed from gene: CIAO1.
Tag Q3_24_NHS_review was removed from gene: CIAO1.
Intellectual disability v8.97 CRELD1 Sarah Leigh Tag Q3_24_promote_green was removed from gene: CRELD1.
Intellectual disability v8.97 DDX17 Sarah Leigh Tag Q3_24_promote_green was removed from gene: DDX17.
Tag Q3_24_NHS_review was removed from gene: DDX17.
Intellectual disability v8.97 DHRSX Sarah Leigh Tag Q3_24_promote_green was removed from gene: DHRSX.
Intellectual disability v8.97 FIBP Sarah Leigh Tag Q3_24_promote_green was removed from gene: FIBP.
Tag Q3_24_NHS_review was removed from gene: FIBP.
Intellectual disability v8.97 FOSL2 Sarah Leigh Tag Q3_24_promote_green was removed from gene: FOSL2.
Intellectual disability v8.97 FRA10AC1 Sarah Leigh Tag Q3_24_promote_green was removed from gene: FRA10AC1.
Intellectual disability v8.97 FUK Sarah Leigh Tag watchlist was removed from gene: FUK.
Tag Q3_24_promote_green was removed from gene: FUK.
Intellectual disability v8.97 FZR1 Sarah Leigh Tag Q3_24_promote_green was removed from gene: FZR1.
Intellectual disability v8.97 WDR83OS Sarah Leigh reviewed gene: WDR83OS: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v8.97 TRMT5 Sarah Leigh reviewed gene: TRMT5: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v8.97 TBC1D7 Sarah Leigh reviewed gene: TBC1D7: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v8.97 SRPK3 Sarah Leigh reviewed gene: SRPK3: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability v8.97 SLC4A10 Sarah Leigh reviewed gene: SLC4A10: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v8.97 RBBP5 Sarah Leigh reviewed gene: RBBP5: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v8.97 PSMC5 Sarah Leigh reviewed gene: PSMC5: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v8.97 PLEKHG2 Sarah Leigh commented on gene: PLEKHG2: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.
Intellectual disability v8.97 PI4K2A Sarah Leigh reviewed gene: PI4K2A: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v8.97 MSL2 Sarah Leigh reviewed gene: MSL2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
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 MAPKAPK5 Sarah Leigh reviewed gene: MAPKAPK5: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v8.97 LRRC7 Sarah Leigh reviewed gene: LRRC7: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v8.97 LINC01578 Sarah Leigh commented on gene: LINC01578: The rating of this gene has been updated to green and the mode of inheritance set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted following NHS Genomic Medicine Service approval.
Intellectual disability v8.97 IREB2 Sarah Leigh reviewed gene: IREB2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v8.97 HDAC3 Sarah Leigh reviewed gene: HDAC3: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v8.97 GNAI2 Sarah Leigh reviewed gene: GNAI2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v8.97 GEMIN4 Sarah Leigh reviewed gene: GEMIN4: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v8.97 FZR1 Sarah Leigh reviewed gene: FZR1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v8.97 FUK Sarah Leigh reviewed gene: FUK: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v8.97 FRA10AC1 Sarah Leigh reviewed gene: FRA10AC1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v8.97 FOSL2 Sarah Leigh reviewed gene: FOSL2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v8.97 FIBP Sarah Leigh commented on gene: FIBP: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.
Intellectual disability v8.97 DHRSX Sarah Leigh reviewed gene: DHRSX: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v8.97 DDX17 Sarah Leigh reviewed gene: DDX17: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v8.97 CRELD1 Sarah Leigh reviewed gene: CRELD1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v8.97 CIAO1 Sarah Leigh commented on gene: CIAO1: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.
Intellectual disability v8.97 CCDC88A Sarah Leigh reviewed gene: CCDC88A: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v8.97 BORCS8 Sarah Leigh reviewed gene: BORCS8: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v8.97 B9D1 Sarah Leigh edited their review of gene: B9D1: Added comment: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.; Changed rating: GREEN
Intellectual disability v8.97 ATXN7L3 Sarah Leigh commented on gene: ATXN7L3: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.
Intellectual disability v8.97 WDR83OS Sarah Leigh Source NHS GMS was added to WDR83OS.
Source Expert Review Green was added to WDR83OS.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v8.97 TRMT5 Sarah Leigh Source NHS GMS was added to TRMT5.
Source Expert Review Green was added to TRMT5.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v8.97 TBC1D7 Sarah Leigh Source NHS GMS was added to TBC1D7.
Source Expert Review Green was added to TBC1D7.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v8.97 SRPK3 Sarah Leigh Source NHS GMS was added to SRPK3.
Source Expert Review Green was added to SRPK3.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v8.97 SLC4A10 Sarah Leigh Source NHS GMS was added to SLC4A10.
Source Expert Review Green was added to SLC4A10.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v8.97 RBBP5 Sarah Leigh Source NHS GMS was added to RBBP5.
Source Expert Review Green was added to RBBP5.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v8.97 PSMC5 Sarah Leigh Source NHS GMS was added to PSMC5.
Source Expert Review Green was added to PSMC5.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v8.97 PLEKHG2 Sarah Leigh Source NHS GMS was added to PLEKHG2.
Source Expert Review Green was added to PLEKHG2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v8.97 PI4K2A Sarah Leigh Source Expert Review Green was added to PI4K2A.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v8.97 MSL2 Sarah Leigh Source NHS GMS was added to MSL2.
Source Expert Review Green was added to MSL2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
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 v8.97 MAPKAPK5 Sarah Leigh Source NHS GMS was added to MAPKAPK5.
Source Expert Review Green was added to MAPKAPK5.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v8.97 LRRC7 Sarah Leigh Source NHS GMS was added to LRRC7.
Source Expert Review Green was added to LRRC7.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v8.97 LINC01578 Sarah Leigh Source NHS GMS was added to LINC01578.
Source Expert Review Green was added to LINC01578.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v8.97 IREB2 Sarah Leigh Source NHS GMS was added to IREB2.
Source Expert Review Green was added to IREB2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v8.97 HDAC3 Sarah Leigh Source NHS GMS was added to HDAC3.
Source Expert Review Green was added to HDAC3.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v8.97 GNAI2 Sarah Leigh Source NHS GMS was added to GNAI2.
Source Expert Review Green was added to GNAI2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v8.97 GEMIN4 Sarah Leigh Source NHS GMS was added to GEMIN4.
Source Expert Review Green was added to GEMIN4.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v8.97 FZR1 Sarah Leigh Source NHS GMS was added to FZR1.
Source Expert Review Green was added to FZR1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v8.97 FUK Sarah Leigh Source NHS GMS was added to FUK.
Source Expert Review Green was added to FUK.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v8.97 FRA10AC1 Sarah Leigh Source NHS GMS was added to FRA10AC1.
Source Expert Review Green was added to FRA10AC1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v8.97 FOSL2 Sarah Leigh Source NHS GMS was added to FOSL2.
Source Expert Review Green was added to FOSL2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v8.97 FIBP Sarah Leigh Source NHS GMS was added to FIBP.
Source Expert Review Green was added to FIBP.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v8.97 DHRSX Sarah Leigh Source NHS GMS was added to DHRSX.
Source Expert Review Green was added to DHRSX.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v8.97 DDX17 Sarah Leigh Source NHS GMS was added to DDX17.
Source Expert Review Green was added to DDX17.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v8.97 CRELD1 Sarah Leigh Source NHS GMS was added to CRELD1.
Source Expert Review Green was added to CRELD1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v8.97 CIAO1 Sarah Leigh Source NHS GMS was added to CIAO1.
Source Expert Review Green was added to CIAO1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v8.97 CCDC88A Sarah Leigh Source NHS GMS was added to CCDC88A.
Source Expert Review Green was added to CCDC88A.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v8.97 BORCS8 Sarah Leigh Source NHS GMS was added to BORCS8.
Source Expert Review Green was added to BORCS8.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v8.97 B9D1 Sarah Leigh Source NHS GMS was added to B9D1.
Source Expert Review Green was added to B9D1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v8.97 ATXN7L3 Sarah Leigh Source NHS GMS was added to ATXN7L3.
Source Expert Review Green was added to ATXN7L3.
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 v8.96 GABBR2 Arina Puzriakova Publications for gene: GABBR2 were set to 29100083; 28061363; 28135719; 28856709; 29369404; 29377213; 39028675
Intellectual disability v8.95 GABBR2 Arina Puzriakova Publications for gene: GABBR2 were set to 29100083; 28061363; 28135719; 28856709; 29369404; 29377213
Intellectual disability v8.94 GABBR2 Arina Puzriakova Phenotypes for gene: GABBR2 were changed from EPILEPTIC ENCEPHALOPATHY; Rett syndrome; Neurodevelopmental disorder with poor language and loss of hand skills, 617903 to Developmental and epileptic encephalopathy 59, OMIM:617904; eurodevelopmental disorder with poor language and loss of hand skills, OMIM:617903
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 v8.90 OPA1 Sarah Leigh Publications for gene: OPA1 were set to 39233737
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 v8.89 FEM1C Julie Evans reviewed gene: FEM1C: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v8.89 OPA1 Sarah Leigh Classified gene: OPA1 as Amber List (moderate evidence)
Intellectual disability v8.89 OPA1 Sarah Leigh Gene: opa1 has been classified as Amber List (Moderate Evidence).
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 v8.87 ZFHX4 Arina Puzriakova Publications for gene: ZFHX4 were set to 26350204; 21802062; 33057194; 24038936
Intellectual disability v8.86 ZFHX4 Arina Puzriakova commented on gene: ZFHX4
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 v8.84 AFF3_GCC Eleanor Williams commented on STR: AFF3_GCC
Intellectual disability v8.84 SLC5A7 Arina Puzriakova Publications for gene: SLC5A7 were set to 30914295; 27569547; 39135055
Intellectual disability v8.83 SLC5A7 Arina Puzriakova Tag watchlist was removed from gene: SLC5A7.
Tag Q1_25_ promote_green tag was added to gene: SLC5A7.
Intellectual disability v8.83 SLC5A7 Arina Puzriakova edited their review of gene: SLC5A7: Changed rating: GREEN; Changed publications to: 27569547, 39135055, 36840359, 36611016, 33250374; Changed phenotypes to: Myasthenic syndrome, congenital, 20, presynaptic, OMIM:617143; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
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 v8.83 SLC5A7 Arina Puzriakova Phenotypes for gene: SLC5A7 were changed from Myasthenic syndrome, congenital, 20, presynaptic,CMS20, 617143 to Myasthenic syndrome, congenital, 20, presynaptic, OMIM:617143
Intellectual disability v8.82 SLC5A7 Arina Puzriakova Mode of inheritance for gene: SLC5A7 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BIALLELIC, autosomal or pseudoautosomal
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 v8.81 SLC5A7 Arina Puzriakova Publications for gene: SLC5A7 were set to 30914295; 27569547
Intellectual disability v8.80 INPP4A Eleanor Williams Tag Q1_25_ promote_green tag was added to gene: INPP4A.
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 v8.80 INPP4A Eleanor Williams Publications for gene: INPP4A were set to 21937992; 31978615; 31938306; 25338135; 20011524
Intellectual disability v8.79 INPP4A Eleanor Williams Classified gene: INPP4A as Amber List (moderate evidence)
Intellectual disability v8.79 INPP4A Eleanor Williams Added comment: Comment on list classification: Leaving as amber, but with a recommendation to promote to green following GMS approval.
Intellectual disability v8.79 INPP4A Eleanor Williams Gene: inpp4a has been classified as Amber List (Moderate Evidence).
Intellectual disability v8.78 INPP4A Eleanor Williams commented on gene: INPP4A
Intellectual disability v8.78 PTRH2 Achchuthan Shanmugasundram Classified gene: PTRH2 as Amber List (moderate evidence)
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 v8.78 PTRH2 Achchuthan Shanmugasundram Gene: ptrh2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v8.77 PTRH2 Achchuthan Shanmugasundram Phenotypes for gene: PTRH2 were changed from Infantile-onset multisystem neurologic, endocrine, and pancreatic disease, 616263; Infantile-onset multisystem neurologic, endocrine, and pancreatic disease (MIM 616263) to Infantile-onset multisystem neurologic, endocrine, and pancreatic disease, OMIM:616263
Intellectual disability v8.76 PTRH2 Achchuthan Shanmugasundram Tag Q1_25_ promote_green tag was added to gene: PTRH2.
Intellectual disability v8.76 PTRH2 Achchuthan Shanmugasundram edited their review of gene: PTRH2: Changed phenotypes to: Infantile-onset multisystem neurologic, endocrine, and pancreatic disease, OMIM:616263
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 v8.76 PTRH2 Achchuthan Shanmugasundram Publications for gene: PTRH2 were set to 25574476; 28175314; 28328138; 25558065; 27129381
Intellectual disability v8.75 PTRH2 Achchuthan Shanmugasundram reviewed gene: PTRH2: Rating: GREEN; Mode of pathogenicity: None; Publications: 39176129, 39766776; Phenotypes: infantile-onset multisystem neurologic, endocrine, and pancreatic disease, OMIM:616263; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
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 v8.75 RUNX1T1 Achchuthan Shanmugasundram Publications for gene: RUNX1T1 were set to 22644616; 39568205
Intellectual disability v8.74 RUNX1T1 Achchuthan Shanmugasundram Classified gene: RUNX1T1 as Amber List (moderate evidence)
Intellectual disability v8.74 RUNX1T1 Achchuthan Shanmugasundram Gene: runx1t1 has been classified as Amber List (Moderate Evidence).
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 Classified gene: NFIB as Amber List (moderate evidence)
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 v8.72 NFIB Achchuthan Shanmugasundram Gene: nfib has been classified as Amber List (Moderate 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 v8.71 NFIB Achchuthan Shanmugasundram Publications for gene: NFIB were set to 30388402; 39567597
Intellectual disability v8.70 NFIB Achchuthan Shanmugasundram Phenotypes for gene: NFIB were changed from Global developmental delay; Intellectual disability; Macrocephaly; Macrocephaly, acquired, with impaired intellectual development, 618286 to Macrocephaly, acquired, with impaired intellectual development, OMIM:618286
Intellectual disability v8.69 NFIB Achchuthan Shanmugasundram Publications for gene: NFIB were set to 30388402
Intellectual disability v8.68 NFIB Achchuthan Shanmugasundram Mode of inheritance for gene: NFIB was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v8.67 NFIB Achchuthan Shanmugasundram reviewed gene: NFIB: Rating: AMBER; Mode of pathogenicity: None; Publications: 39567597; Phenotypes: Macrocephaly, acquired, with impaired intellectual development, OMIM:618286; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v8.67 GPATCH11 Achchuthan Shanmugasundram Phenotypes for gene: GPATCH11 were changed from neuronevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071 to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Intellectual disability v8.66 GPATCH11 Achchuthan Shanmugasundram edited their review of gene: GPATCH11: Changed phenotypes to: neurodevelopmental disorder, MONDO:0700092, intellectual disability, MONDO:0001071
Intellectual disability v8.66 GPATCH11 Achchuthan Shanmugasundram Classified gene: GPATCH11 as Amber List (moderate evidence)
Intellectual disability v8.66 GPATCH11 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the promotion of this gene to green rating in the next GMS update.
Intellectual disability v8.66 GPATCH11 Achchuthan Shanmugasundram Gene: gpatch11 has been classified as Amber List (Moderate Evidence).
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 v8.65 GPATCH11 Achchuthan Shanmugasundram Publications for gene: GPATCH11 were set to 39572588
Intellectual disability v8.64 GPATCH11 Achchuthan Shanmugasundram Tag Q1_25_ promote_green tag was added to gene: GPATCH11.
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 Classified gene: ITGAV as Amber List (moderate evidence)
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 v8.63 ITGAV Achchuthan Shanmugasundram Gene: itgav has been classified as Amber List (Moderate 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 v8.62 ITGAV Achchuthan Shanmugasundram Publications for gene: ITGAV were set to 39526957
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 v8.60 NAA20 Achchuthan Shanmugasundram Classified gene: NAA20 as Amber List (moderate evidence)
Intellectual disability v8.60 NAA20 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (three unrelated families) for the promotion of this gene to green rating on the next GMS update.
Intellectual disability v8.60 NAA20 Achchuthan Shanmugasundram Gene: naa20 has been classified as Amber List (Moderate Evidence).
Intellectual disability v8.59 NAA20 Achchuthan Shanmugasundram Phenotypes for gene: NAA20 were changed from autosomal recessive developmental delay, intellectual disability, and microcephaly to Intellectual developmental disorder, autosomal recessive 73, OMIM:619717
Intellectual disability v8.58 NAA20 Achchuthan Shanmugasundram Tag Q1_25_ promote_green tag was added to gene: NAA20.
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 v8.58 NAA20 Achchuthan Shanmugasundram Publications for gene: NAA20 were set to 34230638
Intellectual disability v8.57 NAA20 Achchuthan Shanmugasundram reviewed gene: NAA20: Rating: GREEN; Mode of pathogenicity: None; Publications: 37191084, 39814713; Phenotypes: Intellectual developmental disorder, autosomal recessive 73, OMIM:619717; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
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 v8.57 EEFSEC Achchuthan Shanmugasundram Classified gene: EEFSEC as Amber List (moderate evidence)
Intellectual disability v8.57 EEFSEC Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (eight unrelated families) for the promotion of this gene to green rating in the next GMS update.
Intellectual disability v8.57 EEFSEC Achchuthan Shanmugasundram Gene: eefsec has been classified as Amber List (Moderate Evidence).
Intellectual disability v8.56 EEFSEC Achchuthan Shanmugasundram Tag Q1_25_ promote_green tag was added to gene: EEFSEC.
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 v8.56 EEFSEC Achchuthan Shanmugasundram Publications for gene: EEFSEC were set to 39753114
Intellectual disability v8.55 EEFSEC Achchuthan Shanmugasundram Phenotypes for gene: EEFSEC were changed from neuroseselopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071 to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Intellectual disability v8.54 EEFSEC Achchuthan Shanmugasundram edited their review of gene: EEFSEC: Changed phenotypes to: neurodevelopmental disorder, MONDO:0700092, intellectual disability, MONDO:0001071
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 v8.53 WDR47 Achchuthan Shanmugasundram Phenotypes for gene: WDR47 were changed from neuronevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071 to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Intellectual disability v8.52 WDR47 Achchuthan Shanmugasundram edited their review of gene: WDR47: Changed phenotypes to: neurodevelopmental disorder, MONDO:0700092, intellectual disability, MONDO:0001071
Intellectual disability v8.52 WDR47 Achchuthan Shanmugasundram Deleted their comment
Intellectual disability v8.52 WDR47 Achchuthan Shanmugasundram Classified gene: WDR47 as Amber List (moderate evidence)
Intellectual disability v8.52 WDR47 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (four unrelated families) for the promotion of this gene to green rating on the next GMS update.
Intellectual disability v8.52 WDR47 Achchuthan Shanmugasundram Gene: wdr47 has been classified as Amber List (Moderate Evidence).
Intellectual disability v8.51 WDR47 Achchuthan Shanmugasundram Classified gene: WDR47 as Amber List (moderate evidence)
Intellectual disability v8.51 WDR47 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (four unrelated families) for the promotion of this gene to green rating on the next GMS update.
Intellectual disability v8.51 WDR47 Achchuthan Shanmugasundram Gene: wdr47 has been classified as Amber List (Moderate Evidence).
Intellectual disability v8.50 WDR47 Achchuthan Shanmugasundram Tag Q1_25_ promote_green tag was added to gene: WDR47.
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 v8.50 WDR47 Achchuthan Shanmugasundram Publications for gene: WDR47 were set to 39609633
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 Tag Q1_25_ NHS_review tag was added to gene: TAOK2.
Tag Q1_25_ promote_green tag was added to gene: TAOK2.
Intellectual disability v8.48 TAOK2 Achchuthan Shanmugasundram Classified gene: TAOK2 as Amber List (moderate evidence)
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 v8.48 TAOK2 Achchuthan Shanmugasundram Gene: taok2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v8.47 TAOK2 Achchuthan Shanmugasundram Phenotypes for gene: TAOK2 were changed from Developmental delay; Intellectual disability; Speech and language delay; Autism spectrum disorder to neuronevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Intellectual disability v8.47 TAOK2 Achchuthan Shanmugasundram Publications for gene: TAOK2 were set to PMID: 39737487; 29467497
Intellectual disability v8.46 TAOK2 Achchuthan Shanmugasundram reviewed gene: TAOK2: Rating: GREEN; Mode of pathogenicity: None; Publications: 39737487; Phenotypes: neuronevelopmental disorder, MONDO:0700092, intellectual disability, MONDO:0001071; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v8.46 TAOK1 Achchuthan Shanmugasundram Phenotypes for gene: TAOK1 were changed from INTELLECTUAL DISABILITY; developmental delay to Developmental delay with or without intellectual impairment or behavioral abnormalities, OMIM:619575
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 Tag dd_review tag was added to gene: PABPC1.
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 v8.45 PABPC1 Achchuthan Shanmugasundram Mode of inheritance for gene: PABPC1 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v8.44 PABPC1 Achchuthan Shanmugasundram Tag Q4_24_MOI tag was added to gene: PABPC1.
Intellectual disability v8.44 PABPC1 Achchuthan Shanmugasundram edited their review of gene: PABPC1: Changed phenotypes to: neurodevelopmental disorder, MONDO:0700092, intellectual disability, MONDO:0001071
Intellectual disability v8.44 PABPC1 Achchuthan Shanmugasundram reviewed gene: PABPC1: Rating: GREEN; Mode of pathogenicity: None; Publications: 35511136; Phenotypes: neuronevelopmental disorder, MONDO:0700092, intellectual disability, MONDO:0001071; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v8.44 REEP2 Achchuthan Shanmugasundram Classified gene: REEP2 as Red List (low evidence)
Intellectual disability v8.44 REEP2 Achchuthan Shanmugasundram Gene: reep2 has been classified as Red List (Low Evidence).
Intellectual disability v8.44 REEP2 Achchuthan Shanmugasundram Classified gene: REEP2 as Red List (low evidence)
Intellectual disability v8.44 REEP2 Achchuthan Shanmugasundram Gene: reep2 has been classified as Red List (Low Evidence).
Intellectual disability v8.43 ARHGAP35 Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: ARHGAP35.
Intellectual disability v8.43 WBP4 Achchuthan Shanmugasundram Tag Q4_22_promote_green was removed from gene: WBP4.
Tag Q4_24_promote_green tag was added to gene: WBP4.
Intellectual disability v8.43 WBP4 Sarah Leigh Publications for gene: WBP4 were set to
Intellectual disability v8.42 WBP4 Sarah Leigh Classified gene: WBP4 as Amber List (moderate evidence)
Intellectual disability v8.42 WBP4 Sarah Leigh Gene: wbp4 has been classified as Amber List (Moderate Evidence).
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 v8.40 CRELD1 Arina Puzriakova Publications for gene: CRELD1 were set to 37947183
Intellectual disability v8.39 KCND1 Sarah Leigh Publications for gene: KCND1 were set to
Intellectual disability v8.38 AFF3_GCC Sarah Leigh edited their review of STR: AFF3_GCC: Added comment: The genomic coordinates of the AFF3_GCC repeat expansion is not available. The number of normal and pathogenic repeats have not been established either.; Changed rating: RED
Intellectual disability v8.38 AFF3_GCC Sarah Leigh Phenotypes for STR: AFF3_GCC were changed from to neurodevelopmental disorder unspecified
Intellectual disability v8.37 AFF3_GCC Sarah Leigh Mode of inheritance for STR: AFF3_GCC was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v8.36 ATXN7L3 Achchuthan Shanmugasundram Tag Q3_24_NHS_review was removed from gene: ATXN7L3.
Tag Q3_24_MOI was removed from gene: ATXN7L3.
Intellectual disability v8.36 AFF3_GCC Sarah Leigh Classified STR: AFF3_GCC as Red List (low evidence)
Intellectual disability v8.36 AFF3_GCC Sarah Leigh Added comment: Comment on list classification: This STR is rated as red, because it is not yet NGS validated.
Intellectual disability v8.36 AFF3_GCC Sarah Leigh Str: aff3_gcc has been classified as Red List (Low Evidence).
Intellectual disability v8.35 AFF3_GCC Sarah Leigh Tag STR tag was added to STR: AFF3_GCC.
Tag NGS Not Validated tag was added to STR: AFF3_GCC.
Intellectual disability v8.35 PABPC1 Cassandra Smith reviewed gene: PABPC1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v8.35 RNU4-2 Eleanor Williams Publications for gene: RNU4-2 were set to 38821540; 38645094
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 Classified gene: GNAI2 as Amber List (moderate evidence)
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 v8.34 GNAI2 Arina Puzriakova Gene: gnai2 has been classified as Amber List (Moderate Evidence).
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 v8.31 GNAI2 Arina Puzriakova Publications for gene: GNAI2 were set to 31036916; 27787898
Intellectual disability v8.30 GNAI2 Arina Puzriakova Tag Q3_24_promote_green tag was added to gene: GNAI2.
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 Classified gene: WDR83OS as Amber List (moderate evidence)
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 v8.30 WDR83OS Achchuthan Shanmugasundram Gene: wdr83os has been classified as Amber List (Moderate Evidence).
Intellectual disability v8.29 WDR83OS Achchuthan Shanmugasundram Phenotypes for gene: WDR83OS were changed from Intellectual disability to complex neurodevelopmental disorder, MONDO:0100038; intellectual disability, MONDO:0001071
Intellectual disability v8.29 WDR83OS Achchuthan Shanmugasundram Publications for gene: WDR83OS were set to 30250217
Intellectual disability v8.28 WDR83OS Achchuthan Shanmugasundram Tag Q3_24_promote_green tag was added to gene: WDR83OS.
Intellectual disability v8.28 WDR83OS Achchuthan Shanmugasundram reviewed gene: WDR83OS: Rating: GREEN; Mode of pathogenicity: None; Publications: 30250217, 39471804; Phenotypes: complex neurodevelopmental disorder, MONDO:0100038, intellectual disability, MONDO:0001071; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
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 Added comment: Comment on phenotypes: This gene has not yet been associated with relevant phenotypes either in OMIM or in Gene2Phenotype.
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 v8.25 SLC4A10 Arina Puzriakova Tag Q3_24_promote_green tag was added to gene: SLC4A10.
Intellectual disability v8.25 SLC4A10 Arina Puzriakova Publications for gene: SLC4A10 were set to 37459438; 38054405
Intellectual disability v8.24 SLC4A10 Arina Puzriakova Classified gene: SLC4A10 as Amber List (moderate evidence)
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 v8.24 SLC4A10 Arina Puzriakova Gene: slc4a10 has been classified as Amber List (Moderate Evidence).
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 v8.22 AFF3_GCC Sarah Leigh Tag NGS Not Validated was removed from STR: AFF3_GCC.
Intellectual disability v8.22 AFF3_GCC Sarah Leigh Tag NGS Not Validated tag was added to STR: AFF3_GCC.
Intellectual disability v8.22 AFF3_GCC Arina Puzriakova Gene was set to AFF3.
Intellectual disability v8.21 AFF3_GCC Arina Puzriakova AFF3 was changed to AFF3_GCC
Source Literature was removed from STR: AFF3_GCC.
Source Expert Review was added to STR: AFF3_GCC.
Publications for STR: AFF3_GCC were updated from PMID: 39313615 to 39313615
Intellectual disability v8.20 LINC01578 Sarah Leigh Tag new-gene-name tag was added to gene: LINC01578.
Tag Q3_24_promote_green tag was added to gene: LINC01578.
Tag Q3_24_NHS_review tag was added to gene: LINC01578.
Intellectual disability v8.20 LINC01578 Sarah Leigh reviewed gene: LINC01578: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v8.20 LINC01578 Sarah Leigh Classified gene: LINC01578 as Amber List (moderate evidence)
Intellectual disability v8.20 LINC01578 Sarah Leigh Gene: linc01578 has been classified as Amber List (Moderate Evidence).
Intellectual disability v8.19 AFF3 Riyaad Aungraheeta reviewed STR: AFF3: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 39313615; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v8.19 AFF3 Riyaad Aungraheeta Deleted their review
Intellectual disability v8.19 AFF3 Riyaad Aungraheeta STR: AFF3 was added
STR: AFF3 was added to Intellectual disability. Sources: Literature
Mode of inheritance for STR: AFF3 was set to Unknown
Publications for STR: AFF3 were set to PMID: 39313615
Penetrance for STR: AFF3 were set to Incomplete
Review for STR: AFF3 was set to GREEN
Added comment: Sources: Literature
Intellectual disability v8.19 MIR17HG Arina Puzriakova Classified gene: MIR17HG as Amber List (moderate evidence)
Intellectual disability v8.19 MIR17HG Arina Puzriakova Gene: mir17hg has been classified as Amber List (Moderate Evidence).
Intellectual disability v8.19 MIR17HG Arina Puzriakova Classified gene: MIR17HG as Amber List (moderate evidence)
Intellectual disability v8.19 MIR17HG Arina Puzriakova Gene: mir17hg has been classified as Amber List (Moderate Evidence).
Intellectual disability v8.18 MIR17HG Arina Puzriakova Source Expert Review was added to MIR17HG.
Rating Changed from No List (delete) to Red List (low evidence)
Intellectual disability v8.17 MIR17HG Arina Puzriakova All sources for gene: MIR17HG were removed
Intellectual disability v8.17 MIR17HG Arina Puzriakova All sources for gene: MIR17HG were removed
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 v8.16 WDR83OS Zornitza Stark reviewed gene: WDR83OS: Rating: GREEN; Mode of pathogenicity: None; Publications: 39471804; Phenotypes: complex neurodevelopmental disorder MONDO:0100038; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v8.16 CCDC88A Arina Puzriakova Publications for gene: CCDC88A were set to 26917597
Intellectual disability v8.15 CCDC88A Arina Puzriakova Phenotypes for gene: CCDC88A were changed from PEHO syndrome to PEHO syndrome-like, OMIM:617507
Intellectual disability v8.14 CCDC88A Arina Puzriakova Classified gene: CCDC88A as Amber List (moderate evidence)
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 v8.14 CCDC88A Arina Puzriakova Gene: ccdc88a has been classified as Amber List (Moderate Evidence).
Intellectual disability v8.13 CCDC88A Arina Puzriakova Tag Q3_24_promote_green tag was added to gene: CCDC88A.
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 Deleted their comment
Intellectual disability v8.13 PI4K2A Achchuthan Shanmugasundram Classified gene: PI4K2A as Amber List (moderate evidence)
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 Gene: pi4k2a has been classified as Amber List (Moderate Evidence).
Intellectual disability v8.13 PI4K2A Achchuthan Shanmugasundram Classified gene: PI4K2A as Amber List (moderate evidence)
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 Gene: pi4k2a has been classified as Amber List (Moderate Evidence).
Intellectual disability v8.12 PI4K2A Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotype in OMIM (MIM #620732), but not yet in Gene2Phenotype.
Intellectual disability v8.12 PI4K2A Achchuthan Shanmugasundram Phenotypes for gene: PI4K2A were changed from Neurodevelopmental disorder with hyperkinetic movements, seizures and structural brain abnormalities, OMIM:620732 to Neurodevelopmental disorder with hyperkinetic movements, seizures and structural brain abnormalities, OMIM:620732
Intellectual disability v8.11 PI4K2A Achchuthan Shanmugasundram Phenotypes for gene: PI4K2A were changed from Neurodevelopmental disorder with hyperkinetic movements, seizures and structural brain abnormalities, OMIM:620732 to Neurodevelopmental disorder with hyperkinetic movements, seizures and structural brain abnormalities, OMIM:620732
Intellectual disability v8.11 PI4K2A Achchuthan Shanmugasundram Phenotypes for gene: PI4K2A were changed from Neurodevelopmental disorder with hyperkinetic movements, seizures and structural brain abnormalities, OMIM:620732 to Neurodevelopmental disorder with hyperkinetic movements, seizures and structural brain abnormalities, OMIM:620732
Intellectual disability v8.10 PI4K2A Achchuthan Shanmugasundram Phenotypes for gene: PI4K2A were changed from Intellectual disability; developmental delay; seizures to Neurodevelopmental disorder with hyperkinetic movements, seizures and structural brain abnormalities, OMIM:620732
Intellectual disability v8.10 PI4K2A Achchuthan Shanmugasundram Publications for gene: PI4K2A were set to 30564627; 32418222'
Intellectual disability v8.10 PI4K2A Achchuthan Shanmugasundram Publications for gene: PI4K2A were set to 30564627; 35880319; 32418222
Intellectual disability v8.9 PI4K2A Achchuthan Shanmugasundram Tag Q3_24_promote_green tag was added to gene: PI4K2A.
Tag Q3_24_NHS_review tag was added to gene: PI4K2A.
Intellectual disability v8.9 PI4K2A Achchuthan Shanmugasundram reviewed gene: PI4K2A: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with hyperkinetic movements, seizures and structural brain abnormalities, OMIM:620732; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
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 v8.8 KIF5B Achchuthan Shanmugasundram changed review comment from: Comment on list classification: Although ID was reported in four of seven cases, all these patients display complex syndromic disease with broad spectrum of phenotypes and the severity of ID was mild in one and not reported in two others. This gene has been added with green rating on the DDG2P panel and hence will be included in the paediatric disorders super panel.

Hence, this gene should be rated amber with current evidence. The 'watchlist' tag has been added to keep track new evidence.; to: Comment on list classification: Although ID was reported in four of seven cases, all these patients display complex syndromic disease with broad spectrum of phenotypes and the severity of ID was mild in one and not reported in two others. This gene has been added with green rating on the DDG2P panel and hence will be included in the paediatric disorders super panel.

Hence, this gene should be rated amber with current evidence. The 'watchlist' tag has been added to keep track of new evidence.
Intellectual disability v8.8 KIF5B Achchuthan Shanmugasundram Deleted their comment
Intellectual disability v8.8 KIF5B Achchuthan Shanmugasundram Classified gene: KIF5B as Amber List (moderate evidence)
Intellectual disability v8.8 KIF5B Achchuthan Shanmugasundram Added comment: Comment on list classification: Although ID was reported in four of seven cases, all these patients display complex syndromic disease with broad spectrum of phenotypes and the severity of ID was mild in one and not reported in two others. This gene has been added with green rating on the DDG2P panel and hence will be included in the paediatric disorders super panel.

Hence, this gene should be rated amber with current evidence. The 'watchlist' tag has been added to keep track new evidence.
Intellectual disability v8.8 KIF5B Achchuthan Shanmugasundram Gene: kif5b has been classified as Amber List (Moderate Evidence).
Intellectual disability v8.8 KIF5B Achchuthan Shanmugasundram Classified gene: KIF5B as Amber List (moderate evidence)
Intellectual disability v8.8 KIF5B Achchuthan Shanmugasundram Added comment: Comment on list classification: Although ID was reported in four of seven cases, all these patients display complex syndromic disease with broad spectrum of phenotypes and the severity of ID was mild in one and not reported in two others. This gene has been added with green rating on the DDG2P panel and hence will be included in the paediatric disorders super panel.

Hence, this gene should be rated amber with current evidence. The 'watchlist' tag has been added to keep track new evidence.
Intellectual disability v8.8 KIF5B Achchuthan Shanmugasundram Gene: kif5b has been classified as Amber List (Moderate Evidence).
Intellectual disability v8.7 KIF5B Achchuthan Shanmugasundram Tag watchlist tag was added to gene: KIF5B.
Intellectual disability v8.7 KIF5B Achchuthan Shanmugasundram Phenotypes for gene: KIF5B were changed from kyphomelic dysplasia; hypotonia; developmental delay; intellectual disability to kyphomelic dysplasia, MONDO:0008881; intellectual disability, MONDO:0001071
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 KIF5B Achchuthan Shanmugasundram reviewed gene: KIF5B: Rating: AMBER; Mode of pathogenicity: None; Publications: 35342932, 36018820; Phenotypes: kyphomelic dysplasia, MONDO:0008881, intellectual disability, MONDO:0001071; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
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 v8.6 PLA2G16 Eleanor Williams Tag Q3_24_promote_green was removed from gene: PLA2G16.
Tag Q3_24_NHS_review was removed from gene: PLA2G16.
Intellectual disability v8.6 PLA2G16 Eleanor Williams Classified gene: PLA2G16 as Amber List (moderate evidence)
Intellectual disability v8.6 PLA2G16 Eleanor Williams Added comment: Comment on list classification: Rating as amber. 3 cases with intellectual disability but the severity is not noted.
Intellectual disability v8.6 PLA2G16 Eleanor Williams Gene: pla2g16 has been classified as Amber List (Moderate Evidence).
Intellectual disability v8.5 PLA2G16 Eleanor Williams Deleted their comment
Intellectual disability v8.5 PLA2G16 Eleanor Williams Deleted their comment
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 v8.4 NOP56 Arina Puzriakova Mode of inheritance for gene: NOP56 was changed from Other to Other
Intellectual disability v8.3 Arina Puzriakova Panel version 8.0 has been signed off on 2024-10-30
Intellectual disability v8.2 Sarah Leigh Panel signed off version 8.0 has been removed
Intellectual disability v8.1 Sarah Leigh Panel version 8.0 has been signed off on 2024-10-30
Intellectual disability v8.0 Sarah Leigh promoted panel to version 8.0
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 v7.66 BORCS8 Arina Puzriakova Phenotypes for gene: BORCS8 were changed from neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071 to Neurodegeneration, infantile-onset, with optic atrophy and brain abnormalities, OMIM:620987
Intellectual disability v7.65 BORCS8 Arina Puzriakova Tag gene-checked was removed from gene: BORCS8.
Intellectual disability v7.65 CENPJ Arina Puzriakova Tag new-gene-name tag was added to gene: CENPJ.
Intellectual disability v7.65 CENPJ Arina Puzriakova commented on gene: CENPJ
Intellectual disability v7.65 CCDC103 Arina Puzriakova Tag new-gene-name tag was added to gene: CCDC103.
Intellectual disability v7.65 CCDC103 Arina Puzriakova commented on gene: CCDC103: Added new-gene-name tag, new approved HGNC gene symbol for CCDC103 is DNAAF19.
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 Tag Q3_24_NHS_review was removed from gene: TRMT5.
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 v7.63 DDX17 Achchuthan Shanmugasundram Classified gene: DDX17 as Amber List (moderate evidence)
Intellectual disability v7.63 DDX17 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the association of this gene with green rating in the next GMS update.
Intellectual disability v7.63 DDX17 Achchuthan Shanmugasundram Gene: ddx17 has been classified as Amber List (Moderate Evidence).
Intellectual disability v7.62 DDX17 Achchuthan Shanmugasundram Phenotypes for gene: DDX17 were changed from Intellectual disability; delayed speech and language; motor delay to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Intellectual disability v7.62 DDX17 Achchuthan Shanmugasundram Publications for gene: DDX17 were set to PMID: 39405200
Intellectual disability v7.61 DDX17 Achchuthan Shanmugasundram Tag Q3_24_promote_green tag was added to gene: DDX17.
Tag Q3_24_NHS_review tag was added to gene: DDX17.
Intellectual disability v7.61 DDX17 Achchuthan Shanmugasundram reviewed gene: DDX17: Rating: GREEN; Mode of pathogenicity: None; Publications: 39405200; Phenotypes: neurodevelopmental disorder, MONDO:0700092, intellectual disability, MONDO:0001071; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
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 v7.61 DHRSX Achchuthan Shanmugasundram Phenotypes for gene: DHRSX were changed from to congenital disorder of glycosylation, MONDO:0015286; intellectual disability, MONDO:0001071
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 v7.60 DHRSX Achchuthan Shanmugasundram Classified gene: DHRSX as Amber List (moderate evidence)
Intellectual disability v7.60 DHRSX Achchuthan Shanmugasundram Added comment: 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.
Intellectual disability v7.60 DHRSX Achchuthan Shanmugasundram Gene: dhrsx has been classified as Amber List (Moderate Evidence).
Intellectual disability v7.59 DHRSX Achchuthan Shanmugasundram Publications for gene: DHRSX were set to
Intellectual disability v7.58 DHRSX Achchuthan Shanmugasundram Mode of inheritance for gene: DHRSX was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v7.58 DHRSX Achchuthan Shanmugasundram Mode of inheritance for gene: DHRSX was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v7.57 DHRSX Achchuthan Shanmugasundram Tag Q3_24_promote_green tag was added to gene: DHRSX.
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 v7.57 DHRSX Achchuthan Shanmugasundram reviewed gene: DHRSX: Rating: GREEN; Mode of pathogenicity: None; Publications: 38821050; Phenotypes: congenital disorder of glycosylation, MONDO:0015286, intellectual disability, MONDO:0001071; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v7.57 XYLT1 Sarah Leigh Phenotypes for gene: XYLT1 were changed from Desbuquois dysplasia 2, 615777 to Desbuquois dysplasia 2, OMIM:615777; Desbuquois dysplasia 2, MONDO:0014343
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 v7.56 XYLT1 Sarah Leigh Publications for gene: XYLT1 were set to 24581741; 22711505; 23982343
Intellectual disability v7.55 XYLT1 Sarah Leigh Tag STR tag was added to gene: XYLT1.
Intellectual disability v7.55 FOSL2 Achchuthan Shanmugasundram Classified gene: FOSL2 as Amber List (moderate evidence)
Intellectual disability v7.55 FOSL2 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Dmitrijs Rots, there is sufficient evidence available for the association of this gene with green rating in the next GMS update.
Intellectual disability v7.55 FOSL2 Achchuthan Shanmugasundram Gene: fosl2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v7.54 FOSL2 Achchuthan Shanmugasundram Publications for gene: FOSL2 were set to PMID: 36197437
Intellectual disability v7.54 FOSL2 Achchuthan Shanmugasundram Phenotypes for gene: FOSL2 were changed from Aplasia cutis-enamel dysplasia syndrome, OMIM:620789 to Aplasia cutis-enamel dysplasia syndrome, OMIM:620789
Intellectual disability v7.54 FOSL2 Achchuthan Shanmugasundram Phenotypes for gene: FOSL2 were changed from Aplasia cutis-enamel dysplasia syndrome to Aplasia cutis-enamel dysplasia syndrome, OMIM:620789
Intellectual disability v7.53 FOSL2 Achchuthan Shanmugasundram Tag Q3_24_promote_green tag was added to gene: FOSL2.
Intellectual disability v7.53 FOSL2 Achchuthan Shanmugasundram reviewed gene: FOSL2: Rating: GREEN; Mode of pathogenicity: None; Publications: 36197437; Phenotypes: Aplasia cutis-enamel dysplasia syndrome, OMIM:620789; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
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 v7.53 LRRC7 Achchuthan Shanmugasundram Classified gene: LRRC7 as Amber List (moderate evidence)
Intellectual disability v7.53 LRRC7 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Andrew Mumford, there is sufficient evidence available for the association of this gene with green rating in the next GMS update.
Intellectual disability v7.53 LRRC7 Achchuthan Shanmugasundram Gene: lrrc7 has been classified as Amber List (Moderate Evidence).
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 v7.52 LRRC7 Achchuthan Shanmugasundram Publications for gene: LRRC7 were set to (PMID: 36928819):(PMID: 39256359)
Intellectual disability v7.51 LRRC7 Achchuthan Shanmugasundram Tag Q3_24_promote_green tag was added to gene: LRRC7.
Tag Q3_24_NHS_review tag was added to gene: LRRC7.
Intellectual disability v7.51 LRRC7 Achchuthan Shanmugasundram reviewed gene: LRRC7: Rating: GREEN; Mode of pathogenicity: None; Publications: 39256359; Phenotypes: neurodevelopmental disorder, MONDO:0700092, intellectual disability, MONDO:0001071; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v7.51 ZBTB11 Arina Puzriakova Tag gene-checked tag was added to gene: ZBTB11.
Intellectual disability v7.51 ZBTB11 Arina Puzriakova Phenotypes for gene: ZBTB11 were changed from Intellectual developmental disorder, autosomal recessive 69, 618383; Intellectual disability to Intellectual developmental disorder, autosomal recessive 69, OMIM:618383
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 v7.49 WDR5 Arina Puzriakova Tag gene-checked tag was added to gene: WDR5.
Intellectual disability v7.49 TUBGCP2 Arina Puzriakova Phenotypes for gene: TUBGCP2 were changed from Lissencephaly; pachygyria; subcortical band heterotopia; microcephaly; intellectual disability to Pachygyria, microcephaly, developmental delay, and dysmorphic facies, with or without seizures, OMIM:618737
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 TBC1D8B Arina Puzriakova Tag gene-checked tag was added to gene: TBC1D8B.
Intellectual disability v7.46 STX1A Arina Puzriakova Tag gene-checked tag was added to gene: STX1A.
Intellectual disability v7.46 ITSN1 Achchuthan Shanmugasundram Deleted their comment
Intellectual disability v7.46 ITSN1 Achchuthan Shanmugasundram Deleted their comment
Intellectual disability v7.46 ITSN1 Achchuthan Shanmugasundram Deleted their comment
Intellectual disability v7.46 ITSN1 Achchuthan Shanmugasundram Deleted their comment
Intellectual disability v7.46 SEPHS1 Arina Puzriakova Tag gene-checked tag was added to gene: SEPHS1.
Intellectual disability v7.46 RNU4-2 Arina Puzriakova Tag gene-checked tag was added to gene: RNU4-2.
Intellectual disability v7.46 RBSN Arina Puzriakova Tag gene-checked was removed from gene: RBSN.
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 v7.45 PLXNB2 Arina Puzriakova Tag gene-checked tag was added to gene: PLXNB2.
Intellectual disability v7.45 MMGT1 Arina Puzriakova Mode of inheritance for gene: MMGT1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability v7.44 METTL5 Arina Puzriakova Phenotypes for gene: METTL5 were changed from Intellectual developmental disorder, autosomal recessive 72, 618665 to Intellectual developmental disorder, autosomal recessive 72, OMIM:618665
Intellectual disability v7.43 KIRREL3 Arina Puzriakova Tag gene-checked tag was added to gene: KIRREL3.
Intellectual disability v7.43 KCNB2 Arina Puzriakova Tag gene-checked tag was added to gene: KCNB2.
Intellectual disability v7.43 KCNA3 Arina Puzriakova Tag gene-checked tag was added to gene: KCNA3.
Intellectual disability v7.43 ITSN1 Arina Puzriakova Tag gene-checked tag was added to gene: ITSN1.
Intellectual disability v7.43 GTF3C5 Arina Puzriakova Tag gene-checked tag was added to gene: GTF3C5.
Intellectual disability v7.43 FEM1B Arina Puzriakova Tag gene-checked tag was added to gene: FEM1B.
Intellectual disability v7.43 FAM177A1 Arina Puzriakova Tag gene-checked tag was added to gene: FAM177A1.
Intellectual disability v7.43 EZH1 Arina Puzriakova Tag gene-checked tag was added to gene: EZH1.
Intellectual disability v7.43 DOCK4 Arina Puzriakova Tag gene-checked tag was added to gene: DOCK4.
Intellectual disability v7.43 DENND5B Arina Puzriakova Tag gene-checked tag was added to gene: DENND5B.
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 v7.42 CLEC16A Arina Puzriakova Tag gene-checked tag was added to gene: CLEC16A.
Intellectual disability v7.42 CCDC47 Arina Puzriakova Phenotypes for gene: CCDC47 were changed from Woolly hair; Abnormality of the liver; Global developmental delay; Intellectual disability; Trichohepatoneurodevelopmental syndrome, 618268 to Trichohepatoneurodevelopmental syndrome, OMIM:618268
Intellectual disability v7.41 CAMK2D Arina Puzriakova Tag gene-checked tag was added to gene: CAMK2D.
Intellectual disability v7.41 BORCS8 Arina Puzriakova Tag gene-checked tag was added to gene: BORCS8.
Intellectual disability v7.41 BAZ2B Arina Puzriakova Tag gene-checked tag was added to gene: BAZ2B.
Intellectual disability v7.41 ANO4 Arina Puzriakova Tag gene-checked tag was added to gene: ANO4.
Intellectual disability v7.41 SOX9 Achchuthan Shanmugasundram Tag Q2_24_demote_amber was removed from gene: SOX9.
Tag Q2_24_NHS_review was removed from gene: SOX9.
Intellectual disability v7.41 GLI3 Achchuthan Shanmugasundram Tag Q2_24_demote_amber was removed from gene: GLI3.
Tag Q2_24_NHS_review was removed from gene: GLI3.
Intellectual disability v7.41 WDR5 Achchuthan Shanmugasundram Tag Q2_24_promote_green was removed from gene: WDR5.
Intellectual disability v7.41 TBC1D2B Achchuthan Shanmugasundram Tag Q2_24_promote_green was removed from gene: TBC1D2B.
Tag Q2_24_NHS_review was removed from gene: TBC1D2B.
Intellectual disability v7.41 STX1A Achchuthan Shanmugasundram Tag Q2_24_promote_green was removed from gene: STX1A.
Intellectual disability v7.41 SEPHS1 Achchuthan Shanmugasundram Tag Q2_24_promote_green was removed from gene: SEPHS1.
Intellectual disability v7.41 RNU4-2 Achchuthan Shanmugasundram Tag Q2_24_promote_green was removed from gene: RNU4-2.
Intellectual disability v7.41 PLXNB2 Achchuthan Shanmugasundram Tag Q2_24_promote_green was removed from gene: PLXNB2.
Intellectual disability v7.41 MAST3 Achchuthan Shanmugasundram Tag Q2_24_promote_green was removed from gene: MAST3.
Tag Q2_24_NHS_review was removed from gene: MAST3.
Intellectual disability v7.41 KCNB2 Achchuthan Shanmugasundram Tag Q2_24_promote_green was removed from gene: KCNB2.
Intellectual disability v7.41 ITSN1 Achchuthan Shanmugasundram Tag Q2_24_promote_green was removed from gene: ITSN1.
Tag Q2_24_NHS_review was removed from gene: ITSN1.
Intellectual disability v7.41 GTF3C5 Achchuthan Shanmugasundram Tag Q2_24_promote_green was removed from gene: GTF3C5.
Intellectual disability v7.41 GAN Achchuthan Shanmugasundram Tag Q2_24_promote_green was removed from gene: GAN.
Tag Q2_24_NHS_review was removed from gene: GAN.
Intellectual disability v7.41 FEM1B Achchuthan Shanmugasundram Tag Q2_24_promote_green was removed from gene: FEM1B.
Intellectual disability v7.41 FAM177A1 Achchuthan Shanmugasundram Tag Q2_24_promote_green was removed from gene: FAM177A1.
Intellectual disability v7.41 EZH1 Achchuthan Shanmugasundram Tag Q2_24_promote_green was removed from gene: EZH1.
Intellectual disability v7.41 DOCK4 Achchuthan Shanmugasundram Tag Q2_24_promote_green was removed from gene: DOCK4.
Intellectual disability v7.41 DENND5B Achchuthan Shanmugasundram Tag Q2_24_promote_green was removed from gene: DENND5B.
Tag Q2_24_NHS_review was removed from gene: DENND5B.
Intellectual disability v7.41 CAMK2D Achchuthan Shanmugasundram Tag Q2_24_promote_green was removed from gene: CAMK2D.
Intellectual disability v7.41 ANO4 Achchuthan Shanmugasundram Tag Q2_24_promote_green was removed from gene: ANO4.
Tag Q2_24_MOI was removed from gene: ANO4.
Intellectual disability v7.41 ADGRL1 Achchuthan Shanmugasundram Tag Q2_24_promote_green was removed from gene: ADGRL1.
Intellectual disability v7.41 ZNFX1 Achchuthan Shanmugasundram Tag Q1_24_promote_green was removed from gene: ZNFX1.
Tag Q1_24_NHS_review was removed from gene: ZNFX1.
Intellectual disability v7.41 ZFX Achchuthan Shanmugasundram Tag Q1_24_promote_green was removed from gene: ZFX.
Tag Q1_24_NHS_review was removed from gene: ZFX.
Intellectual disability v7.41 ZFHX3 Achchuthan Shanmugasundram Tag Q1_24_promote_green was removed from gene: ZFHX3.
Tag Q1_24_NHS_review was removed from gene: ZFHX3.
Intellectual disability v7.41 SNF8 Achchuthan Shanmugasundram Tag Q1_24_promote_green was removed from gene: SNF8.
Intellectual disability v7.41 LGI3 Achchuthan Shanmugasundram Tag Q1_24_promote_green was removed from gene: LGI3.
Intellectual disability v7.41 KIRREL3 Achchuthan Shanmugasundram Tag Q1_24_promote_green was removed from gene: KIRREL3.
Intellectual disability v7.41 KCNA3 Achchuthan Shanmugasundram Tag Q1_24_promote_green was removed from gene: KCNA3.
Tag Q1_24_NHS_review was removed from gene: KCNA3.
Intellectual disability v7.41 HSD17B10 Achchuthan Shanmugasundram Tag Q1_24_MOI was removed from gene: HSD17B10.
Intellectual disability v7.41 DHX37 Achchuthan Shanmugasundram Tag Q1_24_MOI was removed from gene: DHX37.
Tag Q1_24_NHS_review was removed from gene: DHX37.
Intellectual disability v7.41 CLEC16A Achchuthan Shanmugasundram Tag Q1_24_promote_green was removed from gene: CLEC16A.
Intellectual disability v7.41 CAMSAP1 Achchuthan Shanmugasundram Tag Q1_24_promote_green was removed from gene: CAMSAP1.
Intellectual disability v7.41 BAZ2B Achchuthan Shanmugasundram Tag Q1_24_promote_green was removed from gene: BAZ2B.
Intellectual disability v7.41 ACBD6 Achchuthan Shanmugasundram Tag Q1_24_promote_green was removed from gene: ACBD6.
Intellectual disability v7.41 ABCC9 Achchuthan Shanmugasundram Tag Q1_24_MOI was removed from gene: ABCC9.
Tag Q1_24_NHS_review was removed from gene: ABCC9.
Intellectual disability v7.41 ZNFX1 Achchuthan Shanmugasundram reviewed gene: ZNFX1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v7.41 ZFX Achchuthan Shanmugasundram edited their review of gene: ZFX: Added comment: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.; Changed rating: GREEN; 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 v7.41 ZFHX3 Achchuthan Shanmugasundram reviewed gene: ZFHX3: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v7.41 WDR5 Achchuthan Shanmugasundram commented on gene: WDR5: The rating of this gene has been updated to green and the mode of inheritance set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted following NHS Genomic Medicine Service approval.
Intellectual disability v7.41 TBC1D2B Achchuthan Shanmugasundram reviewed gene: TBC1D2B: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v7.41 STX1A Achchuthan Shanmugasundram commented on gene: STX1A: The rating of this gene has been updated to green and the mode of inheritance set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted following NHS Genomic Medicine Service approval.
Intellectual disability v7.41 SOX9 Achchuthan Shanmugasundram reviewed gene: SOX9: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Intellectual disability v7.41 SNF8 Achchuthan Shanmugasundram commented on gene: SNF8: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.
Intellectual disability v7.41 SEPHS1 Achchuthan Shanmugasundram reviewed gene: SEPHS1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v7.41 RNU4-2 Achchuthan Shanmugasundram reviewed gene: RNU4-2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v7.41 PLXNB2 Achchuthan Shanmugasundram commented on gene: PLXNB2: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.
Intellectual disability v7.41 MAST3 Achchuthan Shanmugasundram reviewed gene: MAST3: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v7.41 LGI3 Achchuthan Shanmugasundram commented on gene: LGI3: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.
Intellectual disability v7.41 KIRREL3 Achchuthan Shanmugasundram reviewed gene: KIRREL3: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v7.41 KCNB2 Achchuthan Shanmugasundram commented on gene: KCNB2: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.
Intellectual disability v7.41 KCNA3 Achchuthan Shanmugasundram commented on gene: KCNA3: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.
Intellectual disability v7.41 ITSN1 Achchuthan Shanmugasundram commented on gene: ITSN1: The rating of this gene has been updated to green and the mode of inheritance set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown following NHS Genomic Medicine Service approval.
Intellectual disability v7.41 HSD17B10 Achchuthan Shanmugasundram reviewed gene: HSD17B10: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Intellectual disability v7.41 GTF3C5 Achchuthan Shanmugasundram commented on gene: GTF3C5: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.
Intellectual disability v7.41 GLI3 Achchuthan Shanmugasundram reviewed gene: GLI3: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Intellectual disability v7.41 GAN Achchuthan Shanmugasundram reviewed gene: GAN: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v7.41 FEM1B Achchuthan Shanmugasundram commented on gene: FEM1B: The rating of this gene has been updated to green and the mode of inheritance updated to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted following NHS Genomic Medicine Service approval.
Intellectual disability v7.41 FAM177A1 Achchuthan Shanmugasundram commented on gene: FAM177A1: The rating of this gene has been updated to green and the mode of inheritance set to BIALLELIC, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.
Intellectual disability v7.41 EZH1 Achchuthan Shanmugasundram commented on gene: EZH1: The rating of this gene has been updated to green and the mode of inheritance set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.
Intellectual disability v7.41 DOCK4 Achchuthan Shanmugasundram commented on gene: DOCK4: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.
Intellectual disability v7.41 DHX37 Achchuthan Shanmugasundram reviewed gene: DHX37: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v7.41 DENND5B Achchuthan Shanmugasundram reviewed gene: DENND5B: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v7.41 CLEC16A Achchuthan Shanmugasundram reviewed gene: CLEC16A: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v7.41 CAMSAP1 Achchuthan Shanmugasundram commented on gene: CAMSAP1: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.
Intellectual disability v7.41 CAMK2D Achchuthan Shanmugasundram commented on gene: CAMK2D: The rating of this gene has been updated to green and the mode of inheritance set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted following NHS Genomic Medicine Service approval.
Intellectual disability v7.41 BAZ2B Achchuthan Shanmugasundram commented on gene: BAZ2B: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.
Intellectual disability v7.41 ANO4 Achchuthan Shanmugasundram reviewed gene: ANO4: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v7.41 ADGRL1 Achchuthan Shanmugasundram commented on gene: ADGRL1: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.
Intellectual disability v7.41 ACBD6 Achchuthan Shanmugasundram reviewed gene: ACBD6: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v7.41 ABCC9 Achchuthan Shanmugasundram reviewed gene: ABCC9: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v7.40 ZNFX1 Achchuthan Shanmugasundram Source NHS GMS was added to ZNFX1.
Source Expert Review Green was added to ZNFX1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v7.40 ZFX Achchuthan Shanmugasundram Source NHS GMS was added to ZFX.
Source Expert Review Green was added to ZFX.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v7.40 ZFHX3 Achchuthan Shanmugasundram Source NHS GMS was added to ZFHX3.
Source Expert Review Green was added to ZFHX3.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v7.40 WDR5 Achchuthan Shanmugasundram Source NHS GMS was added to WDR5.
Source Expert Review Green was added to WDR5.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v7.40 TBC1D2B Achchuthan Shanmugasundram Source NHS GMS was added to TBC1D2B.
Source Expert Review Green was added to TBC1D2B.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v7.40 STX1A Achchuthan Shanmugasundram Source NHS GMS was added to STX1A.
Source Expert Review Green was added to STX1A.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v7.40 SOX9 Achchuthan Shanmugasundram Source Expert Review Amber was added to SOX9.
Source NHS GMS was added to SOX9.
Rating Changed from Green List (high evidence) to Amber List (moderate evidence)
Intellectual disability v7.40 SNF8 Achchuthan Shanmugasundram Source NHS GMS was added to SNF8.
Source Expert Review Green was added to SNF8.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v7.40 SEPHS1 Achchuthan Shanmugasundram Source NHS GMS was added to SEPHS1.
Source Expert Review Green was added to SEPHS1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v7.40 RNU4-2 Achchuthan Shanmugasundram Source NHS GMS was added to RNU4-2.
Source Expert Review Green was added to RNU4-2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v7.40 PLXNB2 Achchuthan Shanmugasundram Source NHS GMS was added to PLXNB2.
Source Expert Review Green was added to PLXNB2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v7.40 MAST3 Achchuthan Shanmugasundram Source NHS GMS was added to MAST3.
Source Expert Review Green was added to MAST3.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v7.40 LGI3 Achchuthan Shanmugasundram Source NHS GMS was added to LGI3.
Source Expert Review Green was added to LGI3.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v7.40 KIRREL3 Achchuthan Shanmugasundram Source NHS GMS was added to KIRREL3.
Source Expert Review Green was added to KIRREL3.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v7.40 KCNB2 Achchuthan Shanmugasundram Source NHS GMS was added to KCNB2.
Source Expert Review Green was added to KCNB2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v7.40 KCNA3 Achchuthan Shanmugasundram Source NHS GMS was added to KCNA3.
Source Expert Review Green was added to KCNA3.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v7.40 ITSN1 Achchuthan Shanmugasundram Source NHS GMS was added to ITSN1.
Source Expert Review Green was added to ITSN1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v7.40 HSD17B10 Achchuthan Shanmugasundram Source NHS GMS was added to HSD17B10.
Mode of inheritance for gene HSD17B10 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 v7.40 GTF3C5 Achchuthan Shanmugasundram Source NHS GMS was added to GTF3C5.
Source Expert Review Green was added to GTF3C5.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v7.40 GLI3 Achchuthan Shanmugasundram Source Expert Review Amber was added to GLI3.
Source NHS GMS was added to GLI3.
Rating Changed from Green List (high evidence) to Amber List (moderate evidence)
Intellectual disability v7.40 GAN Achchuthan Shanmugasundram Source NHS GMS was added to GAN.
Source Expert Review Green was added to GAN.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v7.40 FEM1B Achchuthan Shanmugasundram Source NHS GMS was added to FEM1B.
Source Expert Review Green was added to FEM1B.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v7.40 FAM177A1 Achchuthan Shanmugasundram Source NHS GMS was added to FAM177A1.
Source Expert Review Green was added to FAM177A1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v7.40 EZH1 Achchuthan Shanmugasundram Source NHS GMS was added to EZH1.
Source Expert Review Green was added to EZH1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v7.40 DOCK4 Achchuthan Shanmugasundram Source NHS GMS was added to DOCK4.
Source Expert Review Green was added to DOCK4.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v7.40 DHX37 Achchuthan Shanmugasundram Source NHS GMS was added to DHX37.
Mode of inheritance for gene DHX37 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v7.40 DENND5B Achchuthan Shanmugasundram Source NHS GMS was added to DENND5B.
Source Expert Review Green was added to DENND5B.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v7.40 CLEC16A Achchuthan Shanmugasundram Source NHS GMS was added to CLEC16A.
Source Expert Review Green was added to CLEC16A.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v7.40 CAMSAP1 Achchuthan Shanmugasundram Source NHS GMS was added to CAMSAP1.
Source Expert Review Green was added to CAMSAP1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v7.40 CAMK2D Achchuthan Shanmugasundram Source NHS GMS was added to CAMK2D.
Source Expert Review Green was added to CAMK2D.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v7.40 BAZ2B Achchuthan Shanmugasundram Source NHS GMS was added to BAZ2B.
Source Expert Review Green was added to BAZ2B.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v7.40 ANO4 Achchuthan Shanmugasundram Source NHS GMS was added to ANO4.
Source Expert Review Green was added to ANO4.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v7.40 ADGRL1 Achchuthan Shanmugasundram Source NHS GMS was added to ADGRL1.
Source Expert Review Green was added to ADGRL1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v7.40 ACBD6 Achchuthan Shanmugasundram Source NHS GMS was added to ACBD6.
Source Expert Review Green was added to ACBD6.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v7.40 ABCC9 Achchuthan Shanmugasundram Source NHS GMS was added to ABCC9.
Mode of inheritance for gene ABCC9 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BIALLELIC, autosomal or pseudoautosomal
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 v7.39 CRELD1 Achchuthan Shanmugasundram Classified gene: CRELD1 as Amber List (moderate evidence)
Intellectual disability v7.39 CRELD1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (>10 unrelated cases) for the promotion of this gene to green rating in the next GMS update.
Intellectual disability v7.39 CRELD1 Achchuthan Shanmugasundram Gene: creld1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v7.38 CRELD1 Achchuthan Shanmugasundram Phenotypes for gene: CRELD1 were changed from Jeffries-Lakhani neurodevelopmental syndrome, OMIM:620771 to Jeffries-Lakhani neurodevelopmental syndrome, OMIM:620771
Intellectual disability v7.38 CRELD1 Achchuthan Shanmugasundram Phenotypes for gene: CRELD1 were changed from Jeffries-Lakhani neurodevelopmental syndrome, OMIM:620771 to Jeffries-Lakhani neurodevelopmental syndrome, OMIM:620771
Intellectual disability v7.38 CRELD1 Achchuthan Shanmugasundram Phenotypes for gene: CRELD1 were changed from Jeffries-Lakhani neurodevelopmental syndrome, OMIM:620771 to Jeffries-Lakhani neurodevelopmental syndrome, OMIM:620771
Intellectual disability v7.37 CRELD1 Achchuthan Shanmugasundram Phenotypes for gene: CRELD1 were changed from to Jeffries-Lakhani neurodevelopmental syndrome, OMIM:620771
Intellectual disability v7.37 CRELD1 Achchuthan Shanmugasundram Publications for gene: CRELD1 were set to PMID: 37947183
Intellectual disability v7.36 CRELD1 Achchuthan Shanmugasundram Tag Q3_24_promote_green tag was added to gene: CRELD1.
Intellectual disability v7.36 CRELD1 Achchuthan Shanmugasundram reviewed gene: CRELD1: Rating: GREEN; Mode of pathogenicity: None; Publications: 37947183; Phenotypes: Jeffries-Lakhani neurodevelopmental syndrome, OMIM:620771; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v7.36 PRKACB Achchuthan Shanmugasundram Publications for gene: PRKACB were set to 33058759
Intellectual disability v7.36 PRKACB Achchuthan Shanmugasundram Mode of inheritance for gene: PRKACB was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
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 edited their review of gene: PRKACB: Changed rating: AMBER
Intellectual disability v7.35 PRKACB Achchuthan Shanmugasundram Classified gene: PRKACB as Amber List (moderate evidence)
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 v7.35 PRKACB Achchuthan Shanmugasundram Gene: prkacb has been classified as Amber List (Moderate Evidence).
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 Tag watchlist tag was added to gene: PRKACB.
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 reviewed gene: PRKACB: Rating: GREEN; Mode of pathogenicity: None; Publications: 39095811; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
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 v7.34 PSMC5 Achchuthan Shanmugasundram Classified gene: PSMC5 as Amber List (moderate evidence)
Intellectual disability v7.34 PSMC5 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the promotion of this gene to green rating in the next GMS update.
Intellectual disability v7.34 PSMC5 Achchuthan Shanmugasundram Gene: psmc5 has been classified as Amber List (Moderate Evidence).
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 v7.33 PSMC5 Achchuthan Shanmugasundram Phenotypes for gene: PSMC5 were changed from neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071 to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Intellectual disability v7.33 PSMC5 Achchuthan Shanmugasundram Phenotypes for gene: PSMC5 were changed from neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071 to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Intellectual disability v7.33 PSMC5 Achchuthan Shanmugasundram Phenotypes for gene: PSMC5 were changed from Developmental disorders to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Intellectual disability v7.33 PSMC5 Achchuthan Shanmugasundram Publications for gene: PSMC5 were set to 33057194
Intellectual disability v7.32 PSMC5 Achchuthan Shanmugasundram Tag Q3_24_promote_green tag was added to gene: PSMC5.
Intellectual disability v7.32 PSMC5 Achchuthan Shanmugasundram reviewed gene: PSMC5: Rating: GREEN; Mode of pathogenicity: None; Publications: 38776958; Phenotypes: neurodevelopmental disorder, MONDO:0700092, intellectual disability, MONDO:0001071; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v7.32 BORCS8 Achchuthan Shanmugasundram Classified gene: BORCS8 as Amber List (moderate evidence)
Intellectual disability v7.32 BORCS8 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (3 unrelated families) for the promotion of this gene to green rating in the next GMS update.
Intellectual disability v7.32 BORCS8 Achchuthan Shanmugasundram Gene: borcs8 has been classified as Amber List (Moderate Evidence).
Intellectual disability v7.31 BORCS8 Achchuthan Shanmugasundram Tag Q3_24_promote_green tag was added to gene: BORCS8.
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 Classified gene: ZNRF3 as Amber List (moderate evidence)
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 v7.30 ZNRF3 Achchuthan Shanmugasundram Gene: znrf3 has been classified as Amber List (Moderate Evidence).
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 v7.27 IPO8 Sarah Leigh reviewed gene: IPO8: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v7.27 IPO8 Sarah Leigh Publications for gene: IPO8 were set to 34010604; 34010605
Intellectual disability v7.26 IPO8 Sarah Leigh Phenotypes for gene: IPO8 were changed from Intellectual disability to VISS syndrome, OMIM:619472; VISS syndrome, MONDO:0859177
Intellectual disability v7.25 IPO8 Sarah Leigh Publications for gene: IPO8 were set to PMID 34010604; 34010605
Intellectual disability v7.24 IPO8 Sarah Leigh Classified gene: IPO8 as Amber List (moderate evidence)
Intellectual disability v7.24 IPO8 Sarah Leigh Gene: ipo8 has been classified as Amber List (Moderate Evidence).
Intellectual disability v7.23 CTNND2 Arina Puzriakova Classified gene: CTNND2 as Amber List (moderate evidence)
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 v7.23 CTNND2 Arina Puzriakova Gene: ctnnd2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v7.22 IPO8 Nour Elkhateeb changed review comment from: Intellectual disability is reported in some affected individuals with IPO8-related VISS syndrome (PMID 34010604, 34010605).
Sources: Literature; to: Intellectual disability is reported in some affected individuals with IPO8-related VISS syndrome (PMID 34010604, 34010605).
Sources: Literature
Intellectual disability v7.22 IPO8 Nour Elkhateeb gene: IPO8 was added
gene: IPO8 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: IPO8 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: IPO8 were set to PMID 34010604; 34010605
Phenotypes for gene: IPO8 were set to Intellectual disability
Penetrance for gene: IPO8 were set to unknown
Added comment: Intellectual disability is reported in some affected individuals with IPO8-related VISS syndrome (PMID 34010604, 34010605).
Sources: Literature
Intellectual disability v7.22 DPP6 Sarah Leigh Classified gene: DPP6 as Red List (low evidence)
Intellectual disability v7.22 DPP6 Sarah Leigh Gene: dpp6 has been classified as Red List (Low Evidence).
Intellectual disability v7.21 DPP6 Sarah Leigh Classified gene: DPP6 as Red List (low evidence)
Intellectual disability v7.21 DPP6 Sarah Leigh Gene: dpp6 has been classified as Red List (Low Evidence).
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 edited their review of gene: DPP6: Changed rating: AMBER
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 Tag Q3_24_promote_green was removed from gene: DPP6.
Tag Q3_24_expert_review was removed from gene: DPP6.
Intellectual disability v7.20 DPP6 Sarah Leigh Deleted their comment
Intellectual disability v7.20 DPP6 Sarah Leigh Tag Q3_24_promote_green tag was added to gene: DPP6.
Tag Q3_24_expert_review tag was added to gene: DPP6.
Intellectual disability v7.20 DPP6 Sarah Leigh Classified gene: DPP6 as Amber List (moderate evidence)
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 v7.20 DPP6 Sarah Leigh Gene: dpp6 has been classified as Amber List (Moderate Evidence).
Intellectual disability v7.19 DPP6 Sarah Leigh Publications for gene: DPP6 were set to 23832105
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 Tag watchlist was removed from gene: PLEKHG2.
Tag Q3_24_promote_green tag was added to gene: PLEKHG2.
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 v7.18 PLEKHG2 Sarah Leigh reviewed gene: PLEKHG2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v7.18 PLEKHG2 Sarah Leigh Phenotypes for gene: PLEKHG2 were changed from Leukodystrophy and acquired microcephaly with or without dystonia, 616763 to Leukodystrophy and acquired microcephaly with or without dystonia, OMIM:616763; leukodystrophy and acquired microcephaly with or without dystonia; MONDO:0014766
Intellectual disability v7.17 PLEKHG2 Sarah Leigh Publications for gene: PLEKHG2 were set to 26539891; 24001768; 26573021; 35203342
Intellectual disability v7.16 PLEKHG2 Sarah Leigh Publications for gene: PLEKHG2 were set to 26539891; 24001768; 26573021
Intellectual disability v7.15 PLEKHG2 Sarah Leigh Mode of inheritance for gene: PLEKHG2 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BIALLELIC, autosomal or pseudoautosomal
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 v7.13 FIBP Sarah Leigh Tag Q3_24_promote_green tag was added to gene: FIBP.
Tag Q3_24_NHS_review tag was added to gene: FIBP.
Intellectual disability v7.13 FIBP Sarah Leigh reviewed gene: FIBP: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v7.13 FIBP Sarah Leigh Phenotypes for gene: FIBP were changed from Thauvin-Robinet-Faivre syndrome, 617107 to Thauvin-Robinet-Faivre syndrome, OMIM:617107; tall stature-intellectual disability-renal anomalies syndrome, MONDO:0014918
Intellectual disability v7.12 FIBP Sarah Leigh Publications for gene: FIBP were set to 26660953; 27183861
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 PLEKHG2 Hannah Robinson reviewed gene: PLEKHG2: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v7.11 SRPK3 Achchuthan Shanmugasundram Classified gene: SRPK3 as Amber List (moderate evidence)
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 v7.11 SRPK3 Achchuthan Shanmugasundram Gene: srpk3 has been classified as Amber List (Moderate Evidence).
Intellectual disability v7.10 SRPK3 Achchuthan Shanmugasundram Phenotypes for gene: SRPK3 were changed from Neurodevelopmental disorder, MONDO:0700092, SRPK3-related to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Intellectual disability v7.9 SRPK3 Achchuthan Shanmugasundram Tag Q3_24_promote_green tag was added to gene: SRPK3.
Intellectual disability v7.9 SRPK3 Achchuthan Shanmugasundram reviewed gene: SRPK3: Rating: GREEN; Mode of pathogenicity: None; Publications: 39073169; Phenotypes: neurodevelopmental disorder, MONDO:0700092, intellectual disability, MONDO:0001071; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability v7.9 HDAC3 Achchuthan Shanmugasundram Classified gene: HDAC3 as Amber List (moderate evidence)
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 v7.9 HDAC3 Achchuthan Shanmugasundram Gene: hdac3 has been classified as Amber List (Moderate Evidence).
Intellectual disability v7.8 HDAC3 Achchuthan Shanmugasundram Phenotypes for gene: HDAC3 were changed from Neurodevelopmental disorder, MONDO:0700092, HDAC3-related to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Intellectual disability v7.7 HDAC3 Achchuthan Shanmugasundram Tag Q3_24_promote_green tag was added to gene: HDAC3.
Intellectual disability v7.7 HDAC3 Achchuthan Shanmugasundram reviewed gene: HDAC3: Rating: GREEN; Mode of pathogenicity: None; Publications: 39047730; Phenotypes: neurodevelopmental disorder, MONDO:0700092, intellectual disability, MONDO:0001071; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v7.7 RBBP5 Achchuthan Shanmugasundram Deleted their comment
Intellectual disability v7.7 RBBP5 Achchuthan Shanmugasundram Classified gene: RBBP5 as Amber List (moderate evidence)
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 Gene: rbbp5 has been classified as Amber List (Moderate Evidence).
Intellectual disability v7.7 RBBP5 Achchuthan Shanmugasundram Classified gene: RBBP5 as Amber List (moderate evidence)
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 Gene: rbbp5 has been classified as Amber List (Moderate Evidence).
Intellectual disability v7.6 RBBP5 Achchuthan Shanmugasundram Phenotypes for gene: RBBP5 were changed from neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071 to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Intellectual disability v7.6 RBBP5 Achchuthan Shanmugasundram Phenotypes for gene: RBBP5 were changed from neurodevelopmental disorder MONDO:0700092, RBBP5-related to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Intellectual disability v7.5 RBBP5 Achchuthan Shanmugasundram Tag Q3_24_promote_green tag was added to gene: RBBP5.
Intellectual disability v7.5 RBBP5 Achchuthan Shanmugasundram reviewed gene: RBBP5: Rating: GREEN; Mode of pathogenicity: None; Publications: 39036895; Phenotypes: neurodevelopmental disorder, MONDO:0700092, intellectual disability, MONDO:0001071; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v7.5 PCBP2 Achchuthan Shanmugasundram Classified gene: PCBP2 as Amber List (moderate evidence)
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 v7.5 PCBP2 Achchuthan Shanmugasundram Gene: pcbp2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v7.4 PCBP2 Achchuthan Shanmugasundram Phenotypes for gene: PCBP2 were changed from neurodevelopmental disorder, MONDO:0700092 to neurodevelopmental disorder, MONDO:0700092
Intellectual disability v7.4 PCBP2 Achchuthan Shanmugasundram Phenotypes for gene: PCBP2 were changed from neurodevelopmental disorder MONDO:0700092, PCBP2-related to neurodevelopmental disorder, MONDO:0700092
Intellectual disability v7.3 PCBP2 Achchuthan Shanmugasundram reviewed gene: PCBP2: Rating: AMBER; Mode of pathogenicity: None; Publications: 38965372; Phenotypes: neurodevelopmental disorder, MONDO:0700092; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v7.3 ATXN7L3 Sarah Leigh Classified gene: ATXN7L3 as Amber List (moderate evidence)
Intellectual disability v7.3 ATXN7L3 Sarah Leigh Gene: atxn7l3 has been classified as Amber List (Moderate Evidence).
Intellectual disability v7.2 ATXN7L3 Sarah Leigh Tag Q3_24_promote_green tag was added to gene: ATXN7L3.
Tag Q3_24_NHS_review tag was added to gene: ATXN7L3.
Tag Q3_24_MOI tag was added to gene: ATXN7L3.
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 v7.1 DHRSX Miel Theunis reviewed gene: DHRSX: Rating: GREEN; Mode of pathogenicity: Other; Publications: 38821050; Phenotypes: CDG; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v7.1 Arina Puzriakova Panel version 7.0 has been signed off on 2024-08-07
Intellectual disability v7.0 Arina Puzriakova promoted panel to version 7.0
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 RMRP Sarah Leigh commented on gene: RMRP
Intellectual disability v6.77 RMRP Sarah Leigh Tag locus-type-rna-long-non-coding tag was added to gene: RMRP.
Intellectual disability v6.77 XIST Sarah Leigh Tag locus-type-rna-long-non-coding tag was added to gene: XIST.
Intellectual disability v6.77 MT-TP Sarah Leigh Tag locus-type-rna-transfer tag was added to gene: MT-TP.
Intellectual disability v6.77 RNU7-1 Sarah Leigh Tag locus-type-rna-small-nuclear tag was added to gene: RNU7-1.
Intellectual disability v6.77 MSL2 Achchuthan Shanmugasundram Deleted their comment
Intellectual disability v6.77 MSL2 Achchuthan Shanmugasundram Deleted their comment
Intellectual disability v6.77 MSL2 Achchuthan Shanmugasundram Classified gene: MSL2 as Amber List (moderate evidence)
Intellectual disability v6.77 MSL2 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Nour Elkhateeb, there is sufficient evidence available for the promotion of this gene to green rating on the next GMS update.
Intellectual disability v6.77 MSL2 Achchuthan Shanmugasundram Gene: msl2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v6.77 MSL2 Achchuthan Shanmugasundram Classified gene: MSL2 as Amber List (moderate evidence)
Intellectual disability v6.77 MSL2 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Nour Elkhateeb, there is sufficient evidence available for the promotion of this gene to green rating on the next GMS update.
Intellectual disability v6.77 MSL2 Achchuthan Shanmugasundram Gene: msl2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v6.77 MSL2 Achchuthan Shanmugasundram Classified gene: MSL2 as Amber List (moderate evidence)
Intellectual disability v6.77 MSL2 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Nour Elkhateeb, there is sufficient evidence available for the promotion of this gene to green rating on the next GMS update.
Intellectual disability v6.77 MSL2 Achchuthan Shanmugasundram Gene: msl2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v6.76 MSL2 Achchuthan Shanmugasundram Phenotypes for gene: MSL2 were changed from neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071 to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Intellectual disability v6.76 MSL2 Achchuthan Shanmugasundram Phenotypes for gene: MSL2 were changed from neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071 to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Intellectual disability v6.76 MSL2 Achchuthan Shanmugasundram Phenotypes for gene: MSL2 were changed from Developmental disorders; autism to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Intellectual disability v6.76 MSL2 Achchuthan Shanmugasundram Publications for gene: MSL2 were set to 31332282; 33057194; 38702431; 38815585
Intellectual disability v6.76 MSL2 Achchuthan Shanmugasundram Publications for gene: MSL2 were set to 31332282; 33057194
Intellectual disability v6.75 MSL2 Achchuthan Shanmugasundram Tag Q3_24_NHS_review tag was added to gene: MSL2.
Intellectual disability v6.75 MSL2 Achchuthan Shanmugasundram Tag Q3_24_promote_green tag was added to gene: MSL2.
Intellectual disability v6.75 MSL2 Achchuthan Shanmugasundram reviewed gene: MSL2: Rating: GREEN; Mode of pathogenicity: None; Publications: 38702431, 38815585; Phenotypes: neurodevelopmental disorder, MONDO:0700092, intellectual disability, MONDO:0001071; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v6.75 MAPKAPK5 Achchuthan Shanmugasundram Classified gene: MAPKAPK5 as Amber List (moderate evidence)
Intellectual disability v6.75 MAPKAPK5 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (6 unrelated families) for the promotion of this gene to green rating in the next GMS update.
Intellectual disability v6.75 MAPKAPK5 Achchuthan Shanmugasundram Gene: mapkapk5 has been classified as Amber List (Moderate Evidence).
Intellectual disability v6.74 MAPKAPK5 Achchuthan Shanmugasundram Tag Q3_24_promote_green tag was added to gene: MAPKAPK5.
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 v6.72 MAPKAPK5 Achchuthan Shanmugasundram Publications for gene: MAPKAPK5 were set to 33442026
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 v6.71 IREB2 Achchuthan Shanmugasundram Classified gene: IREB2 as Amber List (moderate evidence)
Intellectual disability v6.71 IREB2 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (three unrelated cases) for the promotion of this gene to green rating in the next GMS update.
Intellectual disability v6.71 IREB2 Achchuthan Shanmugasundram Gene: ireb2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v6.70 IREB2 Achchuthan Shanmugasundram Tag Q3_24_promote_green tag was added to gene: IREB2.
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 v6.69 IREB2 Achchuthan Shanmugasundram Publications for gene: IREB2 were set to 11175792; 30915432; 31243445; 35602653
Intellectual disability v6.69 IREB2 Achchuthan Shanmugasundram Publications for gene: IREB2 were set to 30915432; 31243445; 11175792
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 Classified gene: GEMIN4 as Amber List (moderate evidence)
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 v6.68 GEMIN4 Achchuthan Shanmugasundram Gene: gemin4 has been classified as Amber List (Moderate Evidence).
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 v6.66 GEMIN4 Achchuthan Shanmugasundram Publications for gene: GEMIN4 were set to 25558065; 27878435
Intellectual disability v6.65 GEMIN4 Achchuthan Shanmugasundram Tag Q3_24_promote_green tag was added to gene: GEMIN4.
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 v6.65 GABBR1 Achchuthan Shanmugasundram Classified gene: GABBR1 as Amber List (moderate evidence)
Intellectual disability v6.65 GABBR1 Achchuthan Shanmugasundram Gene: gabbr1 has been classified as Amber List (Moderate Evidence).
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 v6.63 FZR1 Achchuthan Shanmugasundram Classified gene: FZR1 as Amber List (moderate evidence)
Intellectual disability v6.63 FZR1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (four unrelated cases) for the promotion of this gene to green rating in the next GMS update.
Intellectual disability v6.63 FZR1 Achchuthan Shanmugasundram Gene: fzr1 has been classified as Amber List (Moderate Evidence).
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 v6.61 FUK Achchuthan Shanmugasundram Phenotypes for gene: FUK were changed from Seizures; Generalized hypotonia; Feeding difficulties; Intellectual disability; Global developmental delay; Congenital disorder of glycosylation with defective fucosylation 2, 618324 to Congenital disorder of glycosylation with defective fucosylation 2, OMIM:618324
Intellectual disability v6.60 FUK Achchuthan Shanmugasundram Classified gene: FUK as Amber List (moderate evidence)
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 v6.60 FUK Achchuthan Shanmugasundram Gene: fuk has been classified as Amber List (Moderate Evidence).
Intellectual disability v6.59 FUK Achchuthan Shanmugasundram Publications for gene: FUK were set to 30503518
Intellectual disability v6.58 FUK Achchuthan Shanmugasundram Tag Q3_24_promote_green tag was added to gene: FUK.
Intellectual disability v6.58 FUK Achchuthan Shanmugasundram reviewed gene: FUK: Rating: GREEN; Mode of pathogenicity: None; Publications: 35718084, 36426412; Phenotypes: Congenital disorder of glycosylation with defective fucosylation 2, OMIM:618324; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v6.58 FRA10AC1 Achchuthan Shanmugasundram Classified gene: FRA10AC1 as Amber List (moderate evidence)
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 v6.58 FRA10AC1 Achchuthan Shanmugasundram Gene: fra10ac1 has been classified as Amber List (Moderate Evidence).
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 v6.56 DCC Achchuthan Shanmugasundram Phenotypes for gene: DCC were changed from Gaze palsy, familial horizontal, with progressive scoliosis, 2, OMIM:617542 to Gaze palsy, familial horizontal, with progressive scoliosis, 2, OMIM:617542
Intellectual disability v6.56 DCC Achchuthan Shanmugasundram Phenotypes for gene: DCC were changed from Midline-bridging neuronal commissure disruption, horizontal gaze palsy, scoliosis, and intellectual disability to Gaze palsy, familial horizontal, with progressive scoliosis, 2, OMIM:617542
Intellectual disability v6.55 DCC Achchuthan Shanmugasundram Classified gene: DCC as Amber List (moderate evidence)
Intellectual disability v6.55 DCC Achchuthan Shanmugasundram Gene: dcc has been classified as Amber List (Moderate Evidence).
Intellectual disability v6.55 DCC Achchuthan Shanmugasundram Classified gene: DCC as Amber List (moderate evidence)
Intellectual disability v6.55 DCC Achchuthan Shanmugasundram Gene: dcc has been classified as Amber List (Moderate Evidence).
Intellectual disability v6.54 DCC Achchuthan Shanmugasundram reviewed gene: DCC: Rating: AMBER; Mode of pathogenicity: None; Publications: 28250456, 33141514; Phenotypes: Gaze palsy, familial horizontal, with progressive scoliosis, 2, OMIM:617542; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v6.54 B9D1 Achchuthan Shanmugasundram Classified gene: B9D1 as Amber List (moderate evidence)
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 v6.54 B9D1 Achchuthan Shanmugasundram Gene: b9d1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v6.53 B9D1 Achchuthan Shanmugasundram Publications for gene: B9D1 were set to 21493627; 24886560; 25920555; 32622957
Intellectual disability v6.53 B9D1 Achchuthan Shanmugasundram Publications for gene: B9D1 were set to 24886560; 25920555; 21493627
Intellectual disability v6.52 B9D1 Achchuthan Shanmugasundram Tag Q3_24_promote_green tag was added to gene: B9D1.
Intellectual disability v6.52 B9D1 Achchuthan Shanmugasundram reviewed gene: B9D1: Rating: GREEN; Mode of pathogenicity: None; Publications: 32622957; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v6.52 MSL2 Nour Elkhateeb reviewed gene: MSL2: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 38815585, 38702431; Phenotypes: Developmental delay, intellectual disability, autism spectrum disorder, hypotonia; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v6.52 TBC1D7 Achchuthan Shanmugasundram Tag watchlist was removed from gene: TBC1D7.
Tag Q3_24_promote_green tag was added to gene: TBC1D7.
Tag Q3_24_NHS_review tag was added to gene: TBC1D7.
Intellectual disability v6.52 TBC1D7 Achchuthan Shanmugasundram Classified gene: TBC1D7 as Amber List (moderate evidence)
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 v6.52 TBC1D7 Achchuthan Shanmugasundram Gene: tbc1d7 has been classified as Amber List (Moderate Evidence).
Intellectual disability v6.51 TBC1D7 Achchuthan Shanmugasundram Publications for gene: TBC1D7 were set to PMID: 23687350; 24515783
Intellectual disability v6.50 TBC1D7 Achchuthan Shanmugasundram reviewed gene: TBC1D7: Rating: GREEN; Mode of pathogenicity: None; Publications: 36669495; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v6.50 TBC1D7 Frances Elmslie reviewed gene: TBC1D7: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 24515783, 23687350, 36669495, 35584673; Phenotypes: Macrocephaly, intellectual disability, megalencephaly; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
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 v6.50 DIP2B Achchuthan Shanmugasundram Deleted their comment
Intellectual disability v6.50 DIP2B Achchuthan Shanmugasundram Classified gene: DIP2B as Red List (low evidence)
Intellectual disability v6.50 DIP2B Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by others, only STRs in DIP2B were previously associated with intellectual disability. Hence, the rating should be changed from amber to red and the STR should be added to this panel.
Intellectual disability v6.50 DIP2B Achchuthan Shanmugasundram Gene: dip2b has been classified as Red List (Low Evidence).
Intellectual disability v6.50 DIP2B Achchuthan Shanmugasundram Classified gene: DIP2B as Red List (low evidence)
Intellectual disability v6.50 DIP2B Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by others, only STRs in DIP2B were previously associated with intellectual disability. Hence, the rating should be changed from amber to red and the STR should be added to this panel.
Intellectual disability v6.50 DIP2B Achchuthan Shanmugasundram Gene: dip2b has been classified as Red List (Low Evidence).
Intellectual disability v6.49 HSD17B10 Achchuthan Shanmugasundram Deleted their review
Intellectual disability v6.49 HSD17B10 Achchuthan Shanmugasundram reviewed gene: HSD17B10: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
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 Classified gene: FEM1B as Amber List (moderate evidence)
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 v6.49 FEM1B Achchuthan Shanmugasundram Gene: fem1b has been classified as Amber List (Moderate Evidence).
Intellectual disability v6.48 FEM1B Achchuthan Shanmugasundram Phenotypes for gene: FEM1B were changed from neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071 to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Intellectual disability v6.48 FEM1B Achchuthan Shanmugasundram Phenotypes for gene: FEM1B were changed from neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071 to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Intellectual disability v6.48 FEM1B Achchuthan Shanmugasundram Phenotypes for gene: FEM1B were changed from Syndromic intellectual disability to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Intellectual disability v6.48 FEM1B Achchuthan Shanmugasundram Publications for gene: FEM1B were set to 31036916; 38465576
Intellectual disability v6.48 FEM1B Achchuthan Shanmugasundram Publications for gene: FEM1B were set to 31036916; 38465576
Intellectual disability v6.48 FEM1B Achchuthan Shanmugasundram Publications for gene: FEM1B were set to 31036916
Intellectual disability v6.47 FEM1B Achchuthan Shanmugasundram Mode of inheritance for gene: FEM1B was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v6.47 FEM1B Achchuthan Shanmugasundram Mode of inheritance for gene: FEM1B was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v6.46 FEM1B Achchuthan Shanmugasundram Tag Q2_24_promote_green tag was added to gene: FEM1B.
Intellectual disability v6.46 FEM1B Achchuthan Shanmugasundram edited their review of gene: FEM1B: Changed rating: GREEN
Intellectual disability v6.46 FEM1B Achchuthan Shanmugasundram reviewed gene: FEM1B: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: neurodevelopmental disorder, MONDO:0700092, intellectual disability, MONDO:0001071; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v6.46 ADGRL1 Achchuthan Shanmugasundram Classified gene: ADGRL1 as Amber List (moderate evidence)
Intellectual disability v6.46 ADGRL1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (five unrelated cases) for the promotion of this gene to green rating in the next GMS update.
Intellectual disability v6.46 ADGRL1 Achchuthan Shanmugasundram Gene: adgrl1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v6.45 ADGRL1 Achchuthan Shanmugasundram Publications for gene: ADGRL1 were set to 30504930; 35907405
Intellectual disability v6.45 ADGRL1 Achchuthan Shanmugasundram Publications for gene: ADGRL1 were set to 35907405
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 v6.44 ADGRL1 Achchuthan Shanmugasundram Phenotypes for gene: ADGRL1 were changed from Developmental delay, behavioral abnormalities, and neuropsychiatric disorders to Developmental delay, behavioral abnormalities, and neuropsychiatric disorders, OMIM:620065
Intellectual disability v6.43 ADGRL1 Achchuthan Shanmugasundram Publications for gene: ADGRL1 were set to PubMed: 35907405
Intellectual disability v6.42 ADGRL1 Achchuthan Shanmugasundram Tag Q2_24_promote_green tag was added to gene: ADGRL1.
Intellectual disability v6.42 ADGRL1 Achchuthan Shanmugasundram reviewed gene: ADGRL1: Rating: GREEN; Mode of pathogenicity: None; Publications: 35907405; Phenotypes: Developmental delay, behavioral abnormalities, and neuropsychiatric disorders, OMIM:620065; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
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 Classified gene: KCNB2 as Amber List (moderate evidence)
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 v6.42 KCNB2 Achchuthan Shanmugasundram Gene: kcnb2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v6.41 KCNB2 Achchuthan Shanmugasundram Phenotypes for gene: KCNB2 were changed from neurodevelopmental disorder MONDO:0700092, KCNB2-related to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Intellectual disability v6.40 KCNB2 Achchuthan Shanmugasundram edited their review of gene: KCNB2: Changed phenotypes to: neurodevelopmental disorder, MONDO:0700092, intellectual disability, MONDO:0001071
Intellectual disability v6.40 KCNB2 Achchuthan Shanmugasundram Tag Q2_24_promote_green tag was added to gene: KCNB2.
Intellectual disability v6.40 KCNB2 Achchuthan Shanmugasundram reviewed gene: KCNB2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v6.40 SOX9 Sarah Leigh Tag Q2_24_demote_amber tag was added to gene: SOX9.
Tag Q2_24_NHS_review tag was added to gene: SOX9.
Intellectual disability v6.40 SOX9 Sarah Leigh reviewed gene: SOX9: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v6.40 SOX9 Sarah Leigh Phenotypes for gene: SOX9 were changed from Campomelic dysplasia with autosomal sex reversal, 114290; Acampomelic campomelic dysplasia, 114290; Campomelic dysplasia, 114290; intellectual disability to Campomelic dysplasia with autosomal sex reversal, OMIM:114290; Acampomelic campomelic dysplasia, OMIM:114290; Campomelic dysplasia, OMIM:114290; campomelic dysplasia, MONDO:0007251
Intellectual disability v6.39 AFF2 Sarah Leigh Publications for gene: AFF2 were set to 25529582; 24896178; 8334699; 8023854; 21739600; 9299237; 11171404; 11923441; 19136466; 2356291
Intellectual disability v6.38 AFF2 Sarah Leigh edited their review of gene: AFF2: Added comment: Intellectual developmental disorder, X-linked 109 (OMIM:3095480, is also associated with deletions of AFF2. Stettner et al. (PMID: 21739600) describe 2 brothers with OMIM:3095480, who have a 121 to 145-kb intragenic deletion within AFF2, while Sahoo et al (PMID: 22065534) report two unrelated males with OMIM:3095480; Patient 1 has a 240 kb intragenic deletion resulting the loss of exons 2-4 of AFF2 and Patient 2 has a 499 kb deletion that removes the exons 1-2.; Changed publications to: 21739600, 22065534
Intellectual disability v6.38 PLXNB2 Achchuthan Shanmugasundram Deleted their comment
Intellectual disability v6.38 PLXNB2 Achchuthan Shanmugasundram Classified gene: PLXNB2 as Amber List (moderate evidence)
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 Gene: plxnb2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v6.38 PLXNB2 Achchuthan Shanmugasundram Classified gene: PLXNB2 as Amber List (moderate evidence)
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 Gene: plxnb2 has been classified as Amber List (Moderate Evidence).
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 Tag Q2_24_promote_green tag was added to gene: PLXNB2.
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 v6.36 CAMK2D Achchuthan Shanmugasundram Deleted their comment
Intellectual disability v6.36 CAMK2D Achchuthan Shanmugasundram Classified gene: CAMK2D as Amber List (moderate evidence)
Intellectual disability v6.36 CAMK2D Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (seven unrelated cases) for the promotion of this gene to green rating in the next GMS update.
Intellectual disability v6.36 CAMK2D Achchuthan Shanmugasundram Gene: camk2d has been classified as Amber List (Moderate Evidence).
Intellectual disability v6.36 CAMK2D Achchuthan Shanmugasundram Classified gene: CAMK2D as Amber List (moderate evidence)
Intellectual disability v6.36 CAMK2D Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (seven unrelated cases) for the promotion of this gene to green rating in the next GMS update.
Intellectual disability v6.36 CAMK2D Achchuthan Shanmugasundram Gene: camk2d has been classified as Amber List (Moderate Evidence).
Intellectual disability v6.35 CAMK2D Achchuthan Shanmugasundram edited their review of gene: CAMK2D: Changed rating: GREEN
Intellectual disability v6.35 CAMK2D Achchuthan Shanmugasundram Tag Q2_24_promote_green tag was added to gene: CAMK2D.
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 Classified gene: EZH1 as Amber List (moderate evidence)
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 v6.34 EZH1 Achchuthan Shanmugasundram Gene: ezh1 has been classified as Amber List (Moderate Evidence).
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 Classified gene: STX1A as Amber List (moderate evidence)
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 Gene: stx1a has been classified as Amber List (Moderate Evidence).
Intellectual disability v6.31 STX1A Achchuthan Shanmugasundram Deleted their comment
Intellectual disability v6.31 STX1A Achchuthan Shanmugasundram Deleted their comment
Intellectual disability v6.31 STX1A Achchuthan Shanmugasundram Classified gene: STX1A as Amber List (moderate evidence)
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 Gene: stx1a has been classified as Amber List (Moderate Evidence).
Intellectual disability v6.31 STX1A Achchuthan Shanmugasundram Classified gene: STX1A as Amber List (moderate evidence)
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 Gene: stx1a has been classified as Amber List (Moderate Evidence).
Intellectual disability v6.30 STX1A Achchuthan Shanmugasundram Classified gene: STX1A as Amber List (moderate evidence)
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 v6.30 STX1A Achchuthan Shanmugasundram Gene: stx1a has been classified as Amber List (Moderate Evidence).
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 v6.28 WDR5 Achchuthan Shanmugasundram Classified gene: WDR5 as Amber List (moderate evidence)
Intellectual disability v6.28 WDR5 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the association of this gene with green rating in the next GMS update.
Intellectual disability v6.28 WDR5 Achchuthan Shanmugasundram Gene: wdr5 has been classified as Amber List (Moderate Evidence).
Intellectual disability v6.28 WDR5 Achchuthan Shanmugasundram Classified gene: WDR5 as Amber List (moderate evidence)
Intellectual disability v6.28 WDR5 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the association of this gene with green rating in the next GMS update.
Intellectual disability v6.28 WDR5 Achchuthan Shanmugasundram Gene: wdr5 has been classified as Amber List (Moderate Evidence).
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 v6.26 FAM177A1 Achchuthan Shanmugasundram Deleted their comment
Intellectual disability v6.26 FAM177A1 Achchuthan Shanmugasundram Classified gene: FAM177A1 as Amber List (moderate evidence)
Intellectual disability v6.26 FAM177A1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (four unrelated cases) for the promotion of this gene to green rating in the next GMS update.
Intellectual disability v6.26 FAM177A1 Achchuthan Shanmugasundram Gene: fam177a1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v6.26 FAM177A1 Achchuthan Shanmugasundram Classified gene: FAM177A1 as Amber List (moderate evidence)
Intellectual disability v6.26 FAM177A1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (four unrelated cases) for the promotion of this gene to green rating in the next GMS update.
Intellectual disability v6.26 FAM177A1 Achchuthan Shanmugasundram Gene: fam177a1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v6.25 FAM177A1 Achchuthan Shanmugasundram Tag Q2_24_promote_green tag was added to gene: FAM177A1.
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 v6.24 AFF2 Sarah Leigh Publications for gene: AFF2 were set to 21739600; 8334699; 25529582; 24896178
Intellectual disability v6.23 AFF2 Sarah Leigh reviewed gene: AFF2: Rating: GREEN; Mode of pathogenicity: None; Publications: 8334699, 8023854, 21739600, 9299237, 11171404, 11923441, 19136466, 2356291; Phenotypes: ; Mode of inheritance: None
Intellectual disability v6.23 AFF2 Sarah Leigh Phenotypes for gene: AFF2 were changed from Intellectual developmental disorder, X-linked 109, OMIM:309548; Fragile XE syndrome (FRAXE) to Intellectual developmental disorder, X-linked 109, OMIM:309548; FRAXE intellectual disability, MONDO:0010659
Intellectual disability v6.22 AFF2 Sarah Leigh Publications for gene: AFF2 were set to 21739600; 8334699
Intellectual disability v6.22 AFF2 Sarah Leigh Publications for gene: AFF2 were set to
Intellectual disability v6.21 ITSN1 Achchuthan Shanmugasundram Classified gene: ITSN1 as Amber List (moderate evidence)
Intellectual disability v6.21 ITSN1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the promotion of this gene to green rating in the next GMS update.
Intellectual disability v6.21 ITSN1 Achchuthan Shanmugasundram Gene: itsn1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v6.21 ITSN1 Achchuthan Shanmugasundram Classified gene: ITSN1 as Amber List (moderate evidence)
Intellectual disability v6.21 ITSN1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the promotion of this gene to green rating in the next GMS update.
Intellectual disability v6.21 ITSN1 Achchuthan Shanmugasundram Gene: itsn1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v6.21 ITSN1 Achchuthan Shanmugasundram Classified gene: ITSN1 as Amber List (moderate evidence)
Intellectual disability v6.21 ITSN1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the promotion of this gene to green rating in the next GMS update.
Intellectual disability v6.21 ITSN1 Achchuthan Shanmugasundram Gene: itsn1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v6.21 ITSN1 Achchuthan Shanmugasundram Classified gene: ITSN1 as Amber List (moderate evidence)
Intellectual disability v6.21 ITSN1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the promotion of this gene to green rating in the next GMS update.
Intellectual disability v6.21 ITSN1 Achchuthan Shanmugasundram Gene: itsn1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v6.20 ITSN1 Achchuthan Shanmugasundram Phenotypes for gene: ITSN1 were changed from neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071 to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Intellectual disability v6.21 ITSN1 Achchuthan Shanmugasundram Classified gene: ITSN1 as Amber List (moderate evidence)
Intellectual disability v6.21 ITSN1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the promotion of this gene to green rating in the next GMS update
Intellectual disability v6.21 ITSN1 Achchuthan Shanmugasundram Gene: itsn1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v6.20 ITSN1 Achchuthan Shanmugasundram Phenotypes for gene: ITSN1 were changed from neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071 to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Intellectual disability v6.20 ITSN1 Achchuthan Shanmugasundram Phenotypes for gene: ITSN1 were changed from neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071 to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Intellectual disability v6.20 ITSN1 Achchuthan Shanmugasundram Phenotypes for gene: ITSN1 were changed from neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071 to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Intellectual disability v6.20 ITSN1 Achchuthan Shanmugasundram Phenotypes for gene: ITSN1 were changed from neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071 to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Intellectual disability v6.20 ITSN1 Achchuthan Shanmugasundram Phenotypes for gene: ITSN1 were changed from neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071 to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Intellectual disability v6.20 ITSN1 Achchuthan Shanmugasundram Phenotypes for gene: ITSN1 were changed from autism spectrum disorders; intellectual disability; epilepsy. to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Intellectual disability v6.19 ITSN1 Achchuthan Shanmugasundram Publications for gene: ITSN1 were set to Bruel et al., 2021 (PMID: 34707297):
Intellectual disability v6.18 ITSN1 Achchuthan Shanmugasundram Tag Q2_24_promote_green tag was added to gene: ITSN1.
Tag Q2_24_NHS_review tag was added to gene: ITSN1.
Intellectual disability v6.18 ITSN1 Achchuthan Shanmugasundram reviewed gene: ITSN1: Rating: GREEN; Mode of pathogenicity: None; Publications: 34707297; Phenotypes: neurodevelopmental disorder, MONDO:0700092, intellectual disability, MONDO:0001071; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v6.18 RNU4-2 Arina Puzriakova Classified gene: RNU4-2 as Amber List (moderate evidence)
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 v6.18 RNU4-2 Arina Puzriakova Gene: rnu4-2 has been classified as Amber List (Moderate Evidence).
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 v6.17 RNU4-2 Arina Puzriakova Publications for gene: RNU4-2 were set to 38645094
Intellectual disability v6.16 RNU4-2 Arina Puzriakova reviewed gene: RNU4-2: Rating: GREEN; Mode of pathogenicity: None; Publications: 38821540, 38645094; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
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 v6.16 ANO4 Sarah Leigh Phenotypes for gene: ANO4 were changed from to sporadic encephalopathic and familial epilepsy
Intellectual disability v6.15 ANO4 Sarah Leigh Classified gene: ANO4 as Amber List (moderate evidence)
Intellectual disability v6.15 ANO4 Sarah Leigh Gene: ano4 has been classified as Amber List (Moderate Evidence).
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 v6.13 RNU4-2 Eleanor Williams commented on gene: RNU4-2
Intellectual disability v6.13 ZBTB47 Eleanor Williams Tag gene-checked tag was added to gene: ZBTB47.
Intellectual disability v6.13 KDM5A Eleanor Williams Phenotypes for gene: KDM5A were changed from autism spectrum disorder, MONDO:0005258; intellectual disability, MONDO:0001071 to autism spectrum disorder, MONDO:0005258; intellectual disability, MONDO:0001071; El Hayek-Chahrour neurodevelopmental syndrome, OMIM:620820
Intellectual disability v6.12 KDM5A Eleanor Williams Tag gene-checked was removed from gene: KDM5A.
Intellectual disability v6.12 TMEM63B Eleanor Williams Tag gene-checked tag was added to gene: TMEM63B.
Intellectual disability v6.12 PPP1R3F Eleanor Williams Tag gene-checked tag was added to gene: PPP1R3F.
Intellectual disability v6.12 MAST4 Eleanor Williams Tag gene-checked tag was added to gene: MAST4.
Intellectual disability v6.12 RAB5C Eleanor Williams Tag gene-checked tag was added to gene: RAB5C.
Intellectual disability v6.12 PABPC1 Eleanor Williams Tag gene-checked tag was added to gene: PABPC1.
Intellectual disability v6.12 MYH10 Eleanor Williams Tag gene-checked tag was added to gene: MYH10.
Intellectual disability v6.12 DHX9 Eleanor Williams Tag gene-checked tag was added to gene: DHX9.
Intellectual disability v6.12 CNOT9 Eleanor Williams Tag gene-checked tag was added to gene: CNOT9.
Intellectual disability v6.12 CDK16 Eleanor Williams Tag gene-checked tag was added to gene: CDK16.
Intellectual disability v6.12 ARF3 Eleanor Williams Tag gene-checked tag was added to gene: ARF3.
Intellectual disability v6.12 MAST3 Sarah Leigh Tag Q2_24_NHS_review tag was added to gene: MAST3.
Intellectual disability v6.12 MAST3 Sarah Leigh Tag Q2_24_MOI was removed from gene: MAST3.
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 FAM111A Achchuthan Shanmugasundram Tag Q4_23_demote_red was removed from gene: FAM111A.
Tag Q4_23_NHS_review was removed from gene: FAM111A.
Tag Q4_23_expert_review was removed from gene: FAM111A.
Intellectual disability v6.11 DPP6 Achchuthan Shanmugasundram Tag Q4_23_demote_red was removed from gene: DPP6.
Tag Q4_23_NHS_review was removed from gene: DPP6.
Tag Q4_23_expert_review was removed from gene: DPP6.
Intellectual disability v6.11 ZBTB47 Achchuthan Shanmugasundram Tag Q4_23_promote_green was removed from gene: ZBTB47.
Intellectual disability v6.11 VCP Achchuthan Shanmugasundram Tag Q4_23_promote_green was removed from gene: VCP.
Intellectual disability v6.11 TEFM Achchuthan Shanmugasundram Tag Q4_23_promote_green was removed from gene: TEFM.
Intellectual disability v6.11 SRSF1 Achchuthan Shanmugasundram Tag Q4_23_promote_green was removed from gene: SRSF1.
Intellectual disability v6.11 SHQ1 Achchuthan Shanmugasundram Tag Q4_23_promote_green was removed from gene: SHQ1.
Intellectual disability v6.11 RPL10 Achchuthan Shanmugasundram Tag Q4_23_MOI was removed from gene: RPL10.
Intellectual disability v6.11 RELN Achchuthan Shanmugasundram Tag Q4_23_MOI was removed from gene: RELN.
Intellectual disability v6.11 RBL2 Achchuthan Shanmugasundram Tag Q4_23_promote_green was removed from gene: RBL2.
Tag Q4_23_NHS_review was removed from gene: RBL2.
Intellectual disability v6.11 RAP1B Achchuthan Shanmugasundram Tag Q4_23_promote_green was removed from gene: RAP1B.
Intellectual disability v6.11 MYH10 Achchuthan Shanmugasundram Tag Q4_23_promote_green was removed from gene: MYH10.
Intellectual disability v6.11 MAST4 Achchuthan Shanmugasundram Tag Q4_23_promote_green was removed from gene: MAST4.
Intellectual disability v6.11 KMT2B Achchuthan Shanmugasundram Tag Q4_23_promote_green was removed from gene: KMT2B.
Intellectual disability v6.11 ERI1 Achchuthan Shanmugasundram Tag Q4_23_promote_green was removed from gene: ERI1.
Intellectual disability v6.11 COX11 Achchuthan Shanmugasundram Tag Q4_23_promote_green was removed from gene: COX11.
Intellectual disability v6.11 CLDN11 Achchuthan Shanmugasundram Tag Q4_23_promote_green was removed from gene: CLDN11.
Intellectual disability v6.11 CLCN6 Achchuthan Shanmugasundram Tag Q4_23_promote_green was removed from gene: CLCN6.
Intellectual disability v6.11 CDK16 Achchuthan Shanmugasundram Tag Q4_23_promote_green was removed from gene: CDK16.
Tag Q4_23_NHS_review was removed from gene: CDK16.
Intellectual disability v6.11 CASP2 Achchuthan Shanmugasundram Tag Q4_23_promote_green was removed from gene: CASP2.
Intellectual disability v6.11 ARF3 Achchuthan Shanmugasundram Tag Q4_23_promote_green was removed from gene: ARF3.
Intellectual disability v6.11 ACACA Achchuthan Shanmugasundram Tag Q4_23_promote_green was removed from gene: ACACA.
Intellectual disability v6.11 FAR1 Achchuthan Shanmugasundram Tag to_be_confirmed_NHSE was removed from gene: FAR1.
Intellectual disability v6.11 U2AF2 Achchuthan Shanmugasundram Tag Q3_23_promote_green was removed from gene: U2AF2.
Tag Q3_23_NHS_review was removed from gene: U2AF2.
Intellectual disability v6.11 TTI1 Achchuthan Shanmugasundram Tag Q3_23_promote_green was removed from gene: TTI1.
Intellectual disability v6.11 TSPOAP1 Achchuthan Shanmugasundram Tag Q3_23_promote_green was removed from gene: TSPOAP1.
Intellectual disability v6.11 TMEM63B Achchuthan Shanmugasundram Tag Q3_23_promote_green was removed from gene: TMEM63B.
Intellectual disability v6.11 SLC30A9 Achchuthan Shanmugasundram Tag Q3_23_promote_green was removed from gene: SLC30A9.
Intellectual disability v6.11 RPS6KA3 Achchuthan Shanmugasundram Tag Q3_23_MOI was removed from gene: RPS6KA3.
Intellectual disability v6.11 RAB5C Achchuthan Shanmugasundram Tag Q3_23_promote_green was removed from gene: RAB5C.
Intellectual disability v6.11 PSMC3 Achchuthan Shanmugasundram Tag Q3_23_promote_green was removed from gene: PSMC3.
Intellectual disability v6.11 PPP1R3F Achchuthan Shanmugasundram Tag Q3_23_promote_green was removed from gene: PPP1R3F.
Intellectual disability v6.11 PIP5K1C Achchuthan Shanmugasundram Tag Q3_23_promote_green was removed from gene: PIP5K1C.
Intellectual disability v6.11 PABPC1 Achchuthan Shanmugasundram Tag Q3_23_promote_green was removed from gene: PABPC1.
Tag Q3_23_MOI was removed from gene: PABPC1.
Tag Q3_23_phenotype was removed from gene: PABPC1.
Intellectual disability v6.11 NR2F2 Achchuthan Shanmugasundram Tag Q3_23_promote_green was removed from gene: NR2F2.
Tag Q3_23_NHS_review was removed from gene: NR2F2.
Intellectual disability v6.11 NEUROG1 Achchuthan Shanmugasundram Tag Q3_23_promote_green was removed from gene: NEUROG1.
Tag Q3_23_NHS_review was removed from gene: NEUROG1.
Intellectual disability v6.11 LETM1 Achchuthan Shanmugasundram Tag Q3_23_promote_green was removed from gene: LETM1.
Tag Q3_23_MOI was removed from gene: LETM1.
Intellectual disability v6.11 KCNH5 Achchuthan Shanmugasundram Tag Q3_23_promote_green was removed from gene: KCNH5.
Intellectual disability v6.11 ESAM Achchuthan Shanmugasundram Tag Q3_23_promote_green was removed from gene: ESAM.
Tag Q3_23_NHS_review was removed from gene: ESAM.
Intellectual disability v6.11 EIF4A2 Achchuthan Shanmugasundram Tag Q3_23_promote_green was removed from gene: EIF4A2.
Intellectual disability v6.11 DHX9 Achchuthan Shanmugasundram Tag Q3_23_promote_green was removed from gene: DHX9.
Intellectual disability v6.11 DAGLA Achchuthan Shanmugasundram Tag Q3_23_promote_green was removed from gene: DAGLA.
Intellectual disability v6.11 CNOT9 Achchuthan Shanmugasundram Tag Q3_23_promote_green was removed from gene: CNOT9.
Intellectual disability v6.11 ATP6V0C Achchuthan Shanmugasundram Tag Q3_23_promote_green was removed from gene: ATP6V0C.
Tag Q3_23_NHS_review was removed from gene: ATP6V0C.
Intellectual disability v6.11 AGTPBP1 Achchuthan Shanmugasundram Tag Q3_23_promote_green was removed from gene: AGTPBP1.
Intellectual disability v6.11 ZBTB47 Sarah Leigh edited their review of gene: ZBTB47: Added comment: The rating of this gene has been updated to Green and the mode of inheritance set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted following NHS Genomic Medicine Service approval.; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v6.11 VCP Sarah Leigh reviewed gene: VCP: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v6.11 U2AF2 Sarah Leigh reviewed gene: U2AF2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v6.11 TTI1 Sarah Leigh commented on gene: TTI1: The rating of this gene has been updated to Green and the mode of inheritance set to BIALLELIC, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.
Intellectual disability v6.11 TSPOAP1 Sarah Leigh edited their review of gene: TSPOAP1: Added comment: The rating of this gene has been updated to Green and the mode of inheritance set to BIALLELIC, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v6.11 TMEM63B Sarah Leigh reviewed gene: TMEM63B: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v6.11 TEFM Sarah Leigh reviewed gene: TEFM: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v6.11 SRSF1 Sarah Leigh reviewed gene: SRSF1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v6.11 SLC30A9 Sarah Leigh edited their review of gene: SLC30A9: Added comment: The rating of this gene has been updated to green and the mode of inheritance updated to BIALLELIC, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.; Changed rating: GREEN
Intellectual disability v6.11 SHQ1 Sarah Leigh edited their review of gene: SHQ1: Added comment: The rating of this gene has been updated to Green and the mode of inheritance set to BIALLELIC, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v6.11 RPS6KA3 Sarah Leigh reviewed gene: RPS6KA3: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Intellectual disability v6.11 RPL10 Sarah Leigh commented on gene: RPL10: The mode of inheritance of this gene has been updated to X-LINKED: hemizygous mutation in males, biallelic mutations in females following NHS Genomic Medicine Service approval.
Intellectual disability v6.11 RELN Sarah Leigh reviewed gene: RELN: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v6.11 RBL2 Sarah Leigh commented on gene: RBL2: The rating of this gene has been updated to green and the mode of inheritance updated to BIALLELIC, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.
Intellectual disability v6.11 RAP1B Sarah Leigh reviewed gene: RAP1B: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v6.11 RAB5C Sarah Leigh reviewed gene: RAB5C: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v6.11 PSMC3 Sarah Leigh reviewed gene: PSMC3: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v6.11 PPP1R3F Sarah Leigh reviewed gene: PPP1R3F: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability v6.11 PIP5K1C Sarah Leigh reviewed gene: PIP5K1C: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v6.11 PABPC1 Sarah Leigh edited their review of gene: PABPC1: Added comment: The rating of this gene has been updated to green and the mode of inheritance updated to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown following NHS Genomic Medicine Service approval.; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v6.11 NR2F2 Sarah Leigh reviewed gene: NR2F2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v6.11 NEUROG1 Sarah Leigh reviewed gene: NEUROG1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v6.11 MYH10 Sarah Leigh reviewed gene: MYH10: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v6.11 MAST4 Sarah Leigh edited their review of gene: MAST4: Added comment: The rating of this gene has been updated to Green and the mode of inheritance set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted following NHS Genomic Medicine Service approval.; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v6.11 LETM1 Sarah Leigh commented on gene: LETM1: The rating of this gene has been updated to Green and the mode of inheritance set to BIALLELIC, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.
Intellectual disability v6.11 KMT2B Sarah Leigh reviewed gene: KMT2B: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v6.11 KCNH5 Sarah Leigh reviewed gene: KCNH5: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
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 FAM111A Sarah Leigh commented on gene: FAM111A: The rating of this gene has been updated to red following NHS Genomic Medicine Service approval.
Intellectual disability v6.11 ESAM Sarah Leigh reviewed gene: ESAM: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v6.11 ERI1 Sarah Leigh reviewed gene: ERI1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v6.11 EIF4A2 Sarah Leigh commented on gene: EIF4A2: The rating of this gene has been updated to Green and the mode of inheritance set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval
Intellectual disability v6.11 DPP6 Sarah Leigh reviewed gene: DPP6: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Intellectual disability v6.11 DHX9 Sarah Leigh reviewed gene: DHX9: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v6.11 DAGLA Sarah Leigh reviewed gene: DAGLA: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v6.11 COX11 Sarah Leigh edited their review of gene: COX11: Added comment: The rating of this gene has been updated to Green and the mode of inheritance set to BIALLELIC, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v6.11 CNOT9 Sarah Leigh reviewed gene: CNOT9: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v6.11 CLDN11 Sarah Leigh reviewed gene: CLDN11: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v6.11 CLCN6 Sarah Leigh commented on gene: CLCN6: The rating of this gene has been updated to Green and the mode of inheritance set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown following NHS Genomic Medicine Service approval.
Intellectual disability v6.11 CDK16 Sarah Leigh commented on gene: CDK16: The rating of this gene has been updated to green and the mode of inheritance updated to X-LINKED: hemizygous mutation in males, biallelic mutations in females following NHS Genomic Medicine Service approval.
Intellectual disability v6.11 CASP2 Sarah Leigh edited their review of gene: CASP2: Added comment: The rating of this gene has been updated to green and the mode of inheritance updated to BIALLELIC, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.; Changed rating: GREEN
Intellectual disability v6.11 ATP6V0C Sarah Leigh reviewed gene: ATP6V0C: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
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 v6.11 AGTPBP1 Sarah Leigh reviewed gene: AGTPBP1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v6.11 ACACA Sarah Leigh edited their review of gene: ACACA: Added comment: The rating of this gene has been updated to Green and the mode of inheritance set to BIALLELIC, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v6.10 ZBTB47 Achchuthan Shanmugasundram Source Expert Review Green was added to ZBTB47.
Source NHS GMS was added to ZBTB47.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v6.10 VCP Achchuthan Shanmugasundram Source Expert Review Green was added to VCP.
Source NHS GMS was added to VCP.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v6.10 U2AF2 Achchuthan Shanmugasundram Source Expert Review Green was added to U2AF2.
Source NHS GMS was added to U2AF2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v6.10 TTI1 Achchuthan Shanmugasundram Source Expert Review Green was added to TTI1.
Source NHS GMS was added to TTI1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v6.10 TSPOAP1 Achchuthan Shanmugasundram Source Expert Review Green was added to TSPOAP1.
Source NHS GMS was added to TSPOAP1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v6.10 TMEM63B Achchuthan Shanmugasundram Source Expert Review Green was added to TMEM63B.
Source NHS GMS was added to TMEM63B.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v6.10 TEFM Achchuthan Shanmugasundram Source Expert Review Green was added to TEFM.
Source NHS GMS was added to TEFM.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v6.10 SRSF1 Achchuthan Shanmugasundram Source Expert Review Green was added to SRSF1.
Source NHS GMS was added to SRSF1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v6.10 SLC30A9 Achchuthan Shanmugasundram Source Expert Review Green was added to SLC30A9.
Source NHS GMS was added to SLC30A9.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v6.10 SHQ1 Achchuthan Shanmugasundram Source Expert Review Green was added to SHQ1.
Source NHS GMS was added to SHQ1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v6.10 RPS6KA3 Achchuthan Shanmugasundram Source NHS GMS was added to RPS6KA3.
Mode of inheritance for gene RPS6KA3 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 v6.10 RPL10 Achchuthan Shanmugasundram Source NHS GMS was added to RPL10.
Mode of inheritance for gene RPL10 was changed from X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability v6.10 RELN Achchuthan Shanmugasundram Source NHS GMS was added to RELN.
Mode of inheritance for gene RELN was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v6.10 RBL2 Achchuthan Shanmugasundram Source Expert Review Green was added to RBL2.
Source NHS GMS was added to RBL2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v6.10 RAP1B Achchuthan Shanmugasundram Source Expert Review Green was added to RAP1B.
Source NHS GMS was added to RAP1B.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v6.10 RAB5C Achchuthan Shanmugasundram Source Expert Review Green was added to RAB5C.
Source NHS GMS was added to RAB5C.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v6.10 PSMC3 Achchuthan Shanmugasundram Source Expert Review Green was added to PSMC3.
Source NHS GMS was added to PSMC3.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v6.10 PPP1R3F Achchuthan Shanmugasundram Source Expert Review Green was added to PPP1R3F.
Source NHS GMS was added to PPP1R3F.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v6.10 PIP5K1C Achchuthan Shanmugasundram Source Expert Review Green was added to PIP5K1C.
Source NHS GMS was added to PIP5K1C.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v6.10 PABPC1 Achchuthan Shanmugasundram Source Expert Review Green was added to PABPC1.
Source NHS GMS was added to PABPC1.
Mode of inheritance for gene PABPC1 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v6.10 NR2F2 Achchuthan Shanmugasundram Source Expert Review Green was added to NR2F2.
Source NHS GMS was added to NR2F2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v6.10 NEUROG1 Achchuthan Shanmugasundram Source Expert Review Green was added to NEUROG1.
Source NHS GMS was added to NEUROG1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v6.10 MYH10 Achchuthan Shanmugasundram Source Expert Review Green was added to MYH10.
Source NHS GMS was added to MYH10.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v6.10 MAST4 Achchuthan Shanmugasundram Source Expert Review Green was added to MAST4.
Source NHS GMS was added to MAST4.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v6.10 LETM1 Achchuthan Shanmugasundram Source Expert Review Green was added to LETM1.
Source NHS GMS was added to LETM1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v6.10 KMT2B Achchuthan Shanmugasundram Source Expert Review Green was added to KMT2B.
Source NHS GMS was added to KMT2B.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v6.10 KCNH5 Achchuthan Shanmugasundram Source Expert Review Green was added to KCNH5.
Source NHS GMS was added to KCNH5.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
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 FAM111A Achchuthan Shanmugasundram Source Expert Review Red was added to FAM111A.
Source NHS GMS was added to FAM111A.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Intellectual disability v6.10 ESAM Achchuthan Shanmugasundram Source Expert Review Green was added to ESAM.
Source NHS GMS was added to ESAM.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v6.10 ERI1 Achchuthan Shanmugasundram Source Expert Review Green was added to ERI1.
Source NHS GMS was added to ERI1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v6.10 EIF4A2 Achchuthan Shanmugasundram Source Expert Review Green was added to EIF4A2.
Source NHS GMS was added to EIF4A2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v6.10 DPP6 Achchuthan Shanmugasundram Source Expert Review Red was added to DPP6.
Source NHS GMS was added to DPP6.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Intellectual disability v6.10 DHX9 Achchuthan Shanmugasundram Source Expert Review Green was added to DHX9.
Source NHS GMS was added to DHX9.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v6.10 DAGLA Achchuthan Shanmugasundram Source Expert Review Green was added to DAGLA.
Source NHS GMS was added to DAGLA.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v6.10 COX11 Achchuthan Shanmugasundram Source Expert Review Green was added to COX11.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v6.10 CNOT9 Achchuthan Shanmugasundram Source Expert Review Green was added to CNOT9.
Source NHS GMS was added to CNOT9.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v6.10 CLDN11 Achchuthan Shanmugasundram Source Expert Review Green was added to CLDN11.
Source NHS GMS was added to CLDN11.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v6.10 CLCN6 Achchuthan Shanmugasundram Source Expert Review Green was added to CLCN6.
Source NHS GMS was added to CLCN6.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v6.10 CDK16 Achchuthan Shanmugasundram Source Expert Review Green was added to CDK16.
Source NHS GMS was added to CDK16.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v6.10 CASP2 Achchuthan Shanmugasundram Source Expert Review Green was added to CASP2.
Source NHS GMS was added to CASP2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v6.10 ATP6V0C Achchuthan Shanmugasundram Source Expert Review Green was added to ATP6V0C.
Source NHS GMS was added to ATP6V0C.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
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 v6.10 AGTPBP1 Achchuthan Shanmugasundram Source Expert Review Green was added to AGTPBP1.
Source NHS GMS was added to AGTPBP1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v6.10 ACACA Achchuthan Shanmugasundram Source Expert Review Green was added to ACACA.
Source NHS GMS was added to ACACA.
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 v6.8 TTI1 Arina Puzriakova Added comment: Comment on phenotypes: Relevant phenotype now listed in OMIM (Neurodevelopmental disorder with microcephaly and movement abnormalities, OMIM:620445)
Intellectual disability v6.8 TTI1 Arina Puzriakova Phenotypes for gene: TTI1 were changed from neurodevelopmental disorder with microcephaly to Neurodevelopmental disorder with microcephaly and movement abnormalities, OMIM:620445
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 v6.6 SPTBN4 Arina Puzriakova Phenotypes for gene: SPTBN4 were changed from Neurodevelopmental disorder with hypotonia, neuropathy, and deafness MIM#617519 to Neurodevelopmental disorder with hypotonia, neuropathy, and deafness, OMIM:617519
Intellectual disability v6.5 ISCA-46292-Loss Arina Puzriakova reviewed Region: ISCA-46292-Loss: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
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 v6.5 ISCA-46743-Gain Arina Puzriakova reviewed Region: ISCA-46743-Gain: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v6.5 ISCA-46743-Loss Arina Puzriakova reviewed Region: ISCA-46743-Loss: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v6.5 ISCA-46292-Loss Arina Puzriakova Publications for Region: ISCA-46292-Loss were set to
Intellectual disability v6.4 ISCA-46743-Loss Arina Puzriakova Publications for Region: ISCA-46743-Loss were set to
Intellectual disability v6.3 ISCA-46743-Gain Arina Puzriakova Publications for Region: ISCA-46743-Gain were set to
Intellectual disability v6.2 ISCA-46292-Loss Arina Puzriakova Region: ISCA-46292-Loss was added
Region: ISCA-46292-Loss was added to Intellectual disability. Sources: Expert Review Green,ClinGen
Mode of inheritance for Region: ISCA-46292-Loss was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v6.2 ISCA-46743-Loss Arina Puzriakova Region: ISCA-46743-Loss was added
Region: ISCA-46743-Loss was added to Intellectual disability. Sources: Expert Review Green,ClinGen
Mode of inheritance for Region: ISCA-46743-Loss was 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 v6.2 ISCA-46743-Gain Arina Puzriakova Region: ISCA-46743-Gain was added
Region: ISCA-46743-Gain was added to Intellectual disability. Sources: Expert Review Green,ClinGen
Mode of inheritance for Region: ISCA-46743-Gain was 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 v6.1 Achchuthan Shanmugasundram Panel version 6.0 has been signed off on 2024-05-01
Intellectual disability v6.0 Achchuthan Shanmugasundram promoted panel to version 6.0
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 DIP2B Dmitrijs Rots reviewed gene: DIP2B: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
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 v5.557 ZNFX1 Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: ZNFX1.
Intellectual disability v5.557 RNPC3 Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: RNPC3.
Intellectual disability v5.557 FILIP1 Achchuthan Shanmugasundram Tag gene-checked was removed from gene: FILIP1.
Intellectual disability v5.557 OTUD7A Achchuthan Shanmugasundram Tag gene-checked was removed from gene: OTUD7A.
Intellectual disability v5.557 CEP295 Achchuthan Shanmugasundram Phenotypes for gene: CEP295 were changed from Seckel syndrome 11, OMIM # 620767 to Seckel syndrome 11, OMIM:620767
Intellectual disability v5.556 CEP295 Achchuthan Shanmugasundram Classified gene: CEP295 as Amber List (moderate evidence)
Intellectual disability v5.556 CEP295 Achchuthan Shanmugasundram Gene: cep295 has been classified as Amber List (Moderate Evidence).
Intellectual disability v5.555 CEP295 Achchuthan Shanmugasundram reviewed gene: CEP295: Rating: AMBER; Mode of pathogenicity: None; Publications: 38154379; Phenotypes: Seckel syndrome 11, OMIM:620767; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v5.555 DOCK4 Achchuthan Shanmugasundram Tag Q2_24_promote_green tag was added to gene: DOCK4.
Intellectual disability v5.555 DOCK4 Achchuthan Shanmugasundram Classified gene: DOCK4 as Amber List (moderate evidence)
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 v5.555 DOCK4 Achchuthan Shanmugasundram Gene: dock4 has been classified as Amber List (Moderate Evidence).
Intellectual disability v5.554 DOCK4 Achchuthan Shanmugasundram Phenotypes for gene: DOCK4 were changed from neuronevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071 to neuronevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Intellectual disability v5.554 DOCK4 Achchuthan Shanmugasundram Phenotypes for gene: DOCK4 were changed from DOCK4-related neurodevelopmental disorder (MONDO:0060490) to neuronevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Intellectual disability v5.553 DOCK4 Achchuthan Shanmugasundram reviewed gene: DOCK4: Rating: GREEN; Mode of pathogenicity: None; Publications: 38526744; Phenotypes: neuronevelopmental disorder, MONDO:0700092, intellectual disability, MONDO:0001071; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v5.553 GTF3C5 Achchuthan Shanmugasundram Publications for gene: GTF3C5 were set to 38520561; 35503477
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 edited their review of gene: GTF3C5: Changed publications to: 35503477, 38520561
Intellectual disability v5.552 GTF3C5 Achchuthan Shanmugasundram Classified gene: GTF3C5 as Amber List (moderate evidence)
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 v5.552 GTF3C5 Achchuthan Shanmugasundram Gene: gtf3c5 has been classified as Amber List (Moderate Evidence).
Intellectual disability v5.551 GTF3C5 Achchuthan Shanmugasundram Phenotypes for gene: GTF3C5 were changed from neurodevelopmental disorder MONDO:0700092, GTF3C5-related to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Intellectual disability v5.550 GTF3C5 Achchuthan Shanmugasundram Tag Q2_24_promote_green tag was added to gene: GTF3C5.
Intellectual disability v5.550 GTF3C5 Achchuthan Shanmugasundram reviewed gene: GTF3C5: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: neurodevelopmental disorder, MONDO:0700092, intellectual disability, MONDO:0001071; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v5.550 CENPF Arina Puzriakova Phenotypes for gene: CENPF were changed from Stromme syndrome 243605; Lethal fetal brain malformation-duodenal atresia-bilateral renal hypoplasia syndrome to Stromme syndrome, OMIM:243605; Lethal fetal brain malformation-duodenal atresia-bilateral renal hypoplasia syndrome
Intellectual disability v5.549 GMNN Arina Puzriakova Phenotypes for gene: GMNN were changed from Meier-Gorlin syndrome 6, 616835 to Meier-Gorlin syndrome 6, OMIM:616835
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 v5.547 LIG4 Arina Puzriakova Phenotypes for gene: LIG4 were changed from LIG4 syndrome, OMIM:606593 to LIG4 syndrome, OMIM:606593
Intellectual disability v5.547 LIG4 Arina Puzriakova Phenotypes for gene: LIG4 were changed from LIG4 syndrome, 606593{Multiple myeloma, resistance to}, 254500Severe combined immunodeficiency with sensitivity to ionizing radiation, 602450; LIG4 SYNDROME to LIG4 syndrome, OMIM:606593
Intellectual disability v5.546 ORC1 Arina Puzriakova Phenotypes for gene: ORC1 were changed from Meier-Gorlin syndrome 1, 224690; MEIER-GORLIN SYNDROME 1 to Meier-Gorlin syndrome 1, OMIM:224690
Intellectual disability v5.545 ORC4 Arina Puzriakova Phenotypes for gene: ORC4 were changed from Meier-Gorlin syndrome 2, 613800 to Meier-Gorlin syndrome 2, OMIM:613800
Intellectual disability v5.544 ORC6 Arina Puzriakova Phenotypes for gene: ORC6 were changed from Meier-Gorlin syndrome 3, 613803 to Meier-Gorlin syndrome 3, OMIM:613803
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 v5.541 TRAIP Arina Puzriakova Phenotypes for gene: TRAIP were changed from Seckel syndrome 9, 616777 to Seckel syndrome 9, OMIM:616777
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 v5.539 CDC6 Arina Puzriakova Phenotypes for gene: CDC6 were changed from MEIER-GORLIN SYNDROME 5 to Meier-Gorlin syndrome 5, OMIM:613805
Intellectual disability v5.538 CDT1 Arina Puzriakova Phenotypes for gene: CDT1 were changed from MEIER-GORLIN SYNDROME 4 to Meier-Gorlin syndrome 4, OMIM:613804
Intellectual disability v5.537 ATR Arina Puzriakova Phenotypes for gene: ATR were changed from Seckel syndrome 1, 210600Cutaneous telangiectasia and cancer syndrome, familial, 614564; SECKEL SYNDROME TYPE 1 (SCKL1) to Seckel syndrome 1, OMIM:210600
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 v5.536 ACBD6 Arina Puzriakova Added comment: Comment on phenotypes: This gene now has a relevant phenotype listed in OMIM (MIM# 620785)
Intellectual disability v5.536 ACBD6 Arina Puzriakova Phenotypes for gene: ACBD6 were changed from Neurodevelopmental disorder, MONDO:0700092 to Neurodevelopmental disorder with progressive movement abnormalities, OMIM:620785
Intellectual disability v5.535 GLI3 Arina Puzriakova Tag Q2_24_demote_amber tag was added to gene: GLI3.
Tag Q2_24_NHS_review tag was added to gene: GLI3.
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 v5.534 GLI3 Arina Puzriakova Publications for gene: GLI3 were set to
Intellectual disability v5.533 GLI3 Arina Puzriakova Classified gene: GLI3 as Green List (high evidence)
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 v5.533 GLI3 Arina Puzriakova Gene: gli3 has been classified as Green List (High Evidence).
Intellectual disability v5.532 CPA6 Arina Puzriakova Tag refuted tag was added to gene: CPA6.
Intellectual disability v5.532 CPA6 Arina Puzriakova commented on gene: CPA6
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 edited their review of gene: CEP295: Changed rating: GREEN
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 v5.532 SMAD3 Achchuthan Shanmugasundram reviewed gene: SMAD3: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v5.532 ZFX Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has now been associated with phenotype in OMIM (MIM #301118), but not yet in Gene2Phenotype.
Intellectual disability v5.532 ZFX Achchuthan Shanmugasundram Phenotypes for gene: ZFX were changed from X-linked neurodevelopmental disorder with recurrent facial gestalt to Intellectual developmental disorder, X-linked syndromic 37, OMIM:301118
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 v5.531 GAN Arina Puzriakova Tag Q2_24_promote_green tag was added to gene: GAN.
Tag Q2_24_NHS_review tag was added to gene: GAN.
Intellectual disability v5.531 GAN Arina Puzriakova Publications for gene: GAN were set to
Intellectual disability v5.530 GAN Arina Puzriakova Classified gene: GAN as Amber List (moderate evidence)
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 v5.530 GAN Arina Puzriakova Gene: gan has been classified as Amber List (Moderate Evidence).
Intellectual disability v5.529 GAN Arina Puzriakova Mode of inheritance for gene: GAN was changed from to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v5.528 GAN Arina Puzriakova Phenotypes for gene: GAN were changed from to Giant axonal neuropathy-1, OMIM:256850
Intellectual disability v5.527 SEPHS1 Arina Puzriakova Classified gene: SEPHS1 as Amber List (moderate evidence)
Intellectual disability v5.527 SEPHS1 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update.
Intellectual disability v5.527 SEPHS1 Arina Puzriakova Gene: sephs1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v5.526 SEPHS1 Arina Puzriakova Classified gene: SEPHS1 as Amber List (moderate evidence)
Intellectual disability v5.526 SEPHS1 Arina Puzriakova Gene: sephs1 has been classified as Amber List (Moderate Evidence).
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 Classified gene: FRYL as Amber List (moderate evidence)
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 v5.523 FRYL Arina Puzriakova Gene: fryl has been classified as Amber List (Moderate Evidence).
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 v5.521 DENND5B Sarah Leigh Classified gene: DENND5B as Amber List (moderate evidence)
Intellectual disability v5.521 DENND5B Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Intellectual disability v5.521 DENND5B Sarah Leigh Gene: dennd5b has been classified as Amber List (Moderate Evidence).
Intellectual disability v5.520 DENND5B Sarah Leigh Tag Q2_24_promote_green tag was added to gene: DENND5B.
Tag Q2_24_NHS_review tag was added to gene: DENND5B.
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 v5.519 TBC1D2B Sarah Leigh Tag watchlist was removed from gene: TBC1D2B.
Tag Q2_24_promote_green tag was added to gene: TBC1D2B.
Tag Q2_24_NHS_review tag was added to gene: TBC1D2B.
Intellectual disability v5.519 TBC1D2B Sarah Leigh Classified gene: TBC1D2B as Amber List (moderate evidence)
Intellectual disability v5.519 TBC1D2B Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Intellectual disability v5.519 TBC1D2B Sarah Leigh Gene: tbc1d2b has been classified as Amber List (Moderate Evidence).
Intellectual disability v5.518 TBC1D2B Sarah Leigh reviewed gene: TBC1D2B: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v5.518 TBC1D2B Sarah Leigh Publications for gene: TBC1D2B were set to 32623794
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 Added comment: Comment on phenotypes: Gene-checked tag removed as this gene now has a relevant phenotype listed in OMIM (Intellectual developmental disorder, autosomal recessive 81, OMIM:620700)
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 ASCC3 Arina Puzriakova Tag gene-checked was removed from gene: ASCC3.
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 v5.513 PTRHD1 Arina Puzriakova Tag gene-checked was removed from gene: PTRHD1.
Intellectual disability v5.513 SLC32A1 Arina Puzriakova Added comment: Comment on phenotypes: Gene-checked tag removed as this gene now has a relevant phenotype listed in OMIM (Developmental and epileptic encephalopathy 114, OMIM:620774)
Intellectual disability v5.513 SLC32A1 Arina Puzriakova Phenotypes for gene: SLC32A1 were changed from developmental and epileptic encephalopathy, MONDO:0100062 to Developmental and epileptic encephalopathy 114, OMIM:620774
Intellectual disability v5.512 SLC32A1 Arina Puzriakova Tag gene-checked was removed from gene: SLC32A1.
Intellectual disability v5.512 BRD4 Arina Puzriakova Added comment: Comment on phenotypes: Gene-checked tag removed as this gene now has a phenotype listed in OMIM (Cornelia de Lange syndrome 6, OMIM:620568)
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 v5.511 BRD4 Arina Puzriakova Tag gene-checked was removed from gene: BRD4.
Intellectual disability v5.511 CAPRIN1 Arina Puzriakova Publications for gene: CAPRIN1 were set to 23849776; 35979925; 36136249
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 v5.509 CAPRIN1 Arina Puzriakova Tag gene-checked was removed from gene: CAPRIN1.
Intellectual disability v5.509 WNK3 Arina Puzriakova Phenotypes for gene: WNK3 were changed from X-linked intellectual disability, MONDO:0100284 to Prieto syndrome, OMIM:309610; Intellectual disability, MONDO:0001071
Intellectual disability v5.508 WNK3 Arina Puzriakova Tag gene-checked was removed from gene: WNK3.
Intellectual disability v5.508 C12orf4 Arina Puzriakova Phenotypes for gene: C12orf4 were changed from Autosomal recessive intellectual disability to Intellectual developmental disorder, autosomal recessive 66, OMIM:618221
Intellectual disability v5.507 C12orf4 Arina Puzriakova commented on gene: C12orf4
Intellectual disability v5.507 C12orf4 Arina Puzriakova Tag new-gene-name tag was added to gene: C12orf4.
Intellectual disability v5.507 IKBKG Arina Puzriakova Phenotypes for gene: IKBKG were changed from Incontinentia pigmenti, type II, 308300Ectodermal dysplasia, hypohidrotic, with immune deficiency, 300291Ectodermal, dysplasia, anhidrotic, lymphedema and immunodeficiency, 300301Immunodeficiency, isolated, 300584{Atypical mycobacteriosis, familial}, 300636Invasive pneumococcal disease, recurrent isolated, 2, 300640; INCONTINENTIA PIGMENTI (IP) to Incontinentia pigmenti, OMIM:308300
Intellectual disability v5.506 ZFX Tracy Lester reviewed gene: ZFX: Rating: GREEN; Mode of pathogenicity: None; Publications: 38325380; Phenotypes: Intellectual disability, developmental delay, behavioural abnormalities, hypotonia, dysmorphic facies; 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 v5.506 CLEC16A Arina Puzriakova Tag Q1_24_promote_green tag was added to gene: CLEC16A.
Intellectual disability v5.506 GLI3 Tracy Lester reviewed gene: GLI3: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
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 v5.503 PIK3R2 Arina Puzriakova Phenotypes for gene: PIK3R2 were changed from Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome, 603387; MEGALENCEPHALY-POLYMICROGYRIA-POLYDACTYLY-HYDROCEPHALUS SYNDROME 1 to Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 1, OMIM:603387
Intellectual disability v5.502 ROBO1 Arina Puzriakova Tag watchlist_moi tag was added to gene: ROBO1.
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 v5.502 CLEC16A Sarah Leigh Classified gene: CLEC16A as Amber List (moderate evidence)
Intellectual disability v5.502 CLEC16A Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be green on this panel.
Intellectual disability v5.502 CLEC16A Sarah Leigh Gene: clec16a has been classified as Amber List (Moderate Evidence).
Intellectual disability v5.501 CLEC16A Sarah Leigh Publications for gene: CLEC16A were set to 36538041
Intellectual disability v5.500 CLEC16A Sarah Leigh Publications for gene: CLEC16A were set to PMID: 36538041
Intellectual disability v5.500 CLEC16A Sarah Leigh Classified gene: CLEC16A as Amber List (moderate evidence)
Intellectual disability v5.500 CLEC16A Sarah Leigh Gene: clec16a has been classified as Amber List (Moderate Evidence).
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 v5.499 ZFHX3 Sarah Leigh Tag Q1_24_promote_green tag was added to gene: ZFHX3.
Tag Q1_24_NHS_review tag was added to gene: ZFHX3.
Intellectual disability v5.499 ZFHX3 Sarah Leigh reviewed gene: ZFHX3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v5.499 ZFHX3 Sarah Leigh Classified gene: ZFHX3 as Amber List (moderate evidence)
Intellectual disability v5.499 ZFHX3 Sarah Leigh Gene: zfhx3 has been classified as Amber List (Moderate Evidence).
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 SOX9 Tracy Lester reviewed gene: SOX9: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Skeletal dysplasia; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
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 Classified gene: SNF8 as Amber List (moderate evidence)
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 v5.496 SNF8 Achchuthan Shanmugasundram Gene: snf8 has been classified as Amber List (Moderate Evidence).
Intellectual disability v5.495 SNF8 Achchuthan Shanmugasundram Tag Q1_24_promote_green tag was added to gene: SNF8.
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 v5.494 CCBE1 Arina Puzriakova Phenotypes for gene: CCBE1 were changed from Hennekam lymphangiectasia-lymphedema syndrome, 235510; HENNEKAM LYMPHANGIECTASIA-LYMPHEDEMA SYNDROME (HLLS) to Hennekam lymphangiectasia-lymphedema syndrome 1, OMIM:235510
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 v5.493 DYNC2H1 Arina Puzriakova Publications for gene: DYNC2H1 were set to
Intellectual disability v5.492 ZNFX1 Sarah Leigh Tag Q1_24_promote_green tag was added to gene: ZNFX1.
Tag Q1_24_NHS_review tag was added to gene: ZNFX1.
Intellectual disability v5.492 ZNFX1 Sarah Leigh Classified gene: ZNFX1 as Amber List (moderate evidence)
Intellectual disability v5.492 ZNFX1 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be green on this panel.
Intellectual disability v5.492 ZNFX1 Sarah Leigh Gene: znfx1 has been classified as Amber List (Moderate Evidence).
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 v5.487 ZFX Sarah Leigh Phenotypes for gene: ZFX were changed from to X-linked neurodevelopmental disorder with recurrent facial gestalt
Intellectual disability v5.486 ZFX Sarah Leigh Publications for gene: ZFX were set to 26350204; 26740508
Intellectual disability v5.486 ZFX Sarah Leigh Classified gene: ZFX as Amber List (moderate evidence)
Intellectual disability v5.486 ZFX Sarah Leigh Added comment: Comment on list classification: There is sufficient evidence for this gene to be green on this panel.
Intellectual disability v5.486 ZFX Sarah Leigh Gene: zfx has been classified as Amber List (Moderate Evidence).
Intellectual disability v5.485 ZFX Sarah Leigh Tag Q1_24_promote_green tag was added to gene: ZFX.
Tag Q1_24_NHS_review tag was added to gene: ZFX.
Intellectual disability v5.485 ZFX Sarah Leigh reviewed gene: ZFX: Rating: GREEN; Mode of pathogenicity: None; Publications: 38325380; Phenotypes: X-linked neurodevelopmental disorder with recurrent facial gestalt; 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 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 v5.484 PPP2R2B Arina Puzriakova Publications for gene: PPP2R2B were set to
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 Classified gene: NXF5 as Red List (low evidence)
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 v5.483 NXF5 Arina Puzriakova Gene: nxf5 has been classified as Red List (Low Evidence).
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 v5.482 NXF5 Arina Puzriakova Publications for gene: NXF5 were set to 11566096; 26350204; 23675524; 22030050; 20096387
Intellectual disability v5.481 NXF5 Arina Puzriakova Publications for gene: NXF5 were set to 11566096; 26350204; 23675524; 22030050
Intellectual disability v5.480 NXF5 Arina Puzriakova reviewed gene: NXF5: Rating: ; Mode of pathogenicity: None; Publications: 11566096, 20096387, 22030050, 23675524; Phenotypes: ; Mode of inheritance: None
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 v5.479 KIRREL3 Arina Puzriakova Publications for gene: KIRREL3 were set to 22965935; 19012874; 29271092; 37605258; 33853164
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 v5.476 INTS1 Arina Puzriakova Publications for gene: INTS1 were set to 28542170; 30622326; 17544522
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 Classified gene: EFNB1 as Amber List (moderate evidence)
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 v5.474 EFNB1 Arina Puzriakova Gene: efnb1 has been classified as Amber List (Moderate Evidence).
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 v5.473 EFNB1 Arina Puzriakova Publications for gene: EFNB1 were set to 23335590
Intellectual disability v5.472 EFNB1 Arina Puzriakova reviewed gene: EFNB1: Rating: AMBER; Mode of pathogenicity: None; Publications: 23335590, 25679214, 27650623, 31088393, 24520368; Phenotypes: Craniofrontonasal dysplasia, OMIM:304110; 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 v5.472 EFNB1 Arina Puzriakova Phenotypes for gene: EFNB1 were changed from Gene2Phenotype confirmed gene with ID HPO to Craniofrontonasal dysplasia, OMIM:304110
Intellectual disability v5.471 EFNB1 Arina Puzriakova Publications for gene: EFNB1 were set to
Intellectual disability v5.470 DYNC2H1 Arina Puzriakova Phenotypes for gene: DYNC2H1 were changed from Short-rib thoracic dysplasia 3 with or without polydactyly, 613091 to Short-rib thoracic dysplasia 3 with or without polydactyly, OMIM:613091
Intellectual disability v5.469 KCNA1 Achchuthan Shanmugasundram Phenotypes for gene: KCNA1 were changed from Episodic ataxia/myokymia syndrome, OMIM:160120 to Episodic ataxia/myokymia syndrome, OMIM:160120
Intellectual disability v5.469 KCNA1 Achchuthan Shanmugasundram Phenotypes for gene: KCNA1 were changed from Episodic ataxia/myokymia syndrome, 160120 to Episodic ataxia/myokymia syndrome, OMIM:160120
Intellectual disability v5.468 KCNA1 Achchuthan Shanmugasundram Publications for gene: KCNA1 were set to 27730449; 30055040; 34778950
Intellectual disability v5.468 KCNA1 Achchuthan Shanmugasundram Publications for gene: KCNA1 were set to 27730449
Intellectual disability v5.467 KCNA1 Achchuthan Shanmugasundram Mode of inheritance for gene: KCNA1 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v5.466 KCNA1 Achchuthan Shanmugasundram Classified gene: KCNA1 as Amber List (moderate evidence)
Intellectual disability v5.466 KCNA1 Achchuthan Shanmugasundram Gene: kcna1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v5.465 KCNA1 Achchuthan Shanmugasundram reviewed gene: KCNA1: Rating: AMBER; Mode of pathogenicity: None; Publications: 30055040, 34778950; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v5.465 CTNND2 Arina Puzriakova commented on gene: CTNND2
Intellectual disability v5.465 CTNND2 Arina Puzriakova Phenotypes for gene: CTNND2 were changed from to CTNND2-related neurodevelopmental disorder
Intellectual disability v5.464 CTNND2 Arina Puzriakova Mode of inheritance for gene: CTNND2 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v5.463 CLIC2 Arina Puzriakova Tag disputed tag was added to gene: CLIC2.
Intellectual disability v5.463 CLIC2 Arina Puzriakova Phenotypes for gene: CLIC2 were changed from Intellectual developmental disorder, X-linked syndromic 32 , OMIM:300886 to Intellectual developmental disorder, X-linked syndromic 32, OMIM:300886
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 v5.458 CAMSAP1 Achchuthan Shanmugasundram Classified gene: CAMSAP1 as Amber List (moderate evidence)
Intellectual disability v5.458 CAMSAP1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the promotion of this gene to green rating in the next GMS review.
Intellectual disability v5.458 CAMSAP1 Achchuthan Shanmugasundram Gene: camsap1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v5.457 CAMSAP1 Achchuthan Shanmugasundram Tag Q1_24_promote_green tag was added to gene: CAMSAP1.
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 v5.456 BAZ2B Achchuthan Shanmugasundram Classified gene: BAZ2B as Amber List (moderate evidence)
Intellectual disability v5.456 BAZ2B Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the promotion of this gene to green rating in the next GMS review.
Intellectual disability v5.456 BAZ2B Achchuthan Shanmugasundram Gene: baz2b has been classified as Amber List (Moderate Evidence).
Intellectual disability v5.455 BAZ2B Achchuthan Shanmugasundram Phenotypes for gene: BAZ2B were changed from neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071 to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Intellectual disability v5.455 BAZ2B Achchuthan Shanmugasundram Phenotypes for gene: BAZ2B were changed from neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071 to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Intellectual disability v5.455 BAZ2B Achchuthan Shanmugasundram Phenotypes for gene: BAZ2B were changed from developmental delay, intellectual disability and autism spectrum disorder to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Intellectual disability v5.454 BAZ2B Achchuthan Shanmugasundram Publications for gene: BAZ2B were set to 31999386; 37872713
Intellectual disability v5.454 BAZ2B Achchuthan Shanmugasundram Publications for gene: BAZ2B were set to 31999386; 37872713
Intellectual disability v5.454 BAZ2B Achchuthan Shanmugasundram Publications for gene: BAZ2B were set to PMID: 31999386
Intellectual disability v5.453 BAZ2B Achchuthan Shanmugasundram Tag Q1_24_promote_green tag was added to gene: BAZ2B.
Intellectual disability v5.453 BAZ2B Achchuthan Shanmugasundram reviewed gene: BAZ2B: Rating: GREEN; Mode of pathogenicity: None; Publications: 37872713; Phenotypes: neurodevelopmental disorder, MONDO:0700092, intellectual disability, MONDO:0001071; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v5.453 KCNA1 Tracy Lester reviewed gene: KCNA1: Rating: GREEN; Mode of pathogenicity: None; Publications: 30055040, 34778950; Phenotypes: epileptic encephalopathy, ataxia; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v5.453 LRRC32 Achchuthan Shanmugasundram Classified gene: LRRC32 as Amber List (moderate evidence)
Intellectual disability v5.453 LRRC32 Achchuthan Shanmugasundram Gene: lrrc32 has been classified as Amber List (Moderate Evidence).
Intellectual disability v5.452 LRRC32 Achchuthan Shanmugasundram Publications for gene: LRRC32 were set to 30976112
Intellectual disability v5.451 LRRC32 Achchuthan Shanmugasundram reviewed gene: LRRC32: Rating: AMBER; Mode of pathogenicity: None; Publications: 30976112, 35656379; Phenotypes: Cleft palate, proliferative retinopathy, and developmental delay, OMIM:619074; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v5.451 ACBD6 Jana Jezkova reviewed gene: ACBD6: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 37951597; Phenotypes: HP:0001263, HP:0001249; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v5.451 MADD Sarah Leigh Phenotypes for gene: MADD were changed from Neurodevelopmental disorder with dysmorphic facies, impaired speech and hypotonia, 619005; DEEAH syndrome, 619004 to DEEAH syndrome, OMIM:619004; deeah syndrome, MONDO:0033561: Neurodevelopmental disorder with dysmorphic facies, impaired speech and hypotonia, OMIM:619005; neurodevelopmental disorder with dysmorphic facies, impaired speech, and hypotonia, MONDO:0033562
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 v5.450 ABCC9 Sarah Leigh Mode of pathogenicity for gene: ABCC9 was changed from None to None
Intellectual disability v5.450 ABCC9 Sarah Leigh Mode of pathogenicity for gene: ABCC9 was changed from Other to None
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 Tag Q1_24_MOI tag was added to gene: DHX37.
Tag Q1_24_NHS_review tag was added to gene: DHX37.
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 v5.449 DHX37 Sarah Leigh Mode of inheritance for gene: DHX37 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
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 v5.448 ABCC9 Sarah Leigh Mode of pathogenicity for gene: ABCC9 was changed from to Other
Intellectual disability v5.447 DHX37 Sarah Leigh Publications for gene: DHX37 were set to 26539891; 31256877
Intellectual disability v5.446 ABCC9 Sarah Leigh Tag watchlist_moi was removed from gene: ABCC9.
Tag Q1_24_MOI tag was added to gene: ABCC9.
Tag Q1_24_NHS_review tag was added to gene: ABCC9.
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 v5.445 ABCC9 Sarah Leigh reviewed gene: ABCC9: Rating: GREEN; Mode of pathogenicity: None; Publications: 38217872; Phenotypes: Intellectual disability and myopathy syndrome, OMIM:619719, intellectual disability and myopathy syndrome, MONDO:0859224; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v5.445 ABCC9 Sarah Leigh Publications for gene: ABCC9 were set to 25529582; 24896178; 31575858; 38217872
Intellectual disability v5.444 ABCC9 Sarah Leigh Publications for gene: ABCC9 were set to 25529582; 24896178; 31575858
Intellectual disability v5.443 ABCC9 Sarah Leigh Publications for gene: ABCC9 were set to
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 Tag Q1_24_promote_green tag was added to gene: KIRREL3.
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 v5.441 KIRREL3 Sarah Leigh Classified gene: KIRREL3 as Amber List (moderate evidence)
Intellectual disability v5.441 KIRREL3 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Intellectual disability v5.441 KIRREL3 Sarah Leigh Gene: kirrel3 has been classified as Amber List (Moderate Evidence).
Intellectual disability v5.440 KIRREL3 Sarah Leigh reviewed gene: KIRREL3: Rating: GREEN; Mode of pathogenicity: None; Publications: 29271092; Phenotypes: ; Mode of inheritance: None
Intellectual disability v5.440 KIRREL3 Sarah Leigh Publications for gene: KIRREL3 were set to 22965935; 19012874; 29271092; 29271092; 37605258
Intellectual disability v5.439 KIRREL3 Sarah Leigh Publications for gene: KIRREL3 were set to 22965935; 19012874; 29271092; 29271092:37605258
Intellectual disability v5.438 KIRREL3 Sarah Leigh Publications for gene: KIRREL3 were set to 22965935; 19012874; 33853164; 37605258
Intellectual disability v5.437 KIRREL3 Sarah Leigh Publications for gene: KIRREL3 were set to 22965935; 19012874; 33853164; 33853164; 37605258
Intellectual disability v5.436 KIRREL3 Sarah Leigh Publications for gene: KIRREL3 were set to 22965935; 19012874; 33853164
Intellectual disability v5.435 KIRREL3 Sarah Leigh Mode of inheritance for gene: KIRREL3 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v5.434 TUSC3 Arina Puzriakova Publications for gene: TUSC3 were set to
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 v5.432 CC2D1A Arina Puzriakova Publications for gene: CC2D1A were set to
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 LRRC32 Hannah Knight reviewed gene: LRRC32: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 35656379; Phenotypes: Cleft palate, proliferative retinopathy, and developmental delay; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
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 v5.428 ASPM Arina Puzriakova Publications for gene: ASPM were set to
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 v5.425 WDR62 Arina Puzriakova Publications for gene: WDR62 were set to
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 v5.423 MCPH1 Arina Puzriakova Publications for gene: MCPH1 were set to
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 v5.421 HSD17B10 Arina Puzriakova Mode of inheritance for gene: HSD17B10 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 v5.420 HSD17B10 Arina Puzriakova Tag Q1_24_MOI tag was added to gene: HSD17B10.
Intellectual disability v5.420 HSD17B10 Arina Puzriakova Publications for gene: HSD17B10 were set to
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