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Intellectual disability v3.1018 NCDN Zornitza Stark gene: NCDN was added
gene: NCDN was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: NCDN was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: NCDN were set to 33711248
Phenotypes for gene: NCDN were set to Intellectual disability; epilepsy
Review for gene: NCDN was set to GREEN
Added comment: Four families reported, all with de novo missense variants except for 1 consanguineous family where 3 affecteds were homozygous and carrier parents unaffected. ID ranged from mild to severe, several had seizures. Green for mono-allelic disease, Red for bi-allelic.
Sources: Literature
Intellectual disability v3.1018 CDH11 Zornitza Stark reviewed gene: CDH11: Rating: GREEN; Mode of pathogenicity: None; Publications: 33811546, 27431290, 28988429, 29271567, 33811546; Phenotypes: Elsahy-Waters syndrome, MIM# 211380, Teebi hypertelorism syndrome; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability v3.1018 INPP4A Zornitza Stark reviewed gene: INPP4A: Rating: AMBER; Mode of pathogenicity: None; Publications: 31978615, 31938306, 25338135, 20011524; Phenotypes: Intellectual disability; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1018 LOXHD1 Arina Puzriakova Mode of inheritance for gene: LOXHD1 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1017 KCNH1 Arina Puzriakova Phenotypes for gene: KCNH1 were changed from Temple-Baraitser syndrome, OMIM:611816; Temple-Baraitser syndrome, MONDO:0012735; Zimmermann-Laband syndrome 1, OMIM:135500; Zimmermann-Laband syndrome 1, MONDO:0024526 to Temple-Baraitser syndrome, OMIM:611816; Zimmermann-Laband syndrome 1, OMIM:135500; Intellectual disability; Encephalopathy without features of TBS/ZLS
Intellectual disability v3.1016 KCNH1 Arina Puzriakova Publications for gene: KCNH1 were set to 25420144; 33594261
Intellectual disability v3.1015 KCNH1 Arina Puzriakova edited their review of gene: KCNH1: Changed phenotypes: Intellectual disability, Encephalopathy without features of TBS/ZLS
Intellectual disability v3.1015 KCNH1 Arina Puzriakova reviewed gene: KCNH1: Rating: GREEN; Mode of pathogenicity: None; Publications: 33811134; Phenotypes: Intellectual disability; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.1015 COPB1 Zornitza Stark gene: COPB1 was added
gene: COPB1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: COPB1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COPB1 were set to 33632302
Phenotypes for gene: COPB1 were set to Baralle-Macken syndrome, MIM# 619255; Severe intellectual disability; variable microcephaly; cataracts
Review for gene: COPB1 was set to AMBER
Added comment: Two unrelated families, some supportive functional data.
Sources: Literature
Intellectual disability v3.1015 IRF2BPL Sarah Leigh Phenotypes for gene: IRF2BPL were changed from Neurodevelopmental disorder with regression, abnormal movements, loss of speech, and seizures; Global developmental delay, Developmental regression, Seizures, Ataxia to Neurodevelopmental disorder with regression, abnormal movements, loss of speech, and seizures OMIM:618088; neurodevelopmental disorder with regression, abnormal movements, loss of speech, and seizures MONDO:0060759
Intellectual disability v3.1014 FBXL4 Sarah Leigh Added comment: Comment on phenotypes: FATAL ENCEPHALOPATHY, LACTIC ACIDOSIS, AND SEVERE MTDNA DEPLETION IN MUSCLE
Intellectual disability v3.1014 FBXL4 Sarah Leigh Phenotypes for gene: FBXL4 were changed from Mitochondrial DNA depletion syndrome 13 (encephalomyopathic type), 615471; FATAL ENCEPHALOPATHY, LACTIC ACIDOSIS, AND SEVERE MTDNA DEPLETION IN MUSCLE to Mitochondrial DNA depletion syndrome 13 (encephalomyopathic type) OMIM:615471; mitochondrial DNA depletion syndrome 13 MONDO:0014198
Intellectual disability v3.1013 EBF3 Sarah Leigh Phenotypes for gene: EBF3 were changed from Hypotonia, ataxia, and delayed development syndrome 617330 to Hypotonia, ataxia, and delayed development syndrome OMIM:617330; hypotonia, ataxia, and delayed development syndrome MONDO:0015021
Intellectual disability v3.1012 DOCK3 Sarah Leigh Phenotypes for gene: DOCK3 were changed from Neurodevelopmental disorder with impaired intellectual development, hypotonia, and ataxia, 618292 to Neurodevelopmental disorder with impaired intellectual development, hypotonia, and ataxia OMIM:618292; neurodevelopmental disorder with impaired intellectual development, hypotonia, and ataxia MONDO:0032661
Intellectual disability v3.1011 KCNQ2 Arina Puzriakova Publications for gene: KCNQ2 were set to
Intellectual disability v3.1010 KCNQ2 Arina Puzriakova Phenotypes for gene: KCNQ2 were changed from Seizures, benign neonatal, 1, 121200Myokymia, 121200Epileptic encephalopathy, early infantile, 7, 613720; BENIGN NEONATAL EPILEPSY TYPE 1 (EBN1) to Developmental and epileptic encephalopathy 7, OMIM:613720
Intellectual disability v3.1009 FAR1 Arina Puzriakova Publications for gene: FAR1 were set to 0
Intellectual disability v3.1008 FAR1 Arina Puzriakova Phenotypes for gene: FAR1 were changed from SEVERE INTELLECTUAL DISABILITY, EPILEPSY, AND CATARACTS to Peroxisomal fatty acyl-CoA reductase 1 disorder, OMIM:616154
Intellectual disability v3.1007 LARS2 Arina Puzriakova Publications for gene: LARS2 were set to
Intellectual disability v3.1006 LARS2 Arina Puzriakova changed review comment from: Comment on list classification: While are a few cases with neurological symptoms including developmental delay have been reported, this manifestation is part of a broader phenotype where cognitive impairment is unlikely to represent a main feature. In the majority of cases, cognitive function is preserved.

Therefore, rating Amber on this panel. The phenotypes associated with LARS2 are better represented in other panels (e.g. Hearing loss) where this gene is already Green.; to: Comment on list classification: While a few cases with neurological symptoms including developmental delay or neurologic decline have been reported (PMID: 29205794; 30737337; 32442335), this manifestation is part of a broader phenotype where cognitive impairment is unlikely to represent the main feature. In the majority of cases, cognitive function is preserved.

Therefore, rating Amber on this panel. The phenotypes associated with LARS2 are better represented in other panels (e.g. Hearing loss) where this gene is already Green.
Intellectual disability v3.1006 LARS2 Arina Puzriakova Classified gene: LARS2 as Amber List (moderate evidence)
Intellectual disability v3.1006 LARS2 Arina Puzriakova Added comment: Comment on list classification: While are a few cases with neurological symptoms including developmental delay have been reported, this manifestation is part of a broader phenotype where cognitive impairment is unlikely to represent a main feature. In the majority of cases, cognitive function is preserved.

Therefore, rating Amber on this panel. The phenotypes associated with LARS2 are better represented in other panels (e.g. Hearing loss) where this gene is already Green.
Intellectual disability v3.1006 LARS2 Arina Puzriakova Gene: lars2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1005 LARS2 Arina Puzriakova Phenotypes for gene: LARS2 were changed from to Perrault syndrome 4, OMIM:615300; Hydrops, lactic acidosis, and sideroblastic anemia, OMIM:617021; Leukodystrophy
Intellectual disability v3.1004 LARS2 Arina Puzriakova Mode of inheritance for gene: LARS2 was changed from to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1003 NCKAP1 Zornitza Stark reviewed gene: NCKAP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 33157009; Phenotypes: Intellectual disability, autism; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.1003 LARS2 Zornitza Stark reviewed gene: LARS2: Rating: GREEN; Mode of pathogenicity: None; Publications: 29205794, 32423379, 30737337, 26537577, 23541342; Phenotypes: Perrault syndrome 4, Hydrops, lactic acidosis, and sideroblastic anemia, MIM# 617021, Leukodystrophy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1003 DPYS Zornitza Stark gene: DPYS was added
gene: DPYS was added to Intellectual disability. Sources: Expert Review
Mode of inheritance for gene: DPYS was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: DPYS were set to Dihydropyrimidinuria, MIM#222748
Review for gene: DPYS was set to GREEN
gene: DPYS was marked as current diagnostic
Added comment: Highly variable phenotype, but many have ID.
Sources: Expert Review
Intellectual disability v3.1003 DPM2 Zornitza Stark edited their review of gene: DPM2: Added comment: Further unrelated individual reported, main clinical features were truncal hypotonia, hypertonicity, congenital heart defects, intellectual disability, and generalized muscle wasting.; Changed rating: GREEN; Changed publications: 23109149, 33129689
Intellectual disability v3.1003 B4GALT1 Zornitza Stark reviewed gene: B4GALT1: Rating: AMBER; Mode of pathogenicity: None; Publications: 11901181, 30653653, 21920538; Phenotypes: Congenital disorder of glycosylation, type Iid, MIM#607091; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1003 AGO1 Zornitza Stark reviewed gene: AGO1: Rating: GREEN; Mode of pathogenicity: None; Publications: 30213762, 22495306, 23020937, 25363768, 25356899, 27620904, 29346770, 28135719; Phenotypes: Intellectual disability, autism; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Intellectual disability v3.1003 CLN5 Sarah Leigh Phenotypes for gene: CLN5 were changed from Ceroid lipofuscinosis, neuronal, 5, 256731; NEURONAL CEROID LIPOFUSCINOSIS TYPE 5 (CLN5) to Ceroid lipofuscinosis, neuronal, 5 OMIM:256731; neuronal ceroid lipofuscinosis 5 MONDO:0009745
Intellectual disability v3.1002 BBS1 Sarah Leigh Publications for gene: BBS1 were set to
Intellectual disability v3.1001 BBS1 Sarah Leigh Phenotypes for gene: BBS1 were changed from Bardet-Biedl syndrome 1, 209900; BARDET-BIEDL SYNDROME TYPE 1 (BBS1) to Bardet-Biedl syndrome 1 OMIM:209900; Bardet-Biedl syndrome 1 MONDO:0008854
Intellectual disability v3.1000 ATP8A2 Sarah Leigh Publications for gene: ATP8A2 were set to 22892528; 27679995; 30012219; 29531481; 29531481; 31612321
Intellectual disability v3.999 ATP8A2 Sarah Leigh Publications for gene: ATP8A2 were set to 22892528; 27679995; 30012219; 29531481
Intellectual disability v3.998 ATP8A2 Sarah Leigh Phenotypes for gene: ATP8A2 were changed from ?Cerebellar ataxia, mental retardation, and dysequilibrium syndrome 4 615268; intellectual disability to ?Cerebellar ataxia, mental retardation, and dysequilibrium syndrome 4 OMIM:615268; cerebellar ataxia, mental retardation, and dysequilibrium syndrome 4 MONDO:0014104
Intellectual disability v3.997 SPEN Arina Puzriakova Publications for gene: SPEN were set to 33057194
Intellectual disability v3.996 SPEN Arina Puzriakova Classified gene: SPEN as Amber List (moderate evidence)
Intellectual disability v3.996 SPEN Arina Puzriakova Added comment: Comment on list classification: There is now enough evidence to promote this gene to Green at the next review - sufficient cases (>20) with truncating SPEN variants and GDD/ID of relevant severity to this panel.
Intellectual disability v3.996 SPEN Arina Puzriakova Gene: spen has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.995 SPEN Arina Puzriakova Tag Q2_21_rating tag was added to gene: SPEN.
Intellectual disability v3.995 MED27 Arina Puzriakova Phenotypes for gene: MED27 were changed from Intellectual disability; cerebellar hypoplasia; dystonia to Intellectual disability; Axial hypotonia; Spasticity; Dystonia; Cerebellar hypoplasia; Cataracts; Epilepsy
Intellectual disability v3.994 MED27 Arina Puzriakova Classified gene: MED27 as Amber List (moderate evidence)
Intellectual disability v3.994 MED27 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next review - at least 11 unrelated families reported with MED27 variants presenting overlapping phenotypes that include ID of relevant severity to this panel.
Intellectual disability v3.994 MED27 Arina Puzriakova Gene: med27 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.993 MED27 Arina Puzriakova Tag Q2_21_rating tag was added to gene: MED27.
Intellectual disability v3.993 MED27 Arina Puzriakova reviewed gene: MED27: Rating: GREEN; Mode of pathogenicity: None; Publications: 33443317; Phenotypes: Intellectual disability, Axial hypotonia, Spasticity, Dystonia, Cerebellar hypoplasia, Cataracts, Epilepsy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.993 EIF5A Arina Puzriakova Tag Q2_21_rating tag was added to gene: EIF5A.
Intellectual disability v3.993 EIF5A Arina Puzriakova Classified gene: EIF5A as Amber List (moderate evidence)
Intellectual disability v3.993 EIF5A Arina Puzriakova Added comment: Comment on list classification: There is enough evidence to rate this gene Green at the next review - PMID: 33547280 (2021) reports 7 unrelated individuals with different de novo heterozygous variants in the EIF5A gene. All were affected by variable degrees of DD and/or ID, mostly within the moderate severity range. Other features such as microcephaly and craniofacial dysmorphism were prominent but overall, the phenotype is best represented by this panel. Supportive functional data included.

EIF5A is currently not associated with any phenotype in OMIM (last edited on 18/07/2019), but is listed in Gene2Phenotype with a 'probable' disease confidence rating for 'EIF5A-related craniofacial-neurodevelopmental disorder'
Intellectual disability v3.993 EIF5A Arina Puzriakova Gene: eif5a has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.992 RAD50 Arina Puzriakova Phenotypes for gene: RAD50 were changed from Nijmegen breakage syndrome-like disorder, 613078 to Nijmegen breakage syndrome-like disorder, OMIM:613078
Intellectual disability v3.991 RAD50 Arina Puzriakova Publications for gene: RAD50 were set to 1887849; 19409520; 32212377
Intellectual disability v3.990 RAD50 Arina Puzriakova edited their review of gene: RAD50: Added comment: - PMID: 33378670 (2020) - single patient described with bone marrow failure, immunodeficiency and developmental defects, who was compound heterozygous for a frameshift and premature stop codon (c.2165dup; p.Glu723Glyfs∗5 - maternally inherited) and in-frame deletion (c.3109_3111del; p.Glu1035del - de novo) in the RAD50 gene.
Functional characterisation using patient-derived fibroblasts indicated defects in DNA replication, DNA repair, and DNA end resection; however, ATM-dependent DNA damage response remained intact. Studies in yeast modelling the variant corresponding to p.Glu1035del produced defects in both DNA repair and Tel1ATM-dependent signalling following thermal activation.

This is the third case published with biallelic variants in the RAD50 gene. Although authors report 'developmental defects', it is unclear whether this individual displayed cognitive impairment. Therefore, maintaining the Red gene rating on this panel.; Changed rating: RED; Changed publications: 19409520, 32212377, 33378670; Changed phenotypes: Nijmegen breakage syndrome-like disorder, OMIM:613078; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.990 ALDH5A1 Sarah Leigh Publications for gene: ALDH5A1 were set to
Intellectual disability v3.989 ALDH5A1 Sarah Leigh Phenotypes for gene: ALDH5A1 were changed from Succinic semialdehyde dehydrogenase deficiency, 271980; SUCCINATE SEMIALDEHYDE DEHYDROGENASE DEFICIENCY to Succinic semialdehyde dehydrogenase deficiency OMIM:271980; succinic semialdehyde dehydrogenase deficiency MONDO:0010083
Intellectual disability v3.988 GNB1 Arina Puzriakova Phenotypes for gene: GNB1 were changed from Intellectual disability; developmental delay; Global developmental delay to Mental retardation, autosomal dominant 42, OMIM:616973
Intellectual disability v3.987 ADPRHL2 Sarah Leigh Phenotypes for gene: ADPRHL2 were changed from Developmental regression; Seizures; Ataxia; Intellectual disability to Neurodegeneration, childhood-onset, stress-induced, with variable ataxia and seizures OMIM:618170; neurodegeneration, childhood-onset, stress-induced, with variable ataxia and seizures MONDO:0100095
Intellectual disability v3.986 ADPRHL2 Sarah Leigh Publications for gene: ADPRHL2 were set to 30100084
Intellectual disability v3.985 TMPRSS9 Arina Puzriakova Added comment: Comment on mode of inheritance: Rating this gene Red as second case is based on unpublished results, but with a watchlist tag as new data on this gene-disease association may become available soon.
Intellectual disability v3.985 TMPRSS9 Arina Puzriakova Mode of inheritance for gene: TMPRSS9 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.984 TMPRSS9 Arina Puzriakova gene: TMPRSS9 was added
gene: TMPRSS9 was added to Intellectual disability. Sources: Other
watchlist tags were added to gene: TMPRSS9.
Mode of inheritance for gene: TMPRSS9 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TMPRSS9 were set to 31943016
Phenotypes for gene: TMPRSS9 were set to Progressive intellectual and neurological deterioration; Global developmental delay; Intellectual disability; Autism; Epilepsy
Review for gene: TMPRSS9 was set to RED
Added comment: TMPRSS9 is currently not associated with any phenotype in OMIM or Gene2Phenotype.

- PMID: 31943016 (2020) - Single female subject with compound heterozygous nonsense variants (paternal: c.286C>T, p.R96*; maternal: c.1267C>T; p.R423*) in TMPRSS9. Early childhood development was normal until 2.5 years of age when she experienced profound developmental regression, including speech, social interaction and motor skills, resulting in ASD and profound ID. Knockout mice showed decreased social interest and recognition, and additionally borderline recognition memory deficit in aged female mice.

- Conference poster (Genomics of Rare Disease 2021) - 'ZOEMBA: combining metabolomics and genomics data to solve the unsolved' by Oud et al, United for Metabolic Diseases (UMD), Netherlands -
Trio WES revealed compound heterozygous variants (paternal: c.143-1G>A, p.?; maternal: c.1864G>A; p.V622M) in the TMPRSS9 gene in a female proband with GDD, PIND, aggression, autism and epilepsy. The individual was recruited on the basis of 'suspicion of an inherited metabolic disorder and extensive genetic and metabolic work-up with no diagnosis'.
Sources: Other
Intellectual disability v3.983 DDB1 Arina Puzriakova Classified gene: DDB1 as Amber List (moderate evidence)
Intellectual disability v3.983 DDB1 Arina Puzriakova Added comment: Comment on list classification: There is enough evidence to promote this gene to Green at the next review - sufficient unrelated cases (8) presenting consistent features primarily characterised by ID/DD and hypotonia, supported by functional data (PMID:33743206)
Intellectual disability v3.983 DDB1 Arina Puzriakova Gene: ddb1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.982 DDB1 Arina Puzriakova changed review comment from: - PMID: 33743206 (2021) - 8 unrelated individuals with de novo variants in DDB1, including one recurrent variant in four individuals (c.637G>A, p.Glu213Lys) and two different substitutions at the same amino acid residue (p.Arg188Trp and p.Arg188Gln). Clinical features were consistent and include hypotonia (7/8) and mild-moderate developmental delay or intellectual disability (8/8) and similar facial gestalt. Brachydactyly was common and most noticeable in the feet (6/8), and two individuals had cutaneous toe syndactyly. All three older individuals had a BMI in the obese range for their age. Functional studies using patient-derived lymphoblasts showed altered DDB1 function resulting in abnormal DNA damage signatures and histone methylation following UV-induced DNA damage.
Sources: Literature; to: - PMID: 33743206 (2021) - 8 unrelated individuals with de novo variants in DDB1, including one recurrent variant in four individuals (c.637G>A, p.Glu213Lys) and two different substitutions at the same amino acid residue (p.Arg188Trp and p.Arg188Gln). Clinical features were consistent and include hypotonia (7/8) and mild-moderate developmental delay or intellectual disability (8/8) and similar facial gestalt. Brachydactyly was common and most noticeable in the feet (6/8), and two individuals had cutaneous toe syndactyly. All three older individuals had a BMI in the obese range for their age. Functional studies using patient-derived lymphoblasts showed altered DDB1 function resulting in abnormal DNA damage signatures and histone methylation following UV-induced DNA damage.

Variants in other CRL4 complex components, such as CUL4B (MIM# 300304) and PHIP (MIM# 612870), have been shown to cause overlapping phenotypes consisting of syndromic ID with hypotonia and obesity.
Sources: Literature
Intellectual disability v3.982 DDB1 Arina Puzriakova Tag Q2_21_rating tag was added to gene: DDB1.
Intellectual disability v3.982 DDB1 Arina Puzriakova gene: DDB1 was added
gene: DDB1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: DDB1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: DDB1 were set to 33743206
Phenotypes for gene: DDB1 were set to Intellectual disability
Review for gene: DDB1 was set to GREEN
Added comment: - PMID: 33743206 (2021) - 8 unrelated individuals with de novo variants in DDB1, including one recurrent variant in four individuals (c.637G>A, p.Glu213Lys) and two different substitutions at the same amino acid residue (p.Arg188Trp and p.Arg188Gln). Clinical features were consistent and include hypotonia (7/8) and mild-moderate developmental delay or intellectual disability (8/8) and similar facial gestalt. Brachydactyly was common and most noticeable in the feet (6/8), and two individuals had cutaneous toe syndactyly. All three older individuals had a BMI in the obese range for their age. Functional studies using patient-derived lymphoblasts showed altered DDB1 function resulting in abnormal DNA damage signatures and histone methylation following UV-induced DNA damage.
Sources: Literature
Intellectual disability v3.981 GSPT2 Arina Puzriakova Tag watchlist tag was added to gene: GSPT2.
Intellectual disability v3.981 GSPT2 Arina Puzriakova commented on gene: GSPT2
Intellectual disability v3.981 PIGU Arina Puzriakova Phenotypes for gene: PIGU were changed from Glycosylphosphatidylinositol biosynthesis defect 2, 618590; Global developmental delay; Intellectual disability; Seizures; Cerebral atrophy; Cerebellar hypoplasia; Scoliosis to Neurodevelopmental disorder with brain anomalies, seizures, and scoliosis, OMIM:618590
Intellectual disability v3.980 SMARCB1 Arina Puzriakova Phenotypes for gene: SMARCB1 were changed from Rhabdoid tumors, somatic, 609322Rhabdoid predisposition syndrome 1, 609322Mental retardation, autosomal dominant 15, 614608; RHABDOID PREDISPOSITION SYNDROME 1 to Coffin-Siris syndrome 3, OMIM:614608
Intellectual disability v3.979 SMARCA4 Arina Puzriakova Added comment: Comment on phenotypes: This gene is also associated with {Rhabdoid tumor predisposition syndrome 2}, OMIM:613325
Intellectual disability v3.979 SMARCA4 Arina Puzriakova Phenotypes for gene: SMARCA4 were changed from Rhabdoid tumor predisposition syndrome 2, 613325Mental retardation, autosomal dominant 16, 614609; COFFIN SIRIS to Coffin-Siris syndrome 4, OMIM:614609
Intellectual disability v3.978 POLD1 Arina Puzriakova Phenotypes for gene: POLD1 were changed from {Colorectal cancer, susceptibility to, 10}, 612591; Mandibular; hypoplasia, deafness, progeroid features, and lipodystrophy syndrome, 615381 to {Colorectal cancer, susceptibility to, 10}, 612591; Mandibular hypoplasia, deafness, progeroid features, and lipodystrophy syndrome, 615381
Intellectual disability v3.977 SIAH1 Arina Puzriakova Classified gene: SIAH1 as Amber List (moderate evidence)
Intellectual disability v3.977 SIAH1 Arina Puzriakova Added comment: Comment on list classification: There are sufficient unrelated cases (5) to promote this gene to Green at the next GMS panel update. Developmental delay, including cognitive impairment, was a key presenting feature of the disease phenotype. Inclusion on this panel would also cover the infantile hypotonia element as the ID panel is a component panel of the 'Hypotonic infant, R69' super panel.
Intellectual disability v3.977 SIAH1 Arina Puzriakova Gene: siah1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.976 SIAH1 Arina Puzriakova gene: SIAH1 was added
gene: SIAH1 was added to Intellectual disability. Sources: Literature
Q2_21_rating tags were added to gene: SIAH1.
Mode of inheritance for gene: SIAH1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SIAH1 were set to 32430360
Phenotypes for gene: SIAH1 were set to Developmental delay; Infantile hypotonia; Dysmorphic features; Laryngomalacia
Review for gene: SIAH1 was set to GREEN
Added comment: - PMID: 32430360 (2021) - Five unrelated individuals with shared features of developmental delay, infantile hypotonia, dysmorphic features and laryngomalacia. All had speech delay and where cognitive assessment was age appropriate individuals exhibited learning difficulties. Trio WES revealed distinct de novo variants in SIAH1. In vitro assays demonstrated that SIAH1 mutants induce loss of Wnt stimulatory activity.
Sources: Literature
Intellectual disability v3.975 EIF5A Zornitza Stark gene: EIF5A was added
gene: EIF5A was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: EIF5A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: EIF5A were set to 33547280
Phenotypes for gene: EIF5A were set to Intellectual disability; microcephaly; dysmorphism
Review for gene: EIF5A was set to GREEN
Added comment: 7 unrelated individuals reported with de novo variants in this gene and variable combinations of developmental delay, microcephaly, micrognathia and dysmorphism.
Sources: Literature
Intellectual disability v3.975 MED27 Zornitza Stark gene: MED27 was added
gene: MED27 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: MED27 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MED27 were set to 33443317
Phenotypes for gene: MED27 were set to Intellectual disability; cerebellar hypoplasia; dystonia
Review for gene: MED27 was set to GREEN
gene: MED27 was marked as current diagnostic
Added comment: 16 patients from 11 families reported
Sources: Literature
Intellectual disability v3.975 SPEN Zornitza Stark edited their review of gene: SPEN: Added comment: PMID: 33596411
- 34 individuals with truncating variants in SPEN reported, most are de novo variants.
- Clinical profile includes developmental delay/intellectual disability, autism spectrum disorder, anxiety, aggressive behavior, attention deficit disorder, hypotonia, brain and spine anomalies, congenital heart defects, high/narrow palate, facial dysmorphisms, and obesity/increased BMI, especially in females.
- Authors showed haploinsufficiency of SPEN is associated with a distinctive DNA methylation episignature of the X chromosome in affected females.; Changed rating: GREEN; Changed publications: 33057194, 33596411; Changed phenotypes: Developmental delay/intellectual disability, autism spectrum disorder, anxiety, aggressive behavior, attention deficit disorder, hypotonia, brain and spine anomalies, congenital heart defects, high/narrow palate, facial dysmorphisms, and obesity/increased BMI; Set current diagnostic: yes
Intellectual disability v3.975 ERBB4 Sarah Leigh Publications for gene: ERBB4 were set to 33603162; 23633123; 15219717; 30498032
Intellectual disability v3.974 ERBB4 Sarah Leigh Tag Q2_21_rating tag was added to gene: ERBB4.
Intellectual disability v3.974 ERBB4 Sarah Leigh Publications for gene: ERBB4 were set to 33603162; 23633123
Intellectual disability v3.973 ERBB4 Sarah Leigh changed review comment from: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review depending on the interpretation of structural variants.; to: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review depending on the interpretation of copy number variants.
Intellectual disability v3.973 ERBB4 Sarah Leigh edited their review of gene: ERBB4: Added comment: Not associated with relevant phenotype in OMIM or Gen2Phen. PMID 33603162 reports that at least six 2q34 deletions resulting in exon loss in ERBB4 may cause autosomal dominant mild to moderate developmental delay, ID or epilepsy. Rhodent knock out models support this finding (PMID 15219717;30498032).; Changed rating: GREEN; Changed publications: 15219717, 30498032; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.973 ERBB4 Sarah Leigh Classified gene: ERBB4 as Amber List (moderate evidence)
Intellectual disability v3.973 ERBB4 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review depending on the interpretation of structural variants.
Intellectual disability v3.973 ERBB4 Sarah Leigh Gene: erbb4 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.972 ERBB4 Sarah Leigh Added comment: Comment on phenotypes: Amyotrophic lateral sclerosis 19 615515 is not appropriate for this panel At present there is no precise ID phenotype associated with variants in this gene.
Intellectual disability v3.972 ERBB4 Sarah Leigh Phenotypes for gene: ERBB4 were changed from intellectual disability; epilepsy to intellectual disability MONDO:0001071
Intellectual disability v3.971 ERBB4 Sarah Leigh Publications for gene: ERBB4 were set to 33603162; 23633123
Intellectual disability v3.971 ERBB4 Sarah Leigh Publications for gene: ERBB4 were set to 33603162
Intellectual disability v3.970 SETD1B Arina Puzriakova Publications for gene: SETD1B were set to 29322246; 27106595; 25428890; 31110234
Intellectual disability v3.969 SETD1B Arina Puzriakova Phenotypes for gene: SETD1B were changed from Epilepsy, developmental delay, intellectual disability, autistic behavior and craniofacial dysmorphic features to Intellectual developmental disorder with seizures and language delay, OMIM:619000; Intellectual developmental disorder with seizures and language delay, MONDO:0033559
Intellectual disability v3.968 ACO2 Arina Puzriakova Phenotypes for gene: ACO2 were changed from INFANTILE CEREBELLAR-RETINAL DEGENERATION to Infantile cerebellar-retinal degeneration, OMIM:614559; Infantile cerebellar-retinal degeneration, MONDO:0013802
Intellectual disability v3.967 KCNN3 Arina Puzriakova Publications for gene: KCNN3 were set to 31155282
Intellectual disability v3.966 KCNN3 Arina Puzriakova edited their review of gene: KCNN3: Added comment: Now at least 6 unrelated individuals with different gain-of-function KCNN3 variants (PMIDs: 31155282 and 33594261). Phenotypes include mild-to-moderate DD and/or ID.; Changed publications: 31155282, 33594261
Intellectual disability v3.966 PPP2R2B_CAG Arina Puzriakova Tag curated_removed tag was added to STR: PPP2R2B_CAG.
Intellectual disability v3.966 CSTB_CCCCGCCCCGCG Arina Puzriakova Tag curated_removed tag was added to STR: CSTB_CCCCGCCCCGCG.
Intellectual disability v3.966 C9orf72_GGGGCC Arina Puzriakova Tag curated_removed tag was added to STR: C9orf72_GGGGCC.
Intellectual disability v3.966 ATXN7_CAG Arina Puzriakova Tag curated_removed tag was added to STR: ATXN7_CAG.
Intellectual disability v3.966 ATXN3_CAG Arina Puzriakova Tag curated_removed tag was added to STR: ATXN3_CAG.
Intellectual disability v3.966 ATXN1_CAG Arina Puzriakova Tag curated_removed tag was added to STR: ATXN1_CAG.
Intellectual disability v3.966 FXN_GAA Arina Puzriakova Tag curated_removed tag was added to STR: FXN_GAA.
Intellectual disability v3.966 ATXN10_ATTCT Arina Puzriakova Tag curated_removed tag was added to STR: ATXN10_ATTCT.
Intellectual disability v3.966 ATXN2_CAG Arina Puzriakova Tag curated_removed tag was added to STR: ATXN2_CAG.
Intellectual disability v3.966 KCNN3 Arina Puzriakova changed review comment from: Comment on mode of pathogenicity: Gain-of-function variants identified in all patients, reported to date.; to: Comment on mode of pathogenicity: Gain-of-function variants identified in all patients reported to date.
Intellectual disability v3.966 KCNN3 Arina Puzriakova Phenotypes for gene: KCNN3 were changed from Zimmermann-Laband syndrome 3; OMIM# 618658 to Zimmermann-Laband syndrome 3, OMIM:618658
Intellectual disability v3.965 KCNH1 Arina Puzriakova Publications for gene: KCNH1 were set to 25420144
Intellectual disability v3.964 KCNH1 Arina Puzriakova Phenotypes for gene: KCNH1 were changed from TEMPLE BARRAISTER SYNDROME to Temple-Baraitser syndrome, OMIM:611816; Temple-Baraitser syndrome, MONDO:0012735; Zimmermann-Laband syndrome 1, OMIM:135500; Zimmermann-Laband syndrome 1, MONDO:0024526
Intellectual disability v3.963 ERBB4 Arina Puzriakova Tag Q2_21_NHS_review tag was added to gene: ERBB4.
Intellectual disability v3.963 CXorf56 Catherine Snow Tag new-gene-name tag was added to gene: CXorf56.
Intellectual disability v3.963 CXorf56 Catherine Snow commented on gene: CXorf56
Intellectual disability v3.963 MPP5 Catherine Snow Tag new-gene-name tag was added to gene: MPP5.
Intellectual disability v3.963 MPP5 Catherine Snow commented on gene: MPP5
Intellectual disability v3.963 ARMC4 Catherine Snow Tag new-gene-name tag was added to gene: ARMC4.
Intellectual disability v3.963 ARMC4 Catherine Snow commented on gene: ARMC4
Intellectual disability v3.963 CCDC114 Catherine Snow Tag new-gene-name tag was added to gene: CCDC114.
Intellectual disability v3.963 CCDC114 Catherine Snow commented on gene: CCDC114
Intellectual disability v3.963 C12orf65 Catherine Snow Tag new-gene-name tag was added to gene: C12orf65.
Intellectual disability v3.963 C12orf65 Catherine Snow commented on gene: C12orf65
Intellectual disability v3.963 FAM160B1 Catherine Snow Tag new-gene-name tag was added to gene: FAM160B1.
Intellectual disability v3.963 FAM160B1 Catherine Snow commented on gene: FAM160B1
Intellectual disability v3.963 LRRC6 Catherine Snow Tag new-gene-name tag was added to gene: LRRC6.
Intellectual disability v3.963 LRRC6 Catherine Snow commented on gene: LRRC6
Intellectual disability v3.963 CDK19 Sarah Leigh edited their review of gene: CDK19: Added comment: There is enough evidence for this gene to be rated GREEN at the next major review.; Changed rating: GREEN
Intellectual disability v3.963 ERBB4 Julia Baptista gene: ERBB4 was added
gene: ERBB4 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: ERBB4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ERBB4 were set to 33603162
Phenotypes for gene: ERBB4 were set to intellectual disability; epilepsy
Penetrance for gene: ERBB4 were set to Incomplete
Review for gene: ERBB4 was set to GREEN
Added comment: Heterozygous intragenic multi-exonic ERBB4 deletions were identified in nine individuals from five unrelated families. Affected individuals had either non-syndromic ID or generalised epilepsy.
The deletion segregated with the phenotype in five affected individuals in one family, it was de novo in a second family and the inheritance was unknown in two families. In the fifth family, the deletion was inherited from a normal parent.
Sources: Literature
Intellectual disability v3.963 KCNH1 Julia Baptista reviewed gene: KCNH1: Rating: GREEN; Mode of pathogenicity: None; Publications: 33594261; Phenotypes: Temple-Baraitser syndrome, Zimmermann-Laband syndrome 1; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Intellectual disability v3.963 KCNN3 Julia Baptista reviewed gene: KCNN3: Rating: GREEN; Mode of pathogenicity: Other; Publications: 33594261; Phenotypes: developmental delay, ID, hypotonia, gingival enlargement, hypertrichosis, nail anomalies; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Intellectual disability v3.963 CDK19 Julia Baptista changed review comment from: De novo missense variants mapped to the kinase domain of CDK19 were described in 11 unrelated individuals (age range: 9 months to 14 years).Two recurrent changes at residues Tyr32 and Gly28 were identified.
One additional case report (PMID:33568421) described a 10-month-old male patient who presented with a neurodevelopmental syndrome characterized by infantile spasms and a de novo missense variant c.92C>A (p.Thr31Asn) (also in the kinase domain). This brings the total of cases reported in the literature to 15.; to: De novo missense variants mapped to the kinase domain of CDK19 were described in 11 unrelated individuals (age range: 9 months to 14 years).Two recurrent changes at residues Tyr32 and Gly28 were identified.
One additional case report (PMID:33568421) described a 10-month-old male patient who presented with a neurodevelopmental syndrome characterized by infantile spasms and a de novo missense variant c.92C>A (p.Thr31Asn) (also in the kinase domain). This brings the total of cases reported in the literature to 15.
Intellectual disability v3.963 CDK19 Julia Baptista reviewed gene: CDK19: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 33495529, 33568421, 32330417; Phenotypes: developmental delay, hypotonia, seizures, autism/autistic traits; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Intellectual disability v3.963 CLP1 Sarah Leigh Phenotypes for gene: CLP1 were changed from PONTOCEREBELLAR HYPOPLASIA, TYPE 10 to Pontocerebellar hypoplasia 10 OMIM:615803; Pontocerebellar hypoplasia type 10 MONDO:0014349
Intellectual disability v3.962 CLP1 Sarah Leigh Tag founder-effect tag was added to gene: CLP1.
Intellectual disability v3.962 ATCAY Catherine Snow Source: Expert Review Amber was removed from gene: ATCAY
Intellectual disability v3.961 ANO3 Catherine Snow Source: Expert Review Amber was removed from gene: ANO3
Intellectual disability v3.960 ADGRV1 Catherine Snow Source: Expert Review Amber was removed from gene: ADGRV1
Intellectual disability v3.959 ABHD12 Catherine Snow Source: Expert Review Amber was removed from gene: ABHD12
Intellectual disability v3.958 CDK16 Catherine Snow Source: Expert Review Red was removed from gene: CDK16
Intellectual disability v3.957 ZC3H14 Catherine Snow Source: Expert Review Red was removed from gene: ZC3H14
Intellectual disability v3.956 XPA Catherine Snow Source: Expert Review Red was removed from gene: XPA
Intellectual disability v3.955 USP27X Catherine Snow Source: Expert Review Red was removed from gene: USP27X
Intellectual disability v3.953 TUBGCP4 Catherine Snow Source: Expert Review Red was removed from gene: TUBGCP4
Intellectual disability v3.952 TRAPPC11 Catherine Snow Source: Expert Review Red was removed from gene: TRAPPC11
Intellectual disability v3.951 TMEM231 Catherine Snow Source: Expert Review Red was removed from gene: TMEM231
Intellectual disability v3.950 SRGAP3 Catherine Snow Source: Expert Review Red was removed from gene: SRGAP3
Intellectual disability v3.949 SMARCD2 Catherine Snow Source: Expert Review Red was removed from gene: SMARCD2
Intellectual disability v3.947 SACS Catherine Snow Source: Expert Review Red was removed from gene: SACS
Intellectual disability v3.946 RAX Catherine Snow Source: Expert Review Red was removed from gene: RAX
Intellectual disability v3.945 WT1 Arina Puzriakova Source: Expert Review Amber was removed from gene: WT1
Intellectual disability v3.944 NUP62 Catherine Snow Source: Expert Review Red was removed from gene: NUP62
Intellectual disability v3.943 NDUFAF2 Catherine Snow Source: Expert Review Red was removed from gene: NDUFAF2
Intellectual disability v3.942 MIR17HG Catherine Snow Source: Expert Review Red was removed from gene: MIR17HG
Intellectual disability v3.941 VPS35 Arina Puzriakova Source: Expert Review Amber was removed from gene: VPS35
Intellectual disability v3.940 TTPA Arina Puzriakova Source: Expert Review Amber was removed from gene: TTPA
Intellectual disability v3.939 MAPK10 Catherine Snow Source: Expert Review Red was removed from gene: MAPK10
Intellectual disability v3.938 TTC7A Arina Puzriakova Source: Expert Review Amber was removed from gene: TTC7A
Intellectual disability v3.937 TTBK2 Arina Puzriakova Source: Expert Review Amber was removed from gene: TTBK2
Intellectual disability v3.936 KLHL15 Catherine Snow Source: Expert Review Red was removed from gene: KLHL15
Intellectual disability v3.935 HAX1 Catherine Snow Source: Expert Review Red was removed from gene: HAX1
Intellectual disability v3.934 TGM6 Arina Puzriakova Source: Expert Review Amber was removed from gene: TGM6
Intellectual disability v3.933 TFG Arina Puzriakova Source: Expert Review Amber was removed from gene: TFG
Intellectual disability v3.932 TFAP2B Arina Puzriakova Source: Expert Review Amber was removed from gene: TFAP2B
Intellectual disability v3.931 TFAP2A Arina Puzriakova Source: Expert Review Amber was removed from gene: TFAP2A
Intellectual disability v3.930 TBP Arina Puzriakova Source: Expert Review Amber was removed from gene: TBP
Intellectual disability v3.929 TARDBP Arina Puzriakova Source: Expert Review Amber was removed from gene: TARDBP
Intellectual disability v3.928 STUB1 Arina Puzriakova Source: Expert Review Amber was removed from gene: STUB1
Intellectual disability v3.927 PLEC Sarah Leigh Source: Expert Review Amber was removed from gene: PLEC
Intellectual disability v3.926 SPG7 Arina Puzriakova Source: Expert Review Amber was removed from gene: SPG7
Intellectual disability v3.926 PLCE1 Sarah Leigh Source: Expert Review Amber was removed from gene: PLCE1
Intellectual disability v3.925 SPG21 Arina Puzriakova Source: Expert Review Amber was removed from gene: SPG21
Intellectual disability v3.924 PINK1 Sarah Leigh Source: Expert Review Amber was removed from gene: PINK1
Intellectual disability v3.923 SNCA Arina Puzriakova Source: Expert Review Amber was removed from gene: SNCA
Intellectual disability v3.922 PDYN Sarah Leigh Source: Expert Review Amber was removed from gene: PDYN
Intellectual disability v3.922 SMO Arina Puzriakova Source: Expert Review Amber was removed from gene: SMO
Intellectual disability v3.922 PDGFB Sarah Leigh Source: Expert Review Amber was removed from gene: PDGFB
Intellectual disability v3.921 PCYT1A Sarah Leigh Source: Expert Review Amber was removed from gene: PCYT1A
Intellectual disability v3.921 SLC20A2 Arina Puzriakova Source: Expert Review Amber was removed from gene: SLC20A2
Intellectual disability v3.920 PARK7 Sarah Leigh Source: Expert Review Amber was removed from gene: PARK7
Intellectual disability v3.919 SIGMAR1 Arina Puzriakova Source: Expert Review Amber was removed from gene: SIGMAR1
Intellectual disability v3.919 PALB2 Sarah Leigh Source: Expert Review Amber was removed from gene: PALB2
Intellectual disability v3.918 NPHS2 Sarah Leigh Source: Expert Review Amber was removed from gene: NPHS2
Intellectual disability v3.917 NOP56 Sarah Leigh Source: Expert Review Amber was removed from gene: NOP56
Intellectual disability v3.916 SH3TC2 Arina Puzriakova Source: Expert Review Amber was removed from gene: SH3TC2
Intellectual disability v3.915 SGCE Arina Puzriakova Source: Expert Review Amber was removed from gene: SGCE
Intellectual disability v3.914 NIPA1 Sarah Leigh Source: Expert Review Amber was removed from gene: NIPA1
Intellectual disability v3.913 SETX Arina Puzriakova Source: Expert Review Amber was removed from gene: SETX
Intellectual disability v3.912 NHLRC1 Sarah Leigh Source: Expert Review Amber was removed from gene: NHLRC1
Intellectual disability v3.911 SCN9A Arina Puzriakova Source: Expert Review Amber was removed from gene: SCN9A
Intellectual disability v3.911 NHEJ1 Sarah Leigh Source: Expert Review Amber was removed from gene: NHEJ1
Intellectual disability v3.910 SCARB2 Arina Puzriakova Source: Expert Review Amber was removed from gene: SCARB2
Intellectual disability v3.909 NEFL Sarah Leigh Source: Expert Review Amber was removed from gene: NEFL
Intellectual disability v3.908 SBF2 Arina Puzriakova Source: Expert Review Amber was removed from gene: SBF2
Intellectual disability v3.908 NDRG1 Sarah Leigh Source: Expert Review Amber was removed from gene: NDRG1
Intellectual disability v3.907 MTPAP Sarah Leigh Source: Expert Review Amber was removed from gene: MTPAP
Intellectual disability v3.906 RTN2 Arina Puzriakova Source: Expert Review Amber was removed from gene: RTN2
Intellectual disability v3.906 MTMR2 Sarah Leigh Source: Expert Review Amber was removed from gene: MTMR2
Intellectual disability v3.905 RNF216 Arina Puzriakova Source: Expert Review Amber was removed from gene: RNF216
Intellectual disability v3.904 RIPK4 Arina Puzriakova Source: Expert Review Amber was removed from gene: RIPK4
Intellectual disability v3.903 RFX6 Arina Puzriakova Source: Expert Review Amber was removed from gene: RFX6
Intellectual disability v3.902 REEP2 Arina Puzriakova Source: Expert Review Amber was removed from gene: REEP2
Intellectual disability v3.901 REEP1 Arina Puzriakova Source: Expert Review Amber was removed from gene: REEP1
Intellectual disability v3.900 MPZ Sarah Leigh Source: Expert Review Amber was removed from gene: MPZ
Intellectual disability v3.899 PSEN1 Arina Puzriakova Source: Expert Review Amber was removed from gene: PSEN1
Intellectual disability v3.899 MMP21 Sarah Leigh Source: Expert Review Amber was removed from gene: MMP21
Intellectual disability v3.898 MITF Sarah Leigh Source: Expert Review Amber was removed from gene: MITF
Intellectual disability v3.897 PRX Arina Puzriakova Source: Expert Review Amber was removed from gene: PRX
Intellectual disability v3.896 MECR Sarah Leigh Source: Expert Review Amber was removed from gene: MECR
Intellectual disability v3.895 MARS2 Sarah Leigh Source: Expert Review Amber was removed from gene: MARS2
Intellectual disability v3.894 PRKRA Arina Puzriakova Source: Expert Review Amber was removed from gene: PRKRA
Intellectual disability v3.894 MAFB Sarah Leigh Source: Expert Review Amber was removed from gene: MAFB
Intellectual disability v3.893 LRRK2 Sarah Leigh Source: Expert Review Amber was removed from gene: LRRK2
Intellectual disability v3.893 PRKN Arina Puzriakova Source: Expert Review Amber was removed from gene: PRKN
Intellectual disability v3.893 LOXHD1 Sarah Leigh Source: Expert Review Amber was removed from gene: LOXHD1
Intellectual disability v3.892 PRKCG Arina Puzriakova Source: Expert Review Amber was removed from gene: PRKCG
Intellectual disability v3.892 LITAF Sarah Leigh Source: Expert Review Amber was removed from gene: LITAF
Intellectual disability v3.891 PRICKLE2 Arina Puzriakova Source: Expert Review Amber was removed from gene: PRICKLE2
Intellectual disability v3.891 KIF1C Sarah Leigh Source: Expert Review Amber was removed from gene: KIF1C
Intellectual disability v3.890 KCNE1 Sarah Leigh Source: Expert Review Amber was removed from gene: KCNE1
Intellectual disability v3.889 PRICKLE1 Arina Puzriakova Source: Expert Review Amber was removed from gene: PRICKLE1
Intellectual disability v3.889 KCNA1 Sarah Leigh Source: Expert Review Amber was removed from gene: KCNA1
Intellectual disability v3.888 ITGA3 Sarah Leigh Source: Expert Review Amber was removed from gene: ITGA3
Intellectual disability v3.887 PPP2R2B Arina Puzriakova Source: Expert Review Amber was removed from gene: PPP2R2B
Intellectual disability v3.886 IGHMBP2 Sarah Leigh Source: Expert Review Amber was removed from gene: IGHMBP2
Intellectual disability v3.885 PNKD Arina Puzriakova Source: Expert Review Amber was removed from gene: PNKD
Intellectual disability v3.884 DCTN1 Sarah Leigh Source: Expert Review Amber was removed from gene: DCTN1
Intellectual disability v3.883 DHODH Sarah Leigh Source: Expert Review Amber was removed from gene: DHODH
Intellectual disability v3.882 DNM2 Sarah Leigh Source: Expert Review Amber was removed from gene: DNM2
Intellectual disability v3.881 EFHC1 Sarah Leigh Source: Expert Review Amber was removed from gene: EFHC1
Intellectual disability v3.880 EIF4G1 Sarah Leigh Source: Expert Review Amber was removed from gene: EIF4G1
Intellectual disability v3.879 ELOVL5 Sarah Leigh Source: Expert Review Amber was removed from gene: ELOVL5
Intellectual disability v3.878 EPM2A Sarah Leigh Source: Expert Review Amber was removed from gene: EPM2A
Intellectual disability v3.877 FAM111B Sarah Leigh Source: Expert Review Amber was removed from gene: FAM111B
Intellectual disability v3.876 GDAP1 Sarah Leigh Source: Expert Review Amber was removed from gene: GDAP1
Intellectual disability v3.875 GNAL Sarah Leigh Source: Expert Review Amber was removed from gene: GNAL
Intellectual disability v3.874 GORAB Sarah Leigh Source: Expert Review Amber was removed from gene: GORAB
Intellectual disability v3.873 GOSR2 Sarah Leigh Source: Expert Review Amber was removed from gene: GOSR2
Intellectual disability v3.872 GRN Sarah Leigh Source: Expert Review Amber was removed from gene: GRN
Intellectual disability v3.871 MDH2 Ivone Leong Source: Expert Review Amber was removed from gene: MDH2
Intellectual disability v3.870 KNL1 Ivone Leong Source: Expert Review Amber was removed from gene: KNL1
Intellectual disability v3.869 KIAA0586 Ivone Leong Source: Expert Review Amber was removed from gene: KIAA0586
Intellectual disability v3.868 HECW2 Ivone Leong commented on gene: HECW2
Intellectual disability v3.868 HECW2 Ivone Leong Phenotypes for gene: HECW2 were changed from Neurodevelopmental disorder with hypotonia, seizures, and absent language to Neurodevelopmental disorder with hypotonia, seizures, and absent language, OMIM:617268
Intellectual disability v3.867 HECW2 Ivone Leong Mode of pathogenicity for gene: HECW2 was changed from to Other
Intellectual disability v3.866 HECW2 Ivone Leong Publications for gene: HECW2 were set to
Intellectual disability v3.865 HECW2 Ivone Leong gene: HECW2 was added
gene: HECW2 was added to Intellectual disability. Sources: Expert Review Green,BRIDGE study SPEED NEURO Tier1 Gene,Victorian Clinical Genetics Services
Mode of inheritance for gene: HECW2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: HECW2 were set to Neurodevelopmental disorder with hypotonia, seizures, and absent language
Intellectual disability v3.864 IFT140 Sarah Leigh Source: Expert Review Amber was removed from gene: IFT140
Intellectual disability v3.863 FLAD1 Sarah Leigh Source: Expert Review Amber was removed from gene: FLAD1
Intellectual disability v3.862 DNMT1 Sarah Leigh Source: Expert Review Amber was removed from gene: DNMT1
Intellectual disability v3.861 Ivone Leong removed gene:HECW2 from the panel
Intellectual disability v3.860 HACE1 Ivone Leong Source: Expert Review Amber was removed from gene: HACE1
Intellectual disability v3.859 GRID2 Ivone Leong Source: Expert Review Amber was removed from gene: GRID2
Intellectual disability v3.858 GLIS3 Ivone Leong Source: Expert Review Amber was removed from gene: GLIS3
Intellectual disability v3.857 FGF12 Ivone Leong Source: Expert Review Amber was removed from gene: FGF12
Intellectual disability v3.857 GJB1 Catherine Snow Source: Expert Review Red was removed from gene: GJB1
Intellectual disability v3.856 EBF3 Ivone Leong Source: Expert Review Amber was removed from gene: EBF3
Intellectual disability v3.855 CHD4 Ivone Leong Source: Expert Review Amber was removed from gene: CHD4
Intellectual disability v3.854 BRPF1 Ivone Leong Source: Expert Review Amber was removed from gene: BRPF1
Intellectual disability v3.854 GBA2 Catherine Snow Source: Expert Review Red was removed from gene: GBA2
Intellectual disability v3.853 BMP4 Ivone Leong Source: Expert Review Amber was removed from gene: BMP4
Intellectual disability v3.852 ACADS Ivone Leong Source: Expert Review Amber was removed from gene: ACADS
Intellectual disability v3.851 AAAS Ivone Leong Source: Expert Review Amber was removed from gene: AAAS
Intellectual disability v3.851 FRAS1 Catherine Snow Source: Expert Review Red was removed from gene: FRAS1
Intellectual disability v3.850 FAM120C Catherine Snow Source: Expert Review Red was removed from gene: FAM120C
Intellectual disability v3.850 MBTPS2 Ivone Leong Source: Expert Review Red was removed from gene: MBTPS2
Intellectual disability v3.850 CSF1R Sarah Leigh Source: Expert Review Amber was removed from gene: CSF1R
Intellectual disability v3.849 FAAH2 Catherine Snow Source: Expert Review Red was removed from gene: FAAH2
Intellectual disability v3.849 UBTF Ivone Leong Source: Expert Review Red was removed from gene: UBTF
Intellectual disability v3.848 ERMARD Catherine Snow Source: Expert Review Red was removed from gene: ERMARD
Intellectual disability v3.847 THOC2 Ivone Leong Source: Expert Review Red was removed from gene: THOC2
Intellectual disability v3.847 CRYGC Sarah Leigh Source: Expert Review Amber was removed from gene: CRYGC
Intellectual disability v3.846 TECPR2 Ivone Leong Source: Expert Review Red was removed from gene: TECPR2
Intellectual disability v3.845 EPB41L1 Catherine Snow Source: Expert Review Red was removed from gene: EPB41L1
Intellectual disability v3.844 TAF1 Ivone Leong Source: Expert Review Red was removed from gene: TAF1
Intellectual disability v3.843 EEF1B2 Catherine Snow Source: Expert Review Red was removed from gene: EEF1B2
Intellectual disability v3.843 SZT2 Ivone Leong Source: Expert Review Red was removed from gene: SZT2
Intellectual disability v3.842 DPM3 Catherine Snow Source: Expert Review Red was removed from gene: DPM3
Intellectual disability v3.842 ST3GAL5 Ivone Leong Source: Expert Review Red was removed from gene: ST3GAL5
Intellectual disability v3.841 DLG2 Catherine Snow Source: Expert Review Red was removed from gene: DLG2
Intellectual disability v3.840 SMC3 Ivone Leong Source: Expert Review Red was removed from gene: SMC3
Intellectual disability v3.840 DLG1 Catherine Snow Source: Expert Review Red was removed from gene: DLG1
Intellectual disability v3.839 SMAD4 Ivone Leong Source: Expert Review Red was removed from gene: SMAD4
Intellectual disability v3.838 DIP2B Catherine Snow Source: Expert Review Red was removed from gene: DIP2B
Intellectual disability v3.838 SLC33A1 Ivone Leong Source: Expert Review Red was removed from gene: SLC33A1
Intellectual disability v3.837 DDX53 Catherine Snow Source: Expert Review Red was removed from gene: DDX53
Intellectual disability v3.836 SERAC1 Ivone Leong Source: Expert Review Red was removed from gene: SERAC1
Intellectual disability v3.835 RTTN Ivone Leong Source: Expert Review Red was removed from gene: RTTN
Intellectual disability v3.834 CYP7B1 Catherine Snow Source: Expert Review Red was removed from gene: CYP7B1
Intellectual disability v3.834 RLIM Ivone Leong Source: Expert Review Red was removed from gene: RLIM
Intellectual disability v3.833 QARS Ivone Leong Source: Expert Review Red was removed from gene: QARS
Intellectual disability v3.833 CHL1 Catherine Snow Source: Expert Review Red was removed from gene: CHL1
Intellectual disability v3.832 PYCR2 Ivone Leong Source: Expert Review Red was removed from gene: PYCR2
Intellectual disability v3.831 CEP63 Catherine Snow Source: Expert Review Red was removed from gene: CEP63
Intellectual disability v3.831 PYCR1 Ivone Leong Source: Expert Review Red was removed from gene: PYCR1
Intellectual disability v3.830 CD96 Catherine Snow Source: Expert Review Red was removed from gene: CD96
Intellectual disability v3.829 PUS1 Ivone Leong Source: Expert Review Red was removed from gene: PUS1
Intellectual disability v3.828 C9orf72 Catherine Snow Source: Expert Review Amber was removed from gene: C9orf72
Intellectual disability v3.828 PUF60 Ivone Leong Source: Expert Review Red was removed from gene: PUF60
Intellectual disability v3.827 PEX11B Ivone Leong Source: Expert Review Red was removed from gene: PEX11B
Intellectual disability v3.827 BEAN1 Catherine Snow Source: Expert Review Amber was removed from gene: BEAN1
Intellectual disability v3.826 NTRK1 Ivone Leong Source: Expert Review Red was removed from gene: NTRK1
Intellectual disability v3.826 CRYBA4 Sarah Leigh Source: Expert Review Amber was removed from gene: CRYBA4
Intellectual disability v3.825 NFIA Ivone Leong Source: Expert Review Red was removed from gene: NFIA
Intellectual disability v3.824 ATXN7 Catherine Snow Source: Expert Review Amber was removed from gene: ATXN7
Intellectual disability v3.823 ATXN3 Catherine Snow Source: Expert Review Amber was removed from gene: ATXN3
Intellectual disability v3.822 ATXN2 Catherine Snow Source: Expert Review Amber was removed from gene: ATXN2
Intellectual disability v3.821 ATXN10 Catherine Snow Source: Expert Review Amber was removed from gene: ATXN10
Intellectual disability v3.820 ATXN1 Catherine Snow Source: Expert Review Amber was removed from gene: ATXN1
Intellectual disability v3.819 NDST1 Ivone Leong Source: Expert Review Red was removed from gene: NDST1
Intellectual disability v3.817 UNC80 Catherine Snow Source: Expert Review Amber was removed from gene: UNC80
Intellectual disability v3.816 LONP1 Ivone Leong Source: Expert Review Red was removed from gene: LONP1
Intellectual disability v3.815 KMT2C Ivone Leong Source: Expert Review Red was removed from gene: KMT2C
Intellectual disability v3.815 UBA5 Catherine Snow Source: Expert Review Amber was removed from gene: UBA5
Intellectual disability v3.814 CDC45 Sarah Leigh Source: Expert Review Amber was removed from gene: CDC45
Intellectual disability v3.813 IER3IP1 Ivone Leong Source: Expert Review Red was removed from gene: IER3IP1
Intellectual disability v3.812 TRMT10A Catherine Snow Source: Expert Review Amber was removed from gene: TRMT10A
Intellectual disability v3.812 HIVEP2 Ivone Leong Source: Expert Review Red was removed from gene: HIVEP2
Intellectual disability v3.811 TMEM240 Catherine Snow Source: Expert Review Amber was removed from gene: TMEM240
Intellectual disability v3.810 GMPPB Ivone Leong Source: Expert Review Red was removed from gene: GMPPB
Intellectual disability v3.810 TBCD Catherine Snow Source: Expert Review Amber was removed from gene: TBCD
Intellectual disability v3.809 GFER Ivone Leong Source: Expert Review Red was removed from gene: GFER
Intellectual disability v3.808 EMX2 Ivone Leong Source: Expert Review Red was removed from gene: EMX2
Intellectual disability v3.808 SPTBN2 Catherine Snow Source: Expert Review Amber was removed from gene: SPTBN2
Intellectual disability v3.807 ELP2 Ivone Leong Source: Expert Review Red was removed from gene: ELP2
Intellectual disability v3.806 DNAJC19 Ivone Leong Source: Expert Review Red was removed from gene: DNAJC19
Intellectual disability v3.805 DAG1 Ivone Leong Source: Expert Review Red was removed from gene: DAG1
Intellectual disability v3.803 CRADD Ivone Leong Source: Expert Review Red was removed from gene: CRADD
Intellectual disability v3.803 SPART Catherine Snow Source: Expert Review Amber was removed from gene: SPART
Intellectual disability v3.802 COG5 Ivone Leong Source: Expert Review Red was removed from gene: COG5
Intellectual disability v3.801 SON Catherine Snow Source: Expert Review Amber was removed from gene: SON
Intellectual disability v3.801 CLCN4 Ivone Leong Source: Expert Review Red was removed from gene: CLCN4
Intellectual disability v3.800 CHMP1A Ivone Leong Source: Expert Review Red was removed from gene: CHMP1A
Intellectual disability v3.800 CCDC115 Sarah Leigh Source: Expert Review Amber was removed from gene: CCDC115
Intellectual disability v3.798 CAMK2A Ivone Leong Source: Expert Review Red was removed from gene: CAMK2A
Intellectual disability v3.798 PRUNE1 Catherine Snow Source: Expert Review Amber was removed from gene: PRUNE1
Intellectual disability v3.797 CACNA1S Sarah Leigh Source: Expert Review Amber was removed from gene: CACNA1S
Intellectual disability v3.797 CACNA1D Ivone Leong Source: Expert Review Red was removed from gene: CACNA1D
Intellectual disability v3.796 CACNA1A Ivone Leong Source: Expert Review Red was removed from gene: CACNA1A
Intellectual disability v3.795 PGAP1 Catherine Snow Source: Expert Review Amber was removed from gene: PGAP1
Intellectual disability v3.795 BRCA2 Sarah Leigh Source: Expert Review Amber was removed from gene: BRCA2
Intellectual disability v3.794 BSCL2 Ivone Leong Source: Expert Review Red was removed from gene: BSCL2
Intellectual disability v3.792 PNPLA6 Catherine Snow Source: Expert Review Amber was removed from gene: PNPLA6
Intellectual disability v3.791 ATP6V0A2 Ivone Leong Source: Expert Review Red was removed from gene: ATP6V0A2
Intellectual disability v3.790 PDE4D Catherine Snow Source: Expert Review Amber was removed from gene: PDE4D
Intellectual disability v3.789 ASL Ivone Leong Source: Expert Review Red was removed from gene: ASL
Intellectual disability v3.789 ATP7B Sarah Leigh Source: Expert Review Amber was removed from gene: ATP7B
Intellectual disability v3.787 PARN Catherine Snow Source: Expert Review Amber was removed from gene: PARN
Intellectual disability v3.787 ARL13B Ivone Leong Source: Expert Review Red was removed from gene: ARL13B
Intellectual disability v3.786 ARID2 Ivone Leong Source: Expert Review Red was removed from gene: ARID2
Intellectual disability v3.785 OPA3 Catherine Snow Source: Expert Review Amber was removed from gene: OPA3
Intellectual disability v3.784 AP3B1 Ivone Leong Source: Expert Review Red was removed from gene: AP3B1
Intellectual disability v3.783 PMP22 Arina Puzriakova Source: Expert Review Amber was removed from gene: PMP22
Intellectual disability v3.782 ADK Ivone Leong Source: Expert Review Red was removed from gene: ADK
Intellectual disability v3.781 CCDC186 Sarah Leigh Classified gene: CCDC186 as Amber List (moderate evidence)
Intellectual disability v3.781 CCDC186 Sarah Leigh Gene: ccdc186 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.780 CCDC186 Sarah Leigh changed review comment from: Not associated with relevant phenotype in OMIM or Gen2Phen. At least 2 terminating variants reported in unrelated cases.
Sources: Literature; to: Not associated with a relevant phenotype in OMIM or Gen2Phen. At least 2 terminating variants reported in cases with failure to thrive and developmental delay.
Sources: Literature
Intellectual disability v3.780 CCDC186 Sarah Leigh gene: CCDC186 was added
gene: CCDC186 was added to Intellectual disability. Sources: Literature
watchlist tags were added to gene: CCDC186.
Mode of inheritance for gene: CCDC186 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CCDC186 were set to 33259146; 28600779
Phenotypes for gene: CCDC186 were set to failure to thrive and developmental delay
Review for gene: CCDC186 was set to AMBER
Added comment: Not associated with relevant phenotype in OMIM or Gen2Phen. At least 2 terminating variants reported in unrelated cases.
Sources: Literature
Intellectual disability v3.779 LMBRD2 Sarah Leigh Added comment: Comment on mode of pathogenicity: Both of the references for this entry suggest a gain-of-function action for LMBRD2 variants.
Intellectual disability v3.779 LMBRD2 Sarah Leigh Mode of pathogenicity for gene: LMBRD2 was changed from None to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Intellectual disability v3.778 ADAM22 Sarah Leigh Classified gene: ADAM22 as Amber List (moderate evidence)
Intellectual disability v3.778 ADAM22 Sarah Leigh Added comment: Comment on list classification: There is just enough evidence for this gene to be rated GREEN at the next major review, which may make it a boarderline case.
Intellectual disability v3.778 ADAM22 Sarah Leigh Gene: adam22 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.777 KCNN2 Arina Puzriakova Classified gene: KCNN2 as Amber List (moderate evidence)
Intellectual disability v3.777 KCNN2 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. There is enough evidence to promote this gene to Green at the next GMS panel update - variable degrees of cognitive impairment were a universal feature amongst individuals with KCNN2 variants (at least 10 unrelated cases with unique variants). Pathogenicity was supported by functional data.
Intellectual disability v3.777 KCNN2 Arina Puzriakova Gene: kcnn2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.776 KCNN2 Arina Puzriakova Tag Q2_21_rating tag was added to gene: KCNN2.
Intellectual disability v3.776 KCNN2 Arina Puzriakova reviewed gene: KCNN2: Rating: GREEN; Mode of pathogenicity: None; Publications: 33242881; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.776 SATB1 Arina Puzriakova Publications for gene: SATB1 were set to 33057194
Intellectual disability v3.775 SATB1 Arina Puzriakova Deleted their comment
Intellectual disability v3.775 SATB1 Arina Puzriakova Classified gene: SATB1 as Amber List (moderate evidence)
Intellectual disability v3.775 SATB1 Arina Puzriakova Added comment: Comment on list classification: There is now enough evidence to promote this gene to Green at the next major review.
Intellectual disability v3.775 SATB1 Arina Puzriakova Gene: satb1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.775 SATB1 Arina Puzriakova Classified gene: SATB1 as Amber List (moderate evidence)
Intellectual disability v3.775 SATB1 Arina Puzriakova Added comment: Comment on list classification: There is now enough evidence to promote this gene to Green at the next major review.
Intellectual disability v3.775 SATB1 Arina Puzriakova Gene: satb1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.774 SATB1 Arina Puzriakova Tag watchlist was removed from gene: SATB1.
Tag Q2_21_rating tag was added to gene: SATB1.
Intellectual disability v3.774 SATB1 Arina Puzriakova reviewed gene: SATB1: Rating: GREEN; Mode of pathogenicity: None; Publications: 33513338; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.774 OTUD5 Arina Puzriakova Classified gene: OTUD5 as Amber List (moderate evidence)
Intellectual disability v3.774 OTUD5 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. There is enough evidence to rate this gene Green at the next GMS panel update.

At least 8 families reported with a multiple congenital anomaly disorder and distinct hemizygous variants in this gene. GDD/ID is part of the disease presentation and was noted in all cases of relevant age (PMIDs: 33131077 and 33523931).
Intellectual disability v3.774 OTUD5 Arina Puzriakova Gene: otud5 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.773 OTUD5 Arina Puzriakova Tag Q2_21_rating tag was added to gene: OTUD5.
Intellectual disability v3.773 OTUD5 Zornitza Stark changed review comment from: PMID 33523931: Another 10 individuals from 7 families reported, promote to Green. X-linked multiple congenital anomalies-neurodevelopmental syndrome (MCAND) is an X-linked recessive congenital multisystemic disorder characterized by poor growth, global developmental delay with impaired intellectual development, and variable abnormalities of the cardiac, skeletal, and genitourinary systems. Most affected individuals also have hypotonia and dysmorphic craniofacial features. Brain imaging typically shows enlarged ventricles and thin corpus callosum; some have microcephaly, whereas others have hydrocephalus. The severity of the disorder is highly variable, ranging from death in early infancy to survival into the second or third decade.; to: PMID 33523931: Another 10 individuals from 7 families reported. Key features include poor growth, global developmental delay with impaired intellectual development, and variable abnormalities of the cardiac, skeletal, and genitourinary systems. Most affected individuals also have hypotonia and dysmorphic craniofacial features. Brain imaging typically shows enlarged ventricles and thin corpus callosum; some have microcephaly, whereas others have hydrocephalus. The severity of the disorder is highly variable, ranging from death in early infancy to survival into the second or third decade.
Intellectual disability v3.773 OTUD5 Zornitza Stark edited their review of gene: OTUD5: Added comment: PMID 33523931: Another 10 individuals from 7 families reported, promote to Green. X-linked multiple congenital anomalies-neurodevelopmental syndrome (MCAND) is an X-linked recessive congenital multisystemic disorder characterized by poor growth, global developmental delay with impaired intellectual development, and variable abnormalities of the cardiac, skeletal, and genitourinary systems. Most affected individuals also have hypotonia and dysmorphic craniofacial features. Brain imaging typically shows enlarged ventricles and thin corpus callosum; some have microcephaly, whereas others have hydrocephalus. The severity of the disorder is highly variable, ranging from death in early infancy to survival into the second or third decade.; Changed rating: GREEN; Changed publications: 33131077, 33523931
Intellectual disability v3.773 PIGF Arina Puzriakova changed review comment from: Comment on list classification: New gene added by Zornitza Stark. Rating Red as 2 families with the same (likely founder) variant reported at present (PMID: 33386993). Phenotypes did include severe ID or DD, respectively - but additional cases with other variants in the LRRC32 gene required to substantiate causation (added founder-effect tag); to: Comment on list classification: New gene added by Zornitza Stark. Rating Red as 2 families with the same (likely founder) variant reported at present (PMID: 33386993). Phenotypes did include severe ID or DD, respectively - but additional cases with other variants in the PIGF gene required to substantiate causation (added founder-effect tag)
Intellectual disability v3.773 PIGF Arina Puzriakova Tag founder-effect tag was added to gene: PIGF.
Intellectual disability v3.773 PIGF Arina Puzriakova Classified gene: PIGF as Red List (low evidence)
Intellectual disability v3.773 PIGF Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. Rating Red as 2 families with the same (likely founder) variant reported at present (PMID: 33386993). Phenotypes did include severe ID or DD, respectively - but additional cases with other variants in the LRRC32 gene required to substantiate causation (added founder-effect tag)
Intellectual disability v3.773 PIGF Arina Puzriakova Gene: pigf has been classified as Red List (Low Evidence).
Intellectual disability v3.772 OTUD5 Arina Puzriakova Publications for gene: OTUD5 were set to 33131077
Intellectual disability v3.771 OTUD5 Arina Puzriakova Phenotypes for gene: OTUD5 were changed from X-linked severe neurodevelopmental delay, hydrocephalus, and early lethality to Multiple congenital anomalies-neurodevelopmental syndrome, X-linked, OMIM:301056
Intellectual disability v3.770 METAP1 Arina Puzriakova Classified gene: METAP1 as Red List (low evidence)
Intellectual disability v3.770 METAP1 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. Rating Red as only one family reported at present (PMID:32764695). Phenotypes do include ID/DD, but additional cases required to corroborate this gene-disease association.
Intellectual disability v3.770 METAP1 Arina Puzriakova Gene: metap1 has been classified as Red List (Low Evidence).
Intellectual disability v3.769 HPDL Arina Puzriakova Classified gene: HPDL as Amber List (moderate evidence)
Intellectual disability v3.769 HPDL Arina Puzriakova Added comment: Comment on list classification: New gene added by Evan Reid (University of Cambridge). There is enough evidence for this gene to be rated Green at the next major review.
Intellectual disability v3.769 HPDL Arina Puzriakova Gene: hpdl has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.768 HPDL Arina Puzriakova Publications for gene: HPDL were set to PMID: 32707086; 33188300
Intellectual disability v3.767 HPDL Arina Puzriakova Tag Q2_21_rating tag was added to gene: HPDL.
Intellectual disability v3.767 HPDL Arina Puzriakova reviewed gene: HPDL: Rating: GREEN; Mode of pathogenicity: None; Publications: 32707086, 33188300; Phenotypes: Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities, OMIM:619026, Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities, MONDO:0033613; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.767 HPDL Arina Puzriakova Phenotypes for gene: HPDL were changed from spastic paraplegia; spastic tetraplegia; microcephaly; brain atrophy; epilepsy; severe intellectual; motor disability to Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities, OMIM:619026; Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities, MONDO:0033613
Intellectual disability v3.766 HIRA Arina Puzriakova Classified gene: HIRA as Amber List (moderate evidence)
Intellectual disability v3.766 HIRA Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. At least 4 unrelated individuals with heterozygous variants in this gene - however, only 1 presented moderate ID (2 had ASD rather than ID, while the phenotype is unclear for the fourth individual). HIRA is a good candidate for neurodevelopmental impairment, supported by an animal model, but additional cases are required to ascertain the relevance of ID.

Therefore, at present there is only enough evidence to rate Amber awaiting further cases/clinical evidence (added 'watchlist' tag)
Intellectual disability v3.766 HIRA Arina Puzriakova Gene: hira has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.765 HIRA Arina Puzriakova Tag watchlist tag was added to gene: HIRA.
Intellectual disability v3.765 HIRA Arina Puzriakova reviewed gene: HIRA: Rating: AMBER; Mode of pathogenicity: None; Publications: 25363760, 28135719, 33417013; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.765 VPS4A Arina Puzriakova Phenotypes for gene: VPS4A were changed from developmental delay; intellectual disability; cerebellar hypoplasia; pontine hypoplasia; thin corpus callosum; microcephaly; growth retardation; congenital anaemia; dyserythropeoitic anaemia; dystonia; congenital cataracts; deafness to CIMDAG syndrome
Intellectual disability v3.764 B4GALNT1 Sarah Leigh Classified gene: B4GALNT1 as Green List (high evidence)
Intellectual disability v3.764 B4GALNT1 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least eight variants reported in at least eight unrelated cases.
Intellectual disability v3.764 B4GALNT1 Sarah Leigh Gene: b4galnt1 has been classified as Green List (High Evidence).
Intellectual disability v3.763 B4GALNT1 Sarah Leigh Publications for gene: B4GALNT1 were set to
Intellectual disability v3.762 B4GALNT1 Sarah Leigh Phenotypes for gene: B4GALNT1 were changed from ID; Spastic paraplegia 26, autosomal recessive to Spastic paraplegia 26, autosomal recessive OMIM:609195; hereditary spastic paraplegia 26 MONDO:0012213
Intellectual disability v3.761 PIGF Zornitza Stark gene: PIGF was added
gene: PIGF was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: PIGF was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PIGF were set to 33386993
Phenotypes for gene: PIGF were set to Glycosylphosphatidylinositol deficiency, onychodystrophy, osteodystrophy, intellectual disability, and seizures
Review for gene: PIGF was set to RED
Added comment: The same homozygous missense variant identified in 2 individuals from different families from the same region of India. Individuals had a phenotype similar to DOORS syndrome without deafness. Impaired glycosylphosphatidylinositol (GPI) biosynthesis was demonstrated.

Rated Red as the two families are likely to be related (founder mutation?).
Sources: Literature
Intellectual disability v3.761 DDX58 Arina Puzriakova reviewed gene: DDX58: Rating: ; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.761 DDX58 Arina Puzriakova Mode of inheritance for gene: DDX58 was changed from to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.760 HPDL Evan Reid gene: HPDL was added
gene: HPDL was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: HPDL was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HPDL were set to PMID: 32707086; 33188300
Phenotypes for gene: HPDL were set to spastic paraplegia; spastic tetraplegia; microcephaly; brain atrophy; epilepsy; severe intellectual; motor disability
Penetrance for gene: HPDL were set to Complete
Review for gene: HPDL was set to GREEN
Added comment: Newly identified gene that can give a phenotype ranging from infantile epileptic encephalopathy with severe developmental delay/intellectual disability to juvenile onset progressive spastic paraplegia.
Sources: Literature
Intellectual disability v3.760 TCTN3 Arina Puzriakova Publications for gene: TCTN3 were set to
Intellectual disability v3.759 TCTN3 Arina Puzriakova changed review comment from: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update (added 'for-review' tag).

At least 3 unrelated cases with Joubert syndrome, presenting with ID, and biallelic variants in this gene (PMIDs: 22883145; 25118024; 26092869); to: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update (added 'for-review' tag).

Independent reports of at least 3 unrelated cases with Joubert syndrome, presenting with ID, and different biallelic variants in this gene (PMIDs: 22883145; 25118024; 26092869)
Intellectual disability v3.759 TCTN3 Arina Puzriakova Classified gene: TCTN3 as Amber List (moderate evidence)
Intellectual disability v3.759 TCTN3 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update (added 'for-review' tag).

At least 3 unrelated cases with Joubert syndrome, presenting with ID, and biallelic variants in this gene (PMIDs: 22883145; 25118024; 26092869)
Intellectual disability v3.759 TCTN3 Arina Puzriakova Gene: tctn3 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.758 PRUNE1 Eleanor Williams Phenotypes for gene: PRUNE1 were changed from Neurodevelopmental disorder with microcephaly, hypotonia, and variable brain anomalies, 617481; NMIHBA; Complex neurological syndrome to Neurodevelopmental disorder with microcephaly, hypotonia, and variable brain anomalies OMIM:617481; neurodevelopmental disorder with microcephaly, hypotonia, and variable brain anomalies MONDO:0060490; NMIHBA; Complex neurological syndrome
Intellectual disability v3.757 PRUNE1 Eleanor Williams Publications for gene: PRUNE1 were set to 26539891; 28334956
Intellectual disability v3.756 PRUNE1 Eleanor Williams reviewed gene: PRUNE1: Rating: GREEN; Mode of pathogenicity: None; Publications: 33105479; Phenotypes: Neurodevelopmental disorder with microcephaly, hypotonia, and variable brain anomalies OMIM:617481, neurodevelopmental disorder with microcephaly, hypotonia, and variable brain anomalies MONDO:0060490; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.756 TCTN3 Arina Puzriakova Tag for-review tag was added to gene: TCTN3.
Intellectual disability v3.756 VPS4A Arina Puzriakova edited their review of gene: VPS4A: Changed publications: 33186545, 33186543, 33460484
Intellectual disability v3.756 VPS4A Arina Puzriakova Classified gene: VPS4A as Amber List (moderate evidence)
Intellectual disability v3.756 VPS4A Arina Puzriakova Added comment: Comment on list classification: New gene added by Evan Reid (University of Cambridge). At least 5 different variants reported in 10 unrelated individuals with a comparable phenotype, including severe-to-profound ID/DD. Pathogenicity is supported by functional data.

There is enough evidence to promote this gene to Green at the next GMS panel update (added 'for-review' tag)
Intellectual disability v3.756 VPS4A Arina Puzriakova Gene: vps4a has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.755 VPS4A Arina Puzriakova Added comment: Comment on mode of inheritance: Setting MOI to 'Monoallelic' as only one biallelic case reported to date, and patients with biallelic variants would still be picked up by the Genomics England pipeline.
Intellectual disability v3.755 VPS4A Arina Puzriakova Mode of inheritance for gene: VPS4A was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.754 VPS4A Arina Puzriakova reviewed gene: VPS4A: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: 33186545, 33186543; Phenotypes: CIMDAG syndrome; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.754 VPS4A Ivone Leong Tag for-review tag was added to gene: VPS4A.
Intellectual disability v3.754 VPS4A Ivone Leong Classified gene: VPS4A as Amber List (moderate evidence)
Intellectual disability v3.754 VPS4A Ivone Leong Gene: vps4a has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.753 VPS4A Ivone Leong Publications for gene: VPS4A were set to (PMID: 33186545; 33186543; 33460484)
Intellectual disability v3.752 ADAM22 Sarah Leigh Phenotypes for gene: ADAM22 were changed from to ?Epileptic encephalopathy, early infantile, 61 OMIM:617933; developmental and epileptic encephalopathy, 61 MONDO:0033370
Intellectual disability v3.751 ADAM22 Sarah Leigh Tag for-review tag was added to gene: ADAM22.
Intellectual disability v3.751 ADAM22 Sarah Leigh reviewed gene: ADAM22: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.751 VPS4A Evan Reid changed review comment from: Multiple families (now 10) described with a consistent phenotype (we have termed it CIMDAG as an acronym for the major features). All have de novo heterozygous missense mutations of VPS4A, with a distinct mutational hotspot (R284) in many families. Mechanism is likely dominant negative. Haplo-insufficiency of VPS4A is tolerated and present in general population databases, so loss of function mutations likely do not cause this disease.
Sources: Literature, Research; to: Multiple families (now 10) described with a consistent phenotype (termed CIMDAG as an acronym for the major features). All have de novo heterozygous missense mutations of VPS4A, with a distinct mutational hotspot (R284) in many families. Mechanism is likely dominant negative. Haplo-insufficiency of VPS4A is tolerated and present in general population databases, so loss of function mutations likely do not cause this disease.
Sources: Literature, Research
Intellectual disability v3.751 VPS4A Evan Reid gene: VPS4A was added
gene: VPS4A was added to Intellectual disability. Sources: Literature,Research
Mode of inheritance for gene: VPS4A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: VPS4A were set to (PMID: 33186545; 33186543; 33460484)
Phenotypes for gene: VPS4A were set to developmental delay; intellectual disability; cerebellar hypoplasia; pontine hypoplasia; thin corpus callosum; microcephaly; growth retardation; congenital anaemia; dyserythropeoitic anaemia; dystonia; congenital cataracts; deafness
Penetrance for gene: VPS4A were set to Complete
Mode of pathogenicity for gene: VPS4A was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: VPS4A was set to GREEN
Added comment: Multiple families (now 10) described with a consistent phenotype (we have termed it CIMDAG as an acronym for the major features). All have de novo heterozygous missense mutations of VPS4A, with a distinct mutational hotspot (R284) in many families. Mechanism is likely dominant negative. Haplo-insufficiency of VPS4A is tolerated and present in general population databases, so loss of function mutations likely do not cause this disease.
Sources: Literature, Research
Intellectual disability v3.751 TET3 Sarah Leigh Phenotypes for gene: TET3 were changed from Beck-Fahrner syndrome 618798 to Beck-Fahrner syndrome OMIM:618798
Intellectual disability v3.751 TET3 Sarah Leigh Publications for gene: TET3 were set to https://doi.org/10.1016/j.ajhg.2019.12.007; 31928709
Intellectual disability v3.750 PIGK Sarah Leigh Phenotypes for gene: PIGK were changed from Neurodevelopmental disorder with hypotonia and cerebellar atrophy, with or without seizures 618879 to Neurodevelopmental disorder with hypotonia and cerebellar atrophy, with or without seizures OMIM:618879
Intellectual disability v3.749 HIRA Zornitza Stark gene: HIRA was added
gene: HIRA was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: HIRA was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: HIRA were set to 33417013; 28135719; 25363760
Phenotypes for gene: HIRA were set to Neurodevelopmental disorder
Review for gene: HIRA was set to GREEN
gene: HIRA was marked as current diagnostic
Added comment: Two unrelated patients with different de novo loss of function variants identified in PMID 33417013:

Individual 1: intragenic deletion, phenotype included psychomotor retardation, ID, growth retardation, microcephaly, and facial features reminiscent of 22q deletion syndrome.
Individual 2: canonical splice variant, phenotype mostly confined to ASD

Another two de novo variants were identified in the literature by the authors of that paper, one stop-gain (DDD study, PMID 28135719) and one missense (large autism cohort, PMID 25363760).

PMID 33417013 also showed that HIRA knockdown in mice results in neurodevelopmental abnormalities.

Rated Green due to 4 unrelated individuals (albeit 2 in large cohort studies) and a mouse model. NB: HIRA is within the common 22q deletion region.
Sources: Literature
Intellectual disability v3.749 SATB1 Zornitza Stark changed review comment from: PMID: 33513338: 42 patients with SNVs. 28 de novo, 3 inherited from an affected parent.
Missense variants - more severe, profound ID
NMD PTCs - milder disease; to: PMID: 33513338: 42 patients with SNVs. 28 de novo, 3 inherited from an affected parent.
Missense variants - more severe, profound ID
NMD PTCs - milder disease

Consider adding to epilepsy and ataxia panels.
Intellectual disability v3.749 SATB1 Zornitza Stark edited their review of gene: SATB1: Added comment: PMID: 33513338: 42 patients with SNVs. 28 de novo, 3 inherited from an affected parent.
Missense variants - more severe, profound ID
NMD PTCs - milder disease; Changed rating: GREEN; Changed publications: 33057194, 33513338; Changed phenotypes: Neurodevelopmental disorder; Set current diagnostic: yes
Intellectual disability v3.749 METAP1 Zornitza Stark gene: METAP1 was added
gene: METAP1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: METAP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: METAP1 were set to 32764695
Phenotypes for gene: METAP1 were set to Intellectual disability, aggression, neurodevelopmental delay
Review for gene: METAP1 was set to RED
Added comment: Biallelic nonsense (NMD-predicted) variant identified in 4 sibs in a consanguineous family with dev delay. One sib had bilateral clinodactyly of her toes and her left 3rd finger, other sibs were not dysmorphic. Rated red due to single consanguineous family.
Sources: Literature
Intellectual disability v3.749 KCNN2 Zornitza Stark gene: KCNN2 was added
gene: KCNN2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: KCNN2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KCNN2 were set to 33242881
Phenotypes for gene: KCNN2 were set to Intellectual disability; seizures; movement disorder
Review for gene: KCNN2 was set to GREEN
gene: KCNN2 was marked as current diagnostic
Added comment: - 11 probands all de novo except for 1 mother-daughter pair.
- a mix of null and missense variants
- 2/11 with microcephaly, 10/11 motor delay, 7/11 language delay (excluding 2 with regression), all with varying degrees of ID, 3/11 seizures, 7/11 movement disorder, 4/11 cerebellar ataxia, 6/11 MRI anomalies
Sources: Literature
Intellectual disability v3.749 OTUD5 Zornitza Stark gene: OTUD5 was added
gene: OTUD5 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: OTUD5 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: OTUD5 were set to 33131077
Phenotypes for gene: OTUD5 were set to X-linked severe neurodevelopmental delay, hydrocephalus, and early lethality
Review for gene: OTUD5 was set to RED
Added comment: 13 male patients from a single family with three generations affected. Patients presented prenatally or during the neonatal period with IUGR, ventriculomegaly, hydrocephalus, hypotonia, congenital heart defects, hypospadias, and severe neurodevelopmental delay. The disease is typically fatal during infancy, mainly due to sepsis (pneumonias). Female carriers are asymptomatic. WGS in four individuals identified a unique candidate variant in the OTUD5 gene (NM_017602.3:c.598G > A, p.Glu200Lys). The variant cosegregated with the disease in 10 tested individuals.
Sources: Literature
Intellectual disability v3.749 MSMO1 Arina Puzriakova Phenotypes for gene: MSMO1 were changed from Microcephaly, congenital cataract, and psoriasiform dermatitis, 616834 to Microcephaly, congenital cataract, and psoriasiform dermatitis, OMIM:616834; Microcephaly-congenital cataract-psoriasiform dermatitis syndrome, MONDO:0014793
Intellectual disability v3.748 MEIS2 Arina Puzriakova Phenotypes for gene: MEIS2 were changed from Cleft palate, cardiac defects, and mental retardation; Oral cleft; Abnormal heart morphology; Intellectual disability; Cleft palate, cardiac defects, and mental retardation, 600987 to Cleft palate, cardiac defects, and mental retardation, OMIM:600987; Cardiac malformation, cleft lip/palate, microcephaly, and digital anomalies, MONDO:0010970
Intellectual disability v3.747 KNL1 Arina Puzriakova Phenotypes for gene: KNL1 were changed from Microcephaly 4, primary, autosomal recessive 604321 to Microcephaly 4, primary, autosomal recessive, OMIM:604321; Microcephaly 4, primary, autosomal recessive, MONDO:0011437
Intellectual disability v3.746 KATNB1 Arina Puzriakova Phenotypes for gene: KATNB1 were changed from Lissencephaly 6, with microcephaly, MIM 616212 to Lissencephaly 6, with microcephaly, OMIM:616212, MONDO:0014534
Intellectual disability v3.745 TOR1A Arina Puzriakova Classified gene: TOR1A as Amber List (moderate evidence)
Intellectual disability v3.745 TOR1A Arina Puzriakova Added comment: Comment on list classification: Upgraded from Red to Amber, but there is sufficient evidence linking biallelic variants to a relevant phenotype to rate this gene Green at the next GMS panel update (added 'for-review' tag)
Intellectual disability v3.745 TOR1A Arina Puzriakova Gene: tor1a has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.744 TOR1A Arina Puzriakova reviewed gene: TOR1A: Rating: GREEN; Mode of pathogenicity: None; Publications: 30244176, 29053766, 28516161; Phenotypes: Arthrogryposis multiplex congenita 5, OMIM:618947, Arthrogryposis multiplex congenita 5, MONDO:0100218; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.744 TOR1A Arina Puzriakova Tag for-review tag was added to gene: TOR1A.
Intellectual disability v3.744 TOR1A Arina Puzriakova Publications for gene: TOR1A were set to 24896178
Intellectual disability v3.743 TOR1A Arina Puzriakova Phenotypes for gene: TOR1A were changed from Dystonia-1, torsion, 128100; Dystonia, early-onset atypical, with myoclonic features; {Dystonia-1, modifier of} to Arthrogryposis multiplex congenita 5, OMIM:618947; Arthrogryposis multiplex congenita 5, MONDO:0100218
Intellectual disability v3.743 TOR1A Arina Puzriakova Mode of inheritance for gene: TOR1A was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.742 TMX2 Arina Puzriakova Phenotypes for gene: TMX2 were changed from Global developmental delay; Intellectual disability; Seizures; Microcephaly; Abnormal cortical gyration; Neurodevelopmental disorder with microcephaly, cortical malformations, and spasticity, 618730 to Neurodevelopmental disorder with microcephaly, cortical malformations, and spasticity, OMIM:618730; Neurodevelopmental disorder with microcephaly, cortical malformations, and spasticity, MONDO:0032887
Intellectual disability v3.741 TENM3 Arina Puzriakova Phenotypes for gene: TENM3 were changed from Microphthalmia, syndromic 15, MIM#615145; coloboma to Microphthalmia, syndromic 15, OMIM:615145; ?Microphthalmia, isolated, with coloboma 9, OMIM:615145; Microphthalmia, isolated, with coloboma 9, MONDO:0014059
Intellectual disability v3.740 ABCC9 Arina Puzriakova changed review comment from: Comment on list classification: Intellectual impairment as been reported in individuals with loss-of-function variants and a percentage of those with gain-of-function variants. However, this is less prominent than other features of the disease presentation (e.g. cardiac, skeletal defects) and often ID is perhaps too mild.

Therefore, ABCC9 will be flagged for review by the GMS team with regards to phenotypic fit for this panel and determine whether it should be demoted from Green to Amber (added for-review tag).; to: Comment on list classification: Intellectual impairment has been reported in individuals with loss-of-function variants and a percentage of those with gain-of-function variants. ID is typically mild, however it is plausible that patients may still be tested for this panel, particularly if recruited under Coffin-Siris-like coarse facial features which can be associated with this gene. Therefore, maintaining Green gene rating.

Comment on mode of inheritance: Leaving MOI as Monoallelic as only 2 families with the same biallelic variant (possible founder variant) reported to date (PMID:31575858), and patients with biallelic variants would still be picked up by the Genomics England pipeline.
Intellectual disability v3.740 ABCC9 Arina Puzriakova Tag for-review was removed from gene: ABCC9.
Intellectual disability v3.740 UBR7 Arina Puzriakova Tag for-review tag was added to gene: UBR7.
Intellectual disability v3.740 UBR7 Arina Puzriakova Classified gene: UBR7 as Amber List (moderate evidence)
Intellectual disability v3.740 UBR7 Arina Puzriakova Added comment: Comment on list classification: In view of recent expert review by Zornitza Stark, upgraded from Red to Amber but with a recommendation of rating Green at the next GMS panel update (added 'for-review' tag)

At least 6 SNVs and 1 intragenic deletion reported in 7 individuals from 6 families with a comparable neurodevelopmental disorder. DD/ID was a feature in all cases (PMID:33340455)
Intellectual disability v3.740 UBR7 Arina Puzriakova Gene: ubr7 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.739 UBR7 Arina Puzriakova Publications for gene: UBR7 were set to 21937992
Intellectual disability v3.738 UBR7 Arina Puzriakova Phenotypes for gene: UBR7 were changed from AUTOSOMAL RECESSIVE MENTAL RETARDATION to Intellectual disability; epilepsy; hypothyroidism; congenital anomalies; dysmorphic features
Intellectual disability v3.737 RNU7-1 Arina Puzriakova Classified gene: RNU7-1 as Amber List (moderate evidence)
Intellectual disability v3.737 RNU7-1 Arina Puzriakova Added comment: Comment on list classification: Various degrees of cognitive impairment reported (PMID:33230297). However, DD is an early feature often preceding other neurological concerns, and there are enough cases with sufficiently severe ID for inclusion on this panel.

Rating Amber but should be promoted to Green at the next GMS panel update (added 'for-review' tag)
Intellectual disability v3.737 RNU7-1 Arina Puzriakova Gene: rnu7-1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.736 RNU7-1 Arina Puzriakova Phenotypes for gene: RNU7-1 were changed from Aicardi–Goutières syndrome-like to Aicardi–Goutières syndrome-like; Type I interferonopathy
Intellectual disability v3.735 RNU7-1 Arina Puzriakova Tag for-review tag was added to gene: RNU7-1.
Intellectual disability v3.735 APC2 Sarah Leigh Phenotypes for gene: APC2 were changed from Global developmental delay; Intellectual disability; Seizures; Morphological abnormality of the central nervous system to Cortical dysplasia, complex, with other brain malformations 10 OMIM:618677
Intellectual disability v3.734 RNU7-1 Arina Puzriakova reviewed gene: RNU7-1: Rating: GREEN; Mode of pathogenicity: None; Publications: 33230297; Phenotypes: Aicardi–Goutières syndrome-like, Type I interferonopathy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.734 FGFR1 Arina Puzriakova Phenotypes for gene: FGFR1 were changed from Hartsfield syndrome, OMIM:615465; Pfeiffer syndrome, OMIM:101600 to Hartsfield syndrome, OMIM:615465; Pfeiffer syndrome, OMIM:101600; Encephalocraniocutaneous lipomatosis, somatic mosaic, OMIM:613001
Intellectual disability v3.733 FGFR1 Arina Puzriakova Publications for gene: FGFR1 were set to 28825856
Intellectual disability v3.732 FGFR1 Arina Puzriakova Phenotypes for gene: FGFR1 were changed from Encephalocraniocutaneous lipomatosis, 613001; KALLMANN SYNDROME TYPE 2; Pfeiffer syndrome,101600 to Hartsfield syndrome, OMIM:615465; Pfeiffer syndrome, OMIM:101600
Intellectual disability v3.731 FGFR1 Arina Puzriakova reviewed gene: FGFR1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.731 TANC2 Arina Puzriakova Classified gene: TANC2 as Amber List (moderate evidence)
Intellectual disability v3.731 TANC2 Arina Puzriakova Added comment: Comment on list classification: This gene should be promoted to Green at the next GMS panel update - multiple unrelated families with a comparable neurodevelopmental disorder (including ID). As highlighted in review by Zornitza Stark, most reported SNVs are de novo putative disruptive variants, or missense variants that are predicted in silico to have a damaging or possibly damaging effect. Gene expression and function are neurodevelopmentally-relevant, and there is some limited functional data.

Gene-disease association is also now listed in both OMIM and Gene2Phenotype.
Intellectual disability v3.731 TANC2 Arina Puzriakova Gene: tanc2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.730 TANC2 Arina Puzriakova Publications for gene: TANC2 were set to 26350204; 31616000
Intellectual disability v3.729 TANC2 Arina Puzriakova commented on gene: TANC2: Removed 'watchlist' tag and added 'for-review' tag as there is now sufficient evidence to promote this gene to Green
Intellectual disability v3.729 TANC2 Arina Puzriakova Tag watchlist was removed from gene: TANC2.
Tag for-review tag was added to gene: TANC2.
Intellectual disability v3.729 TANC2 Arina Puzriakova edited their review of gene: TANC2: Changed phenotypes: Intellectual developmental disorder with autistic features and language delay, with or without seizures, OMIM:618906
Intellectual disability v3.729 TANC2 Arina Puzriakova reviewed gene: TANC2: Rating: GREEN; Mode of pathogenicity: None; Publications: 31616000, 33160097, 30021165; Phenotypes: TANC2-related neurodevelopmental and psychiatric disorder, OMIM:618906; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.729 ATP1A3 Arina Puzriakova Publications for gene: ATP1A3 were set to 22842232; 29396171; 29291920; 22842232; 28969699
Intellectual disability v3.729 ATP1A3 Arina Puzriakova Classified gene: ATP1A3 as Amber List (moderate evidence)
Intellectual disability v3.729 ATP1A3 Arina Puzriakova Added comment: Comment on list classification: Maintaining Amber rating on this panel, in line with the previous comments by Louise Daugherty (Genomics England) and internal clinical review.

Heterozygous variants are associated with several phenotypes, not all of which include cognitive impairment. Gain from inclusion on the ID panel is likely smaller than the risk of incidental information for the majority of the ID cohort. Patients are expected to be tested under the paroxysmal central nervous system disorders or dystonia GMS panels.
Intellectual disability v3.729 ATP1A3 Arina Puzriakova Gene: atp1a3 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.728 LAMB2 Zornitza Stark edited their review of gene: LAMB2: Changed rating: GREEN
Intellectual disability v3.728 PPIL1 Arina Puzriakova Tag for-review tag was added to gene: PPIL1.
Intellectual disability v3.728 PPIL1 Arina Puzriakova Classified gene: PPIL1 as Amber List (moderate evidence)
Intellectual disability v3.728 PPIL1 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. Currently not associated with any phenotype in OMIM (last edited on: 10/07/2001) but has a 'probable' gene rating for 'PPIL1-related Neurodegenerative Pontocerebellar Hypoplasia with Microcephaly' in Gene2Phenotype.

At least 12 variants identified in 17 individuals from 9 unrelated families (PMID: 33220177). All displayed pontocerebellar hypoplasia and congenital microcephaly. Severe ID, with or without seizures, was noted in all subjects (14) where information was provided (see table S1). Pathogenicity is supported by animal model.

Sufficient evidence to promote this gene to Green at the next GMS panel update (added 'for-review' tag)
Intellectual disability v3.728 PPIL1 Arina Puzriakova Gene: ppil1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.727 PPIL1 Arina Puzriakova Phenotypes for gene: PPIL1 were changed from Pontocerebellar hypoplasia; microcephaly; seizures; intellectual disbility to PPIL1-related Neurodegenerative Pontocerebellar Hypoplasia with Microcephaly
Intellectual disability v3.726 FGF13 Arina Puzriakova Classified gene: FGF13 as Amber List (moderate evidence)
Intellectual disability v3.726 FGF13 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. Three variants (c.31C>T, c.41G>C, c.32G>C) identified by WES/WGS in seven individuals from five unrelated families who presented with severe infantile-onset seizures and severe-to-profound ID. Supportive functional data.

Sufficient number of unrelated cases with relevant phenotype; however, early-onset epilepsy represents the main feature of the disorder and ID appears to be a secondary manifestation (see supplemental note in PMID:33245860 for clinical details). Therefore, rating Amber on this panel but will add the FGF13 gene to 'Genetic epilepsy syndromes'
Intellectual disability v3.726 FGF13 Arina Puzriakova Gene: fgf13 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.725 FGF13 Arina Puzriakova Phenotypes for gene: FGF13 were changed from Intellectual disability; epilepsy to Developmental and epileptic encephalopathy; Intellectual disability; Infantile-onset seizures
Intellectual disability v3.724 FGF13 Arina Puzriakova Mode of inheritance for gene: FGF13 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 v3.723 FBRSL1 Arina Puzriakova Phenotypes for gene: FBRSL1 were changed from Intellectual disability; congenital anomalies to Intellectual disability; Microcephaly; Heart defect; Cleft palate; Contractures; Hearing impairment; Skin creases
Intellectual disability v3.722 FBRSL1 Arina Puzriakova Classified gene: FBRSL1 as Amber List (moderate evidence)
Intellectual disability v3.722 FBRSL1 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. There is enough evidence to promote this gene to Green at the next GMS panel update (added 'for-review' tag) - sufficient number of unrelated cases with distinct variants and relevant phenotype, supported by functional data.

Currently not associated with any phenotype in OMIM or Gene2Phenotype.
Intellectual disability v3.722 FBRSL1 Arina Puzriakova Gene: fbrsl1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.721 FBRSL1 Arina Puzriakova Tag for-review tag was added to gene: FBRSL1.
Intellectual disability v3.721 FBRSL1 Arina Puzriakova reviewed gene: FBRSL1: Rating: GREEN; Mode of pathogenicity: None; Publications: 32424618; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.721 DPH2 Arina Puzriakova Classified gene: DPH2 as Amber List (moderate evidence)
Intellectual disability v3.721 DPH2 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. Currently not associated with any phenotype in OMIM or Gene2Phenotype.

At least 2 unrelated families with biallelic variants in this gene. Phenotypes included DD with expressive language delays in the 19-month-old male in PMID: 32576952 (2020); and intellectual disability in both sibs in PMID: 27421267 (2016), albeit within the mild range (Stanford-Binet scale IQ = 58 and 68, respectively). However in the latter case, KALRN was proposed as the causative gene at the time of publication, as scarce data was known for the DPH2 gene.

Additional cases would help corroborate this gene-disease association and so rating Amber, awaiting further cases/clinical evidence.
Intellectual disability v3.721 DPH2 Arina Puzriakova Gene: dph2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.720 CDC40 Arina Puzriakova Tag watchlist tag was added to gene: CDC40.
Intellectual disability v3.720 CDC40 Arina Puzriakova Classified gene: CDC40 as Red List (low evidence)
Intellectual disability v3.720 CDC40 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. CDC40 currently not associated with any phenotype in OMIM (last edited: 23/08/19) but has a 'possible' disease confidence for 'CDC40-related Neurodegenerative Pontocerebellar Hypoplasia with Microcephaly' in Gene2Phenotype.

Rating Red as currently only a single individual reported in PMID: 33220177 (2021). There is some functional and animal model data to support pathogenicity, so have added 'watchlist' tag. If additional cases arise, CDC40 may also be considered for other panels (e.g. Malformations of cortical development, Genetic epilepsy syndromes, Cytopenia - NOT Fanconi anaemia, etc)
Intellectual disability v3.720 CDC40 Arina Puzriakova Gene: cdc40 has been classified as Red List (Low Evidence).
Intellectual disability v3.719 CDC40 Arina Puzriakova Phenotypes for gene: CDC40 were changed from Pontocerebellar hypoplasia; microcephaly; seizures; intellectual disability to CDC40-related Neurodegenerative Pontocerebellar Hypoplasia with Microcephaly
Intellectual disability v3.718 ABCC9 Arina Puzriakova Classified gene: ABCC9 as Green List (high evidence)
Intellectual disability v3.718 ABCC9 Arina Puzriakova Added comment: Comment on list classification: Intellectual impairment as been reported in individuals with loss-of-function variants and a percentage of those with gain-of-function variants. However, this is less prominent than other features of the disease presentation (e.g. cardiac, skeletal defects) and often ID is perhaps too mild.

Therefore, ABCC9 will be flagged for review by the GMS team with regards to phenotypic fit for this panel and determine whether it should be demoted from Green to Amber (added for-review tag).
Intellectual disability v3.718 ABCC9 Arina Puzriakova Gene: abcc9 has been classified as Green List (High Evidence).
Intellectual disability v3.717 ABCC9 Arina Puzriakova Tag for-review tag was added to gene: ABCC9.
Intellectual disability v3.717 ABCC9 Arina Puzriakova reviewed gene: ABCC9: Rating: ; Mode of pathogenicity: None; Publications: 31575858; Phenotypes: mild ID, similar facies, myopathy, cerebral white matter hyperintensities, cardiac systolic dysfunction; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.717 TMEM260 Arina Puzriakova Mode of inheritance for gene: TMEM260 was changed from to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.716 TRAPPC12 Arina Puzriakova Phenotypes for gene: TRAPPC12 were changed from Encephalopathy, progressive, early-onset, with brain atrophy and spasticity, 617669; Developmental delay to Encephalopathy, progressive, early-onset, with brain atrophy and spasticity, OMIM:617669; Early-onset progressive encephalopathy-hearing loss-pons hypoplasia-brain atrophy syndrome, MONDO:0044696
Intellectual disability v3.715 TRAPPC12 Arina Puzriakova Publications for gene: TRAPPC12 were set to 28777934
Intellectual disability v3.714 TRAPPC12 Arina Puzriakova reviewed gene: TRAPPC12: Rating: GREEN; Mode of pathogenicity: None; Publications: 32369837; Phenotypes: Encephalopathy, progressive, early-onset, with brain atrophy and spasticity, OMIM:617669, Early-onset progressive encephalopathy-hearing loss-pons hypoplasia-brain atrophy syndrome, MONDO:0044696; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.714 SMG8 Ivone Leong Tag for-review tag was added to gene: SMG8.
Intellectual disability v3.714 NUP214 Arina Puzriakova Tag for-review was removed from gene: NUP214.
Intellectual disability v3.714 NARS Ivone Leong Tag for-review tag was added to gene: NARS.
Intellectual disability v3.714 FGF13 Helen Lord Deleted their review
Intellectual disability v3.714 FGF13 Helen Lord commented on gene: FGF13
Intellectual disability v3.714 GLS_GCA Arina Puzriakova Tag NGS Not Validated tag was added to STR: GLS_GCA.
Intellectual disability v3.714 GLS_GCA Arina Puzriakova changed review comment from: Comment on list classification: Early developmental delay, which preceded other progressive neurological concerns, was reported in the three unrelated cases from PMID:30970188. Following discussion with Helen Brittain (Genomics England Clinical Team) it was agreed that this is sufficient for inclusion on this panel.

However, detection of this 5' UTR triplet expansion must first be internally validated for the interpretation pipeline. In the meantime, rating Red but will raise the STR for validation with the Rare Disease team.; to: Comment on list classification: Early developmental delay, which preceded other progressive neurological concerns, was reported in the three unrelated cases from PMID:30970188. Following discussion with Helen Brittain (Genomics England Clinical Team) it was agreed that this is sufficient for inclusion on this panel.

However, detection of this 5' UTR triplet expansion must first be validated within the Genomics England pipeline. In the meantime, rating Red but will raise the STR for validation with the Rare Disease team.
Intellectual disability v3.714 GLS_GCA Arina Puzriakova Classified STR: GLS_GCA as Red List (low evidence)
Intellectual disability v3.714 GLS_GCA Arina Puzriakova Added comment: Comment on list classification: Early developmental delay, which preceded other progressive neurological concerns, was reported in the three unrelated cases from PMID:30970188. Following discussion with Helen Brittain (Genomics England Clinical Team) it was agreed that this is sufficient for inclusion on this panel.

However, detection of this 5' UTR triplet expansion must first be internally validated for the interpretation pipeline. In the meantime, rating Red but will raise the STR for validation with the Rare Disease team.
Intellectual disability v3.714 GLS_GCA Arina Puzriakova Str: gls_gca has been classified as Red List (Low Evidence).
Intellectual disability v3.713 GLS_GCA Arina Puzriakova Tag STR tag was added to STR: GLS_GCA.
Tag for-review tag was added to STR: GLS_GCA.
Intellectual disability v3.713 GLS Arina Puzriakova Deleted their comment
Intellectual disability v3.713 GLS Arina Puzriakova Tag STR tag was added to gene: GLS.
Tag for-review tag was added to gene: GLS.
Intellectual disability v3.713 GLS Arina Puzriakova Classified gene: GLS as Amber List (moderate evidence)
Intellectual disability v3.713 GLS Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. Early developmental delay, which preceded other progressive neurological concerns, was reported in the three unrelated cases from PMID:30970188. Following discussion with Helen Brittain (Genomics England Clinical Team) it was agreed that this is sufficient for inclusion on this panel.

However, detection of the 5' UTR triplet expansion must first be internally validated for the interpretation pipeline. In the meantime, rating Amber but will raise the STR for validation with the Rare Disease team.
Intellectual disability v3.713 GLS Arina Puzriakova Gene: gls has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.712 GLS Arina Puzriakova Phenotypes for gene: GLS were changed from Global developmental delay, progressive ataxia, and elevated glutamine, MIM# 618412 to Global developmental delay, progressive ataxia, and elevated glutamine, OMIM:618412; Global developmental delay, progressive ataxia, and elevated glutamine, MONDO:0032733; ?Infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development, OMIM:618339; Infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development, MONDO:0032685
Intellectual disability v3.712 GLS Arina Puzriakova Added comment: Comment on phenotypes: Global developmental delay, progressive ataxia, and elevated glutamine, OMIM:618412; Global developmental delay, progressive ataxia, and elevated glutamine, MONDO:0032733; ?Infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development, OMIM:618339; Infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development, MONDO:0032685
Intellectual disability v3.712 GLS Arina Puzriakova Phenotypes for gene: GLS were changed from Global developmental delay, progressive ataxia, and elevated glutamine, OMIM:618412; Global developmental delay, progressive ataxia, and elevated glutamine, MONDO:0032733 to Global developmental delay, progressive ataxia, and elevated glutamine, MIM# 618412
Intellectual disability v3.711 GLS Arina Puzriakova Phenotypes for gene: GLS were changed from Global developmental delay, progressive ataxia, and elevated glutamine, MIM# 618412 to Global developmental delay, progressive ataxia, and elevated glutamine, OMIM:618412; Global developmental delay, progressive ataxia, and elevated glutamine, MONDO:0032733
Intellectual disability v3.710 GLS Arina Puzriakova Added comment: Comment on mode of inheritance: As evidence for pathogenicity of monoallelic variants is limited (currently only 1 case), MOI will remain as 'Biallelic' until further cases emerge that support an association between monoallelic variants and disease.
Intellectual disability v3.710 GLS Arina Puzriakova Mode of inheritance for gene: GLS was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.709 GLS Arina Puzriakova edited their review of gene: GLS: Added comment: One case reported with a de novo (i.e. monoallelic) gain-of-function variant, associated with profound developmental delay, infantile cataract, skin abnormalities, and glutamate excess. Functional analysis showed the variant causes hyperactivity and compensatory downregulation of GLS expression combined with upregulation of the counteracting enzyme GS (PMID: 30239721).; Changed publications: 30970188, 30239721; Changed phenotypes: Global developmental delay, progressive ataxia, and elevated glutamine, OMIM:618412, Global developmental delay, progressive ataxia, and elevated glutamine, MONDO:0032733
Intellectual disability v3.709 GLS_GCA Arina Puzriakova STR: GLS_GCA was added
STR: GLS_GCA was added to Intellectual disability. Sources: Literature
Mode of inheritance for STR: GLS_GCA was set to BIALLELIC, autosomal or pseudoautosomal
Publications for STR: GLS_GCA were set to 30970188
Phenotypes for STR: GLS_GCA were set to Global developmental delay, progressive ataxia, and elevated glutamine, OMIM:618412; Global developmental delay, progressive ataxia, and elevated glutamine, MONDO:0032733
Review for STR: GLS_GCA was set to GREEN
Added comment: - PMID: 30970188 (2019) - Three unrelated cases who presented with an early-onset global developmental delay, progressive ataxia, and elevated levels of glutamine. One patient also showed cerebellar atrophy.

All 3 individuals harboured a large trinucleotide (GCA) repeat expansion in the 5' UTR (length: 680-1,500-copy repeats). The repeat expansion was found in homozygosity in 1 case, and occurred in compound heterozygosity with an SNV in the other two cases (missense and frameshift variant, respectively). Functional analysis showed the repeat expansion results in reduced expression and glutaminase deficiency.
Sources: Literature
Intellectual disability v3.708 GLS Arina Puzriakova reviewed gene: GLS: Rating: GREEN; Mode of pathogenicity: None; Publications: 30970188; Phenotypes: Global developmental delay, progressive ataxia, and elevated glutamine, OMIM: 618412; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.708 MN1 Arina Puzriakova Phenotypes for gene: MN1 were changed from Central hypotonia; Feeding difficulties; Global developmental delay; Intellectual disability; Hearing impairment; Abnormality of facial skeleton; Craniosynostosis; Abnormality of the face; Abnormality of the cerebellum; Abnormality of the corpus callosum; Polymicrogyria to CEBALID syndrome, OMIM:618774; CEBALID syndrome, MONDO:0032908
Intellectual disability v3.707 KIF14 Arina Puzriakova Phenotypes for gene: KIF14 were changed from Microcephaly 20, primary, autosomal recessive, 617914 to Microcephaly 20, primary, autosomal recessive, OMIM:617914; Microcephaly 20, primary, autosomal recessive, MONDO:0054761
Intellectual disability v3.706 B9D1 Arina Puzriakova Phenotypes for gene: B9D1 were changed from ?Meckel syndrome 9 614209; Joubert syndrome 27 617120 to Meckel syndrome 9, OMIM:614209; Meckel syndrome 9, MONDO:0013630; Joubert syndrome 27, OMIM:617120; Joubert syndrome 27, MONDO:0014927
Intellectual disability v3.705 B9D2 Arina Puzriakova Phenotypes for gene: B9D2 were changed from Joubert syndrome 34 614175; Meckel syndrome 10 614175 to Joubert syndrome 34, OMIM:614175; Meckel syndrome 10, OMIM:614175; Meckel syndrome, type 10, MONDO:0013609
Intellectual disability v3.704 EEF1A2 Eleanor Williams Tag for-review was removed from gene: EEF1A2.
Intellectual disability v3.704 SCN8A Ivone Leong Added comment: Comment on mode of inheritance: MOI was changed back from "Both monoallelic and biallelic" to "Monoallelic", which reflects the original MOI of the signed off panel (version 3.2). The MOI will be changed back to "Both monoallelic and biallelic" after the panel has been reviewed.
Intellectual disability v3.704 SCN8A Ivone Leong Mode of inheritance for gene: SCN8A was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.703 ALKBH8 Ivone Leong Classified gene: ALKBH8 as Green List (high evidence)
Intellectual disability v3.703 ALKBH8 Ivone Leong Added comment: Comment on list classification: This gene has been promoted back to Green status to reflect the rating that was on the signed off version of this panel (version 3.2). This gene should be demoted to Amber at the next review.
Intellectual disability v3.703 ALKBH8 Ivone Leong Gene: alkbh8 has been classified as Green List (High Evidence).
Intellectual disability v3.702 ALKBH8 Ivone Leong Tag for-review tag was added to gene: ALKBH8.
Intellectual disability v3.702 NUS1 Eleanor Williams edited their review of gene: NUS1: Changed rating: GREEN
Intellectual disability v3.702 NUS1 Eleanor Williams Added comment: Comment on mode of inheritance: The mode of inheritance should be considered for change to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal in line with its classification on the Genetic Epilepsy Syndromes panel.
Intellectual disability v3.702 NUS1 Eleanor Williams Mode of inheritance for gene: NUS1 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.701 NUS1 Eleanor Williams Classified gene: NUS1 as Amber List (moderate evidence)
Intellectual disability v3.701 NUS1 Eleanor Williams Added comment: Comment on list classification: Due to further reported cases, and review on the Genetic epilepsy syndromes by Helen Lord this gene should be considered for a green rating as GMS review.
Intellectual disability v3.701 NUS1 Eleanor Williams Gene: nus1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.700 TLK2 Arina Puzriakova Phenotypes for gene: TLK2 were changed from intellectual disability to Mental retardation, autosomal dominant 57, OMIM:618050; Mental retardation, autosomal dominant 57, MONDO:0054837
Intellectual disability v3.699 ZNF526 Arina Puzriakova Classified gene: ZNF526 as Amber List (moderate evidence)
Intellectual disability v3.699 ZNF526 Arina Puzriakova Added comment: Comment on list classification: Upgraded from Red to Amber but can be rated Green at the next GMS panel update (added 'for-review' tag).

Truncating variants associated with a more severe disease presentation; however, ID is the universal feature among individuals with biallelic variants in this gene.
Intellectual disability v3.699 ZNF526 Arina Puzriakova Gene: znf526 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.698 ZNF526 Arina Puzriakova Phenotypes for gene: ZNF526 were changed from Non-syndromic autosomal recessive intellectual disability to Intellectual disability; Microcephaly; Cataracts; Epilepsy; Hypertonia; Dystonia
Intellectual disability v3.697 ZNF526 Arina Puzriakova Publications for gene: ZNF526 were set to 21937992; 27012031
Intellectual disability v3.696 ZNF526 Arina Puzriakova Tag for-review tag was added to gene: ZNF526.
Intellectual disability v3.696 ZNF526 Arina Puzriakova reviewed gene: ZNF526: Rating: GREEN; Mode of pathogenicity: None; Publications: 21937992, 25558065, 33397746; Phenotypes: Intellectual disability, Microcephaly, Cataracts, Epilepsy, Hypertonia, Dystonia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.696 TUBB2A Arina Puzriakova Publications for gene: TUBB2A were set to 24702957
Intellectual disability v3.695 TUBB2A Arina Puzriakova Phenotypes for gene: TUBB2A were changed from CORTICAL DYSPLASIA, COMPLEX, WITH OTHER BRAIN MALFORMATIONS 5 to Cortical dysplasia, complex, with other brain malformations 5, OMIM:615763; Complex cortical dysplasia with other brain malformations 5, MONDO:0014337
Intellectual disability v3.694 FGF13 Zornitza Stark gene: FGF13 was added
gene: FGF13 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: FGF13 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: FGF13 were set to 33245860
Phenotypes for gene: FGF13 were set to Intellectual disability; epilepsy
Mode of pathogenicity for gene: FGF13 was set to Other
Review for gene: FGF13 was set to GREEN
gene: FGF13 was marked as current diagnostic
Added comment: Two sibling pairs and three unrelated males reported who presented in infancy with intractable focal seizures and severe developmental delay. The variants were located in the N-terminal domain of the A isoform of FGF13/FHF2 (FHF2A). The X-linked FHF2 gene (also known as FGF13) has alternative first exons which produce multiple protein isoforms that differ in their N-terminal sequence. The variants were located at highly conserved residues in the FHF2A inactivation particle that competes with the intrinsic fast inactivation mechanism of Nav channels. Functional characterization of mutant FHF2A co-expressed with wild-type Nav1.6 (SCN8A) revealed that mutant FHF2A proteins lost the ability to induce rapid-onset, long-term blockade of the channel while retaining pro-excitatory properties. These gain-of-function effects are likely to increase neuronal excitability consistent with the epileptic potential of FHF2 variants.
Sources: Literature
Intellectual disability v3.694 UBR7 Zornitza Stark reviewed gene: UBR7: Rating: GREEN; Mode of pathogenicity: None; Publications: 33340455; Phenotypes: Intellectual disability, epilepsy, hypothyroidism, congenital anomalies, dysmorphic features; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability v3.694 RNU7-1 Zornitza Stark gene: RNU7-1 was added
gene: RNU7-1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: RNU7-1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RNU7-1 were set to 33230297
Phenotypes for gene: RNU7-1 were set to Aicardi–Goutières syndrome-like
Review for gene: RNU7-1 was set to GREEN
gene: RNU7-1 was marked as current diagnostic
Added comment: Review originally submitted by Ming Wong
- 16 affected individuals from 11 families
- Compared to control fibroblasts, patient fibroblasts were enriched for misprocessed forms of
replication-dependent histone (RDH) mRNAs
Sources: Literature
Intellectual disability v3.694 DPH2 Zornitza Stark gene: DPH2 was added
gene: DPH2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: DPH2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DPH2 were set to 32576952; 27421267
Phenotypes for gene: DPH2 were set to Diphthamide-deficiency syndrome
Review for gene: DPH2 was set to AMBER
Added comment: One 19 month old reported (PMID:32576952) with biallelic (one missense, one nonsense) variants in DPH2, with phenotype similar to DPH1 deficiency (gross motor delay, not walking, fine motor and expressive language delays, macrocephaly)

Another family (sibs) was previously reported with biallelic nonsense variants (PMID:27421267) with a comparable phenotype, this family also has biallelic variants in KALRN and the authors thought those variants more likely causative. Patients had ID and microcephaly (in contrast to the 19 month old above).

In vitro functional assays support reduced diphthamide synthesis activity for the variants identified in PMID:32576952.
Sources: Literature
Intellectual disability v3.694 FBRSL1 Zornitza Stark gene: FBRSL1 was added
gene: FBRSL1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: FBRSL1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FBRSL1 were set to 32424618
Phenotypes for gene: FBRSL1 were set to Intellectual disability; congenital anomalies
Review for gene: FBRSL1 was set to GREEN
gene: FBRSL1 was marked as current diagnostic
Added comment: Three children with de novo PTCs that escape NMD, and an overlapping syndromic phenotype with respiratory insufficiency, postnatal growth restriction, microcephaly, global developmental delay and other malformations. 2/3 had heart defects, cleft palate and hearing impairement.
Supported by Xenopus oocyte functional studies
Sources: Literature
Intellectual disability v3.694 CDC40 Zornitza Stark gene: CDC40 was added
gene: CDC40 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: CDC40 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CDC40 were set to 33220177
Phenotypes for gene: CDC40 were set to Pontocerebellar hypoplasia; microcephaly; seizures; intellectual disability
Review for gene: CDC40 was set to RED
Added comment: Single individual reported with bi-allelic variants in the gene and PCH, microcephaly, hypotonia, seizures, severe DD/ID, thrombocytopaenia, anaemia. Interaction with PPIL1 and mouse model support gene-disease association.

Gene referred to as PRP17 in paper.
Sources: Literature
Intellectual disability v3.694 CCDC40 Zornitza Stark Deleted their comment
Intellectual disability v3.694 CCDC40 Zornitza Stark commented on gene: CCDC40: PMID 33220177, provided in error, refers to CDC40.
Intellectual disability v3.694 CCDC40 Zornitza Stark Deleted their comment
Intellectual disability v3.694 CCDC40 Zornitza Stark changed review comment from: ID is not part of the phenotype.; to: ID is not part of the phenotype.
Intellectual disability v3.694 CCDC40 Zornitza Stark edited their review of gene: CCDC40: Added comment: New publication: Single individual reported with bi-allelic variants in the gene and PCH, microcephaly, hypotonia, seizures, severe DD/ID, thrombocytopaenia, anaemia. Interaction with PPIL1 and mouse model support gene-disease association.; Changed publications: 33220177
Intellectual disability v3.694 PPIL1 Zornitza Stark gene: PPIL1 was added
gene: PPIL1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: PPIL1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PPIL1 were set to 33220177
Phenotypes for gene: PPIL1 were set to Pontocerebellar hypoplasia; microcephaly; seizures; intellectual disbility
Review for gene: PPIL1 was set to GREEN
Added comment: 17 individuals from 9 unrelated families reported with bi-allelic variants in the gene and PCH, microcephaly, hypotonia, seizures, severe DD/ID. Mouse models support gene-disease association.
Sources: Literature
Intellectual disability v3.694 AP4E1 Arina Puzriakova Phenotypes for gene: AP4E1 were changed from Spastic paraplegia 51, autosomal recessive, 613744; CEREBRAL PALSY SPASTIC QUADRIPLEGIC TYPE 4 to Spastic paraplegia 51, autosomal recessive, OMIM:613744; Hereditary spastic paraplegia 51, MONDO:0013401
Intellectual disability v3.693 AP4B1 Arina Puzriakova Phenotypes for gene: AP4B1 were changed from Spastic paraplegia 47, autosomal recessive, 614066; CEREBRAL PALSY SPASTIC QUADRIPLEGIC TYPE 5 to Spastic paraplegia 47, autosomal recessive, OMIM:614066; Hereditary spastic paraplegia 47, MONDO:0013551
Intellectual disability v3.692 TBCD Arina Puzriakova Phenotypes for gene: TBCD were changed from Encephalopathy, progressive, early-onset, with brain atrophy and thin corpus callosum 617193 to Encephalopathy, progressive, early-onset, with brain atrophy and thin corpus callosum, OMIM:617193; Early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome, MONDO:0044646
Intellectual disability v3.691 SMC1A Arina Puzriakova Phenotypes for gene: SMC1A were changed from CORNELIA DE LANGE SYNDROME TYPE 2 (CDLS2) to Cornelia de Lange syndrome 2, OMIM:300590; Cornelia de Lange syndrome 2, MONDO:0010370; Developmental and epileptic encephalopathy 85, with or without midline brain defects, OMIM:301044; Developmental and epileptic encephalopathy, 85, with or without midline brain defects, MONDO:0026771
Intellectual disability v3.690 SLC9A7 Arina Puzriakova Tag watchlist tag was added to gene: SLC9A7.
Intellectual disability v3.690 SLC9A7 Arina Puzriakova Classified gene: SLC9A7 as Amber List (moderate evidence)
Intellectual disability v3.690 SLC9A7 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. Associated with relevant phenotype in OMIM and Gene2Phenotype. However, only 2 unrelated families reported at present (PMID: 30335141) and therefore only sufficient for an Amber rating, awaiting further publications/clinical evidence (added 'watchlist' tag)
Intellectual disability v3.690 SLC9A7 Arina Puzriakova Gene: slc9a7 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.689 SLC9A7 Arina Puzriakova Phenotypes for gene: SLC9A7 were changed from Intellectual developmental disorder, X-linked 108; OMIM #301024 to Intellectual developmental disorder, X-linked 108, OMIM:301024; Intellectual developmental disorder, X-linked 108, MONDO:0026723
Intellectual disability v3.688 MPI Arina Puzriakova Publications for gene: MPI were set to 9525984; 3080572; 9585601
Intellectual disability v3.687 MPI Arina Puzriakova Phenotypes for gene: MPI were changed from CONGENITAL DISORDERS OF GLYCOSYLATION to Congenital disorder of glycosylation, type Ib, OMIM:602579; MPI-CDG, MONDO:0011257
Intellectual disability v3.686 MPI Arina Puzriakova reviewed gene: MPI: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.686 MPI Arina Puzriakova Tag for-review tag was added to gene: MPI.
Intellectual disability v3.686 HDAC4 Arina Puzriakova commented on gene: HDAC4
Intellectual disability v3.686 HDAC4 Arina Puzriakova Tag for-review was removed from gene: HDAC4.
Intellectual disability v3.686 AGO2 Arina Puzriakova Classified gene: AGO2 as Amber List (moderate evidence)
Intellectual disability v3.686 AGO2 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. All patients reported in PMID: 33199684 presented GDD/ID, while other features were relatively heterogenous. However, cognitive impairment was perhaps too mild in majority of cases. Tagged 'for-review' to assess whether there is sufficient evidence for a Green rating in light of the scope of the ID panel.
Intellectual disability v3.686 AGO2 Arina Puzriakova Gene: ago2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.685 AGO2 Arina Puzriakova Tag for-review tag was added to gene: AGO2.
Intellectual disability v3.685 AGO2 Arina Puzriakova reviewed gene: AGO2: Rating: AMBER; Mode of pathogenicity: None; Publications: 33199684; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.685 ZNF407 Arina Puzriakova Classified gene: ZNF407 as Amber List (moderate evidence)
Intellectual disability v3.685 ZNF407 Arina Puzriakova Added comment: Comment on list classification: New gene added by Konstantinos Varvagiannis. Some evidence linking both mono- and biallelic variants with disease but currently not sufficient for a Green rating. Further cases would help validate this gene-disease association (added 'watchlist' tag)
Intellectual disability v3.685 ZNF407 Arina Puzriakova Gene: znf407 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.684 SMG8 Arina Puzriakova Phenotypes for gene: SMG8 were changed from Intellectual disability; Microcephaly; Short stature; Facial dysmorphism Edit to Intellectual disability; Microcephaly; Short stature; Facial dysmorphism
Intellectual disability v3.684 SMG8 Arina Puzriakova Phenotypes for gene: SMG8 were changed from Intellectual disability to Intellectual disability; Microcephaly; Short stature; Facial dysmorphism Edit
Intellectual disability v3.683 SMG8 Arina Puzriakova Classified gene: SMG8 as Amber List (moderate evidence)
Intellectual disability v3.683 SMG8 Arina Puzriakova Added comment: Comment on list classification: Additional cases reported in recent publication (PMID: 33242396) extend the total to at least 5 unrelated families with GDD/ID and different homozygous variants in the SMG8 gene. Also some supporting functional data provided.

Upgraded from Red to Amber, but there is sufficient evidence to promote to Green at the next GMS panel update (added 'for-review' tag)
Intellectual disability v3.683 SMG8 Arina Puzriakova Gene: smg8 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.682 SMG8 Arina Puzriakova Publications for gene: SMG8 were set to 31130284
Intellectual disability v3.681 SMG8 Arina Puzriakova edited their review of gene: SMG8: Added comment: PMID: 33242396 (2020) - 9 affected individuals from 4 consanguineous families with different biallelic variants in the SMG8 gene. Clinical features include GDD (8/8), dysmorphic features (9/9) microcephaly (6/9), short stature (4/9), brain imaging anomalies (4/5), congenital heart disease (3/9) and cataract (3/8). Only two sibs from Family 2 had a formal ID diagnosis, but this can be inferred from the clinical reports of the other cases demonstrating severe language delays, difficulties to follow simple instructions or perform daily activities.
-----
Several features described here overlap with those in the previously reported cases from PMID: 31130284 (e.g. microcephaly, ID, cataract, VSD); Changed rating: GREEN; Changed publications: 31130284, 33242396
Intellectual disability v3.681 LSS Eleanor Williams changed review comment from: In light of the recent expert review green by Zornitza Stark, this gene should be considered for a green rating by the GMS. The phenotype is variable with the ID phenotype being part of the presentation in approx half the families.; to: In light of the recent expert review green by Zornitza Stark, this gene should be considered for a green rating by the GMS, as agreed with Genomics England clinicians. The phenotype is variable with the ID phenotype being part of the presentation in approx half the families.
Intellectual disability v3.681 LSS Eleanor Williams Tag for-review tag was added to gene: LSS.
Intellectual disability v3.681 LSS Eleanor Williams edited their review of gene: LSS: Added comment: In light of the recent expert review green by Zornitza Stark, this gene should be considered for a green rating by the GMS. The phenotype is variable with the ID phenotype being part of the presentation in approx half the families.; Changed rating: GREEN
Intellectual disability v3.681 KCNMA1 Arina Puzriakova changed review comment from: Multiple individuals reported with either mono- or biallelic variants. Developmental delay and intellectual disability of relevant severity to this panel has been reported in a sufficient number of cases for inclusion on this panel. Although in most cases the phenotypes are primarily characterised by seizures or dyskinesia, it is plausible that these individuals may still be tested under the ID panel.

Furthermore, several individuals have been reported with severe GDD/ID and other variable feature such as craniofacial dysmorphism, ataxia, bone dysplasia, visceral malformations, and brain imaging anomalies, but without epilepsy or paroxysmal dyskinesia (namely Liang-Wang syndrome, PMID: 31152168). In less severely affected cases DD with significant speech delay has been noted as the main clinical indication of the presenting phenotypes, further indicating benefit of inclusion on a diagnostic ID panel.; to: Multiple individuals reported with either mono- or biallelic variants. Developmental delay and intellectual disability of relevant severity has been reported in a sufficient number of cases for inclusion on this panel. Although in most cases the phenotypes are primarily characterised by seizures or dyskinesia, it is plausible that these individuals may still be tested under the ID panel in context of the severe intellectual impairment that may be observed.

Furthermore, several individuals have been reported with severe GDD/ID and other variable feature such as craniofacial dysmorphism, ataxia, bone dysplasia, visceral malformations, and brain imaging anomalies, but without epilepsy or paroxysmal dyskinesia (namely Liang-Wang syndrome, PMID: 31152168). In less severely affected cases DD with significant speech delay has been noted as the main clinical indication of the presenting phenotypes, further indicating benefit of inclusion on a diagnostic ID panel.
Intellectual disability v3.681 KCNMA1 Arina Puzriakova Phenotypes for gene: KCNMA1 were changed from Cerebellar atrophy, developmental delay, and seizures, 617643; Paroxysmal nonkinesigenic dyskinesia, 3, with or without generalized epilepsy, 609446 to Cerebellar atrophy, developmental delay, and seizures, OMIM:617643; Cerebellar atrophy, developmental delay, and seizures, MONDO:0060551; Paroxysmal nonkinesigenic dyskinesia, 3, with or without generalized epilepsy, OMIM:609446; Generalized epilepsy-paroxysmal dyskinesia syndrome, MONDO:0012276; Liang-Wang syndrome, OMIM:618729; Liang-Wang syndrome, MONDO:0032886; {Epilepsy, idiopathic generalized, susceptibility to, 16}, OMIM:618596; Epilepsy, idiopathic generalized, susceptibility to, 16, MONDO:0032827
Intellectual disability v3.680 KCNMA1 Arina Puzriakova Publications for gene: KCNMA1 were set to 15937479; 31427379; 31152168; 27567911; 29545233; 26195193
Intellectual disability v3.679 KCNMA1 Arina Puzriakova Classified gene: KCNMA1 as Amber List (moderate evidence)
Intellectual disability v3.679 KCNMA1 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update (added 'for-review' tag)
Intellectual disability v3.679 KCNMA1 Arina Puzriakova Gene: kcnma1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.678 KCNMA1 Arina Puzriakova Tag for-review tag was added to gene: KCNMA1.
Intellectual disability v3.678 KCNMA1 Arina Puzriakova reviewed gene: KCNMA1: Rating: GREEN; Mode of pathogenicity: None; Publications: 26195193, 27567911, 29330545, 29545233, 31152168, 31427379; Phenotypes: Cerebellar atrophy, developmental delay, and seizures, OMIM:617643, Cerebellar atrophy, developmental delay, and seizures, MONDO:0060551, Paroxysmal nonkinesigenic dyskinesia, 3, with or without generalized epilepsy, OMIM:609446, Generalized epilepsy-paroxysmal dyskinesia syndrome, MONDO:0012276, Liang-Wang syndrome, OMIM:618729, Liang-Wang syndrome, MONDO:0032886, {Epilepsy, idiopathic generalized, susceptibility to, 16}, OMIM:618596, Epilepsy, idiopathic generalized, susceptibility to, 16, MONDO:0032827; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.678 LIAS Eleanor Williams commented on gene: LIAS
Intellectual disability v3.678 LIAS Eleanor Williams Tag for-review tag was added to gene: LIAS.
Intellectual disability v3.678 GRIA1 Arina Puzriakova Classified gene: GRIA1 as Amber List (moderate evidence)
Intellectual disability v3.678 GRIA1 Arina Puzriakova Added comment: Comment on list classification: Maintaining Amber rating as no new evidence has been published since previous review. Most commonly reported as a candidate gene in large screening studies with limited segregation/phenotype/functional data. Also variable penetrance of the ID phenotype. Therefore, there is currently not enough evidence to classify as Green.
Intellectual disability v3.678 GRIA1 Arina Puzriakova Gene: gria1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.677 H3F3B Arina Puzriakova changed review comment from: Currently not associated with any phenotype in OMIM or Gene2Phenotype.

- PMID: 33268356 (2020) - De novo missense variants identified in 13 unrelated individuals with a shared phenotype of GDD/ID, usually severe and often progressive, with mostly minor congenital anomalies. 8/13 patients showed abnormalities on brain MRI including hypomyelination (5), cortical atrophy (4), arachnoid cysts (3), and a thin corpus collosum (2). Variable seizure phenotypes were reported in 6/13 cases, all early-onset where specified, mostly during infancy (latest onset at 10 years of age).; to: Currently not associated with any phenotype in OMIM or Gene2Phenotype.

- PMID: 33268356 (2020) - De novo missense variants identified in 13 unrelated individuals with a shared phenotype of GDD/ID, usually severe and often progressive, with mostly minor congenital anomalies. One individual was reported to have a normal IQ at 15 years. 8/13 patients showed abnormalities on brain MRI including hypomyelination (5), cortical atrophy (4), arachnoid cysts (3), and a thin corpus collosum (2). Variable seizure phenotypes were reported in 6/13 cases, all early-onset where specified, mostly during infancy (latest onset at 10 years of age).
Intellectual disability v3.677 H3F3B Arina Puzriakova Publications for gene: H3F3B were set to
Intellectual disability v3.676 H3F3B Arina Puzriakova Phenotypes for gene: H3F3B were changed from to Developmental delay; Intellectual disability; Neurodegeneration; Epilepsy; Facial dysmorphism; Congenital anomalies
Intellectual disability v3.675 H3F3B Arina Puzriakova Mode of inheritance for gene: H3F3B was changed from to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.674 H3F3B Arina Puzriakova Classified gene: H3F3B as Amber List (moderate evidence)
Intellectual disability v3.674 H3F3B Arina Puzriakova Added comment: Comment on list classification: Upgraded from Red to Amber, but there is sufficient evidence to promoted to Green at the next GMS panel update (added 'for-review' tag).

Multiple unrelated cases (at least 12) with GDD/ID associated with de novo variants in this gene.
Intellectual disability v3.674 H3F3B Arina Puzriakova Gene: h3f3b has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.673 H3F3B Arina Puzriakova Tag for-review tag was added to gene: H3F3B.
Intellectual disability v3.673 H3F3B Arina Puzriakova reviewed gene: H3F3B: Rating: GREEN; Mode of pathogenicity: None; Publications: 33268356; Phenotypes: Developmental delay, Neurodegeneration, Epilepsy, Facial dysmorphism, Congenital anomalies; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.673 H3F3A Arina Puzriakova Phenotypes for gene: H3F3A were changed from to Developmental delay; Intellectual disability; Neurodegeneration; Epilepsy; Facial dysmorphism; Congenital anomalies
Intellectual disability v3.672 H3F3A Arina Puzriakova Publications for gene: H3F3A were set to
Intellectual disability v3.671 H3F3A Arina Puzriakova Mode of inheritance for gene: H3F3A was changed from to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.670 H3F3A Arina Puzriakova Deleted their comment
Intellectual disability v3.670 H3F3A Arina Puzriakova Classified gene: H3F3A as Amber List (moderate evidence)
Intellectual disability v3.670 H3F3A Arina Puzriakova Added comment: Comment on list classification: Upgraded from Red to Amber, but there is sufficient evidence to promoted to Green at the next GMS panel update (added 'for-review' tag).

Multiple unrelated cases (>30) with GDD/ID associated with de novo variants in this gene.
Intellectual disability v3.670 H3F3A Arina Puzriakova Gene: h3f3a has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.670 H3F3A Arina Puzriakova Classified gene: H3F3A as Amber List (moderate evidence)
Intellectual disability v3.670 H3F3A Arina Puzriakova Added comment: Comment on list classification: Upgraded from Red to Amber, but there is sufficient evidence to promoted to Green at the next GMS panel update (added 'for-review' tag).

Multiple unrelated cases (>30) with GDD/ID associated with de novo variants in this gene.
Intellectual disability v3.670 H3F3A Arina Puzriakova Gene: h3f3a has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.669 H3F3A Arina Puzriakova Tag for-review tag was added to gene: H3F3A.
Intellectual disability v3.669 H3F3A Arina Puzriakova reviewed gene: H3F3A: Rating: GREEN; Mode of pathogenicity: None; Publications: 31942419, 33268356; Phenotypes: Developmental delay, Neurodegeneration, Epilepsy, Facial dysmorphism, Congenital anomalies; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.669 KDM4B Arina Puzriakova Tag for-review tag was added to gene: KDM4B.
Intellectual disability v3.669 KDM4B Arina Puzriakova Classified gene: KDM4B as Amber List (moderate evidence)
Intellectual disability v3.669 KDM4B Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. Rating Amber but may be promoted to Green at the next GMS panel update (added 'for-review' tag).

9 unrelated individuals reported at present (PMID: 33232677). Although all presented GDD, only 1 individual had severe ID (IQ = 50) and 3 had mild ID. Although ID is too mild in majority of cases, developmental delay was the universal feature amongst affected individuals and other phenotypes were heterogenous (e.g. seizures, brain malformations). Therefore, there may be value in inclusion on this panel for capturing this phenotype.
Intellectual disability v3.669 KDM4B Arina Puzriakova Gene: kdm4b has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.668 HSPG2 Arina Puzriakova Phenotypes for gene: HSPG2 were changed from Schwartz-Jampel syndrome, type 1, 255800 to Schwartz-Jampel syndrome, type 1, OMIM:255800; Schwartz-Jampel syndrome, MONDO:0009717
Intellectual disability v3.667 HSPG2 Arina Puzriakova Classified gene: HSPG2 as Amber List (moderate evidence)
Intellectual disability v3.667 HSPG2 Arina Puzriakova Added comment: Comment on list classification: While there are sufficient cases to support a gene-disease association, DD/ID is part of a broader phenotype and cognitive impairment is unlikely to represent a main feature of the disease presentation.

Maintaining Amber rating as the disorder is better represented in other panels (e.g. Skeletal dysplasia, Arthrogryposis, etc) where this gene is already Green.
Intellectual disability v3.667 HSPG2 Arina Puzriakova Gene: hspg2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.666 CSNK1G1 Arina Puzriakova Classified gene: CSNK1G1 as Amber List (moderate evidence)
Intellectual disability v3.666 CSNK1G1 Arina Puzriakova Added comment: Comment on list classification: Upgraded from Red to Amber as now at least 5 unrelated individuals reported (PMID: 33009664). All present developmental delay of varying severity, although a formal ID assessment was not performed. Tagged 'for-review' to evaluate relevance of the phenotypes to this panel.
Intellectual disability v3.666 CSNK1G1 Arina Puzriakova Gene: csnk1g1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.665 CSNK1G1 Arina Puzriakova Tag for-review tag was added to gene: CSNK1G1.
Intellectual disability v3.665 SHMT2 Arina Puzriakova Tag for-review tag was added to gene: SHMT2.
Intellectual disability v3.665 SHMT2 Arina Puzriakova Classified gene: SHMT2 as Amber List (moderate evidence)
Intellectual disability v3.665 SHMT2 Arina Puzriakova Added comment: Comment on list classification: New gene added by Konstantinos Varvagiannis. Sufficient number of unrelated cases (>3) with ID of relevant severity to this panel. Some functional data indicating variants result in impaired SHMT2 enzymatic function. Rating Amber but should be promoted to Green at the next GMS panel update (added 'for-review' tag)

SHMT2 is listed in Gene2Phenotype with a 'probable' disease confidence rating for 'SHMT2-related neurodevelopmental syndrome', and is also associated with 'Neurodevelopmental disorder with cardiomyopathy, spasticity, and brain abnormalities, MIM# 619121' in OMIM.
Intellectual disability v3.665 SHMT2 Arina Puzriakova Gene: shmt2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.664 SHMT2 Arina Puzriakova Phenotypes for gene: SHMT2 were changed from Congenital microcephaly; Infantile axial hypotonia; Spastic paraparesis; Global developmental delay; Intellectual disability; Abnormality of the corpus callosum; Abnormal cortical gyration; Hypertrophic cardiomyopathy; Abnormality of the face; Proximal placement of thumb; 2-3 toe syndactyly to Neurodevelopmental disorder with cardiomyopathy, spasticity, and brain abnormalities, OMIM:619121
Intellectual disability v3.663 ITFG2 Arina Puzriakova Publications for gene: ITFG2 were set to 28397838; https://doi.org/10.1038/s41525-020-00150-z
Intellectual disability v3.662 ITFG2 Arina Puzriakova Classified gene: ITFG2 as Amber List (moderate evidence)
Intellectual disability v3.662 ITFG2 Arina Puzriakova Added comment: Comment on list classification: New gene added by Konstantinos Varvagiannis. Rating Amber as ITFG2 can only be classified as a possible candidate gene based present evidence. Clinical and pedigree details are limited and there is no supporting functional data. Additional cases required to corroborate this gene-disease association.
Intellectual disability v3.662 ITFG2 Arina Puzriakova Gene: itfg2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.661 RAP1B Ivone Leong Tag watchlist tag was added to gene: RAP1B.
Intellectual disability v3.661 RAP1B Ivone Leong Classified gene: RAP1B as Amber List (moderate evidence)
Intellectual disability v3.661 RAP1B Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in Gene2Phenotype but not OMIM.

PMID: 32627184 describes 2 patients.
36 yo patient of non-consanguineous parents. Had unclear pancytopenia, multiple congenital malformations, mild intellectual disability, endocrine disorders (short stature with growth hormone deficiency), dysmorphism and other features. Parents and sibling unaffected.
13 yo of non-consanguineous parents with thrombocytopenia, multiple congenital anomalies and learning difficulties. He had normal developmental milestones, walk was achieved at 14 months and there was no speech delay. He attended mainstream school with auxiliary help because of learning difficulties with graphism, syntaxic comprehension, logical reasoning and attention deficit. Parents and siblings unaffected.

PMID: 26280580 describes another patient with variant in RAP1B. The clinical features can be found in supplementary table 2. The table lists ID, but doesn't say severity and lists a host of other features including short stature, facial dysmorphism and skeletal findings.

All 3 cases seem to have a very wide spectrum of differing phenotypes and therefore, this gene has been given an Amber rating until further evidence is available.
Intellectual disability v3.661 RAP1B Ivone Leong Gene: rap1b has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.660 MPI Zornitza Stark reviewed gene: MPI: Rating: RED; Mode of pathogenicity: None; Publications: 12414827, 9585601, 10980531, 33098580, 33204592, 32905087, 32266963, 30242110; Phenotypes: Congenital disorder of glycosylation, type Ib, MIM# 602579, MPI-CDG MONDO:0011257; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.660 AASS Arina Puzriakova Phenotypes for gene: AASS were changed from HYPERLYSINEMIA to Hyperlysinemia, OMIM:238700; Hyperlysinemia (disease), MONDO:0009388
Intellectual disability v3.659 AARS Arina Puzriakova Phenotypes for gene: AARS were changed from EARLY-ONSET EPILEPTIC ENCEPHALOPATHY WITH PERSISTENT MYELINATION DEFECT. to Developmental and epileptic encephalopathy 29, OMIM:616339; Developmental and epileptic encephalopathy, 29, MONDO:0014593
Intellectual disability v3.658 AAAS Arina Puzriakova Phenotypes for gene: AAAS were changed from Achalasia-addisonianism-alacrimia syndrome 231550 to Achalasia-addisonianism-alacrimia syndrome, OMIM:231550; Triple-A syndrome, MONDO:0009279
Intellectual disability v3.657 GOT2 Arina Puzriakova Tag watchlist was removed from gene: GOT2.
Intellectual disability v3.657 GOT2 Arina Puzriakova Phenotypes for gene: GOT2 were changed from Global developmental delay; Intellectual disability; Seizures; Increased serum lactate; Hyperammonemia; Microcephaly; Failure to thrive; Feeding difficulties; Abnormality of nervous system morphology to Epileptic encephalopathy, early infantile, 82, OMIM:618721; Developmental and epileptic encephalopathy, 82, MONDO:0032880
Intellectual disability v3.656 GOT2 Arina Puzriakova Classified gene: GOT2 as Amber List (moderate evidence)
Intellectual disability v3.656 GOT2 Arina Puzriakova Added comment: Comment on list classification: ID of relevant severity to this panel (severe-to-profound) is reported in 4/4 individuals (PMID:31422819). However, intellectual impairment was secondary to epilepsy and there is no evidence of neurodevelopmental delay preceding the onset of seizures. Therefore, maintaining Amber rating on this panel (GOT2 is already Green on the Genetic epilepsy syndromes (v2.236) panel)
Intellectual disability v3.656 GOT2 Arina Puzriakova Gene: got2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.655 GOT2 Arina Puzriakova commented on gene: GOT2
Intellectual disability v3.655 GATA6 Arina Puzriakova Classified gene: GATA6 as Amber List (moderate evidence)
Intellectual disability v3.655 GATA6 Arina Puzriakova Added comment: Comment on list classification: Developmental delay has been reported in some patients with GATA6 variants. However, in view of the pancreatic and cardiac abnormalities that constitute the main phenotypes, cognitive impairment is unlikely to represent a key feature of the disease presentation.

Maintaining Amber rating as the disorder is better represented in other panels (e.g. Diabetes, Severe Paediatric Disorders, etc) where this gene is already Green.
Intellectual disability v3.655 GATA6 Arina Puzriakova Gene: gata6 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.654 HS2ST1 Ivone Leong Tag watchlist tag was added to gene: HS2ST1.
Intellectual disability v3.654 HS2ST1 Ivone Leong Classified gene: HS2ST1 as Amber List (moderate evidence)
Intellectual disability v3.654 HS2ST1 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not associated with a relevant phenotype in OMIM or Gene2Phenotype. Only 2 of 3 unrelated families with affected individuals described in PMID: 33159882 were reported to have ID. The affected individuals in the third family could not be assessed for ID. Therefore, there is currently not enough evidence to support a gene-disease association. This gene has been given an Amber rating.
Intellectual disability v3.654 HS2ST1 Ivone Leong Gene: hs2st1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.653 BICRA Ivone Leong Classified gene: BICRA as Amber List (moderate evidence)
Intellectual disability v3.653 BICRA Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not associated with any phenotypes in OMIM or Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Intellectual disability v3.653 BICRA Ivone Leong Gene: bicra has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.652 BICRA Ivone Leong Tag for-review tag was added to gene: BICRA.
Intellectual disability v3.652 EMC10 Ivone Leong Classified gene: EMC10 as Red List (low evidence)
Intellectual disability v3.652 EMC10 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not associated with any phenotypes in OMIM or Gene2Phenotype. As there is only 1 case, this gene has been given a Red rating.
Intellectual disability v3.652 EMC10 Ivone Leong Gene: emc10 has been classified as Red List (Low Evidence).
Intellectual disability v3.651 CSNK1G1 Ivone Leong Phenotypes for gene: CSNK1G1 were changed from severe non-syndromic early-onset epilepsy to severe non-syndromic early-onset epilepsy; Global developmental delay; Intellectual disability; Autism; Seizures; Abnormality of the face; Abnormality of limbs
Intellectual disability v3.650 CSNK1G1 Ivone Leong Publications for gene: CSNK1G1 were set to 24463883
Intellectual disability v3.649 GATA6 Ivone Leong Publications for gene: GATA6 were set to
Intellectual disability v3.648 NARS Arina Puzriakova changed review comment from: Associated with relevant phenotype in OMIM, and in Gene2Phenotype with 'confirmed' disease confidence for 'NARS1 Neurodevelopmental Disorder (monoallelic)' and 'probable' for 'NARS1 Neurodevelopmental Disorder (biallelic)'

Total of 23 patients from 13 unrelated families with biallelic variants in the NARS1 gene (PMIDs: 32738225 and 32788587) and 8 unrelated patients with de novo heterozygous nonsense variants (PMIDs: 32738225). All individuals had GDD and ID, which varied in severity from moderate to profound. Other features include microcephaly, seizures, ataxia, and dysmorphism. Supportive functional data.; to: Associated with relevant phenotype in OMIM, and in Gene2Phenotype with 'confirmed' disease confidence for 'NARS1 Neurodevelopmental Disorder (monoallelic)' and 'probable' for 'NARS1 Neurodevelopmental Disorder (biallelic)'

Total of 24 patients from 13 unrelated families with biallelic variants in the NARS1 gene (PMIDs: 32738225 and 32788587) and 8 unrelated patients with de novo heterozygous variants (PMIDs: 32738225). All individuals had GDD and ID, which varied in severity from moderate to profound. Other features include microcephaly, seizures, ataxia, and dysmorphism. Supportive functional data.
Intellectual disability v3.648 NARS Arina Puzriakova changed review comment from: Associated with relevant phenotype in OMIM, and in Gene2Phenotype with 'confirmed' disease confidence for 'NARS1 Neurodevelopmental Disorder (monoallelic)' and 'probable' for 'NARS1 Neurodevelopmental Disorder (biallelic)'

Total of 23 patients from 13 unrelated families with biallelic variants in the NARS1 gene (PMIDs: 32738225 and 32788587) and 6 unrelated patients with de novo heterozygous nonsense variants (PMIDs: 32738225). All individuals had GDD and ID, which varied in severity from moderate to profound. Other features include microcephaly, seizures, ataxia, and dysmorphism. Supportive functional data.; to: Associated with relevant phenotype in OMIM, and in Gene2Phenotype with 'confirmed' disease confidence for 'NARS1 Neurodevelopmental Disorder (monoallelic)' and 'probable' for 'NARS1 Neurodevelopmental Disorder (biallelic)'

Total of 23 patients from 13 unrelated families with biallelic variants in the NARS1 gene (PMIDs: 32738225 and 32788587) and 8 unrelated patients with de novo heterozygous nonsense variants (PMIDs: 32738225). All individuals had GDD and ID, which varied in severity from moderate to profound. Other features include microcephaly, seizures, ataxia, and dysmorphism. Supportive functional data.
Intellectual disability v3.648 NARS Arina Puzriakova commented on gene: NARS: Added new-gene-name tag, new approved HGNC gene symbol for NARS is NARS1
Intellectual disability v3.648 NARS Arina Puzriakova Classified gene: NARS as Amber List (moderate evidence)
Intellectual disability v3.648 NARS Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to rate this gene Green at the next GMS panel update (added 'for-review' tag)
Intellectual disability v3.648 NARS Arina Puzriakova Gene: nars has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.647 NARS Arina Puzriakova reviewed gene: NARS: Rating: GREEN; Mode of pathogenicity: None; Publications: 32738225, 32788587; Phenotypes: Neurodevelopmental disorder with microcephaly, impaired language, and gait abnormalities, autosomal recessive, OMIM:619091, Neurodevelopmental disorder with microcephaly, impaired language, epilepsy, and gait abnormalities, autosomal dominant, OMIM:619092; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.647 NARS Arina Puzriakova Publications for gene: NARS were set to 32738225
Intellectual disability v3.646 NARS Arina Puzriakova Phenotypes for gene: NARS were changed from Abnormal muscle tone; Microcephaly; Global developmental delay; Intellectual disability; Seizures; Ataxia; Abnormality of the face; Demyelinating peripheral neuropathy to Neurodevelopmental disorder with microcephaly, impaired language, and gait abnormalities, autosomal recessive, OMIM:619091; Neurodevelopmental disorder with microcephaly, impaired language, epilepsy, and gait abnormalities, autosomal dominant, OMIM:619092
Intellectual disability v3.645 ATP2A2 Ivone Leong reviewed gene: ATP2A2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.645 ISCA-37418-Loss Arina Puzriakova Phenotypes for Region: ISCA-37418-Loss were changed from Potocki-Lupski syndrome; hypotonia, poor feeding, failure to thrive, developmental delay particularly cognitive and language deficity, mild-moderate intellectual deficit, and neuropsychiatric disorders; Smith-Magenis syndrome; Structural cardiovascular anomalies (dilated aortic root, bicommissural aortic valve, atrial/ventricular and septal defects) and sleep disturbance; 182290; moderate intellectual disability, delayed speech and language skills, distinctive facial features, sleep disturbances, and behavioral problems; hypotonia, failure to thrive, mental retardation, pervasive developmental disorders, congenital anomalies; Dental abnormalities to Smith-Magenis syndrome, OMIM:182290; Smith-Magenis syndrome, MONDO:0008434
Intellectual disability v3.644 RAP1B Zornitza Stark gene: RAP1B was added
gene: RAP1B was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: RAP1B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RAP1B were set to 32627184; 26280580
Phenotypes for gene: RAP1B were set to Syndromic intellectual disability
Review for gene: RAP1B was set to GREEN
Added comment: Three unrelated individuals reported with de novo variants, some functional data. One of them described as Kabuki-like but lacks typical facial gestalt.
Sources: Literature
Intellectual disability v3.644 EMC10 Zornitza Stark gene: EMC10 was added
gene: EMC10 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: EMC10 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EMC10 were set to 32869858
Phenotypes for gene: EMC10 were set to Intellectual disability
Review for gene: EMC10 was set to RED
Added comment: Homozygous variants of EMC1 are associated with GDD, scoliosis, and cerebellar atrophy, indicating the relevance of this pathway for neurogenetic disorders.

One Saudi family with 2 affected individuals with mild ID, speech delay, and GDD.
WES and Sanger sequencing revealed a homozygous splice acceptor site variant (c.679‐1G>A) in EMC10 . Variant segregated within the family. RT‐qPCR showed a substantial decrease in the relative EMC10 gene expression in the patients.
Sources: Literature
Intellectual disability v3.644 BICRA Zornitza Stark gene: BICRA was added
gene: BICRA was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: BICRA was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: BICRA were set to 33232675
Phenotypes for gene: BICRA were set to Developmental delay, intellectual disability, autism spectrum disorder,behavioral abnormalities, dysmorphic features
Review for gene: BICRA was set to GREEN
Added comment: 12 individuals reported, 11 de novo (1 not resolved), with neurodevelopmental phenotypes—developmental delay (HP:0001263), intellectual disability (HP:0001249), autism spectrum disorder (HP:0000729), and/or behavioral phenotypes (HP:0000708)—and variable structural birth defects and dysmorphic features. Mostly LoF or gene deletions, but 2 missense reported. Zebrafish model supports the gene-disease association.
Sources: Literature
Intellectual disability v3.644 HS2ST1 Zornitza Stark gene: HS2ST1 was added
gene: HS2ST1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: HS2ST1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HS2ST1 were set to 33159882
Phenotypes for gene: HS2ST1 were set to Intellectual disability; dysmorphic features; congenital anomalies
Review for gene: HS2ST1 was set to GREEN
Added comment: Four affected individuals from 3 unrelated families. 3 unique missense and 2 PTCs. Clinical features included developmental delay, corpus callosum hypoplasia or aplasia, and skeletal and renal abnormalities as well as joint contractures/arthrogryposis.
Sources: Literature
Intellectual disability v3.644 KDM4B Zornitza Stark gene: KDM4B was added
gene: KDM4B was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: KDM4B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KDM4B were set to 33232677
Phenotypes for gene: KDM4B were set to Global developmental delay, intellectual disability and neuroanatomical defects
Review for gene: KDM4B was set to GREEN
Added comment: Nine individuals with mono-allelic de novo or inherited variants in KDM4B.

All individuals presented with dysmorphic features and global developmental delay (GDD) with language and motor skills most affected. Three individuals had a history of seizures, and four had anomalies on brain imaging ranging from agenesis of the corpus callosum with hydrocephalus to cystic formations, abnormal hippocampi, and polymicrogyria.

In a knockout mouse the total brain volume was significantly reduced with decreased
size of the hippocampal dentate gyrus, partial agenesis of the corpus callosum, and ventriculomegaly.
Sources: Literature
Intellectual disability v3.644 SMG8 Zornitza Stark edited their review of gene: SMG8: Added comment: Four more families reported in PMID 33242396. Some functional data also provided.; Changed rating: GREEN; Changed publications: 31130284, 33242396
Intellectual disability v3.644 AGO2 Zornitza Stark gene: AGO2 was added
gene: AGO2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: AGO2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: AGO2 were set to 33199684
Phenotypes for gene: AGO2 were set to Intellectual disability; regression; seizures
Review for gene: AGO2 was set to GREEN
Added comment: 21 individuals reported, five variants (p.L192P, p.G201V, p.T357M, p.M364T, p.C751Y) were recurrent. Variable ID.
Sources: Literature
Intellectual disability v3.644 H3F3B Zornitza Stark reviewed gene: H3F3B: Rating: GREEN; Mode of pathogenicity: None; Publications: 33268356; Phenotypes: Intellectual disability, regression, seizures; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.644 H3F3A Zornitza Stark reviewed gene: H3F3A: Rating: GREEN; Mode of pathogenicity: None; Publications: 33268356; Phenotypes: Intellectual disability, regression, seizures; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.644 HDAC4 Zornitza Stark edited their review of gene: HDAC4: Added comment: New report of 4 different missense present in the 14-3-3 binding site, identified de novo in 7 individuals with an intellectual disability syndrome, and supporting in vitro functional assays.; Changed rating: GREEN; Changed publications: 24715439, 20691407, 31209962, https://doi.org/10.1016/j.xhgg.2020.100015
Intellectual disability v3.644 ATP2A2 Ivone Leong Publications for gene: ATP2A2 were set to 19250991; 20456342
Intellectual disability v3.643 SMARCA2 Arina Puzriakova Phenotypes for gene: SMARCA2 were changed from Nicolaides-Baraitser syndrome, 601358; COFFIN SIRIS to Nicolaides-Baraitser syndrome, OMIM:601358; Coffin-siris syndrome; Blepharophimosis intellectual disability syndrome
Intellectual disability v3.642 SMARCA2 Arina Puzriakova Publications for gene: SMARCA2 were set to
Intellectual disability v3.641 MORC2 Arina Puzriakova Phenotypes for gene: MORC2 were changed from Charcot-Marie-Tooth disease, axonal, type 2Z, MIM #616688 to Developmental delay; Intellectual disability; Growth retardation; Microcephaly; Craniofacial dysmorphism; Charcot-Marie-Tooth disease, axonal, type 2Z, OMIM:616688
Intellectual disability v3.640 MORC2 Arina Puzriakova Publications for gene: MORC2 were set to https://doi.org/10.1016/j.ajhg.2020.06.013
Intellectual disability v3.639 MORC2 Arina Puzriakova Classified gene: MORC2 as Amber List (moderate evidence)
Intellectual disability v3.639 MORC2 Arina Puzriakova Added comment: Comment on list classification: Though signs suggestive of neuropathy were observed in the cohort presented by Sacoto et al (PMID:32693025), these were not the predominant feature of the disease presentation or the primary indication for diagnostic testing. Inclusion on this panel would be of value for detecting such cases, and so this gene should be promoted to Green at the next GMS panel update (added 'for-review' tag)
Intellectual disability v3.639 MORC2 Arina Puzriakova Gene: morc2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.638 MORC2 Arina Puzriakova Tag for-review tag was added to gene: MORC2.
Intellectual disability v3.638 MORC2 Arina Puzriakova reviewed gene: MORC2: Rating: GREEN; Mode of pathogenicity: None; Publications: 32693025; Phenotypes: Developmental delay, Intellectual disability, Growth retardation, Microcephaly, Craniofacial dysmorphism; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.638 LARS Arina Puzriakova commented on gene: LARS: Added new-gene-name tag, new approved HGNC gene symbol for LARS is LARS1
Intellectual disability v3.638 LARS Arina Puzriakova Classified gene: LARS as Amber List (moderate evidence)
Intellectual disability v3.638 LARS Arina Puzriakova Added comment: Comment on list classification: New gene added by Konstantinos Varvagiannis. Developmental delay is prevalent among affected individuals, and there are sufficient unrelated cases (>3) presenting with relevant severity to this panel. This may serve as a possible route for diagnostic testing as currently there are no relevant panels for detecting the hepatic phenotype of the disease presentation, and so there may be value in rating Green at the next major panel review (added 'for-review tag).
Intellectual disability v3.638 LARS Arina Puzriakova Gene: lars has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.637 LARS Arina Puzriakova Tag new-gene-name tag was added to gene: LARS.
Tag for-review tag was added to gene: LARS.
Intellectual disability v3.637 NUS1 Arina Puzriakova Classified gene: NUS1 as Amber List (moderate evidence)
Intellectual disability v3.637 NUS1 Arina Puzriakova Gene: nus1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.636 NUS1 Arina Puzriakova Tag for-review tag was added to gene: NUS1.
Intellectual disability v3.636 SOX3 Arina Puzriakova Phenotypes for gene: SOX3 were changed from Mental retardation, X-linked, with isolated growth hormone deficiency, 300123Panhypopituitarism, X-linked, 312000; SEX REVERSAL TYPE 3 (SRXX3) to Mental retardation, X-linked, with isolated growth hormone deficiency, OMIM:300123; Intellectual disability, X-linked, with panhypopituitarism, MONDO:0010252
Intellectual disability v3.635 SOX3 Arina Puzriakova commented on gene: SOX3
Intellectual disability v3.635 SOX3 Arina Puzriakova Tag for-review tag was added to gene: SOX3.
Intellectual disability v3.635 PSAT1 Arina Puzriakova Publications for gene: PSAT1 were set to 17436247
Intellectual disability v3.634 PSAT1 Arina Puzriakova Phenotypes for gene: PSAT1 were changed from PHOSPHOSERINE AMINOTRANSFERASE DEFICIENCY to Phosphoserine aminotransferase deficiency, OMIM:610992; Neu-Laxova syndrome 2, OMIM:616038
Intellectual disability v3.633 PRKAR1A Arina Puzriakova Phenotypes for gene: PRKAR1A were changed from Gene2Phenotype confirmed gene with ID HPO to Acrodysostosis 1, with or without hormone resistance, OMIM:101800
Intellectual disability v3.632 SH3PXD2B Arina Puzriakova Classified gene: SH3PXD2B as Red List (low evidence)
Intellectual disability v3.632 SH3PXD2B Arina Puzriakova Added comment: Comment on list classification: Following discussion with the Genomics England clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark (Australian Genomics)
Intellectual disability v3.632 SH3PXD2B Arina Puzriakova Gene: sh3pxd2b has been classified as Red List (Low Evidence).
Intellectual disability v3.631 SEC23B Arina Puzriakova Classified gene: SEC23B as Red List (low evidence)
Intellectual disability v3.631 SEC23B Arina Puzriakova Added comment: Comment on list classification: Following discussion with the Genomics England clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark (Australian Genomics)
Intellectual disability v3.631 SEC23B Arina Puzriakova Gene: sec23b has been classified as Red List (Low Evidence).
Intellectual disability v3.630 SCN11A Arina Puzriakova Classified gene: SCN11A as Red List (low evidence)
Intellectual disability v3.630 SCN11A Arina Puzriakova Added comment: Comment on list classification: Following discussion with the Genomics England clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark (Australian Genomics)
Intellectual disability v3.630 SCN11A Arina Puzriakova Gene: scn11a has been classified as Red List (Low Evidence).
Intellectual disability v3.629 SCARF2 Arina Puzriakova Classified gene: SCARF2 as Red List (low evidence)
Intellectual disability v3.629 SCARF2 Arina Puzriakova Added comment: Comment on list classification: Following discussion with the Genomics England clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark (Australian Genomics)
Intellectual disability v3.629 SCARF2 Arina Puzriakova Gene: scarf2 has been classified as Red List (Low Evidence).
Intellectual disability v3.628 SBDS Arina Puzriakova Classified gene: SBDS as Red List (low evidence)
Intellectual disability v3.628 SBDS Arina Puzriakova Added comment: Comment on list classification: Following discussion with the Genomics England clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark (Australian Genomics)
Intellectual disability v3.628 SBDS Arina Puzriakova Gene: sbds has been classified as Red List (Low Evidence).
Intellectual disability v3.627 SALL4 Arina Puzriakova Classified gene: SALL4 as Red List (low evidence)
Intellectual disability v3.627 SALL4 Arina Puzriakova Added comment: Comment on list classification: Following discussion with the Genomics England clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark (Australian Genomics)
Intellectual disability v3.627 SALL4 Arina Puzriakova Gene: sall4 has been classified as Red List (Low Evidence).
Intellectual disability v3.626 PRSS56 Arina Puzriakova Classified gene: PRSS56 as Red List (low evidence)
Intellectual disability v3.626 PRSS56 Arina Puzriakova Added comment: Comment on list classification: Following discussion with the Genomics England clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark (Australian Genomics)
Intellectual disability v3.626 PRSS56 Arina Puzriakova Gene: prss56 has been classified as Red List (Low Evidence).
Intellectual disability v3.625 PROP1 Arina Puzriakova Classified gene: PROP1 as Red List (low evidence)
Intellectual disability v3.625 PROP1 Arina Puzriakova Added comment: Comment on list classification: Following discussion with the Genomics England clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark (Australian Genomics)
Intellectual disability v3.625 PROP1 Arina Puzriakova Gene: prop1 has been classified as Red List (Low Evidence).
Intellectual disability v3.624 PRDM12 Arina Puzriakova Classified gene: PRDM12 as Red List (low evidence)
Intellectual disability v3.624 PRDM12 Arina Puzriakova Added comment: Comment on list classification: Following discussion with the Genomics England clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark (Australian Genomics)
Intellectual disability v3.624 PRDM12 Arina Puzriakova Gene: prdm12 has been classified as Red List (Low Evidence).
Intellectual disability v3.623 PPA2 Arina Puzriakova Classified gene: PPA2 as Red List (low evidence)
Intellectual disability v3.623 PPA2 Arina Puzriakova Added comment: Comment on list classification: Following discussion with the Genomics England clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark (Australian Genomics)
Intellectual disability v3.623 PPA2 Arina Puzriakova Gene: ppa2 has been classified as Red List (Low Evidence).
Intellectual disability v3.622 POLR1D Arina Puzriakova Classified gene: POLR1D as Red List (low evidence)
Intellectual disability v3.622 POLR1D Arina Puzriakova Added comment: Comment on list classification: Following discussion with the Genomics England clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark (Australian Genomics)
Intellectual disability v3.622 POLR1D Arina Puzriakova Gene: polr1d has been classified as Red List (Low Evidence).
Intellectual disability v3.621 POLD1 Arina Puzriakova Classified gene: POLD1 as Red List (low evidence)
Intellectual disability v3.621 POLD1 Arina Puzriakova Added comment: Comment on list classification: Following discussion with the Genomics England clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark (Australian Genomics)
Intellectual disability v3.621 POLD1 Arina Puzriakova Gene: pold1 has been classified as Red List (Low Evidence).
Intellectual disability v3.620 POC1B Arina Puzriakova Classified gene: POC1B as Red List (low evidence)
Intellectual disability v3.620 POC1B Arina Puzriakova Added comment: Comment on list classification: Following discussion with the Genomics England clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark (Australian Genomics)
Intellectual disability v3.620 POC1B Arina Puzriakova Gene: poc1b has been classified as Red List (Low Evidence).
Intellectual disability v3.619 PMS2 Arina Puzriakova Classified gene: PMS2 as Red List (low evidence)
Intellectual disability v3.619 PMS2 Arina Puzriakova Added comment: Comment on list classification: Following discussion with the Genomics England clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark (Australian Genomics)
Intellectual disability v3.619 PMS2 Arina Puzriakova Gene: pms2 has been classified as Red List (Low Evidence).
Intellectual disability v3.618 PLOD2 Arina Puzriakova Classified gene: PLOD2 as Red List (low evidence)
Intellectual disability v3.618 PLOD2 Arina Puzriakova Added comment: Comment on list classification: Following discussion with the Genomics England clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark (Australian Genomics)
Intellectual disability v3.618 PLOD2 Arina Puzriakova Gene: plod2 has been classified as Red List (Low Evidence).
Intellectual disability v3.617 PKHD1 Arina Puzriakova Classified gene: PKHD1 as Red List (low evidence)
Intellectual disability v3.617 PKHD1 Arina Puzriakova Added comment: Comment on list classification: Following discussion with the Genomics England clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark (Australian Genomics)
Intellectual disability v3.617 PKHD1 Arina Puzriakova Gene: pkhd1 has been classified as Red List (Low Evidence).
Intellectual disability v3.616 PKD1L1 Arina Puzriakova Classified gene: PKD1L1 as Red List (low evidence)
Intellectual disability v3.616 PKD1L1 Arina Puzriakova Added comment: Comment on list classification: Following discussion with the Genomics England clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark (Australian Genomics)
Intellectual disability v3.616 PKD1L1 Arina Puzriakova Gene: pkd1l1 has been classified as Red List (Low Evidence).
Intellectual disability v3.615 PITX3 Arina Puzriakova Classified gene: PITX3 as Red List (low evidence)
Intellectual disability v3.615 PITX3 Arina Puzriakova Added comment: Comment on list classification: Following discussion with the Genomics England clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark (Australian Genomics)
Intellectual disability v3.615 PITX3 Arina Puzriakova Gene: pitx3 has been classified as Red List (Low Evidence).
Intellectual disability v3.614 PITX2 Arina Puzriakova Classified gene: PITX2 as Red List (low evidence)
Intellectual disability v3.614 PITX2 Arina Puzriakova Added comment: Comment on list classification: Following discussion with the Genomics England clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark (Australian Genomics)
Intellectual disability v3.614 PITX2 Arina Puzriakova Gene: pitx2 has been classified as Red List (Low Evidence).
Intellectual disability v3.613 PIK3R1 Arina Puzriakova Classified gene: PIK3R1 as Red List (low evidence)
Intellectual disability v3.613 PIK3R1 Arina Puzriakova Added comment: Comment on list classification: Following discussion with the Genomics England clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark
Intellectual disability v3.613 PIK3R1 Arina Puzriakova Gene: pik3r1 has been classified as Red List (Low Evidence).
Intellectual disability v3.612 POLR1C Arina Puzriakova Phenotypes for gene: POLR1C were changed from Treacher Collins syndrome 3, 248390 to Leukodystrophy, hypomyelinating, 11, OMIM:616494
Intellectual disability v3.611 POLR1C Arina Puzriakova Publications for gene: POLR1C were set to
Intellectual disability v3.610 POLR1C Arina Puzriakova Tag for-review tag was added to gene: POLR1C.
Intellectual disability v3.610 POLR1C Arina Puzriakova Classified gene: POLR1C as Amber List (moderate evidence)
Intellectual disability v3.610 POLR1C Arina Puzriakova Added comment: Comment on list classification: Cognitive impairment (ID and/or cognitive regression) may be variable amongst affected individuals; however, there are sufficient unrelated cases (>3) for inclusion on this panel as Green.
Intellectual disability v3.610 POLR1C Arina Puzriakova Gene: polr1c has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.609 PNPT1 Arina Puzriakova Phenotypes for gene: PNPT1 were changed from Combined oxidative phosphorylation deficiency 13, 614932; Deafness, autosomal recessive 70, 614934; developmental delay; intellectual disability to Combined oxidative phosphorylation deficiency 13, OMIM:614932; Combined oxidative phosphorylation defect type 13, MONDO:0013977
Intellectual disability v3.608 PNPT1 Arina Puzriakova Classified gene: PNPT1 as Amber List (moderate evidence)
Intellectual disability v3.608 PNPT1 Arina Puzriakova Added comment: Comment on list classification: GDD/ID is a prominent feature of the disease presentation and there are sufficient unrelated cases (>3) presenting with relevant severity to this panel. This is a possible route for diagnostic testing and so there may be value in classifying as Green - PNPT1 will be flagged for review at the next GMS panel update (added 'for-review' tag)
Intellectual disability v3.608 PNPT1 Arina Puzriakova Gene: pnpt1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.607 SCN1B Arina Puzriakova Classified gene: SCN1B as Amber List (moderate evidence)
Intellectual disability v3.607 SCN1B Arina Puzriakova Added comment: Comment on list classification: Biallelic variants associated with developmental epileptic encephalopathy characterised by early onset epileptic seizures followed by cognitive decline. At least 5 unrelated families in literature (PMIDs: 19710327; 23148524; 28218389).

Rating Amber as seizures are the prominent feature of the disease presentation, to which cognitive impairment is secondary. Cases would be detected via the epilepsy route (SCN1B is already Green on Genetic epilepsy syndromes panel).
Intellectual disability v3.607 SCN1B Arina Puzriakova Gene: scn1b has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.606 SCN1B Arina Puzriakova Phenotypes for gene: SCN1B were changed from EPILEPSY, GENERALIZED, WITH FEBRILE SEIZURES PLUS, TYPE 1 to Developmental and epileptic encephalopathy 52, OMIM:617350; Developmental and epileptic encephalopathy, 52, MONDO:0033361
Intellectual disability v3.605 SCN1B Arina Puzriakova Publications for gene: SCN1B were set to 18464934
Intellectual disability v3.604 SCN1B Arina Puzriakova Mode of inheritance for gene: SCN1B was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.603 ZFHX4 Ivone Leong Publications for gene: ZFHX4 were set to 26350204; 21802062
Intellectual disability v3.602 ZFHX4 Ivone Leong Phenotypes for gene: ZFHX4 were changed from to Developmental disorders; intellectual disability, dysmorphic features
Intellectual disability v3.601 ZFHX4 Ivone Leong Classified gene: ZFHX4 as Amber List (moderate evidence)
Intellectual disability v3.601 ZFHX4 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in OMIM. Based on the available evidence there is enough evidence to support a gene-disease association. This gene should be promoted to Green at the next review.
Intellectual disability v3.601 ZFHX4 Ivone Leong Gene: zfhx4 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.600 ZFHX4 Ivone Leong Mode of inheritance for gene: ZFHX4 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.599 ZFHX4 Ivone Leong Tag for-review tag was added to gene: ZFHX4.
Intellectual disability v3.599 UPF1 Ivone Leong Classified gene: UPF1 as Amber List (moderate evidence)
Intellectual disability v3.599 UPF1 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics).

PMID: 28539120 describes a patient with significant ID. The patient has SNVs in SQSTM1 and UPF1. The authors suggests that it is plausible that the haploinsufficiency of SQSTM1 may have caused neurofunctional defects, which the haploinsufficiency of UPF1 may have exacerbated.

As the patient in the second case has another variant in another gene, there is not enough evidence to support a gene-disease association so this gene has been given an Amber rating.
Intellectual disability v3.599 UPF1 Ivone Leong Gene: upf1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.598 UPF1 Ivone Leong Publications for gene: UPF1 were set to 33057194
Intellectual disability v3.597 U2AF2 Ivone Leong Classified gene: U2AF2 as Amber List (moderate evidence)
Intellectual disability v3.597 U2AF2 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). There is not enough evidence to support a gene-disease association so this gene has been given an Amber rating.
Intellectual disability v3.597 U2AF2 Ivone Leong Gene: u2af2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.596 TCF7L2 Ivone Leong Classified gene: TCF7L2 as Amber List (moderate evidence)
Intellectual disability v3.596 TCF7L2 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). There is not enough evidence to support a gene-disease association so this gene has been given an Amber rating.
Intellectual disability v3.596 TCF7L2 Ivone Leong Gene: tcf7l2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.595 SRRM2 Ivone Leong Classified gene: SRRM2 as Amber List (moderate evidence)
Intellectual disability v3.595 SRRM2 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). There is not enough evidence to support a gene-disease association so this gene has been given an Amber rating.
Intellectual disability v3.595 SRRM2 Ivone Leong Gene: srrm2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.594 SPEN Ivone Leong Classified gene: SPEN as Amber List (moderate evidence)
Intellectual disability v3.594 SPEN Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). There is not enough evidence to support a gene-disease association so this gene has been given an Amber rating.
Intellectual disability v3.594 SPEN Ivone Leong Gene: spen has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.593 SATB1 Ivone Leong Phenotypes for gene: SATB1 were changed from intellectual disability to intellectual disability; developmental disorders
Intellectual disability v3.592 SATB1 Ivone Leong Classified gene: SATB1 as Amber List (moderate evidence)
Intellectual disability v3.592 SATB1 Ivone Leong Added comment: Comment on list classification: Gene promoted from Red to Amber based on the provided evidence.
Intellectual disability v3.592 SATB1 Ivone Leong Gene: satb1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.591 SATB1 Ivone Leong Publications for gene: SATB1 were set to
Intellectual disability v3.590 MSL2 Ivone Leong Classified gene: MSL2 as Amber List (moderate evidence)
Intellectual disability v3.590 MSL2 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). There is not enough evidence to support a gene-disease association so this gene has been given an Amber rating.
Intellectual disability v3.590 MSL2 Ivone Leong Gene: msl2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.590 MSL2 Ivone Leong Classified gene: MSL2 as Amber List (moderate evidence)
Intellectual disability v3.590 MSL2 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). There is not enough evidence to support a gene-disease association so this gene has been given an Amber rating.
Intellectual disability v3.590 MSL2 Ivone Leong Gene: msl2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.589 RAB14 Ivone Leong Classified gene: RAB14 as Amber List (moderate evidence)
Intellectual disability v3.589 RAB14 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). There is not enough evidence to support a gene-disease association so this gene has been given an Amber rating.
Intellectual disability v3.589 RAB14 Ivone Leong Gene: rab14 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.588 PSMC5 Ivone Leong Classified gene: PSMC5 as Amber List (moderate evidence)
Intellectual disability v3.588 PSMC5 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). There is not enough evidence to support a gene-disease association so this gene has been given an Amber rating.
Intellectual disability v3.588 PSMC5 Ivone Leong Gene: psmc5 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.587 MMGT1 Ivone Leong Classified gene: MMGT1 as Amber List (moderate evidence)
Intellectual disability v3.587 MMGT1 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). There is not enough evidence to support a gene-disease association so this gene has been given an Amber rating.
Intellectual disability v3.587 MMGT1 Ivone Leong Gene: mmgt1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.586 HNRNPD Ivone Leong Classified gene: HNRNPD as Amber List (moderate evidence)
Intellectual disability v3.586 HNRNPD Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). There is not enough evidence to support a gene-disease association so this gene has been given an Amber rating.
Intellectual disability v3.586 HNRNPD Ivone Leong Gene: hnrnpd has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.585 FBXO31 Ivone Leong Classified gene: FBXO31 as Amber List (moderate evidence)
Intellectual disability v3.585 FBXO31 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). There is not enough evidence to support a gene-disease association so this gene has been given an Amber rating.
Intellectual disability v3.585 FBXO31 Ivone Leong Gene: fbxo31 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.584 FBXO31 Ivone Leong Tag watchlist tag was added to gene: FBXO31.
Intellectual disability v3.584 PIK3C2A Arina Puzriakova Classified gene: PIK3C2A as Amber List (moderate evidence)
Intellectual disability v3.584 PIK3C2A Arina Puzriakova Added comment: Comment on list classification: Maintaining Amber rating as only 2/2 individuals assessed for ID (both from the same family) are reported with it (PMID:31034465). Although authors state that 'most affected individuals exhibited neurological involvement including developmental delay', this was not formally assessed or otherwise reported on in the remaining cases.
Intellectual disability v3.584 PIK3C2A Arina Puzriakova Gene: pik3c2a has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.583 FBXO31 Ivone Leong Phenotypes for gene: FBXO31 were changed from Mental retardation, autosomal recessive 45, MIM#615979; Intellectual disability, autosomal dominant to ?Mental retardation, autosomal recessive 45, OMIM:615979; Intellectual disability, autosomal dominant
Intellectual disability v3.582 FOXP4 Ivone Leong Classified gene: FOXP4 as Amber List (moderate evidence)
Intellectual disability v3.582 FOXP4 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). As ID is not present in the majority of affected patients, and the affected individuals only show mild ID, this gene has been given an Amber rating.
Intellectual disability v3.582 FOXP4 Ivone Leong Gene: foxp4 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.581 DHX32 Ivone Leong Classified gene: DHX32 as Amber List (moderate evidence)
Intellectual disability v3.581 DHX32 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). There is not enough evidence to support a gene-disease association so this gene has been given an Amber rating.
Intellectual disability v3.581 DHX32 Ivone Leong Gene: dhx32 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.580 GIGYF1 Ivone Leong Classified gene: GIGYF1 as Amber List (moderate evidence)
Intellectual disability v3.580 GIGYF1 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). There is not enough evidence to support a gene-disease association so this gene has been given an Amber rating.
Intellectual disability v3.580 GIGYF1 Ivone Leong Gene: gigyf1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.579 ATP6V0A1 Ivone Leong Classified gene: ATP6V0A1 as Amber List (moderate evidence)
Intellectual disability v3.579 ATP6V0A1 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). There is not enough evidence to support a gene-disease association so this gene has been given an Amber rating.
Intellectual disability v3.579 ATP6V0A1 Ivone Leong Gene: atp6v0a1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.578 DDX23 Ivone Leong Classified gene: DDX23 as Amber List (moderate evidence)
Intellectual disability v3.578 DDX23 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). There is not enough evidence to support a gene-disease association so this gene has been given an Amber rating.
Intellectual disability v3.578 DDX23 Ivone Leong Gene: ddx23 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.577 DDX23 Ivone Leong Tag watchlist tag was added to gene: DDX23.
Intellectual disability v3.577 ARHGAP35 Ivone Leong Classified gene: ARHGAP35 as Amber List (moderate evidence)
Intellectual disability v3.577 ARHGAP35 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). There is not enough evidence to support a gene-disease association so this gene has been given an Amber rating.
Intellectual disability v3.577 ARHGAP35 Ivone Leong Gene: arhgap35 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.576 ARHGAP35 Ivone Leong Tag watchlist tag was added to gene: ARHGAP35.
Intellectual disability v3.576 SVBP Arina Puzriakova Phenotypes for gene: SVBP were changed from Neurodevelopmental disorder with ataxia, hypotonia, and microcephaly, 618569 to Neurodevelopmental disorder with ataxia, hypotonia, and microcephaly, OMIM:618569; Neurodevelopmental disorder with ataxia, hypotonia, and microcephaly, MONDO:0032816
Intellectual disability v3.575 AP2S1 Ivone Leong Classified gene: AP2S1 as Amber List (moderate evidence)
Intellectual disability v3.575 AP2S1 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). There is not enough evidence to support a gene-disease association so this gene has been given an Amber rating.
Intellectual disability v3.575 AP2S1 Ivone Leong Gene: ap2s1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.574 AP2S1 Ivone Leong Tag watchlist tag was added to gene: AP2S1.
Intellectual disability v3.574 ALDH7A1 Eleanor Williams reviewed gene: ALDH7A1: Rating: ; Mode of pathogenicity: None; Publications: 32969477; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.574 TFE3 Arina Puzriakova Tag Skewed X-inactivation tag was added to gene: TFE3.
Intellectual disability v3.574 TFE3 Arina Puzriakova Phenotypes for gene: TFE3 were changed from to TFE3-related intellectual disability with pigmentary mosaicism
Intellectual disability v3.574 TFE3 Arina Puzriakova Mode of inheritance for gene: TFE3 was changed from to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Intellectual disability v3.573 ISCA-37418-Loss Zornitza Stark reviewed Region: ISCA-37418-Loss: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Smith-Magenis syndrome, MIM# 182290; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.573 CDH2 Arina Puzriakova reviewed gene: CDH2: Rating: GREEN; Mode of pathogenicity: None; Publications: 31650526; Phenotypes: Agenesis of corpus callosum, cardiac, ocular, and genital syndrome, OMIM:618929; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.573 CDH2 Arina Puzriakova Phenotypes for gene: CDH2 were changed from Agenesis of corpus callosum, cardiac, ocular, and genital syndrome 618929 to Agenesis of corpus callosum, cardiac, ocular, and genital syndrome, OMIM:618929; Agenesis of corpus callosum, cardiac, ocular, and genital syndrome, MONDO:0030065
Intellectual disability v3.572 CDH2 Arina Puzriakova Publications for gene: CDH2 were set to 31585109; 9015265; 17222817
Intellectual disability v3.571 ISCA-37415-Gain Arina Puzriakova Phenotypes for Region: ISCA-37415-Gain were changed from to Intellectual disability; Developmental delay; Autism; Aortopathy
Intellectual disability v3.570 ISCA-37415-Gain Arina Puzriakova Publications for Region: ISCA-37415-Gain were set to 23637818; 24352232; 21614007
Intellectual disability v3.569 ISCA-37415-Gain Zornitza Stark reviewed Region: ISCA-37415-Gain: Rating: GREEN; Mode of pathogenicity: None; Publications: 30287593; Phenotypes: Intellectual disability, autism, aortopathy; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.569 ATP2A2 Andrea Nemeth reviewed gene: ATP2A2: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 25704118; Phenotypes: Intellectual disability; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.569 RNPC3 Ivone Leong gene: RNPC3 was added
gene: RNPC3 was added to Intellectual disability. Sources: Expert Review,Literature
Mode of inheritance for gene: RNPC3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RNPC3 were set to 24480542; 29866761; 32462814
Phenotypes for gene: RNPC3 were set to isolated growth hormone deficiency; ?Growth hormone deficiency, isolated, type V, 618160; developmental delay/intellectual deficiency and delayed puberty
Review for gene: RNPC3 was set to RED
Added comment: This gene is an Amber gene on the Growth failure in early childhood panel (v1.16). The following reviews are present for this gene on that panel:

"Comment on list classification: Based on the available evidence and expert review, this gene has been promoted from Red to Amber. This gene is associated with a relevant phenotype on OMIM. The family described in PMIDs 24480542 and 29866761 are the same. The 3 sisters in this family had GH deficiency only. PMID: 32462814 had GH deficiency and almost undetectable levels of prolactin as well.
Ivone Leong (Genomics England Curator), 15 Oct 2020

Two families reported. PMID 29866761: isolated growth deficiency and pituitary hypoplasia. PMID 32462814: growth hormone deficiency, central congenital hypothyroidism, congenital cataract, developmental delay/intellectual deficiency and delayed puberty. Full spectrum of phenotype unclear at present.
Zornitza Stark (Australian Genomics), 5 Oct 2020"

As only 1 affected family has developmental delay/intellectual deficiency, this gene is given a Red rating.
Sources: Expert Review, Literature
Intellectual disability v3.568 DNMT3A Sarah Leigh Mode of pathogenicity for gene: DNMT3A was changed from None to Other
Intellectual disability v3.568 DNMT3A Sarah Leigh Phenotypes for gene: DNMT3A were changed from OVERGROWTH SYNDROME WITH INTELLECTUAL DISABILITY to Tatton-Brown-Rahman syndrome OMIM:615879; Heyn-Sproul-Jackson syndrome OMIM:618724; MONDO:0032882
Intellectual disability v3.567 DNMT3A Sarah Leigh Added comment: Comment on mode of pathogenicity: Tatton-Brown-Rahman syndrome 615879 is associated with loss of function variants and Heyn-Sproul-Jackson syndrome OMIM:618724 is associated with gain of function variants.
Intellectual disability v3.567 DNMT3A Sarah Leigh Mode of pathogenicity for gene: DNMT3A was changed from to None
Intellectual disability v3.566 LMNB2 Sarah Leigh Classified gene: LMNB2 as Amber List (moderate evidence)
Intellectual disability v3.566 LMNB2 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 v3.566 LMNB2 Sarah Leigh Gene: lmnb2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.565 LMNB2 Sarah Leigh reviewed gene: LMNB2: Rating: GREEN; Mode of pathogenicity: None; Publications: 33033404; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.565 DDC Arina Puzriakova Publications for gene: DDC were set to 20505134
Intellectual disability v3.564 DDC Arina Puzriakova Phenotypes for gene: DDC were changed from AROMATIC L-AMINO-ACID DECARBOXYLASE DEFICIENCY to Aromatic L-amino acid decarboxylase deficiency, OMIM:608643; Aromatic L-amino acid decarboxylase deficiency, MONDO:0012084
Intellectual disability v3.563 AGAP1 Arina Puzriakova Classified gene: AGAP1 as Amber List (moderate evidence)
Intellectual disability v3.563 AGAP1 Arina Puzriakova Added comment: Comment on list classification: New gene added as Amber. Clinical reports are generally limited and the contribution of secondary variants in other genes in 2 subjects cannot be ruled out. Additional cases necessary to corroborate this gene-disease association.
Intellectual disability v3.563 AGAP1 Arina Puzriakova Gene: agap1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.562 AGAP1 Arina Puzriakova reviewed gene: AGAP1: Rating: AMBER; Mode of pathogenicity: None; Publications: 31700678, 30472483, 25666757; Phenotypes: Cerebral palsy, Developmental delay; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.562 MPP5 Arina Puzriakova Classified gene: MPP5 as Amber List (moderate evidence)
Intellectual disability v3.562 MPP5 Arina Puzriakova Added comment: Comment on list classification: New gene added by Konstantinos Varvagiannis. ased on the evidence provided in PMID:33073849, this gene should be promoted to Green at the next GMS panel update (added 'for-review' tag) - 3 unrelated individuals with de novo variants in the MPP5 gene associated with ID/GDD, language delay/regression and behavioural changes. Supportive animal model.
Intellectual disability v3.562 MPP5 Arina Puzriakova Gene: mpp5 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.561 MPP5 Arina Puzriakova Tag for-review tag was added to gene: MPP5.
Intellectual disability v3.561 JARID2 Arina Puzriakova Classified gene: JARID2 as Amber List (moderate evidence)
Intellectual disability v3.561 JARID2 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to rate this gene Green at the next GMS panel update (added 'for-review' tag). Multiple unrelated individuals all with DD as the common feature, as well as ID in the majority of cases.
Intellectual disability v3.561 JARID2 Arina Puzriakova Gene: jarid2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.560 JARID2 Arina Puzriakova Phenotypes for gene: JARID2 were changed from Intellectual disability to Intellectual disability; Neurodevelopmental syndrome
Intellectual disability v3.559 JARID2 Arina Puzriakova Tag for-review tag was added to gene: JARID2.
Intellectual disability v3.559 JARID2 Arina Puzriakova reviewed gene: JARID2: Rating: GREEN; Mode of pathogenicity: None; Publications: 33077894; Phenotypes: Neurodevelopmental syndrome; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.559 LMNB1 Sarah Leigh changed review comment from: Not associated with relevant phenotype in OMIM (19/11/2020), but as confirmed Gen2Phen gene for LMNB1-associated developmental disorder. At least 7 variants reported in at least 7 unrelated cases. Each variant was associated with intellectual disability and microcephaly (PMID 32910914; 33033404).; to: Not associated with relevant phenotype in OMIM (19/11/2020), but as confirmed Gen2Phen gene for LMNB1-associated developmental disorder. At least 5 variants reported in at least 5 unrelated cases. Each variant was associated with intellectual disability and microcephaly (PMID 32910914; 33033404).
Intellectual disability v3.559 LMNB1 Sarah Leigh Phenotypes for gene: LMNB1 were changed from Global developmental delay; Intellectual disability; Microcephaly; Short stature; Seizures; Abnormality of the corpus callosum; Cortical gyral simplification; Feeding difficulties; Scoliosis to Global developmental delay; Intellectual disability; Microcephaly; Short stature; Seizures; Abnormality of the corpus callosum; Cortical gyral simplification; Feeding difficulties; Scoliosis; LMNB1-associated developmental disorder
Intellectual disability v3.558 LMNB1 Sarah Leigh edited their review of gene: LMNB1: Added comment: Not associated with relevant phenotype in OMIM (19/11/2020), but as confirmed Gen2Phen gene for LMNB1-associated developmental disorder. At least 7 variants reported in at least 7 unrelated cases. Each variant was associated with intellectual disability and microcephaly (PMID 32910914; 33033404).; Changed rating: GREEN; Changed phenotypes: LMNB1-associated developmental disorder
Intellectual disability v3.558 LMNB1 Sarah Leigh Classified gene: LMNB1 as Amber List (moderate evidence)
Intellectual disability v3.558 LMNB1 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 v3.558 LMNB1 Sarah Leigh Gene: lmnb1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.557 LMNB1 Sarah Leigh Tag for-review tag was added to gene: LMNB1.
Intellectual disability v3.557 PJA1 Arina Puzriakova Classified gene: PJA1 as Amber List (moderate evidence)
Intellectual disability v3.557 PJA1 Arina Puzriakova Added comment: Comment on list classification: Upgraded rating from Red to Amber - 7 individuals reported in PMID:32530565 all with ID, albeit due to a founder variant. Some cases with deletions encompassing this gene reported with mild DD, however contribution of other affected genes cannot be ruled out. Evidence of pathogenicity of other PJA1 variants is required prior to inclusion on a diagnostic panel.
Intellectual disability v3.557 PJA1 Arina Puzriakova Gene: pja1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.556 PJA1 Arina Puzriakova Tag founder-effect tag was added to gene: PJA1.
Intellectual disability v3.556 PJA1 Arina Puzriakova Publications for gene: PJA1 were set to 17941886; 12036302; 11533224
Intellectual disability v3.555 LMNB1 Sarah Leigh Publications for gene: LMNB1 were set to 32910914
Intellectual disability v3.554 MAPK1 Catherine Snow Tag for-review tag was added to gene: MAPK1.
Intellectual disability v3.554 MAPK1 Catherine Snow Classified gene: MAPK1 as Amber List (moderate evidence)
Intellectual disability v3.554 MAPK1 Catherine Snow Gene: mapk1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.553 MAPK1 Catherine Snow reviewed gene: MAPK1: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: 32721402; Phenotypes: Noonan syndrome 13, OMIM:619087, MONDO:0018997; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.553 FAM50A Arina Puzriakova Phenotypes for gene: FAM50A were changed from Mental retardation syndrome, X-linked, Armfield type (MIM #300261) to Mental retardation syndrome, X-linked, Armfield type, OMIM:300261; Armfield syndrome, MONDO:0010284
Intellectual disability v3.552 FAM50A Arina Puzriakova Classified gene: FAM50A as Amber List (moderate evidence)
Intellectual disability v3.552 FAM50A Arina Puzriakova Added comment: Comment on list classification: New gene added by Konstantinos Varvagiannis. Based on the evidence provided in PMID:32703943, this gene should be promoted to Green at the next GMS panel update (added 'for-review' tag) - 6 individuals from 5 families, all exhibiting GDD/ID as the common presenting feature.
Intellectual disability v3.552 FAM50A Arina Puzriakova Gene: fam50a has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.551 FAM50A Arina Puzriakova Tag for-review tag was added to gene: FAM50A.
Intellectual disability v3.551 PRKACB Arina Puzriakova Classified gene: PRKACB as Amber List (moderate evidence)
Intellectual disability v3.551 PRKACB Arina Puzriakova Added comment: Comment on list classification: New gene added by Konstantinos Varvagiannis. Rating Amber based on the evidence provided in one publication (PMID:33058759) reporting 2/4 unrelated individuals with ID among other features, although this presentation was mild in one of these cases.
Intellectual disability v3.551 PRKACB Arina Puzriakova Gene: prkacb has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.550 PIGQ Sarah Leigh Added comment: Comment on phenotypes: According to Joanna Peas-Welch (OMIM), Multiple congenital anomalies-hypotonia-seizures syndrome-4 (MCAHS4) will replace Epileptic encephalopathy, early infantile, 77, OMIM:618548 as the name for this phenotype (12/11/2020).
Intellectual disability v3.550 PIGQ Sarah Leigh Phenotypes for gene: PIGQ were changed from Epileptic encephalopathy, early infantile 77, OMIM:618548 to Multiple congenital anomalies-hypotonia-seizures syndrome-4 OMIM:618548
Intellectual disability v3.549 NARS Sarah Leigh Tag new-gene-name tag was added to gene: NARS.
Intellectual disability v3.549 PIGQ Sarah Leigh edited their review of gene: PIGQ: Added comment: Associated with relevant phenotype in OMIM and as possible Gen2Phen gene for severe early onset epilepsy. At least 11 variants reported in seven unrelated cases of multiple congenital anomalies-hypotonia-seizures syndrome-4 (MCAHS4)(Epileptic encephalopathy, early infantile, 77 618548)(OMIM:618548).; Changed rating: GREEN; Changed phenotypes: OMIM:618548; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.549 PIGQ Sarah Leigh Classified gene: PIGQ as Amber List (moderate evidence)
Intellectual disability v3.549 PIGQ 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 v3.549 PIGQ Sarah Leigh Gene: pigq has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.548 PIGQ Sarah Leigh Tag for-review tag was added to gene: PIGQ.
Intellectual disability v3.548 COX6B1 Arina Puzriakova Phenotypes for gene: COX6B1 were changed from MITOCHONDRIAL COMPLEX IV DEFICIENCY (MT-C4D) to Mitochondrial complex IV deficiency, nuclear type 7, OMIM:619051
Intellectual disability v3.547 COX6B1 Arina Puzriakova Publications for gene: COX6B1 were set to 0
Intellectual disability v3.546 COX6B1 Arina Puzriakova Classified gene: COX6B1 as Green List (high evidence)
Intellectual disability v3.546 COX6B1 Arina Puzriakova Added comment: Comment on list classification: This gene should be demoted from Green to Red and will be flagged for evaluation at the next GMS panel update (added 'for-review' tag) in view of the recent review by Zornitza Stark. As discussed the disease presentation is not prominent for ID, and rather is primarily characterised by lactate acidosis and encephalopathy which should be sufficient indications for diagnostic testing - COX6B1 is already Green on relevant metabolic/mitochondrial panels.
Intellectual disability v3.546 COX6B1 Arina Puzriakova Gene: cox6b1 has been classified as Green List (High Evidence).
Intellectual disability v3.545 PIGQ Sarah Leigh Phenotypes for gene: PIGQ were changed from Epileptic encephalopathy, early infantile 77, 618548 to Epileptic encephalopathy, early infantile 77, OMIM:618548
Intellectual disability v3.544 PIGQ Sarah Leigh Phenotypes for gene: PIGQ were changed from SEVERE EARLY-ONSET EPILEPSY; Epileptic encephalopathy, early infantile, 77, 618548 to Epileptic encephalopathy, early infantile 77, 618548
Intellectual disability v3.543 PIGQ Sarah Leigh Publications for gene: PIGQ were set to 24463883
Intellectual disability v3.542 COX6B1 Arina Puzriakova Tag for-review tag was added to gene: COX6B1.
Intellectual disability v3.542 TFE3 Sarah Leigh changed review comment from: Not associated with a relevant phenotype in OMIM, but as a confirmed Gen2Phen gene for X-linked dominant Intellectual disability with pigmentary mosaicism and storage disorder and hemizygous TFE3-related intellectual disability with pigmentary mosaicism. At least 14 variants reported as de novo events in 17 unrelated cases of severe intellectual disability with pigmentary mosaicism and storage disorder-like features (no relevant OMIM or MONDO title as of 16/11/2020).

There is enough evidence for this gene to be rated GREEN at the next major review.; to: Not associated with a relevant phenotype in OMIM, but as a confirmed Gen2Phen gene for X-linked dominant Intellectual disability with pigmentary mosaicism and storage disorder and hemizygous TFE3-related intellectual disability with pigmentary mosaicism. At least 14 variants reported as de novo events in 17 unrelated cases of severe intellectual disability with pigmentary mosaicism and storage disorder-like features (no relevant OMIM or MONDO title as of 16/11/2020).
Intellectual disability v3.542 TFE3 Sarah Leigh Classified gene: TFE3 as Amber List (moderate evidence)
Intellectual disability v3.542 TFE3 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 v3.542 TFE3 Sarah Leigh Gene: tfe3 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.541 TFE3 Sarah Leigh changed review comment from: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least 14 variants reported as de novo events in 17 unrelated cases of severe intellectual disability with pigmentary mosaicism and storage disorder-like features (no OMIM or MONDO title as of 16/11/2020).

There is enough evidence for this gene to be rated GREEN at the next major review.; to: Not associated with a relevant phenotype in OMIM, but as a confirmed Gen2Phen gene for X-linked dominant Intellectual disability with pigmentary mosaicism and storage disorder and hemizygous TFE3-related intellectual disability with pigmentary mosaicism. At least 14 variants reported as de novo events in 17 unrelated cases of severe intellectual disability with pigmentary mosaicism and storage disorder-like features (no relevant OMIM or MONDO title as of 16/11/2020).

There is enough evidence for this gene to be rated GREEN at the next major review.
Intellectual disability v3.541 TFE3 Sarah Leigh reviewed gene: TFE3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.541 SCO1 Arina Puzriakova Phenotypes for gene: SCO1 were changed from MITOCHONDRIAL COMPLEX IV DEFICIENCY (MT-C4D) to Mitochondrial complex IV deficiency, nuclear type 4, OMIM:619048
Intellectual disability v3.540 SCO1 Arina Puzriakova Classified gene: SCO1 as Green List (high evidence)
Intellectual disability v3.540 SCO1 Arina Puzriakova Added comment: Comment on list classification: This gene should be demoted from Green to Red and will be flagged for evaluation at the next GMS panel update (added 'for-review' tag), in view of the recent review by Zornitza Stark. As discussed the phenotype is primarily characterised by lactate acidosis and encephalopathy which should be sufficient indications for diagnostic testing - SCO1 is already Green on relevant metabolic/mitochondrial panels.
Intellectual disability v3.540 SCO1 Arina Puzriakova Gene: sco1 has been classified as Green List (High Evidence).
Intellectual disability v3.539 TFE3 Sarah Leigh Publications for gene: TFE3 were set to
Intellectual disability v3.538 TFE3 Sarah Leigh Tag for-review tag was added to gene: TFE3.
Intellectual disability v3.538 SCO1 Arina Puzriakova Publications for gene: SCO1 were set to 0
Intellectual disability v3.537 SCO1 Arina Puzriakova Tag for-review tag was added to gene: SCO1.
Intellectual disability v3.537 EXOC2 Arina Puzriakova Classified gene: EXOC2 as Amber List (moderate evidence)
Intellectual disability v3.537 EXOC2 Arina Puzriakova Added comment: Comment on list classification: New gene added by Konstantinos Varvagiannis. Updating rating from Grey to Amber based on one publication (PMID:32639540) reporting 2 families with EXOC2 variants and variable ID, among other features. Additional cases with a significant ID phenotype are required before inclusion of this gene on a diagnostic panel.
Intellectual disability v3.537 EXOC2 Arina Puzriakova Gene: exoc2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.536 TBC1D2B Arina Puzriakova Tag watchlist tag was added to gene: TBC1D2B.
Intellectual disability v3.536 TBC1D2B Arina Puzriakova Classified gene: TBC1D2B as Amber List (moderate evidence)
Intellectual disability v3.536 TBC1D2B Arina Puzriakova Added comment: Comment on list classification: New gene added by Konstantinos Varvagiannis. Updating rating from Grey to Amber based on one publication (PMID:32623794). Manifestation of ID is variable amongst cases, but is mostly within the mild range. Additional cases would help determine the relevance of ID to the overall disease presentation (added 'watchlist' tag)
Intellectual disability v3.536 TBC1D2B Arina Puzriakova Gene: tbc1d2b has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.535 PAX1 Arina Puzriakova Classified gene: PAX1 as Amber List (moderate evidence)
Intellectual disability v3.535 PAX1 Arina Puzriakova Added comment: Comment on list classification: New gene added and rated Amber by Konstantinos Varvagiannis. Updating rating from Grey to Amber based on 2 papers (PMID:29681087 and PMID:23851939) reporting 2 unrelated cases with mild ID.
Intellectual disability v3.535 PAX1 Arina Puzriakova Gene: pax1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.534 ABCA2 Arina Puzriakova Phenotypes for gene: ABCA2 were changed from Intellectual developmental disorder with poor growth and with or without seizures or ataxia, 618808 to Intellectual developmental disorder with poor growth and with or without seizures or ataxia, OMIM:618808; Intellectual developmental disorder with poor growth and with or without seizures or ataxia, MONDO:0032930
Intellectual disability v3.533 ABCA2 Arina Puzriakova Tag for-review tag was added to gene: ABCA2.
Intellectual disability v3.533 ABCA2 Arina Puzriakova Classified gene: ABCA2 as Amber List (moderate evidence)
Intellectual disability v3.533 ABCA2 Arina Puzriakova Added comment: Comment on list classification: Although not all published cases have a diagnosis of ID (and of those that do, only 1 family with moderate ID), global developmental delay is the most commonly observed features and therefore, this panel may be the most applicable for detecting patients.

Rating Amber, but this will be flagged for review at the next GMS panel update to assess the relevance of the phenotype and determine whether there is sufficient evidence to rate this gene Green (added 'for-review' tag).
Intellectual disability v3.533 ABCA2 Arina Puzriakova Gene: abca2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.532 ABCA2 Arina Puzriakova reviewed gene: ABCA2: Rating: ; Mode of pathogenicity: None; Publications: 30237576, 29302074, 31047799; Phenotypes: Intellectual developmental disorder with poor growth and with or without seizures or ataxia, OMIM: 618808; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.532 CEP120 Arina Puzriakova Tag for-review tag was added to gene: CEP120.
Intellectual disability v3.532 CEP120 Arina Puzriakova Classified gene: CEP120 as Amber List (moderate evidence)
Intellectual disability v3.532 CEP120 Arina Puzriakova Added comment: Comment on list classification: New gene added by Konstantinos Varvagiannis. Based on the evidence provided, this gene should be promoted to Green at the next GMS panel update (added 'for-review' tag)

4 unrelated individuals with distinct variants in the CEP120 gene and Joubert syndrome, including a neurological phenotype in all consisting of hypotonia, developmental delay and cognitive impairment (PMID:27208211).
Intellectual disability v3.532 CEP120 Arina Puzriakova Gene: cep120 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.531 NUS1 Eleanor Williams edited their review of gene: NUS1: Added comment: As reported by reviewer Konstantinos Varvagiannis another 2 cases now reported by Den et al 2019 (PMID: 31656175). 2 unrelated Japanese patients with a novel, recurrent, de novo NUS1 variant, who presented with epileptic seizures with involuntary movement, ataxia, intellectual disability and scoliosis. The variant c.691 + 1C > A, creates a new splice donor site resulting in a 91 bp deletion in exon 3.

This now gives a total of 5 families with heterozygous variants in NUS1 and a presentation of developmental delay and epileptic encephalopathy.; Changed publications: 31656175
Intellectual disability v3.531 PET100 Eleanor Williams Classified gene: PET100 as Amber List (moderate evidence)
Intellectual disability v3.531 PET100 Eleanor Williams Added comment: Comment on list classification: Leaving this gene rating as amber until the next GMS review, but as reviewer Zornitza Stark notes there are 8 Lebanese familes with the same variant, plus an Asian British family with a similar phenotype and a different variant, plus functional data to support the disease causation, so would recommend Green rating.
Intellectual disability v3.531 PET100 Eleanor Williams Gene: pet100 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.530 PET100 Eleanor Williams Tag for-review tag was added to gene: PET100.
Intellectual disability v3.530 PET100 Eleanor Williams Added comment: Comment on phenotypes: Removing MIM# 220110 as this is associated with variants in SURF1
Intellectual disability v3.530 PET100 Eleanor Williams Phenotypes for gene: PET100 were changed from Mitochondrial complex IV deficiency,220110; Intellectual disability; Complex IV-deficient Leigh syndrome to Intellectual disability; Complex IV-deficient Leigh syndrome; Mitochondrial complex IV deficiency, nuclear type 12 OMIM:619055
Intellectual disability v3.529 PET100 Eleanor Williams Publications for gene: PET100 were set to 26425749; 24462369; 25293719
Intellectual disability v3.528 PET100 Eleanor Williams reviewed gene: PET100: Rating: GREEN; Mode of pathogenicity: None; Publications: 24462369, 25293719, 31406627; Phenotypes: Mitochondrial complex IV deficiency, nuclear type 12 OMIM:619055, Leigh syndrome; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.528 PIGH Eleanor Williams Phenotypes for gene: PIGH were changed from Glycosylphosphatidylinositol biosynthesis defect, 17; 618010; Hypotonia, moderate developmental delay, and autism, two episodes of febrile seizures to Glycosylphosphatidylinositol biosynthesis defect, 17 OMIM:618010; Hypotonia, moderate developmental delay, and autism, two episodes of febrile seizures
Intellectual disability v3.527 PIGH Eleanor Williams Classified gene: PIGH as Amber List (moderate evidence)
Intellectual disability v3.527 PIGH Eleanor Williams Added comment: Comment on list classification: Leaving as amber for now, but this gene should be reviewed at the next GMS update. It is borderline green as there are 5 families reported with DD/ID but only two without epilepsy.
Intellectual disability v3.527 PIGH Eleanor Williams Gene: pigh has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.526 PIGH Eleanor Williams Tag for-review tag was added to gene: PIGH.
Intellectual disability v3.526 PIGH Eleanor Williams reviewed gene: PIGH: Rating: GREEN; Mode of pathogenicity: None; Publications: 33156547, 29573052, 29603516; Phenotypes: Glycosylphosphatidylinositol biosynthesis defect 17 OMIM:618010; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.526 TMEM106B Arina Puzriakova Phenotypes for gene: TMEM106B were changed from Leukodystrophy, hypomyelinating, 16 (MIM #617964) to Leukodystrophy, hypomyelinating, 16, OMIM:617964; Leukodystrophy, hypomyelinating, 16, MONDO:0054791
Intellectual disability v3.525 PRKAR1B Ivone Leong Tag watchlist tag was added to gene: PRKAR1B.
Intellectual disability v3.525 PRKAR1B Ivone Leong Classified gene: PRKAR1B as Amber List (moderate evidence)
Intellectual disability v3.525 PRKAR1B Ivone Leong Added comment: Comment on list classification: New gene added by Konstantinos Varvagiannis. Based on the provided evidence this gene has been given an Amber rating.
Intellectual disability v3.525 PRKAR1B Ivone Leong Gene: prkar1b has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.524 KCNC3 Catherine Snow Tag for-review tag was added to gene: KCNC3.
Intellectual disability v3.524 KCNC3 Catherine Snow Phenotypes for gene: KCNC3 were changed from Spinocerebellar ataxia 13, OMIM:605259; MONDO:0011529 to Spinocerebellar ataxia 13, OMIM:605259; MONDO:0011529
Intellectual disability v3.523 KCNC3 Catherine Snow Phenotypes for gene: KCNC3 were changed from SPINOCEREBELLAR ATAXIA TYPE 13 (SCA13) to Spinocerebellar ataxia 13, OMIM:605259; MONDO:0011529
Intellectual disability v3.523 KCNC3 Catherine Snow Publications for gene: KCNC3 were set to 32655623; 25756792
Intellectual disability v3.523 KCNC3 Catherine Snow Publications for gene: KCNC3 were set to 0
Intellectual disability v3.522 KCNC3 Catherine Snow reviewed gene: KCNC3: Rating: AMBER; Mode of pathogenicity: None; Publications: 32655623; Phenotypes: Spinocerebellar ataxia 13, OMIM:605259, MONDO:0011529; Mode of inheritance: None
Intellectual disability v3.522 LSS Eleanor Williams commented on gene: LSS
Intellectual disability v3.522 TMEM106B Arina Puzriakova Classified gene: TMEM106B as Amber List (moderate evidence)
Intellectual disability v3.522 TMEM106B Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to rate this gene Green at the next GMS panel update (added 'for-review' tag) in view of 6 cases with the same variant and phenotype, supported by some evidence of altered gene function.

Inclusion on this panel would also cover the hypotonia feature exhibited by most cases in the neonatal period (as ID is a sub-panel of the Hypotonic Infant super panel)
Intellectual disability v3.522 TMEM106B Arina Puzriakova Gene: tmem106b has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.521 TMEM106B Arina Puzriakova Publications for gene: TMEM106B were set to 29186371; 29444210; 32595021
Intellectual disability v3.520 TMEM106B Arina Puzriakova Tag missense tag was added to gene: TMEM106B.
Intellectual disability v3.520 TMEM106B Arina Puzriakova Tag for-review tag was added to gene: TMEM106B.
Intellectual disability v3.520 TMEM106B Arina Puzriakova reviewed gene: TMEM106B: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: 29186371, 29444210, 30643851, 32595021; Phenotypes: Leukodystrophy, hypomyelinating, 16 OMIM:617964; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.520 AFF3 Sarah Leigh changed review comment from: Not associated with relevant phenotype in OMIM and as probable Gen2Phen gene for Skeletal dysplasia with severe neurological disease. At least 2 variants have been reported in peer reviewed literature, further four variants have been reported in a preprint (July 2019). This preprint has not been published in a peer reviewed (as of 06/08/2020). There are convincing aminal models; to: Not associated with relevant phenotype in OMIM and as probable Gen2Phen gene for Skeletal dysplasia with severe neurological disease. At least 2 variants have been reported in peer reviewed literature, further four variants have been reported in a preprint (July 2019). This preprint has not been published in a peer reviewed (as of 06/08/2020). There are convincing aminal models. If the preprint is peer reviewed and the evidence is relevant, then this gene could be rated green at the next major review (as of 12/11/2020).
Intellectual disability v3.520 ZMYM2 Ivone Leong Classified gene: ZMYM2 as Amber List (moderate evidence)
Intellectual disability v3.520 ZMYM2 Ivone Leong Added comment: Comment on list classification: New gene added by Konstantinos Varvagiannis. This gene is probably associated with a phenotype on Gene2Phenotype. This gene has been given an Amber rating based on the expert review and the evidence provided. As ID is not an identifying part of the phenotype and not all affected individuals had ID, this gene has been given an Amber rating.
Intellectual disability v3.520 ZMYM2 Ivone Leong Gene: zmym2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.519 AFF3 Sarah Leigh Tag for-review tag was added to gene: AFF3.
Intellectual disability v3.519 AFF3 Sarah Leigh changed review comment from: Not associated with relevant phenotype in OMIM and as probable Gen2Phen gene for Skeletal dysplasia with severe neurological disease. At least 2 variants have been reported in peer reviewed literature, further four variants have been reported in a preprint (July 2019). This preprint has not been published in a peer reviewed (as of 06/08/2020). There are confvincing aminal models; to: Not associated with relevant phenotype in OMIM and as probable Gen2Phen gene for Skeletal dysplasia with severe neurological disease. At least 2 variants have been reported in peer reviewed literature, further four variants have been reported in a preprint (July 2019). This preprint has not been published in a peer reviewed (as of 06/08/2020). There are convincing aminal models
Intellectual disability v3.519 WNT5A Arina Puzriakova commented on gene: WNT5A
Intellectual disability v3.519 WFS1 Arina Puzriakova Phenotypes for gene: WFS1 were changed from to Wolfram syndrome 1, 222300; Wolfram-like syndrome, autosomal dominant, 614296
Intellectual disability v3.518 WFS1 Arina Puzriakova Mode of inheritance for gene: WFS1 was changed from to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.517 WFS1 Arina Puzriakova commented on gene: WFS1
Intellectual disability v3.517 MAPRE2 Arina Puzriakova Phenotypes for gene: MAPRE2 were changed from Circumferential Skin Creases Kunze Type to Symmetric circumferential skin creases, congenital, 2, 616734
Intellectual disability v3.516 MAPRE2 Arina Puzriakova Publications for gene: MAPRE2 were set to
Intellectual disability v3.515 MAPRE2 Arina Puzriakova Mode of inheritance for gene: MAPRE2 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 v3.514 MAPRE2 Arina Puzriakova Classified gene: MAPRE2 as Amber List (moderate evidence)
Intellectual disability v3.514 MAPRE2 Arina Puzriakova Added comment: Comment on list classification: There are sufficient cases to promote this gene rating to Green at the next GMS panel update (added 'for-review' tag). Also not all patients present other associated features for which this gene is on a panel (e.g. Clefting, Structural eye disease) and so ID should be a sufficient indication for detecting these cases.
Intellectual disability v3.514 MAPRE2 Arina Puzriakova Gene: mapre2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.513 MAPRE2 Arina Puzriakova edited their review of gene: MAPRE2: Changed mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Intellectual disability v3.513 MAPRE2 Arina Puzriakova edited their review of gene: MAPRE2: Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.513 MAPRE2 Arina Puzriakova Tag for-review tag was added to gene: MAPRE2.
Intellectual disability v3.513 MAPRE2 Arina Puzriakova reviewed gene: MAPRE2: Rating: GREEN; Mode of pathogenicity: None; Publications: 26637975, 31903734, 31502381; Phenotypes: Symmetric circumferential skin creases, congenital, 2, 616734; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.513 MAP1B Arina Puzriakova Deleted their comment
Intellectual disability v3.513 MAP1B Arina Puzriakova Classified gene: MAP1B as Amber List (moderate evidence)
Intellectual disability v3.513 MAP1B Arina Puzriakova Added comment: Comment on list classification: Maintaining Amber rating as although cognitive impairment is reported in multiple (but not all) cases, often this is mild and not sufficient for a clinical diagnosis of ID. Affected individuals are more likely to be assessed in view of the brain malformations - MAP1B will be added to the 'Malformations of cortical development' panel.
Intellectual disability v3.513 MAP1B Arina Puzriakova Gene: map1b has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.512 MAP1B Arina Puzriakova Phenotypes for gene: MAP1B were changed from Intellectual disability; No OMIM number to Periventricular nodular heterotopia 9, 618918
Intellectual disability v3.511 MAP1B Arina Puzriakova Publications for gene: MAP1B were set to 30150678; 29738522
Intellectual disability v3.510 MAP1B Arina Puzriakova commented on gene: MAP1B: Only one homozygous case identified in a screening study of a congenital microcephaly cohort. Other features included hypochromic microcytic anaemia, lymphocytic colitis, retinal coloboma, dysmorphic features, and normal brain MRI. As this is only considered a candidate variant and the phenotype is not compatible with other monoallelic reports, the evidence is currently insufficient for a disease association with biallelic variants (PMID:30214071)
Intellectual disability v3.510 MAP1B Arina Puzriakova reviewed gene: MAP1B: Rating: AMBER; Mode of pathogenicity: None; Publications: 30150678, 29738522, 30214071, 31317654; Phenotypes: Periventricular nodular heterotopia 9, 618918; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.510 SPTBN4 Arina Puzriakova commented on gene: SPTBN4: Review by Helen Brittain (Genomics England Clinical Team): the phenotype is characterised by marked hypotonia in infancy and developmental delay / ID. Adding as Green to the ID panel would therefore cover both of these GMS indications (as the Hypotonic Infant super panel has the ID panel as a sub-panel).
Intellectual disability v3.510 HDAC4 Sarah Leigh changed review comment from: There are many cases of 2q37.3 terminal region (includes HDAC4) loss in PMID 30848064, however, there are only two intragenic variants in HDAC4, with a rating of VUS and as such this gene should be rated as amber.; to: There are many cases of 2q37.3 terminal region (includes HDAC4) loss in PMID 30848064, however, there are only two intragenic variants in HDAC4, with a rating of VUS.
This gene should be rated as amber at the next major review.
Intellectual disability v3.510 HDAC4 Sarah Leigh Tag for-review tag was added to gene: HDAC4.
Intellectual disability v3.510 HDAC4 Sarah Leigh changed review comment from: There are many cases of 2q37.3 terminal region (includes HDAC4) loss in PMID 30848064, however, there are only two intragenic variants in HDAC4, with a rating of VUS and as such the this gene should be rated as amber.; to: There are many cases of 2q37.3 terminal region (includes HDAC4) loss in PMID 30848064, however, there are only two intragenic variants in HDAC4, with a rating of VUS and as such this gene should be rated as amber.
Intellectual disability v3.510 HDAC4 Sarah Leigh reviewed gene: HDAC4: Rating: AMBER; Mode of pathogenicity: None; Publications: 30848064; Phenotypes: Chromosome 2q37 deletion syndrome 600430; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.510 ISCA-37394-Loss Sarah Leigh reviewed Region: ISCA-37394-Loss: Rating: GREEN; Mode of pathogenicity: None; Publications: 30848064; Phenotypes: Chromosome 2q37 deletion syndrome 600430; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.510 ZFHX4 Zornitza Stark edited their review of gene: ZFHX4: Changed rating: GREEN
Intellectual disability v3.510 ZFHX4 Zornitza Stark reviewed gene: ZFHX4: Rating: AMBER; Mode of pathogenicity: None; Publications: 33057194, 24038936; Phenotypes: Developmental disorders, intellectual disability, dysmorphic features; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.510 UPF1 Zornitza Stark gene: UPF1 was added
gene: UPF1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: UPF1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: UPF1 were set to 33057194
Phenotypes for gene: UPF1 were set to Developmental disorders
Review for gene: UPF1 was set to AMBER
Added comment: PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio study from the Deciphering Developmental Disorders study. 16 de novo variants (1 frameshift, 11 missense, 4 synonymous) identified in ~10,000 cases with developmental disorders (no other phenotype info provided, hence Amber rating).
Sources: Literature
Intellectual disability v3.510 U2AF2 Zornitza Stark gene: U2AF2 was added
gene: U2AF2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: U2AF2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: U2AF2 were set to 33057194
Phenotypes for gene: U2AF2 were set to Developmental disorders
Review for gene: U2AF2 was set to AMBER
Added comment: PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio study from the Deciphering Developmental Disorders study. 10 de novo variants (1 in-frame, 8 missense, 1 synoymous) identified in ~10,000 cases with developmental disorders (no other phenotype info provided, hence Amber rating).
Sources: Literature
Intellectual disability v3.510 TCF7L2 Zornitza Stark gene: TCF7L2 was added
gene: TCF7L2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: TCF7L2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TCF7L2 were set to 33057194
Phenotypes for gene: TCF7L2 were set to Developmental disorders
Review for gene: TCF7L2 was set to AMBER
Added comment: A diabetes susceptibility locus associated with common SNVs, see OMIM for details.

PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio study from the Deciphering Developmental Disorders study. 12 de novo variants (2 frameshift, 6 missense, 1 splice acceptor, 2 stopgain, 1 synonymous) identified in ~10,000 cases with developmental disorders (no other phenotype info provided, hence Amber rating).
Sources: Literature
Intellectual disability v3.510 SRRM2 Zornitza Stark gene: SRRM2 was added
gene: SRRM2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: SRRM2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SRRM2 were set to 33057194
Phenotypes for gene: SRRM2 were set to Developmental disorders
Review for gene: SRRM2 was set to AMBER
Added comment: PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio study from the Deciphering Developmental Disorders study. 28 de novo variants (11 frameshift, 7 missense, 1 splice acceptor, 5 stopgain, 4 synonymous) identified in ~10,000 cases with developmental disorders (no other phenotype info provided hence Amber rating).
Sources: Literature
Intellectual disability v3.510 SPEN Zornitza Stark gene: SPEN was added
gene: SPEN was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: SPEN was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SPEN were set to 33057194
Phenotypes for gene: SPEN were set to Developmental disorders
Review for gene: SPEN was set to AMBER
Added comment: PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio study from the Deciphering Developmental Disorders study. 25 de novo variants (6 frameshift, 1 in-frame, 7 missense, 8 stopgain, 3 synonymous) identified in ~10,000 cases with developmental disorders (no other phenotype info provided, hence Amber rating).
Sources: Literature
Intellectual disability v3.510 SATB1 Zornitza Stark reviewed gene: SATB1: Rating: AMBER; Mode of pathogenicity: None; Publications: 33057194; Phenotypes: Developmental disorders; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.510 RAB14 Zornitza Stark gene: RAB14 was added
gene: RAB14 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: RAB14 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RAB14 were set to 33057194
Phenotypes for gene: RAB14 were set to Developmental disorders
Review for gene: RAB14 was set to AMBER
Added comment: PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio study from the Deciphering Developmental Disorders study. 8 de novo variants (1 in-frame, 7 missense) identified in ~10,000 cases with developmental disorders (no other phenotype info provided hence Amber rating).
Sources: Literature
Intellectual disability v3.510 PSMC5 Zornitza Stark gene: PSMC5 was added
gene: PSMC5 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: PSMC5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PSMC5 were set to 33057194
Phenotypes for gene: PSMC5 were set to Developmental disorders
Review for gene: PSMC5 was set to AMBER
Added comment: PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio study from the Deciphering Developmental Disorders study. 10 de novo variants (1 in-frame, 9 missense) identified in ~10,000 cases with developmental disorders (no other phenotype info provided hence Amber rating).
Sources: Literature
Intellectual disability v3.510 MSL2 Zornitza Stark gene: MSL2 was added
gene: MSL2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: MSL2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MSL2 were set to 31332282; 33057194
Phenotypes for gene: MSL2 were set to Developmental disorders; autism
Review for gene: MSL2 was set to AMBER
Added comment: PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio study from the Deciphering Developmental Disorders study. 13 de novo variants (9 frameshift, 4 missense) identified in ~10,000 cases with developmental disorders (no other phenotype info provided hence Amber rating).
PMID: 31332282 - candidate gene in a single autism study, with recurrent de novo variants in a potential oligogenic model
Sources: Literature
Intellectual disability v3.510 MMGT1 Zornitza Stark gene: MMGT1 was added
gene: MMGT1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: MMGT1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MMGT1 were set to 33057194
Phenotypes for gene: MMGT1 were set to Developmental disorders
Review for gene: MMGT1 was set to AMBER
Added comment: PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio study from the Deciphering Developmental Disorders study. 3 de novo missense identified in ~10,000 cases with developmental disorders (no other phenotype info provided hence Amber rating).
Sources: Literature
Intellectual disability v3.510 HNRNPD Zornitza Stark gene: HNRNPD was added
gene: HNRNPD was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: HNRNPD was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: HNRNPD were set to 33057194
Phenotypes for gene: HNRNPD were set to Developmental disorders
Review for gene: HNRNPD was set to AMBER
Added comment: PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio study from the Deciphering Developmental Disorders study. 8 de novo variants (5 frameshift, 1 missense, 1 splice acceptor, 1 synonymous) identified in ~10,000 cases with developmental disorders (no other phenotype info provided hence Amber rating).
Sources: Literature
Intellectual disability v3.510 GIGYF1 Zornitza Stark gene: GIGYF1 was added
gene: GIGYF1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: GIGYF1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: GIGYF1 were set to 33057194
Phenotypes for gene: GIGYF1 were set to Developmental disorder
Review for gene: GIGYF1 was set to AMBER
Added comment: PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio study from the Deciphering Developmental Disorders study. 14 de novo variants (4 frameshift, 5 missense, 1 splice donor, 3 stopgain, 1 synonymous) identified in ~10,000 cases with developmental disorders (no other phenotype info provided hence Amber rating).
Sources: Literature
Intellectual disability v3.510 FOXP4 Zornitza Stark gene: FOXP4 was added
gene: FOXP4 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: FOXP4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FOXP4 were set to 33110267
Phenotypes for gene: FOXP4 were set to Neurodevelopmental disorder; multiple congenital abnormalities
Review for gene: FOXP4 was set to AMBER
Added comment: This gene is a little bit difficult to place, may be Green on Fetal Anomalies panel?

Eight unrelated individuals reported, seven de novo missense, and one individual with a truncating variant. Detailed phenotypic information available on 6. Overlapping features included speech and language delays, growth abnormalities, congenital diaphragmatic hernia (2/6), cervical spine abnormalities, and ptosis. Intellectual disability described as mild in 2, some had normal intellect despite the early speech and language delays, hence Amber rating here.
Sources: Literature
Intellectual disability v3.510 DHX32 Zornitza Stark gene: DHX32 was added
gene: DHX32 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: DHX32 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: DHX32 were set to 32989326
Phenotypes for gene: DHX32 were set to Intellectual disability, spastic diplegia, dystonia, brain abnormalities
Review for gene: DHX32 was set to AMBER
Added comment: PMID: 32989326 - Large cohort study of cerebral palsy cases identified two de novo variants in two unrelated patients with intellectual disability, one with spastic diplegia, and the other characterised as generalised dystonia. Brain abnormalities were identified also.
Sources: Literature
Intellectual disability v3.510 FBXO31 Zornitza Stark edited their review of gene: FBXO31: Changed phenotypes: Mental retardation, autosomal recessive 45, MIM#615979, Intellectual disability, spasticity, autosomal dominant
Intellectual disability v3.510 FBXO31 Zornitza Stark gene: FBXO31 was added
gene: FBXO31 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: FBXO31 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: FBXO31 were set to 24623383; 32989326
Phenotypes for gene: FBXO31 were set to Mental retardation, autosomal recessive 45, MIM#615979; Intellectual disability, autosomal dominant
Review for gene: FBXO31 was set to AMBER
Added comment: Bi-allelic variants: Single consanguineous family reported with homozygous truncating variant, limited functional evidence.

Mono-allelic variants: 2 unrelated probands reported as part of a 'cerebral palsy' cohort harbouring the same de novo missense variant (p.Asp334Asn). The variant affects the cyclin D interaction site, leading to an apparent gain of function of cyclin D degradation, supported by Western blots from patient fibroblasts which showed decreased cyclin D expression.

Patient phenotypes: Spastic diplegia, with esotropia, ID, dysarthria, mixed receptive/expressive language disorder, ADHD, cleft palate, intestinal malrotation and midgut volvulus (patient 1); Spastic paraplegia with ventricular dilation and thin corpus callosum, ID, attention deficit, anxiety, language impairments, strabismus, severe constipation (patient 2).
Sources: Literature
Intellectual disability v3.510 AP2S1 Zornitza Stark gene: AP2S1 was added
gene: AP2S1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: AP2S1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: AP2S1 were set to 33057194
Phenotypes for gene: AP2S1 were set to Developmental disorder
Review for gene: AP2S1 was set to AMBER
Added comment: Established hypercalcaemia gene. PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio developmental disorder study. 5 de novo missense identified in ~10,000 cases with developmental disorders (no other phenotype info provided, hence Amber rating).
Sources: Literature
Intellectual disability v3.510 ARHGAP35 Zornitza Stark gene: ARHGAP35 was added
gene: ARHGAP35 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: ARHGAP35 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ARHGAP35 were set to 33057194
Phenotypes for gene: ARHGAP35 were set to Developmental disorder
Review for gene: ARHGAP35 was set to AMBER
Added comment: Has been identified as a gene with significant de novo enrichment in a large trio developmental disorder study. 16 de novo variants (3 frameshift, 2 in-frame, 10 missense, 1 stopgain) identified in ~10,000 cases with developmental disorders (no other phenotype info provided, hence Amber rating).
Sources: Literature
Intellectual disability v3.510 ATP6V0A1 Zornitza Stark gene: ATP6V0A1 was added
gene: ATP6V0A1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: ATP6V0A1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ATP6V0A1 were set to 30842224; 33057194
Phenotypes for gene: ATP6V0A1 were set to Developmental disorder; Rett syndrome-like
Review for gene: ATP6V0A1 was set to AMBER
Added comment: PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio developmental disorder study. 11 de novo missense identified in ~10,000 cases with developmental disorders (no other phenotype info provided hence Amber rating).
PMID: 30842224 - identified a de novo missense variant in a single individual with atypical Rett syndrome phenotype
Sources: Literature
Intellectual disability v3.510 DDX23 Zornitza Stark gene: DDX23 was added
gene: DDX23 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: DDX23 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: DDX23 were set to 33057194
Phenotypes for gene: DDX23 were set to Developmental disorder
Review for gene: DDX23 was set to AMBER
Added comment: PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio developmental disorder study. 6 de novo missense identified in ~10,000 cases with developmental disorders (rated Amber as no other phenotype info provided).
Sources: Literature
Intellectual disability v3.510 NUDT2 Arina Puzriakova Classified gene: NUDT2 as Amber List (moderate evidence)
Intellectual disability v3.510 NUDT2 Arina Puzriakova Added comment: Comment on list classification: This gene should be promoted to Green at the next GMS panel update (added 'for-review' tag). There are now at least 2 biallelic variants reported in 6 families - 3 of which present GDD and ID, while the remaining had delay but borderline intelligence.
Intellectual disability v3.510 NUDT2 Arina Puzriakova Gene: nudt2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.509 NUDT2 Arina Puzriakova Tag founder-effect was removed from gene: NUDT2.
Tag for-review tag was added to gene: NUDT2.
Intellectual disability v3.509 NUDT2 Arina Puzriakova Phenotypes for gene: NUDT2 were changed from Muscular hypotonia; Global developmental delay; Intellectual disability; no OMIM number to Muscular hypotonia; Global developmental delay; Intellectual disability; Polyneuropathy; no OMIM number
Intellectual disability v3.508 NUDT2 Arina Puzriakova Publications for gene: NUDT2 were set to 27431290; 30059600
Intellectual disability v3.507 NUDT2 Arina Puzriakova commented on gene: NUDT2
Intellectual disability v3.507 NEMF Arina Puzriakova Classified gene: NEMF as Amber List (moderate evidence)
Intellectual disability v3.507 NEMF Arina Puzriakova Added comment: Comment on list classification: Rating Amber but there is sufficient evidence to promote to Green at the next GMS panel update (added 'for-review' tag)
Intellectual disability v3.507 NEMF Arina Puzriakova Gene: nemf has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.506 NEMF Arina Puzriakova Publications for gene: NEMF were set to 32934225
Intellectual disability v3.505 NEMF Arina Puzriakova Added comment: Comment on mode of inheritance: Set MOI to 'Biallelic' as currently only 1 case (total 14) with a monoallelic variant described but with normal intellectual development.
Intellectual disability v3.505 NEMF Arina Puzriakova Mode of inheritance for gene: NEMF was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.504 NEMF Arina Puzriakova Tag for-review tag was added to gene: NEMF.
Intellectual disability v3.504 NEMF Arina Puzriakova commented on gene: NEMF: At least 14 unrelated families reported with variants in NEMF (13 biallelic, 1 monoallelic). GDD/ID is reported in all but 2 cases (USA1 and USA3 in PMID: 32934225) albeit mostly within the mild range. Nonetheless, there are sufficient cases with moderate-severe ID to warrant a Green rating on this panel. Some cases also do not present all other features associated with NEMF variants (e.g. neuropathy) providing further support for inclusion.
Intellectual disability v3.504 NEMF Arina Puzriakova reviewed gene: NEMF: Rating: GREEN; Mode of pathogenicity: None; Publications: 27431290, 33048237; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.504 SETD1A Arina Puzriakova Phenotypes for gene: SETD1A were changed from Schizophrenia; developmental disorder; Intellectual disability to Neurodevelopmental disorder with speech impairment and dysmorphic facies, 619056; Epilepsy, early-onset, with or without developmental delay, 618832
Intellectual disability v3.503 SETD1A Arina Puzriakova Publications for gene: SETD1A were set to 28135719; 26974950; 31197650
Intellectual disability v3.502 SETD1A Arina Puzriakova Tag watchlist was removed from gene: SETD1A.
Intellectual disability v3.502 SETD1A Arina Puzriakova commented on gene: SETD1A
Intellectual disability v3.502 SETD1A Arina Puzriakova Tag for-review tag was added to gene: SETD1A.
Intellectual disability v3.502 JARID2 Konstantinos Varvagiannis reviewed gene: JARID2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.502 ARID2 Arina Puzriakova Added comment: Comment on publications: Added new publication (Kang et al. 2020) reviewing phenotypes of patients with ARID2 variants, and supporting the current Green rating on this panel.
Intellectual disability v3.502 ARID2 Arina Puzriakova Publications for gene: ARID2 were set to 28124119; 26238514
Intellectual disability v3.501 ARID2 Arina Puzriakova Phenotypes for gene: ARID2 were changed from Coffin-Siris syndrome-like phenotype to Coffin-Siris syndrome 6, 617808; ARID2-Coffin-Siris like disorder
Intellectual disability v3.500 JARID2 Zornitza Stark gene: JARID2 was added
gene: JARID2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: JARID2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: JARID2 were set to 23294540; 33077894
Phenotypes for gene: JARID2 were set to Intellectual disability
Review for gene: JARID2 was set to GREEN
gene: JARID2 was marked as current diagnostic
Added comment: 13 individuals reported recently, note CNVs common but LOF sequence variants identified too.
Sources: Literature
Intellectual disability v3.500 NUDT2 Zornitza Stark reviewed gene: NUDT2: Rating: GREEN; Mode of pathogenicity: None; Publications: 27431290, 30059600, 33058507; Phenotypes: Muscular hypotonia, Global developmental delay, Intellectual disability, Polyneuropathy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability v3.500 AGAP1 Zornitza Stark gene: AGAP1 was added
gene: AGAP1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: AGAP1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: AGAP1 were set to 31700678; 25666757; 30472483
Phenotypes for gene: AGAP1 were set to Cerebral palsy
Review for gene: AGAP1 was set to AMBER
Added comment: Two individuals reported with de novo variants in this gene and a CP phenotype. Rare variants over-represented in a case-control study. Supportive zebrafish model. Another individual with a deletion (+1 other gene) reported with ID and autism. This seems the most appropriate panel?
Sources: Literature
Intellectual disability v3.500 PRKAR1B Konstantinos Varvagiannis gene: PRKAR1B was added
gene: PRKAR1B was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: PRKAR1B was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: PRKAR1B were set to https://doi.org/10.1101/2020.09.10.20190314; 25414040
Phenotypes for gene: PRKAR1B were set to Global developmental delay; Intellectual disability; Autism; Attention deficit hyperactivity disorder; Aggressive behavior; Abnormality of movement; Upslanted palpebral fissure
Penetrance for gene: PRKAR1B were set to unknown
Review for gene: PRKAR1B was set to AMBER
Added comment: Please consider inclusion of this gene with amber rating pending publication of the preprint and/or additional evidence.

Marbach et al. (2020 - medRxiv : https://doi.org/10.1101/2020.09.10.20190314 - last author : C. Schaaf) report 6 unrelated individuals with heterozygous missense PRKAR1B variants.

All presented formal ASD diagnosis (6/6), global developmental delay (6/6) and intellectual disability (all - formal evaluations were lacking though). Additional features included neurologic anomalies (movement disorders : dyspraxia, apraxia, clumsiness in all, with tremor/dystonia or involuntary movements as single occurrences). Three displayed high pain tolerance. Regression in speech was a feature in two. Additional behavior anomalies included ADHD (4-5/6) or aggression (3/6). There was no consistent pattern of malformations, physical anomalies or facial features (with the exception of uplsanted palpebral fissures reported in 4).

3 different missense variants were identified (NM_00116470:c.1003C>T - p.Arg335Trp, c.586G>A - p.Glu196Lys, c.500_501delAAinsTT - p.Gln167Leu) with Arg355Trp being a recurrent one within this cohort (4/6 subjects). A possible splicing effect may apply for the MNV. All variants are absent from gnomAD and the SNVs had CADD scores > 24.

In all cases were parental samples were available (5/6), the variant had occurred as a de novo event.

Protein kinase A (PKA) is a tetrameric holoenzyme formed by the association of 2 catalytic (C) subunits with a regulatory (R) subunit dimer. Activation of PKA is achieved through binding of 2 cAMP molecules to each R-subunit, and unleashing(/dissociation) of C-subunits to engage substrates. PRKACA/B genes encode the Cα- and Cβ-subunits while the 4 functionally non-redundant regulatory subunits are encoded by PRKAR1A/1B/2A/2B genes. As the authors comment, the RIβ subunit is primarily expressed in brain with higher expression in cortex and hypothalamus.

The functional consequences of the variants at cellular level were not studied.

Previous studies have demonstrated that downregulation of RIβ in murine hippocampal cultures, reduced phosphorylation of CREB, a transcription factor involved in long-term memory formation. The authors speculate that a similar effect on cAMP/PKA/CREB cascade may mediate the cognitive effects in humans. RIβ deficient mice also display diminished nociceptive pain, similar to the human phenotype. [Several refs provided].

The authors cite the study by Kaplanis et al (2020 - PMID: 33057194), where in a large sample of 31,058 trio exomes of children with developmental disorders, PRKAR1B was among the genes with significant enrichment for de novo missense variants. [The gene has a pLI score of 0.18 in gnomAD / o/e = 0.26 - so pLoF variants may not be deleterious].

Please note that a specific PRKAR1B variant (NM_002735.2:c.149T>G - p.Leu50Arg) has been previous reported to segregate with a late-onset neurodegenerative disorder characterized by dementia and/or parkinsonism within a large pedigree with 12 affected individuals [Wong et al 2014 - PMID: 25414040].
Sources: Literature
Intellectual disability v3.500 MPP5 Konstantinos Varvagiannis gene: MPP5 was added
gene: MPP5 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: MPP5 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: MPP5 were set to 33073849
Phenotypes for gene: MPP5 were set to Global developmental delay; Intellectual disability; Delayed speech and language development; Developmental regression; Behavioral abnormality
Penetrance for gene: MPP5 were set to unknown
Review for gene: MPP5 was set to GREEN
Added comment: Sterling et al (2020 - PMID: 33073849) provide information on the phenotype of 3 individuals with de novo MPP5 variants.

Common features included global developmental delay, intellectual disability (3/3 - severe in 2/3), speech delay/regression (the latter in at least 2) and behavioral abnormalities. Variable other features were reported, among others microcephaly (1/3), abnormal vision (1/3 : CVI, retinal dystrophy, nystagmus), brain MRI abnormalities (2/3), late-onset seizures (1/3). These subjects displayed variable and non-specific dysmorphic features.

All were investigated by exome sequencing (previous tests not mentioned).

One subject was found to harbor a de novo mosaic (5/25 reads) stopgain variant, further confirmed by Sanger sequencing [NM_022474.4:c.1555C>T - p.(Arg519Ter). The specific variant is reported once in gnomAD (1/251338). Two de novo missense variants were identified in the remaining individuals [c.1289A>G - p.Glu430Gly / c.974A>C - p.His325Pro).

All variants had in silico predictions in favor of a deleterious effect (CADD score >24).

The authors comment that MPP5 encodes an apical complex protein with asymmetric localization to the apical side of polarized cells. It is expressed in brain, peripheral nervous system and other tissues. MPP5 is a member of the membrane-associated guanylate kinase family of proteins (MAGUK, p55 subfamily), determining cell polarity at tight junctions.

Previous animal models suggest that complete Mpp5(Pals1) KO in mice leads to near absence of cerebral cortical neurons. Htz KO mice display reduction in size of cerebral cortex and hippocampus. The gene is expressed in proliferating cell populations of cerebellum and important for establishment cerebellar architecture. Conditional KO of Mpp5(Pals1) in retinal progenitor cells mimics the retinal pathology observed in LCA. [Several refs. provided]

The authors studied a heterozygous CNS-specific Mpp5 KO mouse model. These mice presented microcephaly, decreased cerebellar volume and cortical thickness, decreased ependymal cells and Mpp5 at the apical surface of cortical vertrical zone. The proportion of cortical cells undergoing apoptotic cell death was increased. Mice displayed behavioral abnormalities (hyperactivity) and visual deficits, with ERG traces further suggesting retinal blindness.

Overall the mouse model was thought to recapitulate the behavioral abnormalities observed in affected subjects as well as individual rare features such as microcephaly and abnormal vision.

Haploinsufficiency (rather than a dominant negative effect) is favored as the underlying disease mechanism. This is also in line with a dose dependent effect observed in mice.
Sources: Literature
Intellectual disability v3.500 CEP120 Ivone Leong Phenotypes for gene: CEP120 were changed from Joubert syndrome 31 (MIM 617761); Short-rib thoracic dysplasia 13 with or without polydactyly (MIM 616300) to Joubert syndrome 31 (617761); Short-rib thoracic dysplasia 13 with or without polydactyly (616300)
Intellectual disability v3.499 METTL5 Arina Puzriakova Phenotypes for gene: METTL5 were changed from Autosomal-Recessive Intellectual Disability and Microcephaly; Delayed speech and language development; Intellectual disability; Microcephaly; Behavioral abnormality to Intellectual developmental disorder, autosomal recessive 72, 618665
Intellectual disability v3.498 METTL5 Arina Puzriakova Tag for-review tag was added to gene: METTL5.
Intellectual disability v3.498 METTL5 Arina Puzriakova reviewed gene: METTL5: Rating: ; Mode of pathogenicity: None; Publications: 29302074, 31564433; Phenotypes: Intellectual developmental disorder, autosomal recessive 72, 618665; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.498 MFSD2A Arina Puzriakova Classified gene: MFSD2A as Amber List (moderate evidence)
Intellectual disability v3.498 MFSD2A Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence for this gene to be rated Green at the next GMS panel update.
Intellectual disability v3.498 MFSD2A Arina Puzriakova Gene: mfsd2a has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.497 MFSD2A Arina Puzriakova Phenotypes for gene: MFSD2A were changed from NA to Neurodevelopmental disorder with progressive microcephaly, spasticity, and brain imaging abnormalities, 616486
Intellectual disability v3.496 MFSD2A Arina Puzriakova Publications for gene: MFSD2A were set to
Intellectual disability v3.495 MFSD2A Arina Puzriakova Mode of inheritance for gene: MFSD2A was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.494 MFSD2A Arina Puzriakova Tag for-review tag was added to gene: MFSD2A.
Intellectual disability v3.494 MFSD2A Arina Puzriakova reviewed gene: MFSD2A: Rating: GREEN; Mode of pathogenicity: None; Publications: 26005868, 26005865, 29302074, 30043326, 32572202; Phenotypes: Neurodevelopmental disorder with progressive microcephaly, spasticity, and brain imaging abnormalities, 616486; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.494 NPHP3 Arina Puzriakova Publications for gene: NPHP3 were set to
Intellectual disability v3.493 NPHP3 Arina Puzriakova Classified gene: NPHP3 as Amber List (moderate evidence)
Intellectual disability v3.493 NPHP3 Arina Puzriakova Added comment: Comment on list classification: Kept rating Amber as affected individuals are more likely to be assessed under renal and ciliopathy panels, for which this gene is already Green.
Intellectual disability v3.493 NPHP3 Arina Puzriakova Gene: nphp3 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.492 NPHP3 Arina Puzriakova reviewed gene: NPHP3: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Nephronophthisis 3, 604387, Renal-hepatic-pancreatic dysplasia 1, 208540, Meckel syndrome 7, 267010; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.492 ZIC1 Arina Puzriakova Publications for gene: ZIC1 were set to
Intellectual disability v3.491 ZIC1 Arina Puzriakova changed review comment from: Associated with phenotype in OMIM, and a 'confirmed' gene for Craniosynostosis 6 in Gene2Phenotype.

At least 5 variants reported in 6 unrelated families with intellectual disability (2 mild, 1 moderate, 2 moderate-severe, 1 severe) among other variable CNS abnormalities including craniosynostosis, callosal dysgenesis, anomaly in cerebellar hemispheres, vermis and pons, spinal dysraphism, as well as skull abnormalities not associated with craniosynostosis.

; to: Associated with phenotype in OMIM, and a 'confirmed' gene for Craniosynostosis 6 in Gene2Phenotype.

At least 5 variants reported in 6 unrelated families with intellectual disability (2 mild, 1 moderate, 2 moderate-severe, 1 severe) among other variable CNS abnormalities including craniosynostosis, callosal dysgenesis, anomaly in cerebellar hemispheres, vermis and pons, spinal dysraphism, as well as skull abnormalities not associated with craniosynostosis.

Predicted that both gain- and loss-of-function variants can be deleterious.
Intellectual disability v3.491 ZIC1 Arina Puzriakova changed review comment from: Associated with phenotype in OMIM, and a 'confirmed' gene for Craniosynostosis 6 in Gene2Phenotype.

At least 5 variants reported in 6 unrelated families with craniosynostosis and associated variable intellectual disability (2 mild, 1 moderate, 2 moderate-severe, 1 severe); to: Associated with phenotype in OMIM, and a 'confirmed' gene for Craniosynostosis 6 in Gene2Phenotype.

At least 5 variants reported in 6 unrelated families with intellectual disability (2 mild, 1 moderate, 2 moderate-severe, 1 severe) among other variable CNS abnormalities including craniosynostosis, callosal dysgenesis, anomaly in cerebellar hemispheres, vermis and pons, spinal dysraphism, as well as skull abnormalities not associated with craniosynostosis.
Intellectual disability v3.491 ZIC1 Arina Puzriakova Phenotypes for gene: ZIC1 were changed from CRANIOSYNOSTOSIS 6 to Structural brain anomalies with impaired intellectual development and craniosynostosis, 618736; ?Craniosynostosis 6, 616602
Intellectual disability v3.490 ZIC1 Arina Puzriakova Classified gene: ZIC1 as Amber List (moderate evidence)
Intellectual disability v3.490 ZIC1 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence for this gene to be rated Green at the next GMS panel update (added 'for-review' tag)
Intellectual disability v3.490 ZIC1 Arina Puzriakova Gene: zic1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.489 ZIC1 Arina Puzriakova Tag for-review tag was added to gene: ZIC1.
Intellectual disability v3.489 ZIC1 Arina Puzriakova reviewed gene: ZIC1: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: 26340333, 30391508; Phenotypes: ?Craniosynostosis 6, 616602, Structural brain anomalies with impaired intellectual development and craniosynostosis, 618736; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.489 ZNF335 Arina Puzriakova Publications for gene: ZNF335 were set to 23178126
Intellectual disability v3.488 ZNF335 Arina Puzriakova Classified gene: ZNF335 as Amber List (moderate evidence)
Intellectual disability v3.488 ZNF335 Arina Puzriakova Added comment: Comment on list classification: There is enough evidence for this gene to be rated Green at the next GMS panel update (added 'for-review' tag).
Intellectual disability v3.488 ZNF335 Arina Puzriakova Gene: znf335 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.487 ZNF335 Arina Puzriakova Tag watchlist was removed from gene: ZNF335.
Tag for-review tag was added to gene: ZNF335.
Intellectual disability v3.487 ZNF335 Arina Puzriakova commented on gene: ZNF335: Removed 'watchlist' tag as there are now sufficient cases to support a gene-disease association, and for this gene to be rated Green.
Intellectual disability v3.487 ZNF335 Arina Puzriakova reviewed gene: ZNF335: Rating: GREEN; Mode of pathogenicity: None; Publications: 23178126, 27540107, 29652087, 30500859, 31187448; Phenotypes: Microcephaly 10, primary, autosomal recessive, 615095; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.487 ZNF335 Arina Puzriakova Phenotypes for gene: ZNF335 were changed from ?Microcephaly 10, primary, autosomal recessive, 615095; developmental delay; intellectual disability to Microcephaly 10, primary, autosomal recessive, 615095
Intellectual disability v3.486 ZNF335 Arina Puzriakova Mode of inheritance for gene: ZNF335 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.485 ZNF148 Arina Puzriakova reviewed gene: ZNF148: Rating: AMBER; Mode of pathogenicity: None; Publications: 27964749; Phenotypes: Global developmental delay, absent or hypoplastic corpus callosum, and dysmorphic facies, 617260; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.485 KIF21B Arina Puzriakova Classified gene: KIF21B as Amber List (moderate evidence)
Intellectual disability v3.485 KIF21B Arina Puzriakova Added comment: Comment on list classification: Rating Amber, but should be promoted to Green at the next GMS panel update (added 'for-review' tag)
Intellectual disability v3.485 KIF21B Arina Puzriakova Gene: kif21b has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.484 KIF21B Arina Puzriakova Tag for-review tag was added to gene: KIF21B.
Intellectual disability v3.484 KIF21B Arina Puzriakova commented on gene: KIF21B
Intellectual disability v3.484 COX6B1 Zornitza Stark reviewed gene: COX6B1: Rating: RED; Mode of pathogenicity: None; Publications: 18499082, 24781756; Phenotypes: Mitochondrial complex IV deficiency, nuclear type 7, MIM# 619051; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.484 SCO1 Zornitza Stark reviewed gene: SCO1: Rating: RED; Mode of pathogenicity: None; Publications: 11013136, 19295170, 31352446, 23878101; Phenotypes: Mitochondrial complex IV deficiency, nuclear type 4, MIM# 619048; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.484 PRKACB Konstantinos Varvagiannis gene: PRKACB was added
gene: PRKACB was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: PRKACB was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: PRKACB were set to 33058759
Phenotypes for gene: PRKACB were set to Postaxial hand polydactyly; Postaxial foot polydactyly; Common atrium; Atrioventricular canal defect; Narrow chest; Abnormality of the teeth; Intellectual disability
Penetrance for gene: PRKACB were set to unknown
Mode of pathogenicity for gene: PRKACB was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: PRKACB was set to AMBER
Added comment: ID was a feature in 2/4 individuals with PRKACB pathogenic variant reported to date.

Please consider inclusion of PRKACB (and PRKACA) in other relevant gene panels e.g. for polydactyly, congenital heart defects. The disorder may be considered in the DD of ciliopathies.

-----


Palencia-Campos et al (2020 - PMID: 33058759) report on the phenotype of 3 individuals heterozygous for PRKACA and 4 individuals heterozygous for PRKACB pathogenic variants.

The most characteristic features in all individuals with PRKACA/PRKACB mutation, included postaxial polydactyly of hands (6/7 bilateral, 1/7 unilateral) and feet (4/7 bilateral, 1/7 unilateral), brachydactyly and congenital heart defects (CHD 5/7) namely a common atrium or AVSD. Two individuals with PRKACA variant who did not have CHD had offspring with the same variant and an AVSD.

Other variably occurring features included short stature, limbs, narrow chest, abnormal teeth, oral frenula, nail dysplasia. One individual with PRKACB variant presented tumors.

Intellectual disability was reported in 2/4 individuals with PRKACB variant (1/4: mild, 1/4: severe). The 3 individuals with PRKACA variant did not present ID.

As the phenotype was overall suggestive of Ellis-van Creveld syndrome (or the allelic Weyers acrofacial dysostosis), although these diagnoses were ruled out following analysis of EVC and EVC2 genes.

WES was carried out in all.

PRKACA : A single heterozygous missense variant was identified in 3 individuals from 3 families (NM_002730.4:c.409G>A / p.Gly137Arg) with 1 of the probands harboring the variant in mosaic state (28% of reads) and having 2 similarly affected offspring. The variant was de novo in one individual and inherited in a third one having a similarly affected fetus (narrow thorax, postaxial polyd, AVSD).

PRKACB : 4 different variants were identified (NM_002731.3: p.His88Arg/Asn, p.Gly235Arg, c.161C>T - p.Ser54Leu). One of the individuals was mosaic for the latter variant, while in all other cases the variant had occurred de novo.

Protein kinase A (PKA) is a tetrameric holoenzyme formed by the association of 2 catalytic (C) subunits with a regulatory (R) subunit dimer. Activation of PKA is achieved through binding of 2 cAMP molecules to each R-subunit, and unleashing(/dissociation) of C-subunits to engage substrates. PRKACA/B genes encode the Cα- and Cβ-subunits while the 4 functionally non-redundant regulatory subunits are encoded by PRKAR1A/1B/2A/2B genes.

The authors provide evidence that the variants confer increased sensitivity of PKA holoenzymes to activation by cAMP (compared to wt).

By performing ectopic expression of wt or mt PRKACA/B (variants studied : PRKACA p.Gly137Arg / PRKACB p.Gly235Arg) in NIH 3T3 fibroblasts, the authors demonstrate that inhibition of hedgehog signaling likely underlyies the developmental defects observed in affected individuals.

As for PRKACA, the authors cite another study where a 31-month old female with EvC syndrome diagnosis was found to harbor the aforementioned variant (NM_001304349.1:c.637G>A:p.Gly213Arg corresponding to NM_002730.4:c.409G>A / p.Gly137Arg) as a de novo event. Without additional evidence at the time, the variant was considered to be a candidate for this subject's phenotype (Monies et al 2019 – PMID: 31130284).
Sources: Literature
Intellectual disability v3.484 FA2H Sarah Leigh Tag for-review tag was added to gene: FA2H.
Intellectual disability v3.484 FA2H Sarah Leigh reviewed gene: FA2H: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.484 CDH2 Sarah Leigh Phenotypes for gene: CDH2 were changed from Abnormality of the corpus callosum; Abnormality of neuronal migration; Bimanual synkinesia; Duane anomaly; Abnormality of cardiovascular system; Abnormality of the eye; Abnormality of the genital system; Global developmental delay; Intellectual disability to Agenesis of corpus callosum, cardiac, ocular, and genital syndrome 618929
Intellectual disability v3.483 CDH2 Sarah Leigh Tag for-review tag was added to gene: CDH2.
Intellectual disability v3.483 CDH2 Sarah Leigh reviewed gene: CDH2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.483 SCN8A Arina Puzriakova Tag for-review tag was added to gene: SCN8A.
Intellectual disability v3.483 SCN8A Arina Puzriakova commented on gene: SCN8A
Intellectual disability v3.483 PIGP Arina Puzriakova Tag for-review tag was added to gene: PIGP.
Intellectual disability v3.483 PIGP Arina Puzriakova Classified gene: PIGP as Amber List (moderate evidence)
Intellectual disability v3.483 PIGP Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Intellectual disability v3.483 PIGP Arina Puzriakova Gene: pigp has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.482 PUM1 Arina Puzriakova Classified gene: PUM1 as Amber List (moderate evidence)
Intellectual disability v3.482 PUM1 Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Intellectual disability v3.482 PUM1 Arina Puzriakova Gene: pum1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.481 PUM1 Arina Puzriakova Tag for-review tag was added to gene: PUM1.
Intellectual disability v3.481 RALGAPA1 Arina Puzriakova Classified gene: RALGAPA1 as Amber List (moderate evidence)
Intellectual disability v3.481 RALGAPA1 Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Intellectual disability v3.481 RALGAPA1 Arina Puzriakova Gene: ralgapa1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.480 RALGAPA1 Arina Puzriakova Tag for-review tag was added to gene: RALGAPA1.
Intellectual disability v3.480 RARS Arina Puzriakova Classified gene: RARS as Amber List (moderate evidence)
Intellectual disability v3.480 RARS Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Intellectual disability v3.480 RARS Arina Puzriakova Gene: rars has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.479 RARS Arina Puzriakova Tag for-review tag was added to gene: RARS.
Intellectual disability v3.479 RNF113A Arina Puzriakova Classified gene: RNF113A as Amber List (moderate evidence)
Intellectual disability v3.479 RNF113A Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Intellectual disability v3.479 RNF113A Arina Puzriakova Gene: rnf113a has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.478 RNF113A Arina Puzriakova Tag for-review tag was added to gene: RNF113A.
Intellectual disability v3.478 RNF13 Arina Puzriakova Classified gene: RNF13 as Amber List (moderate evidence)
Intellectual disability v3.478 RNF13 Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Intellectual disability v3.478 RNF13 Arina Puzriakova Gene: rnf13 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.477 RNF13 Arina Puzriakova Tag for-review tag was added to gene: RNF13.
Intellectual disability v3.477 GAD1 Arina Puzriakova Classified gene: GAD1 as Amber List (moderate evidence)
Intellectual disability v3.477 GAD1 Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Intellectual disability v3.477 GAD1 Arina Puzriakova Gene: gad1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.476 GAD1 Arina Puzriakova Tag for-review tag was added to gene: GAD1.
Intellectual disability v3.476 CEP55 Arina Puzriakova Classified gene: CEP55 as Amber List (moderate evidence)
Intellectual disability v3.476 CEP55 Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Intellectual disability v3.476 CEP55 Arina Puzriakova Gene: cep55 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.475 CEP55 Arina Puzriakova Tag for-review tag was added to gene: CEP55.
Intellectual disability v3.475 CTU2 Arina Puzriakova Classified gene: CTU2 as Amber List (moderate evidence)
Intellectual disability v3.475 CTU2 Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Intellectual disability v3.475 CTU2 Arina Puzriakova Gene: ctu2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.474 CTU2 Arina Puzriakova Tag for-review tag was added to gene: CTU2.
Intellectual disability v3.474 ALG9 Arina Puzriakova Classified gene: ALG9 as Amber List (moderate evidence)
Intellectual disability v3.474 ALG9 Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Intellectual disability v3.474 ALG9 Arina Puzriakova Gene: alg9 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.473 ALG9 Arina Puzriakova Tag for-review tag was added to gene: ALG9.
Intellectual disability v3.473 EXT2 Arina Puzriakova Classified gene: EXT2 as Amber List (moderate evidence)
Intellectual disability v3.473 EXT2 Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Intellectual disability v3.473 EXT2 Arina Puzriakova Gene: ext2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.472 EXT2 Arina Puzriakova Tag for-review tag was added to gene: EXT2.
Intellectual disability v3.472 PTRHD1 Arina Puzriakova Classified gene: PTRHD1 as Amber List (moderate evidence)
Intellectual disability v3.472 PTRHD1 Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Intellectual disability v3.472 PTRHD1 Arina Puzriakova Gene: ptrhd1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.471 PTRHD1 Arina Puzriakova Tag for-review tag was added to gene: PTRHD1.
Intellectual disability v3.471 TRAPPC4 Arina Puzriakova Classified gene: TRAPPC4 as Amber List (moderate evidence)
Intellectual disability v3.471 TRAPPC4 Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Intellectual disability v3.471 TRAPPC4 Arina Puzriakova Gene: trappc4 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.470 TRAPPC4 Arina Puzriakova Tag for-review tag was added to gene: TRAPPC4.
Intellectual disability v3.470 UGP2 Arina Puzriakova Classified gene: UGP2 as Amber List (moderate evidence)
Intellectual disability v3.470 UGP2 Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Intellectual disability v3.470 UGP2 Arina Puzriakova Gene: ugp2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.469 CXorf56 Arina Puzriakova Classified gene: CXorf56 as Amber List (moderate evidence)
Intellectual disability v3.469 CXorf56 Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Intellectual disability v3.469 CXorf56 Arina Puzriakova Gene: cxorf56 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.468 KAT8 Arina Puzriakova Classified gene: KAT8 as Amber List (moderate evidence)
Intellectual disability v3.468 KAT8 Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Intellectual disability v3.468 KAT8 Arina Puzriakova Gene: kat8 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.467 SLC5A6 Arina Puzriakova Classified gene: SLC5A6 as Amber List (moderate evidence)
Intellectual disability v3.467 SLC5A6 Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Intellectual disability v3.467 SLC5A6 Arina Puzriakova Gene: slc5a6 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.466 SNX27 Arina Puzriakova Classified gene: SNX27 as Amber List (moderate evidence)
Intellectual disability v3.466 SNX27 Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Intellectual disability v3.466 SNX27 Arina Puzriakova Gene: snx27 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.465 UGP2 Arina Puzriakova Tag for-review tag was added to gene: UGP2.
Intellectual disability v3.465 CXorf56 Arina Puzriakova Tag for-review tag was added to gene: CXorf56.
Intellectual disability v3.465 KAT8 Arina Puzriakova Tag for-review tag was added to gene: KAT8.
Intellectual disability v3.465 SLC5A6 Arina Puzriakova Tag for-review tag was added to gene: SLC5A6.
Intellectual disability v3.465 SNX27 Arina Puzriakova Tag for-review tag was added to gene: SNX27.
Intellectual disability v3.465 WNT1 Arina Puzriakova Classified gene: WNT1 as Amber List (moderate evidence)
Intellectual disability v3.465 WNT1 Arina Puzriakova Added comment: Comment on list classification: Changed rating to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Intellectual disability v3.465 WNT1 Arina Puzriakova Gene: wnt1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.464 WNT1 Arina Puzriakova Tag for-review tag was added to gene: WNT1.
Intellectual disability v3.464 PIGK Arina Puzriakova Classified gene: PIGK as Amber List (moderate evidence)
Intellectual disability v3.464 PIGK Arina Puzriakova Added comment: Comment on list classification: Changed rating to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Intellectual disability v3.464 PIGK Arina Puzriakova Gene: pigk has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.463 PIGK Arina Puzriakova Tag for-review tag was added to gene: PIGK.
Intellectual disability v3.463 HSPG2 Ivone Leong Phenotypes for gene: HSPG2 were changed from Schwartz-Jampel syndrome, type 1, 255800; Dyssegmental dysplasia, Silverman-Handmaker type, 224410 to Schwartz-Jampel syndrome, type 1, 255800
Intellectual disability v3.462 KDM3B Ivone Leong commented on gene: KDM3B
Intellectual disability v3.462 KCNMA1 Ivone Leong Publications for gene: KCNMA1 were set to 15937479; 31427379; 31152168; 27567911
Intellectual disability v3.461 KCNK4 Ivone Leong Tag watchlist tag was added to gene: KCNK4.
Intellectual disability v3.461 KCNK4 Ivone Leong commented on gene: KCNK4: As the 2 unrelated patients who have the same de novo variants have severe ID/DD and 3rd patient has low average ID, this gene will be kept as Amber until further evidence is available. Watchlist tag has been added as well.
Intellectual disability v3.461 IQSEC1 Ivone Leong Tag watchlist tag was added to gene: IQSEC1.
Intellectual disability v3.461 LMBRD2 Arina Puzriakova changed review comment from: Comment on list classification: There is a sufficient number of unrelated cases to rate this gene GREEN at the next major review.; to: Comment on list classification: New gene added by Konstantinos Varvagiannis. Rating Amber but there is a sufficient number of unrelated cases with the relevant phenotype to rate this gene GREEN at the next major review.
Intellectual disability v3.461 KCNK4 Ivone Leong Phenotypes for gene: KCNK4 were changed from Neurodevelopmental delay; Intellectual disability; Seizures; Gingival overgrowth; Hypertrichosis to Facial dysmorphism, hypertrichosis, epilepsy, intellectual/developmental delay, and gingival overgrowth syndrome, 618381
Intellectual disability v3.460 IQSEC1 Ivone Leong commented on gene: IQSEC1
Intellectual disability v3.460 IQSEC1 Ivone Leong Phenotypes for gene: IQSEC1 were changed from Central hypotonia; Global developmental delay; Intellectual disability; Behavioral abnormality; Short stature to Central hypotonia; Global developmental delay; Intellectual disability; Behavioral abnormality; Short stature; Intellectual developmental disorder with short stature and behavioral abnormalities, 618687
Intellectual disability v3.459 ALG14 Arina Puzriakova Classified gene: ALG14 as Amber List (moderate evidence)
Intellectual disability v3.459 ALG14 Arina Puzriakova Added comment: Comment on list classification: Changed rating to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update.
Intellectual disability v3.459 ALG14 Arina Puzriakova Gene: alg14 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.458 XYLT1 Arina Puzriakova Publications for gene: XYLT1 were set to
Intellectual disability v3.457 XYLT1 Arina Puzriakova Phenotypes for gene: XYLT1 were changed from {Pseudoxanthoma elasticum, modifier of severity of}, 264800; Desbuquois dysplasia 2, 615777 to Desbuquois dysplasia 2, 615777
Intellectual disability v3.456 XYLT1 Arina Puzriakova reviewed gene: XYLT1: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Desbuquois dysplasia 2, 615777; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.456 XYLT1 Arina Puzriakova Tag for-review tag was added to gene: XYLT1.
Intellectual disability v3.456 CSNK1G1 Konstantinos Varvagiannis reviewed gene: CSNK1G1: Rating: AMBER; Mode of pathogenicity: None; Publications: 33009664; Phenotypes: Global developmental delay, Intellectual disability, Autism, Seizures, Abnormality of the face, Abnormality of limbs; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.456 LMNB2 Konstantinos Varvagiannis gene: LMNB2 was added
gene: LMNB2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: LMNB2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: LMNB2 were set to 33033404
Phenotypes for gene: LMNB2 were set to Congenital microcephaly; Global developmental delay; Intellectual disability
Penetrance for gene: LMNB2 were set to Complete
Mode of pathogenicity for gene: LMNB2 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: LMNB2 was set to GREEN
Added comment: Parry et al (2020 - PMID: 33033404) in a study to identify novel microcephaly genes using the DDD and 100k genomes project (100kGP) patient cohort, report on the phenotype of 13 individuals with heterozygous variant in LMNB1 (N=7) and LMNB2 (N=6).

LMNB1 : The authors identified 3 recurrent variants (c.97A>G - p.Lys33Glu (3), c.97_99del - p.Lys33del (2) , c.269G>C - p.Arg90Pro (2) / NM_005573.4) in seven individuals (3 from the DDD study, 4 from the 100kGP). In all cases were segregation studies were possible, the variant had occurred as a de novo event.

LMNB2 : 4 individuals from the DDD cohort and 1 from the 100kGP were found to harbor the same missense SNV (NM_032737.4:c.1192G>A, p.Glu398Lys). The variant had occurred de novo in 3 subjects and was inherited from a mosaic - unaffected - parent in a further case. Another individual was found to harbor c.160A>C - p.Asn54His.

LMNB1/2 common phenotypes :
All cases had congenital microcephaly (OFC -5.85 +/- 1.14 SD) apart from one individual, without history of IUGR or postnatally abnormal height (the latter in most).

Neuroimaging suggested structurally normal brain without abnormal migration. Gyral simplification / global reduction in white matter / increased extra axial spaces / enlarged ventricles were reported in 2.

LMNB1 - Global developmental delay was a feature in all (mild to severe) with some having occasional words at 7y (P3), absent speech (P9 - age category 5-10y) or ID not further specified (P13).

LMNB2 - DD was a feature in all 6 subjects (5/6 moderate to severe - 1/6 GDD). 5/6 were 10y or older with language (in 3 language not achieved) and motor deficits (walking not achieved in 1/6 - occurred at the age of 6y in 1/6).

Facial features were not consistent nor suggestive of a syndromic diagnosis (sloping forehead in some).

Overall, as the authors comment, the phenotype corresponded to a severe nonsyndromic microcephaly (although additional features were reported in some).

Animal model:
Microcephaly is supported by Lmnb1 ko mouse model. Lmnb1/2 ko mice however display migration defects, while Lmnb2 ko mice do not have reduced size at birth. Heterozygous Lmnb1 mice do not present microcephaly. It is suggested that while animal models support a similar (to the human) phenotype the underlying mechanism is different.

Variant effect :
variants were shown to affect highly conserved residues within the lamin a-helical rod-domain. As affected residues are conserved in LMNA, modelling with available LMNA PDB structures, suggested disrupted interactions required for higher-order assembly of lamin filaments.

Recurrence of specific variants at specific residues, absence of pLoF ones, the htz mouse Lmnb1 phenotype (absence of microcephaly) and the proposed mechanism (perturbation of complex formation) suggest a gain-of-function/dominant-negative effect rather than happloinsufficiency.

[Please also note the additional OMIM phenotypes for LMNB1 / LMNB2 - not here reviewed]
Sources: Literature
Intellectual disability v3.456 LMNB1 Konstantinos Varvagiannis edited their review of gene: LMNB1: Added comment: There is an additional report on LMBN1/2-associated phenotypes supporting green rating of the gene in the current panel.

Parry et al (2020 - PMID: 33033404) in a study to identify novel microcephaly genes using the DDD and 100k genomes project (100kGP) patient cohort, report on the phenotype of 13 individuals with heterozygous variant in LMNB1 (N=7) and LMNB2 (N=6).

LMNB1 : The authors identified 3 recurrent variants (c.97A>G - p.Lys33Glu (3), c.97_99del - p.Lys33del (2) , c.269G>C - p.Arg90Pro (2) / NM_005573.4) in seven individuals (3 from the DDD study, 4 from the 100kGP). In all cases were segregation studies were possible, the variant had occurred as a de novo event.

LMNB2 : 4 individuals from the DDD cohort and 1 from the 100kGP were found to harbor the same missense SNV (NM_032737.4:c.1192G>A, p.Glu398Lys). The variant had occurred de novo in 3 subjects and was inherited from a mosaic - unaffected - parent in a further case. Another individual was found to harbor c.160A>C - p.Asn54His.

LMNB1/2 common phenotypes :
All cases had congenital microcephaly (OFC -5.85 +/- 1.14 SD) appart from one individual, without history of IUGR or postnatally abnormal height (the latter in most).

Neuroimaging suggested structurally normal brain without abnormal migration. Gyral simplification / global reduction in white matter / increased extra axial spaces / enlarged ventricles were reported in 2.

LMNB1 - Global developmental delay was a feature in all (mild to severe) with some having occasional words at 7y (P3), absent speech (P9 - age category 5-10y) or ID not further specified (P13).

LMNB2 - DD was a feature in all 6 subjects (5/6 moderate to severe - 1/6 GDD). 5/6 were 10y or older with language (in 3 language not achieved) and motor deficits (walking not achieved in 1/6 - occured at the age of 6y in 1/6).

Facial features were not consistent nor suggestive of a syndromic diagnosis (sloping forehead in some).

Overall, as the authors comment, the phenotype corresponded to a severe nonsyndromic microcephaly (although additional features were reported in some).

Animal model:
Microcephaly is supported by Lmnb1 ko mouse model. Lmnb1/2 ko mice however display migration defects, while Lmnb2 ko mice do not have reduced size at birth. Heterozygous Lmnb1 mice do not present microcephaly. It is suggested that while animal models support a similar (to the human) phenotype the underlying mechanism is different.

Variant effect :
variants were shown to affect highly conserved residues within the lamin a-helical rod-domain. As affected residues are conserved in LMNA, modelling with available LMNA PDB structures, suggested disrupted interactions required for higher-order assembly of lamin filaments.

Recurrence of specific variants at specific residues, absence of pLoF ones, the htz mouse Lmnb1 phenotype (absence of microcephaly) and the proposed mechanism (perturbation of complex formation) suggest a gain-of-function/dominant-negative effect rather than happloinsufficiency.

[Please also note the additional OMIM phenotypes for LMNB1 / LMNB2 - not here reviewed]; Changed publications: 32910914, 33033404
Intellectual disability v3.456 CNPY3 Arina Puzriakova Classified gene: CNPY3 as Amber List (moderate evidence)
Intellectual disability v3.456 CNPY3 Arina Puzriakova Added comment: Comment on list classification: New gene added and reviewed by Konstantinos Varvagiannis. Although there are sufficient cases to support a gene-disease association, this disorder is mainly characterised by severe epileptic encephalopathy and ID manifests secondarily to seizures.

Rating Amber, but this may be reviewed if new evidence emerges indicating that neurodevelopmental impairment precedes onset of seizures.
Intellectual disability v3.456 CNPY3 Arina Puzriakova Gene: cnpy3 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.455 HSPG2 Ivone Leong Publications for gene: HSPG2 were set to
Intellectual disability v3.454 USP7 Arina Puzriakova Publications for gene: USP7 were set to 30679821; 26365382; 19946331
Intellectual disability v3.453 USP7 Arina Puzriakova Phenotypes for gene: USP7 were changed from Intellectual disability, autism, epilepsy, aggressive behaviour, hypotonia, and hypogonadism to Hao-Fountain syndrome, 616863
Intellectual disability v3.452 USP7 Arina Puzriakova Classified gene: USP7 as Amber List (moderate evidence)
Intellectual disability v3.452 USP7 Arina Puzriakova Added comment: Comment on list classification: Based on published evidence and expert reviews, this gene should be promoted from Amber to Green at the next GMS panel update (added 'for-review' tag)
Intellectual disability v3.452 USP7 Arina Puzriakova Gene: usp7 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.451 USP7 Arina Puzriakova Tag for-review tag was added to gene: USP7.
Intellectual disability v3.451 USP7 Arina Puzriakova reviewed gene: USP7: Rating: GREEN; Mode of pathogenicity: None; Publications: 26365382, 30679821, 33012787; Phenotypes: Hao-Fountain syndrome, 616863; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.451 STT3A Arina Puzriakova Classified gene: STT3A as Amber List (moderate evidence)
Intellectual disability v3.451 STT3A Arina Puzriakova Added comment: Comment on list classification: There is enough evidence to support a gene-disease association, and so STT3A should be promoted from Amber to Green at the next GMS panel update (added 'for-review' tag).

ID/DD reported in all cases (at least 7 individuals from 3 unrelated families, with 2 different homozygous variants in STT3A)
Intellectual disability v3.451 STT3A Arina Puzriakova Gene: stt3a has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.450 STT3A Arina Puzriakova commented on gene: STT3A
Intellectual disability v3.450 STT3A Arina Puzriakova Phenotypes for gene: STT3A were changed from ?Congenital disorder of glycosylation, type Iw, 615596; developmental delay; intellectual disability to Congenital disorder of glycosylation, type Iw, 615596
Intellectual disability v3.449 STT3A Arina Puzriakova Publications for gene: STT3A were set to 28424003; 23842455
Intellectual disability v3.448 STT3A Arina Puzriakova Tag watchlist was removed from gene: STT3A.
Tag for-review tag was added to gene: STT3A.
Intellectual disability v3.448 CARS2 Arina Puzriakova changed review comment from: Comment on list classification: Kept rating Amber as developmental regression and progressive cognitive decline appear secondary to seizures, which represent the key phenotypic feature of this disorder.

This gene is Green on the Inborn errors of metabolism (v2.2) panel, a component the Epilepsy super panel, which should be a sufficient route for detecting these cases.; to: Comment on list classification: Kept rating Amber as developmental regression and progressive cognitive decline appear secondary to seizures, which represent the key phenotypic feature of this disorder.

This gene is Green on Inborn errors of metabolism (v2.3) and has been added to the Genetic epilepsy syndromes (v2.176) panel, which should be sufficient routes for detecting these cases.
Intellectual disability v3.448 TRPM3 Arina Puzriakova Classified gene: TRPM3 as Amber List (moderate evidence)
Intellectual disability v3.448 TRPM3 Arina Puzriakova Added comment: Comment on list classification: Excluding the individual harbouring a VUS, 8 unrelated individuals with ID and the same p.Val837Met variant have been reported (PMID:31278393, 32439617). Also now available is functional data demonstrating variants render the channel overactive.

With addition of the recent publications, there is enough evidence to support a Green rating on this panel. Therefore added 'for-review' tag, for reassessment at next GMS panel update.
Intellectual disability v3.448 TRPM3 Arina Puzriakova Gene: trpm3 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.447 TRPM3 Arina Puzriakova Publications for gene: TRPM3 were set to 31278393
Intellectual disability v3.446 TRPM3 Arina Puzriakova Tag for-review tag was added to gene: TRPM3.
Intellectual disability v3.446 TRPM3 Arina Puzriakova reviewed gene: TRPM3: Rating: ; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: 32439617, 32343227, 32427099; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.446 FGF14 Arina Puzriakova Classified gene: FGF14 as Amber List (moderate evidence)
Intellectual disability v3.446 FGF14 Arina Puzriakova Added comment: Comment on list classification: Cognitive impairment has been reported in several patients, mostly mild but few cases with moderate deficits have also been described. However, the phenotype is mainly characterised by ataxia which would be the expected CI for diagnostic testing - FGF14 is already Green on Ataxia panels.

The utility of calling variants in this gene in a cohort of ID patients without the ataxic component is unlikely to be of benefit, and therefore the rating has been kept Amber on this panel.
Intellectual disability v3.446 FGF14 Arina Puzriakova Gene: fgf14 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.445 FGF14 Arina Puzriakova Publications for gene: FGF14 were set to 15470364
Intellectual disability v3.444 FDFT1 Arina Puzriakova Phenotypes for gene: FDFT1 were changed from Profound global developmental delay; Intellectual disability; Seizures; Abnormality of nervous system morphology; Cortical visual impairment; Abnormality of the skin; Abnormality of the face to Squalene synthase deficiency, 618156
Intellectual disability v3.443 FDFT1 Arina Puzriakova Tag watchlist tag was added to gene: FDFT1.
Intellectual disability v3.443 DENND5A Arina Puzriakova Phenotypes for gene: DENND5A were changed from EPILEPTIC ENCEPHALOPATHY to Epileptic encephalopathy, early infantile, 49 617281
Intellectual disability v3.442 DENND5A Arina Puzriakova Classified gene: DENND5A as Amber List (moderate evidence)
Intellectual disability v3.442 DENND5A Arina Puzriakova Added comment: Comment on list classification: Kept rating Amber as disorder is mainly characterised by severe early-infantile encephalopathy, and cognitive arrest appears secondary to the onset of seizures.

This gene is Green on the Genetic epilepsy syndromes (v2.170) panel, which should be a sufficient route for detecting cases.
Intellectual disability v3.442 DENND5A Arina Puzriakova Gene: dennd5a has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.441 CEP104 Arina Puzriakova changed review comment from: Four related cases reported (PMID:26477546 and 31625690). Moderate-severe ID recorded in two patients and was formally assessed in the remaining two due to young age. However, significant DD was noted in both and in line with the diagnosis of Joubert, it can be anticipated that their presentation is within the scope of this panel.; to: Four unrelated cases reported (PMID:26477546 and 31625690). Moderate-severe ID recorded in two patients and was formally assessed in the remaining two due to young age. However, significant DD was noted in both and in line with the diagnosis of Joubert, it can be anticipated that their presentation is within the scope of this panel.
Intellectual disability v3.441 CEP104 Arina Puzriakova Phenotypes for gene: CEP104 were changed from JOUBERT SYNDROME to Joubert syndrome 25, 616781
Intellectual disability v3.440 CEP104 Arina Puzriakova Publications for gene: CEP104 were set to
Intellectual disability v3.439 CEP104 Arina Puzriakova Classified gene: CEP104 as Amber List (moderate evidence)
Intellectual disability v3.439 CEP104 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to support a Green rating on this panel, and so this gene will be flagged for review at the next GMS panel update (added 'for-review' tag)
Intellectual disability v3.439 CEP104 Arina Puzriakova Gene: cep104 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.438 CEP104 Arina Puzriakova Tag for-review tag was added to gene: CEP104.
Intellectual disability v3.438 CEP104 Arina Puzriakova edited their review of gene: CEP104: Added comment: Four related cases reported (PMID:26477546 and 31625690). Moderate-severe ID recorded in two patients and was formally assessed in the remaining two due to young age. However, significant DD was noted in both and in line with the diagnosis of Joubert, it can be anticipated that their presentation is within the scope of this panel.; Changed publications: 26477546, 31625690
Intellectual disability v3.438 CEP104 Arina Puzriakova reviewed gene: CEP104: Rating: GREEN; Mode of pathogenicity: None; Publications: 31625690; Phenotypes: Joubert syndrome 25, 616781; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.438 CACNA2D2 Arina Puzriakova Classified gene: CACNA2D2 as Amber List (moderate evidence)
Intellectual disability v3.438 CACNA2D2 Arina Puzriakova Added comment: Comment on list classification: Kept rating Amber as severe GDD is a neurodegenerative manifestation that is secondary to the onset of seizures, which represent the key phenotypic feature of this disorder.

This gene is Green on the Genetic epilepsy syndromes (v2.170) panel, which should be a sufficient route for detecting these cases.
Intellectual disability v3.438 CACNA2D2 Arina Puzriakova Gene: cacna2d2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.437 CARS2 Arina Puzriakova Publications for gene: CARS2 were set to 25787132
Intellectual disability v3.436 CARS2 Arina Puzriakova Classified gene: CARS2 as Amber List (moderate evidence)
Intellectual disability v3.436 CARS2 Arina Puzriakova Added comment: Comment on list classification: Kept rating Amber as developmental regression and progressive cognitive decline appear secondary to seizures, which represent the key phenotypic feature of this disorder.

This gene is Green on the Inborn errors of metabolism (v2.2) panel, a component the Epilepsy super panel, which should be a sufficient route for detecting these cases.
Intellectual disability v3.436 CARS2 Arina Puzriakova Gene: cars2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.435 C2CD3 Arina Puzriakova Classified gene: C2CD3 as Amber List (moderate evidence)
Intellectual disability v3.435 C2CD3 Arina Puzriakova Added comment: Comment on list classification: Despite phenotypic diversity among cases with C2CD3 variants, ID/DD is consistently reported in living patients.

Therefore, this gene could be promoted from Amber to Green at the next GMS panel update (added 'for-review' tag).
Intellectual disability v3.435 C2CD3 Arina Puzriakova Gene: c2cd3 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.434 C2CD3 Arina Puzriakova Phenotypes for gene: C2CD3 were changed from ?Orofaciodigital syndrome XIV 615948 to Orofaciodigital syndrome XIV, 615948; Joubert-related disorder
Intellectual disability v3.433 C2CD3 Arina Puzriakova Publications for gene: C2CD3 were set to 27094867; 24997988
Intellectual disability v3.432 C2CD3 Arina Puzriakova Tag for-review tag was added to gene: C2CD3.
Intellectual disability v3.432 C2CD3 Arina Puzriakova edited their review of gene: C2CD3: Changed publications: 24997988, 26092869, 26477546, 27094867, 30097616
Intellectual disability v3.432 C2CD3 Arina Puzriakova changed review comment from: - PMID: 24997988 (2014) - Two unrelated cases with OFD syndrome and biallelic variants (p.Arg62* and p.Cys1029Gly; p.Ala1304Valfs*3, respectively) in C2CD3. In a 4-year-old male, additional manifestations included severe microcephaly (-5 SD), severe ID, micropenis, and brain malformations including Molar Tooth Sign. In the second patient, a terminated foetus, severe microcephaly (-4 SD) was combined with canonical OFD symptoms, but assessment of ID was not possible. No functional studies of the variants; however, some data supporting a role of C2CD3 in cilium assembly and function.

- PMID: 26092869 (2015) - Two unrelated individuals with biallelic variants in C2CD3. Clinical details are limited but both had features of Joubert syndrome (as JBTS screening study), as well as oral features including oral frenulae and/or cleft palate. No report on ID status, but could possibly be present in view of the JBTS diagnosis. One patient also harboured biallelic variants in TTC21B.

- PMID: 26477546 (2015) - Compound het variants identified in two affected sibs with a classic form of JBTS and severe GDD but without any extraneural manifestations, as described in previous cases.

- PMID: 27094867 (2016) - Two sibling fetuses with skeletal dysplasia, brain malformations but no microcephaly, in association with compound het variants in C2CD3. Due to termination of pregnancies, ID status could not be established. Analysis of patient-derived fibroblasts showed impaired cilium assembly.

- PMID: 30097616 (2018) - Four individuals from three unrelated families with different biallelic variants in C2CD3. Each family exhibited distinct clinical phenotypes and severity of disease:
Family 1: two sibs with a diagnosis of OFD including polydactyly, cleft palate and/or incomplete cleft lip, microcephaly, brain malformations and bilateral colobomas. GDD was noted in both sibs.
Family 2: fetus with occipital encephalocele and a ventricular septal defect. Similar abnormalities were identified in another sib (also a terminated fetus), but DNA analysis was not performed on the latter.
Family 3: one male with various fetal anomalies, and subsequent diagnosis of JBTS following identification of consistent findings on brain MRI. Other features included DD and bilateral retina colobomas.; to: - PMID: 24997988 (2014) - Two unrelated cases with OFD syndrome and biallelic variants (p.Arg62* and p.Cys1029Gly; p.Ala1304Valfs*3, respectively) in C2CD3. In a 4-year-old male, additional manifestations included severe microcephaly (-5 SD), severe ID, micropenis, and brain malformations including Molar Tooth Sign. In the second patient, a terminated foetus, severe microcephaly (-4 SD) was combined with canonical OFD symptoms, but assessment of ID was not possible. No functional studies of the variants; however, some data supporting a role of C2CD3 in cilium assembly and function.

- PMID: 26092869 (2015) - Two unrelated individuals with biallelic variants in C2CD3. Clinical details are limited but both had features of Joubert syndrome (as JBTS screening study), as well as oral features including oral frenulae and/or cleft palate. No report on ID status, but could possibly be present in view of the JBTS diagnosis. One patient also harboured biallelic variants in TTC21B.

- PMID: 26477546 (2015) - Compound het variants identified in two affected sibs with a classic form of JBTS and severe GDD but without any extraneural manifestations, as described in previous cases.

- PMID: 27094867 (2016) - Two sibling fetuses with skeletal dysplasia, brain malformations but no microcephaly, in association with compound het variants in C2CD3. Due to termination of pregnancies, ID status could not be established. Analysis of patient-derived fibroblasts showed impaired cilium assembly.

- PMID: 30097616 (2018) - Four individuals from three unrelated families with different biallelic variants in C2CD3. Each family exhibited distinct clinical phenotypes and severity of disease:
Family 1: two sibs with a diagnosis of OFD including polydactyly, cleft palate and/or incomplete cleft lip, microcephaly, brain malformations and bilateral colobomas. GDD was noted in both sibs.
Family 2: fetus with encephalocele and a ventricular septal defect. Similar abnormalities were identified in a sib (also a terminated fetus), but DNA analysis was not performed on the latter.
Family 3: one male with various fetal anomalies, and subsequent diagnosis of JBTS following identification of consistent findings on brain MRI. Other features included DD and bilateral retina colobomas.
Intellectual disability v3.432 C2CD3 Arina Puzriakova reviewed gene: C2CD3: Rating: ; Mode of pathogenicity: None; Publications: 24997988, 26092869, 26477546, 27094867; Phenotypes: Orofaciodigital syndrome XIV, 615948, Joubert-related disorder; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.432 BCORL1 Arina Puzriakova Phenotypes for gene: BCORL1 were changed from Intellectual disability, developmental delay and dysmorphism; Behavioral abnormality to Shukla-Vernon syndrome, 301029
Intellectual disability v3.431 BCORL1 Arina Puzriakova Publications for gene: BCORL1 were set to 24123876; 24896178; 26350204; 30941876
Intellectual disability v3.430 BCORL1 Arina Puzriakova Classified gene: BCORL1 as Amber List (moderate evidence)
Intellectual disability v3.430 BCORL1 Arina Puzriakova Added comment: Comment on list classification: Kept rating Amber in line with the previous review by Rebecca Foulger. Severe ID only exhibited by 2/4 families. No additional papers recently published.
Intellectual disability v3.430 BCORL1 Arina Puzriakova Gene: bcorl1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.429 MPV17 Ivone Leong Classified gene: MPV17 as Amber List (moderate evidence)
Intellectual disability v3.429 MPV17 Ivone Leong Added comment: Comment on list classification: Promoted from Red to Amber. While there are enough cases to support a gene-disease association, ID is part of a broader phenotype for this disorder. Affected individuals will more likely be assessed under mitchondrial panels. This gene is green in Mitochondrial liver disease, inborn errors of metabolism, possible mitochondrial disorder - nuclear genes and mitochondrial disorders panels.
Intellectual disability v3.429 MPV17 Ivone Leong Gene: mpv17 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.428 MPV17 Ivone Leong Phenotypes for gene: MPV17 were changed from Gene2Phenotype confirmed gene with ID HPO to Gene2Phenotype confirmed gene with ID HPO; Mitochondrial DNA depletion syndrome 6 (hepatocerebral type), 256810
Intellectual disability v3.427 MPV17 Ivone Leong Publications for gene: MPV17 were set to
Intellectual disability v3.426 LAS1L Ivone Leong changed review comment from: Comment on list classification: Based on the expert reviews and available evidence, this gene has been promoted from Red to Amber. As the ID severity in the second case in (PMID: 25644381) is unknown and the variant in 1 case reported by (PMID: 26358559) is predicted to be benign. Until there is further evidence this gene has been given an Amber rating.; to: Comment on list classification: Based on the expert reviews and available evidence, this gene has been promoted from Red to Amber. This gene is listed in OMIM and Gene2Phenotype with a relevant phenotype. In Gene2Phenotype it has been classified as probable course for the phenotype. As the ID severity in the second case in (PMID: 25644381) is unknown and the variant in 1 case reported by (PMID: 26358559) is predicted to be benign. Until there is further evidence this gene has been given an Amber rating.
Intellectual disability v3.426 LAS1L Ivone Leong Classified gene: LAS1L as Amber List (moderate evidence)
Intellectual disability v3.426 LAS1L Ivone Leong Added comment: Comment on list classification: Based on the expert reviews and available evidence, this gene has been promoted from Red to Amber. As the ID severity in the second case in (PMID: 25644381) is unknown and the variant in 1 case reported by (PMID: 26358559) is predicted to be benign. Until there is further evidence this gene has been given an Amber rating.
Intellectual disability v3.426 LAS1L Ivone Leong Gene: las1l has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.425 LAS1L Ivone Leong Tag watchlist tag was added to gene: LAS1L.
Intellectual disability v3.425 NUP214 Arina Puzriakova Tag for-review tag was added to gene: NUP214.
Intellectual disability v3.425 TINF2 Arina Puzriakova Phenotypes for gene: TINF2 were changed from Dyskeratosis congenita, autosomal dominant 3 613990 to Dyskeratosis congenita, autosomal dominant 3, 613990; Revesz syndrome, 268130
Intellectual disability v3.424 HDAC4 Sarah Leigh Publications for gene: HDAC4 were set to
Intellectual disability v3.423 TINF2 Arina Puzriakova Classified gene: TINF2 as Red List (low evidence)
Intellectual disability v3.423 TINF2 Arina Puzriakova Added comment: Comment on list classification: Although DD can be a feature, the condition is expected to present in a syndromic manner with cytopenia, cerebellar hypoplasia and retinopathy representing key characteristics. It is expected that these indications should be sufficient for detecting cases - TINF2 is already Green on the relevant panels.

Calling variants in this gene in a cohort of ID patients is therefore unlikely to be of benefit and so the rating has been kept Red.
Intellectual disability v3.423 TINF2 Arina Puzriakova Gene: tinf2 has been classified as Red List (Low Evidence).
Intellectual disability v3.421 ZMPSTE24 Arina Puzriakova Source Expert Review Red was added to ZMPSTE24.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 ZIC3 Arina Puzriakova Source Expert Review Red was added to ZIC3.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 XPC Arina Puzriakova Source Expert Review Red was added to XPC.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 WRAP53 Arina Puzriakova Source Expert Review Red was added to WRAP53.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 WNT7A Arina Puzriakova Source Expert Review Red was added to WNT7A.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 WNT3 Arina Puzriakova Source Expert Review Red was added to WNT3.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 WNT10B Arina Puzriakova Source Expert Review Red was added to WNT10B.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 WDR35 Arina Puzriakova Source Expert Review Red was added to WDR35.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 WDR34 Arina Puzriakova Source Expert Review Red was added to WDR34.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 WDR19 Arina Puzriakova Source Expert Review Red was added to WDR19.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 VSX2 Arina Puzriakova Source Expert Review Red was added to VSX2.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 UVSSA Arina Puzriakova Source Expert Review Red was added to UVSSA.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 USB1 Arina Puzriakova Source Expert Review Red was added to USB1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 UROS Arina Puzriakova Source Expert Review Red was added to UROS.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 UGT1A1 Arina Puzriakova Source Expert Review Red was added to UGT1A1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 TYRP1 Arina Puzriakova Source Expert Review Red was added to TYRP1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 TYR Arina Puzriakova Source Expert Review Red was added to TYR.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 TXNL4A Arina Puzriakova Source Expert Review Red was added to TXNL4A.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 TUBA8 Arina Puzriakova Source Expert Review Red was added to TUBA8.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 TSHR Arina Puzriakova Source Expert Review Red was added to TSHR.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 TRPV4 Arina Puzriakova Source Expert Review Red was added to TRPV4.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 TRPS1 Arina Puzriakova Source Expert Review Red was added to TRPS1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 TRPM1 Arina Puzriakova Source Expert Review Red was added to TRPM1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 TRIP11 Arina Puzriakova Source Expert Review Red was added to TRIP11.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 TRAPPC2 Arina Puzriakova Source Expert Review Red was added to TRAPPC2.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 TP63 Arina Puzriakova Source Expert Review Red was added to TP63.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 TMPRSS6 Arina Puzriakova Source Expert Review Red was added to TMPRSS6.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 TMEM126B Arina Puzriakova Source Expert Review Red was added to TMEM126B.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 TGFB3 Arina Puzriakova Source Expert Review Red was added to TGFB3.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 TGFB2 Arina Puzriakova Source Expert Review Red was added to TGFB2.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 TEK Arina Puzriakova Source Expert Review Red was added to TEK.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 TCF12 Arina Puzriakova Source Expert Review Red was added to TCF12.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 TBXAS1 Arina Puzriakova Source Expert Review Red was added to TBXAS1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 TBX5 Arina Puzriakova Source Expert Review Red was added to TBX5.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 TBX4 Arina Puzriakova Source Expert Review Red was added to TBX4.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 TBX3 Arina Puzriakova Source Expert Review Red was added to TBX3.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 TBX22 Arina Puzriakova Source Expert Review Red was added to TBX22.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 TBX20 Arina Puzriakova Source Expert Review Red was added to TBX20.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 TBX15 Arina Puzriakova Source Expert Review Red was added to TBX15.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 TAB2 Arina Puzriakova Source Expert Review Red was added to TAB2.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 STAR Arina Puzriakova Source Expert Review Red was added to STAR.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 SRY Arina Puzriakova Source Expert Review Red was added to SRY.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 SPEG Arina Puzriakova Source Expert Review Red was added to SPEG.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 SPAG1 Arina Puzriakova Source Expert Review Red was added to SPAG1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 SOX17 Arina Puzriakova Source Expert Review Red was added to SOX17.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 SMCHD1 Arina Puzriakova Source Expert Review Red was added to SMCHD1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 SCN4A Arina Puzriakova Source Expert Review Red was added to SCN4A.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 RUNX2 Arina Puzriakova Source Expert Review Red was added to RUNX2.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 RSPO4 Arina Puzriakova Source Expert Review Red was added to RSPO4.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 RSPH3 Arina Puzriakova Source Expert Review Red was added to RSPH3.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 RSPH1 Arina Puzriakova Source Expert Review Red was added to RSPH1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 RPS19 Arina Puzriakova Source Expert Review Red was added to RPS19.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 RPGRIP1 Arina Puzriakova Source Expert Review Red was added to RPGRIP1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 RPE65 Arina Puzriakova Source Expert Review Red was added to RPE65.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 ROBO3 Arina Puzriakova Source Expert Review Red was added to ROBO3.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 RETREG1 Arina Puzriakova Source Expert Review Red was added to RETREG1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 PGM1 Arina Puzriakova Source Expert Review Red was added to PGM1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 PDE6G Arina Puzriakova Source Expert Review Red was added to PDE6G.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 PAX9 Arina Puzriakova Source Expert Review Red was added to PAX9.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 PAX3 Arina Puzriakova Source Expert Review Red was added to PAX3.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 PAPSS2 Arina Puzriakova Source Expert Review Red was added to PAPSS2.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 OTULIN Arina Puzriakova Source Expert Review Red was added to OTULIN.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 OTOGL Arina Puzriakova Source Expert Review Red was added to OTOGL.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 ORC6 Arina Puzriakova Source Expert Review Red was added to ORC6.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 NRXN2 Arina Puzriakova Source Expert Review Red was added to NRXN2.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 NR5A1 Arina Puzriakova Source Expert Review Red was added to NR5A1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 NR2F2 Arina Puzriakova Source Expert Review Red was added to NR2F2.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 NPR2 Arina Puzriakova Source Expert Review Red was added to NPR2.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 NPHS1 Arina Puzriakova Source Expert Review Red was added to NPHS1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 NPHP4 Arina Puzriakova Source Expert Review Red was added to NPHP4.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 NOTCH2 Arina Puzriakova Source Expert Review Red was added to NOTCH2.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 NOG Arina Puzriakova Source Expert Review Red was added to NOG.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 NODAL Arina Puzriakova Source Expert Review Red was added to NODAL.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 NMNAT1 Arina Puzriakova Source Expert Review Red was added to NMNAT1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 NKX3-2 Arina Puzriakova Source Expert Review Red was added to NKX3-2.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 NEK1 Arina Puzriakova Source Expert Review Red was added to NEK1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 MYO5B Arina Puzriakova Source Expert Review Red was added to MYO5B.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 MYH9 Arina Puzriakova Source Expert Review Red was added to MYH9.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 MYH8 Arina Puzriakova Source Expert Review Red was added to MYH8.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 MYH6 Arina Puzriakova Source Expert Review Red was added to MYH6.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 MSX2 Arina Puzriakova Source Expert Review Red was added to MSX2.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 MSX1 Arina Puzriakova Source Expert Review Red was added to MSX1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 MNX1 Arina Puzriakova Source Expert Review Red was added to MNX1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 MMP13 Arina Puzriakova Source Expert Review Red was added to MMP13.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 MFRP Arina Puzriakova Source Expert Review Red was added to MFRP.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 MESP2 Arina Puzriakova Source Expert Review Red was added to MESP2.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 MC2R Arina Puzriakova Source Expert Review Red was added to MC2R.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 MATN3 Arina Puzriakova Source Expert Review Red was added to MATN3.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 MAP3K1 Arina Puzriakova Source Expert Review Red was added to MAP3K1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 LTBP3 Arina Puzriakova Source Expert Review Red was added to LTBP3.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 LTBP2 Arina Puzriakova Source Expert Review Red was added to LTBP2.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 LRRC6 Arina Puzriakova Source Expert Review Red was added to LRRC6.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 LRP4 Arina Puzriakova Source Expert Review Red was added to LRP4.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 LMX1B Arina Puzriakova Source Expert Review Red was added to LMX1B.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 LMNA Arina Puzriakova Source Expert Review Red was added to LMNA.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 LHX4 Arina Puzriakova Source Expert Review Red was added to LHX4.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 LHX3 Arina Puzriakova Source Expert Review Red was added to LHX3.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 LFNG Arina Puzriakova Source Expert Review Red was added to LFNG.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 LEMD3 Arina Puzriakova Source Expert Review Red was added to LEMD3.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 LDB3 Arina Puzriakova Source Expert Review Red was added to LDB3.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 KLHL40 Arina Puzriakova Source Expert Review Red was added to KLHL40.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 KLF1 Arina Puzriakova Source Expert Review Red was added to KLF1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 KIT Arina Puzriakova Source Expert Review Red was added to KIT.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 KIRREL3 Arina Puzriakova Source Expert Review Red was added to KIRREL3.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 KIF22 Arina Puzriakova Source Expert Review Red was added to KIF22.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 KCTD1 Arina Puzriakova Source Expert Review Red was added to KCTD1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 KCNQ1 Arina Puzriakova Source Expert Review Red was added to KCNQ1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 KCND3 Arina Puzriakova Source Expert Review Red was added to KCND3.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 KBTBD13 Arina Puzriakova Source Expert Review Red was added to KBTBD13.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 JAK3 Arina Puzriakova Source Expert Review Red was added to JAK3.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 JAGN1 Arina Puzriakova Source Expert Review Red was added to JAGN1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 JAG1 Arina Puzriakova Source Expert Review Red was added to JAG1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 IRF6 Arina Puzriakova Source Expert Review Red was added to IRF6.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 INPPL1 Arina Puzriakova Source Expert Review Red was added to INPPL1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 IMPAD1 Arina Puzriakova Source Expert Review Red was added to IMPAD1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 IL11RA Arina Puzriakova Source Expert Review Red was added to IL11RA.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 IHH Arina Puzriakova Source Expert Review Red was added to IHH.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 IGF2 Arina Puzriakova Source Expert Review Red was added to IGF2.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 IFT80 Arina Puzriakova Source Expert Review Red was added to IFT80.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 IFT122 Arina Puzriakova Source Expert Review Red was added to IFT122.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 IFITM5 Arina Puzriakova Source Expert Review Red was added to IFITM5.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 HYDIN Arina Puzriakova Source Expert Review Red was added to HYDIN.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 HYAL1 Arina Puzriakova Source Expert Review Red was added to HYAL1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 HSF4 Arina Puzriakova Source Expert Review Red was added to HSF4.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 HSD3B7 Arina Puzriakova Source Expert Review Red was added to HSD3B7.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 HR Arina Puzriakova Source Expert Review Red was added to HR.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 HPSE2 Arina Puzriakova Source Expert Review Red was added to HPSE2.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 HPS1 Arina Puzriakova Source Expert Review Red was added to HPS1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 HPGD Arina Puzriakova Source Expert Review Red was added to HPGD.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 HOXD13 Arina Puzriakova Source Expert Review Red was added to HOXD13.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 HOXC13 Arina Puzriakova Source Expert Review Red was added to HOXC13.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 HOXA13 Arina Puzriakova Source Expert Review Red was added to HOXA13.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 HNF4A Arina Puzriakova Source Expert Review Red was added to HNF4A.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 HMGCS2 Arina Puzriakova Source Expert Review Red was added to HMGCS2.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 GUCY2C Arina Puzriakova Source Expert Review Red was added to GUCY2C.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 GRM6 Arina Puzriakova Source Expert Review Red was added to GRM6.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 GRHL3 Arina Puzriakova Source Expert Review Red was added to GRHL3.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 GPR179 Arina Puzriakova Source Expert Review Red was added to GPR179.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 GNAI3 Arina Puzriakova Source Expert Review Red was added to GNAI3.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 GLMN Arina Puzriakova Source Expert Review Red was added to GLMN.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 GLE1 Arina Puzriakova Source Expert Review Red was added to GLE1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 GJA8 Arina Puzriakova Source Expert Review Red was added to GJA8.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 GJA3 Arina Puzriakova Source Expert Review Red was added to GJA3.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 GJA1 Arina Puzriakova Source Expert Review Red was added to GJA1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 GHR Arina Puzriakova Source Expert Review Red was added to GHR.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 GDF6 Arina Puzriakova Source Expert Review Red was added to GDF6.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 GDF5 Arina Puzriakova Source Expert Review Red was added to GDF5.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 GATA4 Arina Puzriakova Source Expert Review Red was added to GATA4.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 GATA2 Arina Puzriakova Source Expert Review Red was added to GATA2.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 GAS8 Arina Puzriakova Source Expert Review Red was added to GAS8.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 GALK1 Arina Puzriakova Source Expert Review Red was added to GALK1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 GAA Arina Puzriakova Source Expert Review Red was added to GAA.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 FZD6 Arina Puzriakova Source Expert Review Red was added to FZD6.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 FYCO1 Arina Puzriakova Source Expert Review Red was added to FYCO1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 FXN Arina Puzriakova Source Expert Review Red was added to FXN.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 FTL Arina Puzriakova Source Expert Review Red was added to FTL.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 FOXN1 Arina Puzriakova Source Expert Review Red was added to FOXN1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 FOXF1 Arina Puzriakova Source Expert Review Red was added to FOXF1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 FOXE3 Arina Puzriakova Source Expert Review Red was added to FOXE3.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 FOXE1 Arina Puzriakova Source Expert Review Red was added to FOXE1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 FOXC2 Arina Puzriakova Source Expert Review Red was added to FOXC2.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 FOXC1 Arina Puzriakova Source Expert Review Red was added to FOXC1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 FLT4 Arina Puzriakova Source Expert Review Red was added to FLT4.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 FLNB Arina Puzriakova Source Expert Review Red was added to FLNB.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 FKBP14 Arina Puzriakova Source Expert Review Red was added to FKBP14.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 FHL1 Arina Puzriakova Source Expert Review Red was added to FHL1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 FGF3 Arina Puzriakova Source Expert Review Red was added to FGF3.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 FGF10 Arina Puzriakova Source Expert Review Red was added to FGF10.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 FBXW4 Arina Puzriakova Source Expert Review Red was added to FBXW4.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 FBP1 Arina Puzriakova Source Expert Review Red was added to FBP1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 FBN1 Arina Puzriakova Source Expert Review Red was added to FBN1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 FAM20A Arina Puzriakova Source Expert Review Red was added to FAM20A.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 FAM161A Arina Puzriakova Source Expert Review Red was added to FAM161A.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 EYA1 Arina Puzriakova Source Expert Review Red was added to EYA1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 EVC2 Arina Puzriakova Source Expert Review Red was added to EVC2.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 EVC Arina Puzriakova Source Expert Review Red was added to EVC.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 ERF Arina Puzriakova Source Expert Review Red was added to ERF.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 ERCC4 Arina Puzriakova Source Expert Review Red was added to ERCC4.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 EOGT Arina Puzriakova Source Expert Review Red was added to EOGT.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 ENPP1 Arina Puzriakova Source Expert Review Red was added to ENPP1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 EDNRA Arina Puzriakova Source Expert Review Red was added to EDNRA.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 EDA Arina Puzriakova Source Expert Review Red was added to EDA.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 ECEL1 Arina Puzriakova Source Expert Review Red was added to ECEL1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 DYNC2H1 Arina Puzriakova Source Expert Review Red was added to DYNC2H1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 DVL1 Arina Puzriakova Source Expert Review Red was added to DVL1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 DSTYK Arina Puzriakova Source Expert Review Red was added to DSTYK.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 DSPP Arina Puzriakova Source Expert Review Red was added to DSPP.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 DNAAF4 Arina Puzriakova Source Expert Review Red was added to DNAAF4.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 DNAAF3 Arina Puzriakova Source Expert Review Red was added to DNAAF3.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 DMP1 Arina Puzriakova Source Expert Review Red was added to DMP1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 DLL4 Arina Puzriakova Source Expert Review Red was added to DLL4.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 DLL3 Arina Puzriakova Source Expert Review Red was added to DLL3.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 DDB2 Arina Puzriakova Source Expert Review Red was added to DDB2.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 DCC Arina Puzriakova Source Expert Review Red was added to DCC.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 CYP1B1 Arina Puzriakova Source Expert Review Red was added to CYP1B1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 CTSK Arina Puzriakova Source Expert Review Red was added to CTSK.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 CTSF Arina Puzriakova Source Expert Review Red was added to CTSF.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 CTNS Arina Puzriakova Source Expert Review Red was added to CTNS.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 CRYGD Arina Puzriakova Source Expert Review Red was added to CRYGD.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 CRYBB3 Arina Puzriakova Source Expert Review Red was added to CRYBB3.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 CRYBB2 Arina Puzriakova Source Expert Review Red was added to CRYBB2.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 CRYBB1 Arina Puzriakova Source Expert Review Red was added to CRYBB1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 CRYBA1 Arina Puzriakova Source Expert Review Red was added to CRYBA1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 CRYAA Arina Puzriakova Source Expert Review Red was added to CRYAA.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 CRX Arina Puzriakova Source Expert Review Red was added to CRX.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 CRB1 Arina Puzriakova Source Expert Review Red was added to CRB1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 COMP Arina Puzriakova Source Expert Review Red was added to COMP.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 COL9A3 Arina Puzriakova Source Expert Review Red was added to COL9A3.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 COL9A2 Arina Puzriakova Source Expert Review Red was added to COL9A2.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 COL9A1 Arina Puzriakova Source Expert Review Red was added to COL9A1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 COL6A1 Arina Puzriakova Source Expert Review Red was added to COL6A1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 COL4A4 Arina Puzriakova Source Expert Review Red was added to COL4A4.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 COL4A3 Arina Puzriakova Source Expert Review Red was added to COL4A3.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 COL2A1 Arina Puzriakova Source Expert Review Red was added to COL2A1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 COL1A1 Arina Puzriakova Source Expert Review Red was added to COL1A1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 COL18A1 Arina Puzriakova Source Expert Review Red was added to COL18A1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 COL11A1 Arina Puzriakova Source Expert Review Red was added to COL11A1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 COL10A1 Arina Puzriakova Source Expert Review Red was added to COL10A1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 CLDN19 Arina Puzriakova Source Expert Review Red was added to CLDN19.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 CLCN7 Arina Puzriakova Source Expert Review Red was added to CLCN7.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 CIB2 Arina Puzriakova Source Expert Review Red was added to CIB2.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 CHUK Arina Puzriakova Source Expert Review Red was added to CHUK.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 CHSY1 Arina Puzriakova Source Expert Review Red was added to CHSY1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 CHST3 Arina Puzriakova Source Expert Review Red was added to CHST3.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 CHRNG Arina Puzriakova Source Expert Review Red was added to CHRNG.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 CHRDL1 Arina Puzriakova Source Expert Review Red was added to CHRDL1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 CHM Arina Puzriakova Source Expert Review Red was added to CHM.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 CDH3 Arina Puzriakova Source Expert Review Red was added to CDH3.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 CDH23 Arina Puzriakova Source Expert Review Red was added to CDH23.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 CCT5 Arina Puzriakova Source Expert Review Red was added to CCT5.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 CCNO Arina Puzriakova Source Expert Review Red was added to CCNO.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 CCDC65 Arina Puzriakova Source Expert Review Red was added to CCDC65.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 CCDC40 Arina Puzriakova Source Expert Review Red was added to CCDC40.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 CCDC114 Arina Puzriakova Source Expert Review Red was added to CCDC114.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 CCDC103 Arina Puzriakova Source Expert Review Red was added to CCDC103.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 C4orf26 Arina Puzriakova Source Expert Review Red was added to C4orf26.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 C2orf71 Arina Puzriakova Source Expert Review Red was added to C2orf71.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 C19orf12 Arina Puzriakova Source Expert Review Red was added to C19orf12.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 BMPR1B Arina Puzriakova Source Expert Review Red was added to BMPR1B.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 BMPER Arina Puzriakova Source Expert Review Red was added to BMPER.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 BICD2 Arina Puzriakova Source Expert Review Red was added to BICD2.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 BHLHA9 Arina Puzriakova Source Expert Review Red was added to BHLHA9.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 BGN Arina Puzriakova Source Expert Review Red was added to BGN.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 BFSP2 Arina Puzriakova Source Expert Review Red was added to BFSP2.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 ATP6V1B1 Arina Puzriakova Source Expert Review Red was added to ATP6V1B1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 ARHGEF6 Arina Puzriakova Source Expert Review Red was added to ARHGEF6.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.420 ITFG2 Konstantinos Varvagiannis gene: ITFG2 was added
gene: ITFG2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: ITFG2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ITFG2 were set to 28397838; https://doi.org/10.1038/s41525-020-00150-z
Phenotypes for gene: ITFG2 were set to Neurodevelopmental abnormality; Intellectual disability; Developmental regression; Ataxia
Penetrance for gene: ITFG2 were set to Complete
Review for gene: ITFG2 was set to AMBER
Added comment: ITFG2 was suggested to be a candidate gene for autosomal recessive ID in the study by Harripaul et al (2018 - PMID: 28397838). The authors performed microarray and exome sequencing in 192 consanguineous families and identified a homozygous ITGF2 stopgain variant (NM_018463.3:c.472G>T / p.Glu158*) along with 3 additional variants segregating with ID within an investigated family (PK51).

Cheema et al (2020 - https://doi.org/10.1038/s41525-020-00150-z) report briefly on a male, born to consanguineous parents presenting with NDD, seizures, regression and ataxia. There was a similarly affected female sibling. Evaluation of ROH revealed a homozygous ITFG2 nonsense variant [NM_018463.3:c.361C>T / p.(Gln121*)]. Families in this study were investigated by trio WES or WGS.

Evaluation of data of the same lab revealed 3 additional unrelated subjects with overlapping phenotypes, notably NDD and ataxia. These individuals were - each - homozygous for pLoF variants [NM_018463.3:c.848-1G>A; NM_018463.3:c.704dupC, p.(Ala236fs), NM_018463.3:c.1000_1001delAT, p.(Ile334fs)].

As discussed in OMIM, ITFG2 encodes a subunit of the KICSTOR protein complex, having a role in regulating nutrient sensing by MTOR complex-1 (Wolfson et al 2017 - PMID : 28199306).

Please consider inclusion in the ID panel with amber rating, pending further details.
Sources: Literature
Intellectual disability v3.420 USP7 Konstantinos Varvagiannis edited their review of gene: USP7: Changed publications: 26365382, 19946331, 33012787
Intellectual disability v3.420 USP7 Konstantinos Varvagiannis changed review comment from: Please consider also PMID : 33012787 for Green rating (several cases reported).; to: Please consider also PMID : 33012787 for Green rating (several cases reported to date).
Intellectual disability v3.420 USP7 Konstantinos Varvagiannis commented on gene: USP7: Please consider also PMID : 33012787 for Green rating (several cases reported).
Intellectual disability v3.420 SHMT2 Konstantinos Varvagiannis gene: SHMT2 was added
gene: SHMT2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: SHMT2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SHMT2 were set to 33015733
Phenotypes for gene: SHMT2 were set to Congenital microcephaly; Infantile axial hypotonia; Spastic paraparesis; Global developmental delay; Intellectual disability; Abnormality of the corpus callosum; Abnormal cortical gyration; Hypertrophic cardiomyopathy; Abnormality of the face; Proximal placement of thumb; 2-3 toe syndactyly
Penetrance for gene: SHMT2 were set to Complete
Review for gene: SHMT2 was set to GREEN
Added comment: García‑Cazorla et al. (2020 - PMID: 33015733) report 5 individuals (from 4 families) with a novel brain and heart developmental syndrome caused by biallelic SHMT2 pathogenic variants.

All affected subjects presented similar phenotype incl. microcephaly at birth (5/5 OFC < -2 SD though in 2/5 cases N OFC was observed later), DD and ID (1/5 mild-moderate, 1/5 moderate, 3/5 severe), motor dysfunction in the form of spastic (5/5) paraparesis, ataxia/dysmetria (3/4), intention tremor (in 3/?) and/or peripheral neuropathy (2 sibs). They exhibited corpus callosum hypoplasia (5/5) and perisylvian microgyria-like pattern (4/5). Cardiac problems were reported in all, with hypertrophic cardiomyopathy in 4/5 (from 3 families) and atrial-SD in the 5th individual (1/5). Common dysmorphic features incl. long palpebral/fissures, eversion of lateral third of lower eylids, arched eyebrows, long eyelashes, thin upper lip, short Vth finger, fetal pads, mild 2-3 toe syndactyly, proximally placed thumbs.

Biallelic variants were identified following exome sequencing in all (other investigations not mentioned). Identified variants were in all cases missense SNVs or in-frame del, which together with evidence from population databases and mouse model might suggest a hypomorphic effect of variants and intolerance/embryonic lethality for homozygous LoF ones.

SHMT2 encodes the mitohondrial form of serine hydroxymethyltransferase. The enzyme transfers one-carbon units from serine to tetrahydrofolate (THF) and generates glycine and 5,10,methylene-THF.

Mitochondrial defect was suggested by presence of ragged red fibers in myocardial biopsy of one patient. Quadriceps and myocardial biopsies of the same individual were overall suggestive of myopathic changes.

While plasma metabolites were within N range and SHMT2 protein levels not significantly altered in patient fibroblasts, the authors provide evidence for impaired enzymatic function eg. presence of the SHMT2 substrate (THF) in patient but not control (mitochondria-enriched) fibroblasts , decrease in glycine/serine ratios, impared folate metabolism. Patient fibroblasts displayed impaired oxidative capacity (reduced ATP levels in a medium without glucose, diminished oxygen consumption rates). Mitochondrial membrane potential and ROS levels were also suggestive of redox malfunction.

Shmt2 ko in mice was previously shown to be embryonically lethal attributed to severe mitochondrial respiration defects, although there was no observed brain metabolic defect.

The authors performed Shmt2 knockdown in motoneurons in Drosophila, demonstrating neuromuscular junction (# of satellite boutons) and motility defects (climbing distance/velocity).

Overall this gene can be considered for inclusion with (probably) green rating in gene panels for ID, metabolic / mitochondrial disorders, cardiomyopathy, congenital microcephaly, corpus callosum anomalies, etc.
Sources: Literature
Intellectual disability v3.420 ABCB11 Arina Puzriakova Classified gene: ABCB11 as Red List (low evidence)
Intellectual disability v3.420 ABCB11 Arina Puzriakova Added comment: Comment on list classification: Downgraded from Amber to Red in context of the review by Konstantinos Varvagiannis
Intellectual disability v3.420 ABCB11 Arina Puzriakova Gene: abcb11 has been classified as Red List (Low Evidence).
Intellectual disability v3.419 ACAN Arina Puzriakova Classified gene: ACAN as Red List (low evidence)
Intellectual disability v3.419 ACAN Arina Puzriakova Added comment: Comment on list classification: Downgraded from Amber to Red in context of the review by Konstantinos Varvagiannis
Intellectual disability v3.419 ACAN Arina Puzriakova Gene: acan has been classified as Red List (Low Evidence).
Intellectual disability v3.418 ATP8B1 Arina Puzriakova Classified gene: ATP8B1 as Red List (low evidence)
Intellectual disability v3.418 ATP8B1 Arina Puzriakova Gene: atp8b1 has been classified as Red List (Low Evidence).
Intellectual disability v3.417 ATP8B1 Arina Puzriakova changed review comment from: Following discussion with the clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark; to: Following discussion with the clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark and Konstantinos Varvagiannis
Intellectual disability v3.417 KAT5 Arina Puzriakova Phenotypes for gene: KAT5 were changed from to Severe global developmental delay; Intellectual disability; Seizures; Microcephaly; Behavioral abnormality; Sleep disturbance; Morphological abnormality of the central nervous system; Short stature; Oral cleft; Abnormality of the face
Intellectual disability v3.416 KAT5 Arina Puzriakova Publications for gene: KAT5 were set to
Intellectual disability v3.415 KAT5 Arina Puzriakova Mode of inheritance for gene: KAT5 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.415 KAT5 Arina Puzriakova Mode of inheritance for gene: KAT5 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.414 KAT5 Arina Puzriakova Classified gene: KAT5 as Amber List (moderate evidence)
Intellectual disability v3.414 KAT5 Arina Puzriakova Added comment: Comment on list classification: Rating upgraded from Red to Amber. There is a sufficient number of unrelated cases reported in PMID:32822602 to promoted this gene to Green at the next GMS panel update.
Intellectual disability v3.414 KAT5 Arina Puzriakova Gene: kat5 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.413 KAT5 Arina Puzriakova Tag for-review tag was added to gene: KAT5.
Intellectual disability v3.413 SCAF4 Arina Puzriakova Phenotypes for gene: SCAF4 were changed from to SCAF4-related Neurodevelopmental Disorder; Intellectual disability; Seizures; Behavioural abnormalities
Intellectual disability v3.412 SCAF4 Arina Puzriakova Classified gene: SCAF4 as Amber List (moderate evidence)
Intellectual disability v3.412 SCAF4 Arina Puzriakova Added comment: Comment on list classification: At least 8 unrelated individuals reported in PMID:32730804 with a neurodevelopmental disorder characterised by DD/ID, mostly in the mild range (severe in only one individual).

Rating Amber in view of the mild ID presentation. This may be reviewed if further cases are reported with more severe manifestations of relevant phenotypes.
Intellectual disability v3.412 SCAF4 Arina Puzriakova Gene: scaf4 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.411 SCAF4 Arina Puzriakova commented on gene: SCAF4
Intellectual disability v3.411 SCAF4 Arina Puzriakova Publications for gene: SCAF4 were set to
Intellectual disability v3.410 NEDD4L Eleanor Williams changed review comment from: Associated with Periventricular nodular heterotopia 7 #617201 (AD) in OMIM.

PMID: 27694961 - Broix et al 2016 - report 4 different de novo missense changes in NEDD4L in a total of five unrelated patients with periventricular nodular heterotopia and neurodevelopmental delay, and in a additional familial case with a similar phenotype and a previously found missense variant. In the familial case, two affected siblings were found to be heterozygous for the variant, the father and an unaffected sibling did not carry the variant, and the mother was found to show somatic mosaicism of NEDD4L variant. Functional studies showed a sensitivity of PNH-associated mutants to proteasome degradation.; to: Associated with Periventricular nodular heterotopia 7 #617201 (AD) in OMIM.

PMID: 27694961 - Broix et al 2016 - report 4 different de novo missense changes in NEDD4L in a total of five unrelated patients with periventricular nodular heterotopia and neurodevelopmental delay, and in a additional familial case with a similar phenotype and a previously found missense variant. In the familial case, two affected siblings were found to be heterozygous for the variant, the father and an unaffected sibling did not carry the variant, and the mother was found to show somatic mosaicism of NEDD4L variant. Functional studies showed a sensitivity of PNH-associated mutants to proteasome degradation. Seizures were reported in some but not all affected individuals.
Intellectual disability v3.410 NEDD4L Eleanor Williams Tag for-review tag was added to gene: NEDD4L.
Intellectual disability v3.410 NEDD4L Eleanor Williams Classified gene: NEDD4L as Amber List (moderate evidence)
Intellectual disability v3.410 NEDD4L Eleanor Williams Gene: nedd4l has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.409 NEDD4L Eleanor Williams Classified gene: NEDD4L as Red List (low evidence)
Intellectual disability v3.409 NEDD4L Eleanor Williams Added comment: Comment on list classification: Promoting this gene from red to amber, but there are sufficient cases with a severe developmental delay phenotype for it to be rated green. It should therefore be reviewed at the next GMS update.
Intellectual disability v3.409 NEDD4L Eleanor Williams Gene: nedd4l has been classified as Red List (Low Evidence).
Intellectual disability v3.408 NEDD4L Eleanor Williams Phenotypes for gene: NEDD4L were changed from EPILEPTIC ENCEPHALOPATHY to Periventricular nodular heterotopia 7, 617201
Intellectual disability v3.408 NEDD4L Eleanor Williams Publications for gene: NEDD4L were set to 23934111
Intellectual disability v3.407 NEDD4L Eleanor Williams reviewed gene: NEDD4L: Rating: GREEN; Mode of pathogenicity: None; Publications: 27694961; Phenotypes: Periventricular nodular heterotopia 7, 617201; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.407 NUP214 Eleanor Williams Publications for gene: NUP214 were set to 31178128
Intellectual disability v3.406 NUP214 Eleanor Williams Classified gene: NUP214 as Amber List (moderate evidence)
Intellectual disability v3.406 NUP214 Eleanor Williams Added comment: Comment on list classification: Promoting this gene from Grey to Amber.

Several cases reported, but developmental delay not reported in some cases until after febrile events.
Intellectual disability v3.406 NUP214 Eleanor Williams Gene: nup214 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.405 NUP214 Eleanor Williams changed review comment from: Associated with {Encephalopathy, acute, infection-induced, susceptibility to, 9} 618426 in OMIM and Gene2Phenotype (probable).

PMID: 31178128 - Fichtman et al 2019 - report on two families one of Palestinian decent, the other Northern European (not Finnish descent). Each had two affected siblings in which neurological decline was seen after febrile events. The older son in family A, exhibited minor developmental delay from infancy. A homozygous missense variant was identified in NUP214 (p.Arg38Cys) in family A and segregated with the disease in available family members. In family B affected sisters were compound heterozygous for a frameshift and a missense variant in NUP214 (p.Pro387Ser and p.Pro525Leufs∗6). Functional studies with fibroblasts from one patient in family A showed a decrease in NUP214 and NUP88 levels compared to controls,

PMID: 30758658 - Shamseldin et al 2019 - describe a multiplex consanguineous family in which four affected members presented with severe neonatal hypotonia, profound global developmental delay, progressive microcephaly and early death. Whole exome sequencing revealed the presence of a novel homozygous missense variant in NUP214, p.D154G.

PMID: 29483668 - Egloff et al 2018 - report a 4-year-old girl presenting with developmental delay, growth retardation and facial dysmorphism. She was found to have a 9q deletion inherited from her healthy mother and a a hemizygous one-base pair deletion in the NUP214 gene inherited from her father. From patient leukocytes it was found that the expression level of the NUP214 transcript was significantly decreased and close to zero in the patient compared to the controls. ; to: Associated with {Encephalopathy, acute, infection-induced, susceptibility to, 9} 618426 in OMIM and Gene2Phenotype (probable).

PMID: 31178128 - Fichtman et al 2019 - report on two families one of Palestinian decent, the other Northern European (not Finnish descent). Each had two affected siblings in which neurological decline was seen after febrile events. The older son in family A, exhibited minor developmental delay from infancy. A homozygous missense variant was identified in NUP214 (p.Arg38Cys) in family A and segregated with the disease in available family members. In family B affected sisters were compound heterozygous for a frameshift and a missense variant in NUP214 (p.Pro387Ser and p.Pro525Leufs∗6). Functional studies with fibroblasts from one patient in family A showed a decrease in NUP214 and NUP88 levels compared to controls,

PMID: 30758658 - Shamseldin et al 2019 - describe a multiplex consanguineous family in which four affected members presented with severe neonatal hypotonia, profound global developmental delay, progressive microcephaly and early death (<2 year old). Whole exome sequencing revealed the presence of a novel homozygous missense variant in NUP214, p.D154G.

PMID: 29483668 - Egloff et al 2018 - report a 4-year-old girl presenting with developmental delay, growth retardation and facial dysmorphism. She was found to have a 9q deletion inherited from her healthy mother and a hemizygous one-base pair deletion in the NUP214 gene inherited from her father. From patient leukocytes it was found that the expression level of the NUP214 transcript was significantly decreased and close to zero in the patient compared to the controls.
Intellectual disability v3.405 NUP214 Eleanor Williams changed review comment from: Associated with {Encephalopathy, acute, infection-induced, susceptibility to, 9} 618426 in OMIM and Gene2Phenotype (probable).

PMID: 31178128 - Fichtman et al 2019 - report on two families. Family A have first-cousin parents of Palestinian descent. The proband exhibited minor developmental delay from infancy, presented with ataxia, mental retardation, and intractable epilepsy and died at 11 years. He suffered deterioration in association with febrile illnesses. His cousin presented at 5.5 months with partially reversible encephalopathy and developmental regression after a febrile illness. Family B were sisters born to non-consanguineous parents of Northern European (non-Finnish) descent. The older sister had nystagmus at 2 months and mild hypotonia, but she was otherwise meeting milestones appropriately . At 15 months of age, she developed a fever that led to a rapid neurological decline, seizures, and abnormal movements. The younger sister presented at 7 months with failure to thrive and hyponatremia but was meeting developmental milestones appropriately. By 24 months of age, she had motor and speech delay, ataxic gait, and occasional very mild head bobbing. In family A a homozygous NUP214 p.Arg38Cys variant segregated with the disease in available family members. In family B the sisters were found to be compound heterozygous for a frameshift and a missense variant in NUP214 (p.Pro387Ser and p.Pro525Leufs∗6).; to: Associated with {Encephalopathy, acute, infection-induced, susceptibility to, 9} 618426 in OMIM and Gene2Phenotype (probable).

PMID: 31178128 - Fichtman et al 2019 - report on two families one of Palestinian decent, the other Northern European (not Finnish descent). Each had two affected siblings in which neurological decline was seen after febrile events. The older son in family A, exhibited minor developmental delay from infancy. A homozygous missense variant was identified in NUP214 (p.Arg38Cys) in family A and segregated with the disease in available family members. In family B affected sisters were compound heterozygous for a frameshift and a missense variant in NUP214 (p.Pro387Ser and p.Pro525Leufs∗6). Functional studies with fibroblasts from one patient in family A showed a decrease in NUP214 and NUP88 levels compared to controls,

PMID: 30758658 - Shamseldin et al 2019 - describe a multiplex consanguineous family in which four affected members presented with severe neonatal hypotonia, profound global developmental delay, progressive microcephaly and early death. Whole exome sequencing revealed the presence of a novel homozygous missense variant in NUP214, p.D154G.

PMID: 29483668 - Egloff et al 2018 - report a 4-year-old girl presenting with developmental delay, growth retardation and facial dysmorphism. She was found to have a 9q deletion inherited from her healthy mother and a a hemizygous one-base pair deletion in the NUP214 gene inherited from her father. From patient leukocytes it was found that the expression level of the NUP214 transcript was significantly decreased and close to zero in the patient compared to the controls.
Intellectual disability v3.405 NUP214 Eleanor Williams Phenotypes for gene: NUP214 were changed from developmental delay; intellectual disability; epileptic encephalopathy; developmental regression; microcephaly to developmental delay; intellectual disability; epileptic encephalopathy; developmental regression; microcephaly; {Encephalopathy, acute, infection-induced, susceptibility to, 9}, 618426
Intellectual disability v3.404 NUP214 Eleanor Williams reviewed gene: NUP214: Rating: AMBER; Mode of pathogenicity: None; Publications: 31178128; Phenotypes: {Encephalopathy, acute, infection-induced, susceptibility to, 9}, 618426; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.404 GPSM2 Eleanor Williams edited their review of gene: GPSM2: Changed rating: AMBER
Intellectual disability v3.404 GPSM2 Eleanor Williams Classified gene: GPSM2 as Green List (high evidence)
Intellectual disability v3.404 GPSM2 Eleanor Williams Added comment: Comment on list classification: Leaving this gene as green just now, but as there are only 2 families out of 19 in which mild cognitive delay is seen then the recommendation would be to rate this gene amber. This gene should be reviewed at the next GMS update.
Intellectual disability v3.404 GPSM2 Eleanor Williams Gene: gpsm2 has been classified as Green List (High Evidence).
Intellectual disability v3.403 GPSM2 Eleanor Williams Tag for-review tag was added to gene: GPSM2.
Intellectual disability v3.403 GPSM2 Eleanor Williams Phenotypes for gene: GPSM2 were changed from DEAFNESS AUTOSOMAL RECESSIVE TYPE 82 to Chudley-McCullough syndrome, 604213
Intellectual disability v3.402 GPSM2 Eleanor Williams Publications for gene: GPSM2 were set to 22578326
Intellectual disability v3.401 GPSM2 Eleanor Williams changed review comment from: Associated with Chudley-McCullough syndrome604213 in OMIM

Summary: From 19 reported families, 3 individuals from 2 families showed cognitive delay.

PMID: 27180139 - Hemzeh et al 2016 - report two brothers from a Yemeni family who were diagnosed clinically with CMS then tested for GPSM2 mutations using Sanger sequencing. A homozygous mutation in GPSM2 was found in both brothers (c.1055C > A) leading to a truncating protein change; (p.Ser352*). The 12 year old brother showed cognitive delay, noted by the inability to tell the time in minutes, or to follow complex commands. The 11 year old brother could speak in sentences but with poor articulation, and could not respond to complex commands.

PMID: 23494849 - Almomani et al 2013 - report three patients from two unrelated Dutch families with CMS were investigated in which the same c.1473delG variant observed in 4 of the Menonite families by Doherty et al was observed. All three patients had normal cognitive abilities.

PMID: 22578326 - Doherty et al 2012 - report on 5 Menonite, 1 European-American, 1 Dutch and 1 Mexican-American family in which probands had severe/profound hearing loss and ventriculomegaly (total of 12 affected individuals). They also look again at the patients reported with autosomal recessive nonsyndromic deafness (DFNB82) by Walsh et al 2010 (PMID: 20602914, 1 proband ina Pakistani family) and Yariz et al 2012 (PMID: 21348867, 3 probands in a Turkish family) who they found had brain abnormalities consistent with with a diagnosis of Chudley-McCullough syndrome.
Oout of the 16 patients reported, only one had developmental issues beyond what is typically seen in individuals with severe hearing loss.



- -; to: Associated with Chudley-McCullough syndrome604213 in OMIM

Summary: From 19 reported families, 3 individuals from 2 families showed cognitive delay.

PMID: 27180139 - Hemzeh et al 2016 - report two brothers from a Yemeni family who were diagnosed clinically with CMS then tested for GPSM2 mutations using Sanger sequencing. A homozygous mutation in GPSM2 was found in both brothers (c.1055C > A) leading to a truncating protein change; (p.Ser352*). The 12 year old brother showed cognitive delay, noted by the inability to tell the time in minutes, or to follow complex commands. The 11 year old brother could speak in sentences but with poor articulation, and could not respond to complex commands. The poor articulation was thought to be due to late cochlear implant surgery.

PMID: 23494849 - Almomani et al 2013 - report three patients from two unrelated Dutch families with CMS were investigated in which the same c.1473delG variant observed in 4 of the Menonite families by Doherty et al was observed. All three patients had normal cognitive abilities.

PMID: 22578326 - Doherty et al 2012 - report on 5 Menonite, 1 European-American, 1 Dutch and 1 Mexican-American family in which probands had severe/profound hearing loss and ventriculomegaly (total of 12 affected individuals). They also look again at the patients reported with autosomal recessive nonsyndromic deafness (DFNB82) by Walsh et al 2010 (PMID: 20602914, 1 proband ina Pakistani family) and Yariz et al 2012 (PMID: 21348867, 3 probands in a Turkish family) who they found had brain abnormalities consistent with with a diagnosis of Chudley-McCullough syndrome.
Oout of the 16 patients reported, only one had developmental issues beyond what is typically seen in individuals with severe hearing loss.



- -
Intellectual disability v3.401 GPSM2 Eleanor Williams edited their review of gene: GPSM2: Changed publications: 27180139, 23494849, 22578326, 20602914, 21348867; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.401 GPSM2 Eleanor Williams commented on gene: GPSM2
Intellectual disability v3.401 USP18 Arina Puzriakova Classified gene: USP18 as Red List (low evidence)
Intellectual disability v3.401 USP18 Arina Puzriakova Added comment: Comment on list classification: DD reported in one surviving patient. However, this only became apparent following treatment which was administered after genetic diagnosis was already achieved. DD is therefore unlikely represent the clinical indication to prompt testing in the neonatal period.

Therefore keeping rating Red on the ID panel. USP18 is Green on other relevant panels (White matter disorders and cerebral calcification, PID) which should be adequate for detecting these cases.
Intellectual disability v3.401 USP18 Arina Puzriakova Gene: usp18 has been classified as Red List (Low Evidence).
Intellectual disability v3.400 USP18 Arina Puzriakova commented on gene: USP18: Added 'treatable' tag as clinical remission was achieved in a patient following rapid genetic diagnosis and subsequent treatment with the JAK inhibitor ruxolitinib
Intellectual disability v3.400 FLVCR1 Eleanor Williams Tag for-review tag was added to gene: FLVCR1.
Intellectual disability v3.400 USP18 Arina Puzriakova Tag treatable tag was added to gene: USP18.
Intellectual disability v3.400 FLVCR1 Eleanor Williams Classified gene: FLVCR1 as Green List (high evidence)
Intellectual disability v3.400 FLVCR1 Eleanor Williams Added comment: Comment on list classification: Leaving this gene green for now, but only one case where intellectual disability was reported. This gene should be updated at the next GMS review.
Intellectual disability v3.400 FLVCR1 Eleanor Williams Gene: flvcr1 has been classified as Green List (High Evidence).
Intellectual disability v3.399 USP18 Arina Puzriakova Publications for gene: USP18 were set to
Intellectual disability v3.398 USP18 Arina Puzriakova Mode of inheritance for gene: USP18 was changed from to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.397 FLVCR1 Eleanor Williams edited their review of gene: FLVCR1: Changed rating: RED; Changed publications: 30656474, 22279524, 21267618, 21070897, 9409377, 30444160; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.397 USP18 Arina Puzriakova reviewed gene: USP18: Rating: ; Mode of pathogenicity: None; Publications: 12833411, 27325888, 31940699; Phenotypes: Pseudo-TORCH syndrome 2, 617397; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.397 B9D1 Ivone Leong Classified gene: B9D1 as Amber List (moderate evidence)
Intellectual disability v3.397 B9D1 Ivone Leong Added comment: Comment on list classification: This gene has been promoted from Red to Amber. Mild ID was only seen in 1 case.
Intellectual disability v3.397 B9D1 Ivone Leong Gene: b9d1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.396 MGP Sarah Leigh Publications for gene: MGP were set to 15810001; 9916809
Intellectual disability v3.395 HYLS1 Catherine Snow Tag for-review tag was added to gene: HYLS1.
Intellectual disability v3.395 HYLS1 Catherine Snow reviewed gene: HYLS1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Hydrolethalus syndrome, MIM#236680; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.395 MGP Sarah Leigh Tag for-review tag was added to gene: MGP.
Intellectual disability v3.395 MGP Sarah Leigh reviewed gene: MGP: Rating: RED; Mode of pathogenicity: None; Publications: 24458983, 29928182, 25123378, 26349188, 26758921; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.395 B9D1 Ivone Leong Publications for gene: B9D1 were set to 24886560; 25920555
Intellectual disability v3.394 FLVCR1 Eleanor Williams commented on gene: FLVCR1
Intellectual disability v3.394 MGP Sarah Leigh Phenotypes for gene: MGP were changed from KEUTEL SYNDROME to Keutel syndrome 245150
Intellectual disability v3.393 MADD Ivone Leong Tag for-review tag was added to gene: MADD.
Intellectual disability v3.393 LGI4 Sarah Leigh reviewed gene: LGI4: Rating: RED; Mode of pathogenicity: None; Publications: 28318499; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.393 MADD Ivone Leong Classified gene: MADD as Amber List (moderate evidence)
Intellectual disability v3.393 MADD Ivone Leong Added comment: Comment on list classification: Based on expert review provided by Konstantinos Varvagiannis and Zornitza Stark, there is enough evidence to support a gene-disease association. This gene has been promoted from Red to Amber and will be promoted to Green status at next panel review.
Intellectual disability v3.393 MADD Ivone Leong Gene: madd has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.392 MADD Ivone Leong Publications for gene: MADD were set to
Intellectual disability v3.391 MADD Ivone Leong Phenotypes for gene: MADD were changed from to Neurodevelopmental disorder with dysmorphic facies, impaired speech and hypotonia, 619005; DEEAH syndrome, 619004
Intellectual disability v3.390 USP18 Arina Puzriakova Phenotypes for gene: USP18 were changed from to Pseudo-TORCH syndrome 2, 617397
Intellectual disability v3.389 DLL1 Catherine Snow Publications for gene: DLL1 were set to 31353024
Intellectual disability v3.388 LGI4 Sarah Leigh Tag for-review tag was added to gene: LGI4.
Intellectual disability v3.388 DLL1 Catherine Snow Classified gene: DLL1 as Amber List (moderate evidence)
Intellectual disability v3.388 DLL1 Catherine Snow Added comment: Comment on list classification: Comment on list classification: There is a sufficient number of cases to rate this gene Green at the next GMS panel update.
Intellectual disability v3.388 DLL1 Catherine Snow Gene: dll1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.387 DLL1 Catherine Snow Tag for-review tag was added to gene: DLL1.
Intellectual disability v3.387 DLL1 Catherine Snow edited their review of gene: DLL1: Changed rating: GREEN
Intellectual disability v3.387 DLL1 Catherine Snow reviewed gene: DLL1: Rating: AMBER; Mode of pathogenicity: None; Publications: 31353024, 31602192; Phenotypes: Neurodevelopmental disorder with nonspecific brain abnormalities and with or without seizures 618709; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.387 TBR1 Ivone Leong Publications for gene: TBR1 were set to 23160955
Intellectual disability v3.386 TBR1 Ivone Leong Phenotypes for gene: TBR1 were changed from AUTISM to Autism; Intellectual developmental disorder with autism and speech delay, 606053; Abnormal cortical gyration
Intellectual disability v3.385 RHEB Arina Puzriakova Classified gene: RHEB as Amber List (moderate evidence)
Intellectual disability v3.385 RHEB Arina Puzriakova Added comment: Comment on list classification: Three individuals from two unrelated families reported in PMID:29051493 with severe-profound ID - sufficient evidence to rate this gene Amber (previously erroneously demoted to Red).
Intellectual disability v3.385 RHEB Arina Puzriakova Gene: rheb has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.384 CTNND1 Eleanor Williams Classified gene: CTNND1 as Amber List (moderate evidence)
Intellectual disability v3.384 CTNND1 Eleanor Williams Added comment: Comment on list classification: Rating as amber but could potentially be green. Individuals from 5/9 families have reported developmental delay/learning difficulty. This gene should be reviewed at the next GMS update.
Intellectual disability v3.384 CTNND1 Eleanor Williams Gene: ctnnd1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.383 CTNND1 Eleanor Williams Tag for-review tag was added to gene: CTNND1.
Intellectual disability v3.383 CTNND1 Eleanor Williams Phenotypes for gene: CTNND1 were changed from to developmental delay
Intellectual disability v3.382 CTNND1 Eleanor Williams gene: CTNND1 was added
gene: CTNND1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: CTNND1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CTNND1 were set to 32196547
Review for gene: CTNND1 was set to GREEN
Added comment: PMID: 32196547 - Alharatani et al 2020 - report an expanded phenotype for CTNND1 patients. They report 13 individuals from nine families with novel protein-truncating variants in CTNND1 identified by WES. The mutations were not previously described in blepharocheilodontic (BCD), orofacial cleft cases nor in gnomAD. 8 patients had de novo variants, 2 inherited from affected parents, 2 participants inherited a variant from a parent with a mild phenotype. 8/13 patients showed cleft palate. Additional phenotypic features seen include mild limb phenotypes (9/13), cardiovascular anomalies (6/13) and Developmental delay and other neurodevelopmental problems (8/13)
Sources: Literature
Intellectual disability v3.381 WDR83OS Ivone Leong gene: WDR83OS was added
gene: WDR83OS was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: WDR83OS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: WDR83OS were set to 30250217
Phenotypes for gene: WDR83OS were set to Intellectual disability
Review for gene: WDR83OS was set to RED
Added comment: One consanguineous family with three affected individuals with homozygous split site variant in this gene. All three have ID.
Sources: Literature
Intellectual disability v3.380 YIF1B Arina Puzriakova changed review comment from: Comment on list classification: There is a sufficient number of cases to rate this gene Green at the next GMS panel update.

GDD was reported in all 6 patients (5 families). At ages 4-11yrs, the best achieved social and language skills were limited to sounds in 4 individuals, and partial babbling or vocalisation in the remaining two, respectively.; to: Comment on list classification: There is a sufficient number of cases to rate this gene Green at the next GMS panel update.

- PMID: 32006098: GDD was reported in all 6 patients (5 families). At ages 4-11yrs, the best achieved social and language skills were limited to sounds in 4 individuals, and partial babbling or vocalisation in the remaining two, respectively.
Intellectual disability v3.380 YIF1B Arina Puzriakova changed review comment from: Comment on list classification: There are a sufficient number of cases to rate this gene Green at the next GMS panel update.

GDD was reported in all 6 patients (5 families). At ages 4-11yrs, the best achieved social and language skills were limited to sounds in 4 individuals, and partial babbling or vocalisation in the remaining two, respectively.; to: Comment on list classification: There is a sufficient number of cases to rate this gene Green at the next GMS panel update.

GDD was reported in all 6 patients (5 families). At ages 4-11yrs, the best achieved social and language skills were limited to sounds in 4 individuals, and partial babbling or vocalisation in the remaining two, respectively.
Intellectual disability v3.380 YIF1B Arina Puzriakova Classified gene: YIF1B as Amber List (moderate evidence)
Intellectual disability v3.380 YIF1B Arina Puzriakova Added comment: Comment on list classification: There are a sufficient number of cases to rate this gene Green at the next GMS panel update.

GDD was reported in all 6 patients (5 families). At ages 4-11yrs, the best achieved social and language skills were limited to sounds in 4 individuals, and partial babbling or vocalisation in the remaining two, respectively.
Intellectual disability v3.380 YIF1B Arina Puzriakova Gene: yif1b has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.379 YIF1B Arina Puzriakova Tag for-review tag was added to gene: YIF1B.
Intellectual disability v3.379 UGDH Arina Puzriakova Classified gene: UGDH as Amber List (moderate evidence)
Intellectual disability v3.379 UGDH Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to rate this gene Green at the next GMS panel update.

Multiple patients from over 20 unrelated families, all with moderate-to-severe ID in association with biallelic variants in UGDH.
Intellectual disability v3.379 UGDH Arina Puzriakova Gene: ugdh has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.378 UGDH Arina Puzriakova Tag for-review tag was added to gene: UGDH.
Intellectual disability v3.378 SPTBN4 Arina Puzriakova Classified gene: SPTBN4 as Amber List (moderate evidence)
Intellectual disability v3.378 SPTBN4 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to rate this gene Green at the next GMS panel update.

Severe-to-profound DD and/or ID reported in all but one family with a milder phenotype (at least 9 total families described with different biallelic variants in SPTBN4).
Intellectual disability v3.378 SPTBN4 Arina Puzriakova Gene: sptbn4 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.377 SPTBN4 Arina Puzriakova Tag for-review tag was added to gene: SPTBN4.
Intellectual disability v3.377 NR4A2 Arina Puzriakova Classified gene: NR4A2 as Amber List (moderate evidence)
Intellectual disability v3.377 NR4A2 Arina Puzriakova Added comment: Comment on list classification: This gene will be flagged for review at the date of next GMS panel update (added 'for-review' tag).

The recent paper flagged by Konstantinos Varvagiannis (PMID:32366965) includes 2 unrelated patients with severe ID and 2 with moderate-severe ID. This is within the scope of the panel and the number of cases now reach threshold for inclusion with a Green rating.
Intellectual disability v3.377 NR4A2 Arina Puzriakova Gene: nr4a2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.376 NR4A2 Arina Puzriakova Tag for-review tag was added to gene: NR4A2.
Intellectual disability v3.376 NR4A2 Arina Puzriakova Publications for gene: NR4A2 were set to 29770430; 30504930; 28544326; 27569545; 23554088; 28135719; 27479843; 25363768; https://doi.org/10.1101/516625
Intellectual disability v3.375 TNRC6B Arina Puzriakova Tag for-review tag was added to gene: TNRC6B.
Intellectual disability v3.375 TNRC6B Arina Puzriakova Classified gene: TNRC6B as Amber List (moderate evidence)
Intellectual disability v3.375 TNRC6B Arina Puzriakova Added comment: Comment on list classification: This is a borderline Amber/Green gene, and should be reviewed at the date of next GMS panel update (added 'for-review' tag).

Phenotype is primarily characterised by neurobehavioral abnormalities, including DD (particularly speech impairment) in all cases, as well as variable features of autism, ADHD, impulsivity, anger and aggressiveness. Cognitive abilities were varied, and a formal diagnosis of ID was only attained in 4 patients. Nonetheless, this likely represents the most appropriate panel for capturing these cases and therefore a Green rating should be considered.
Intellectual disability v3.375 TNRC6B Arina Puzriakova Gene: tnrc6b has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.374 TNRC6B Arina Puzriakova Phenotypes for gene: TNRC6B were changed from to Global developmental delay; Intellectual disability; Autistic behaviour
Intellectual disability v3.373 TNRC6B Arina Puzriakova Publications for gene: TNRC6B were set to
Intellectual disability v3.372 TNRC6B Arina Puzriakova Mode of inheritance for gene: TNRC6B was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.371 STS Arina Puzriakova changed review comment from: Following discussion with the clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark; to: Following discussion with the clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark and Helen Brittain
Intellectual disability v3.371 STS Arina Puzriakova Classified gene: STS as Red List (low evidence)
Intellectual disability v3.371 STS Arina Puzriakova Gene: sts has been classified as Red List (Low Evidence).
Intellectual disability v3.370 STS Arina Puzriakova Added comment: Comment on publications: Added publication (PMID: 32139392) describing psychiatric/behavioural phenotypes in patients with ichthyosis caused by X-linked deletions spanning STS.
Intellectual disability v3.370 STS Arina Puzriakova Publications for gene: STS were set to
Intellectual disability v3.369 NEMF Konstantinos Varvagiannis changed review comment from: Martin et al (2020 - PMID:32934225) report on 8 individuals from 6 families with a juvenile neuromuscular disease due to biallelic NEMF variants. (In one of these 8 cases it could not be ruled out that a de novo and maternally inherited variant were on the same allele, as phase was not determined). A ninth individual with similar presentation was found to harbor a single NEMF missense SNV as de novo event (due to a speculated dominant-negative effect). This individual had a similar presentation.

Features incl. hypotonia (4/8 with biallelic variant (B) | 1/1 monoallelic (M) ), DD/ID (7/8B | 0/1M) with speech delay as universal feature (8/8B | 1/1M), axonal neuropathy (3/3B | 1/1M), ataxia (3/8B | 0/1M). Other findings included tremor (1/7B | 1/1M), abnormal brain imaging (2/6B / ?/1M), kyphosis/scoliosis (4/8B | 0/1M), respiratory distress (1/8B | 0/1M).

NEMF (Rqc2 in yeast) encodes the nuclear export mediator factor, a component of the Ribosome-associated Quality Control (RCQ) complex which is involved in proteolytic targeting of incomplete polypeptides prodduced by ribosome stalling. NEMF facilitates the recruitment of E3 ligase Listerin (LTN1) which ubiquitinates nascent polypeptide chains for subsequent proteasomal degradation.

The author provide evidence that mice homozygous for Nemf missense mutations display progressive motor phenotypes, exhibit neurogenic atrophy and progressive axonal degeneration. A further NEMF-null mouse model displayed more severe phenotype (with heterozygous mice being unaffected).

Equivalent mutations (of those in the above mouse model) in yeast (Rqc2) were shown to interfere with its ability to modify aberrant translation products with C-terminal tails which assist RQC-mediated protein degradation.

Mutation of Ltn1 (belonging to the same protein control pathway) has been also shown to lead to neurodegeneration im mice.

Overall NEMF is thought to play a role in neuronal translational homeostasis and the disorder to be mediated by dysfunction of the RQC pathway (normally protecting neurons against degeneration).
Sources: Literature; to: Martin et al (2020 - PMID:32934225) report on 8 individuals from 6 families with a juvenile neuromuscular disease due to biallelic NEMF variants. (In one of these 8 cases it could not be ruled out that a de novo and maternally inherited variant were on the same allele, as phase was not determined). A ninth individual with similar presentation was found to harbor a single NEMF missense SNV as de novo event (due to a speculated dominant-negative effect). This individual had a similar presentation.

Features incl. hypotonia (4/8 with biallelic variant (B) | 1/1 monoallelic (M) ), DD/ID (7/8B | 0/1M) with speech delay as universal feature (8/8B | 1/1M), axonal neuropathy (3/3B | 1/1M), ataxia (3/8B | 0/1M). Other findings included tremor (1/7B | 1/1M), abnormal brain imaging (2/6B / ?/1M), kyphosis/scoliosis (4/8B | 0/1M), respiratory distress (1/8B | 0/1M).

NEMF (Rqc2 in yeast) encodes the nuclear export mediator factor, a component of the Ribosome-associated Quality Control (RCQ) complex which is involved in proteolytic targeting of incomplete polypeptides produced by ribosome stalling. NEMF facilitates the recruitment of E3 ligase Listerin (LTN1) which ubiquitinates nascent polypeptide chains for subsequent proteasomal degradation.

The author provide evidence that mice homozygous for Nemf missense mutations display progressive motor phenotypes, exhibit neurogenic atrophy and progressive axonal degeneration. A further NEMF-null mouse model displayed more severe phenotype (with heterozygous mice being unaffected).

Equivalent mutations (of those in the above mouse model) in yeast (Rqc2) were shown to interfere with its ability to modify aberrant translation products with C-terminal tails which assist RQC-mediated protein degradation.

Mutation of Ltn1 (belonging to the same protein control pathway) has been also shown to lead to neurodegeneration in mice.

Overall NEMF is thought to play a role in neuronal translational homeostasis and the disorder to be mediated by dysfunction of the RQC pathway (normally protecting neurons against degeneration).
Sources: Literature
Intellectual disability v3.369 NEMF Konstantinos Varvagiannis changed review comment from: Martin et al (2020 - PMID:32934225) report on 8 individuals from 6 families with a juvenile neuromuscular disease due to biallelic NEMF variants. (In one of these 8 cases it could be ruled out that the de novo and maternally inherited variants were on the same allele, as phase was not been determined). A ninth individual with similar presentation was found to harbor a single NEMF missense SNV as de novo event (due to a speculated dominant-negative effect). This individual had a similar presentation.

Features incl. hypotonia (4/8 with biallelic variant (B) | 1/1 monoallelic (M) ), DD/ID (7/8B | 0/1M) with speech delay as universal feature (8/8B | 1/1M), axonal neuropathy (3/3B | 1/1M), ataxia (3/8B | 0/1M). Other findings included tremor (1/7B | 1/1M), abnormal brain imaging (2/6B / ?/1M), kyphosis/scoliosis (4/8B | 0/1M), respiratory distress (1/8B | 0/1M).

NEMF (Rqc2 in yeast) encodes the nuclear export mediator factor, a component of the Ribosome-associated Quality Control (RCQ) complex which is involved in proteolytic targeting of incomplete polypeptides prodduced by ribosome stalling. NEMF facilitates the recruitment of E3 ligase Listerin (LTN1) which ubiquitinates nascent polypeptide chains for subsequent proteasomal degradation.

The author provide evidence that mice homozygous for Nemf missense mutations display progressive motor phenotypes, exhibit neurogenic atrophy and progressive axonal degeneration. A further NEMF-null mouse model displayed more severe phenotype (with heterozygous mice being unaffected).

Equivalent mutations (of those in the above mouse model) in yeast (Rqc2) were shown to interfere with its ability to modify aberrant translation products with C-terminal tails which assist RQC-mediated protein degradation.

Mutation of Ltn1 (belonging to the same protein control pathway) has been also shown to lead to neurodegeneration im mice.

Overall NEMF is thought to play a role in neuronal translational homeostasis and the disorder to be mediated by dysfunction of the RQC pathway (normally protecting neurons against degeneration).
Sources: Literature; to: Martin et al (2020 - PMID:32934225) report on 8 individuals from 6 families with a juvenile neuromuscular disease due to biallelic NEMF variants. (In one of these 8 cases it could not be ruled out that a de novo and maternally inherited variant were on the same allele, as phase was not determined). A ninth individual with similar presentation was found to harbor a single NEMF missense SNV as de novo event (due to a speculated dominant-negative effect). This individual had a similar presentation.

Features incl. hypotonia (4/8 with biallelic variant (B) | 1/1 monoallelic (M) ), DD/ID (7/8B | 0/1M) with speech delay as universal feature (8/8B | 1/1M), axonal neuropathy (3/3B | 1/1M), ataxia (3/8B | 0/1M). Other findings included tremor (1/7B | 1/1M), abnormal brain imaging (2/6B / ?/1M), kyphosis/scoliosis (4/8B | 0/1M), respiratory distress (1/8B | 0/1M).

NEMF (Rqc2 in yeast) encodes the nuclear export mediator factor, a component of the Ribosome-associated Quality Control (RCQ) complex which is involved in proteolytic targeting of incomplete polypeptides prodduced by ribosome stalling. NEMF facilitates the recruitment of E3 ligase Listerin (LTN1) which ubiquitinates nascent polypeptide chains for subsequent proteasomal degradation.

The author provide evidence that mice homozygous for Nemf missense mutations display progressive motor phenotypes, exhibit neurogenic atrophy and progressive axonal degeneration. A further NEMF-null mouse model displayed more severe phenotype (with heterozygous mice being unaffected).

Equivalent mutations (of those in the above mouse model) in yeast (Rqc2) were shown to interfere with its ability to modify aberrant translation products with C-terminal tails which assist RQC-mediated protein degradation.

Mutation of Ltn1 (belonging to the same protein control pathway) has been also shown to lead to neurodegeneration im mice.

Overall NEMF is thought to play a role in neuronal translational homeostasis and the disorder to be mediated by dysfunction of the RQC pathway (normally protecting neurons against degeneration).
Sources: Literature
Intellectual disability v3.369 NEMF Konstantinos Varvagiannis changed review comment from: Martin et al (2020 - PMID:32934225) report on 8 individuals from 6 families with a juvenile neuromuscular disease due to biallelic NEMF variants. A ninth individual with similar presentation was found to harbor a single NEMF missense SNV as de novo event (due to a speculated dominant-negative effect). This individual had a similar presentation.

Features incl. hypotonia (4/8 with biallelic variant (B) | 1/1 monoallelic (M) ), DD/ID (7/8B | 0/1M) with speech delay as universal feature (8/8B | 1/1M), axonal neuropathy (3/3B | 1/1M), ataxia (3/8B | 0/1M). Other findings included tremor (1/7B | 1/1M), abnormal brain imaging (2/6B / ?/1M), kyphosis/scoliosis (4/8B | 0/1M), respiratory distress (1/8B | 0/1M).

NEMF (Rqc2 in yeast) encodes the nuclear export mediator factor, a component of the Ribosome-associated Quality Control (RCQ) complex which is involved in proteolytic targeting of incomplete polypeptides prodduced by ribosome stalling. NEMF facilitates the recruitment of E3 ligase Listerin (LTN1) which ubiquitinates nascent polypeptide chains for subsequent proteasomal degradation.

The author provide evidence that mice homozygous for Nemf missense mutations display progressive motor phenotypes, exhibit neurogenic atrophy and progressive axonal degeneration. A further NEMF-null mouse model displayed more severe phenotype (with heterozygous mice being unaffected).

Equivalent mutations (of those in the above mouse model) in yeast (Rqc2) were shown to interfere with its ability to modify aberrant translation products with C-terminal tails which assist RQC-mediated protein degradation.

Mutation of Ltn1 (belonging to the same protein control pathway) has been also shown to lead to neurodegeneration im mice.

Overall NEMF is thought to play a role in neuronal translational homeostasis and the disorder to be mediated by dysfunction of the RQC pathway (normally protecting neurons against degeneration).
Sources: Literature; to: Martin et al (2020 - PMID:32934225) report on 8 individuals from 6 families with a juvenile neuromuscular disease due to biallelic NEMF variants. (In one of these 8 cases it could be ruled out that the de novo and maternally inherited variants were on the same allele, as phase was not been determined). A ninth individual with similar presentation was found to harbor a single NEMF missense SNV as de novo event (due to a speculated dominant-negative effect). This individual had a similar presentation.

Features incl. hypotonia (4/8 with biallelic variant (B) | 1/1 monoallelic (M) ), DD/ID (7/8B | 0/1M) with speech delay as universal feature (8/8B | 1/1M), axonal neuropathy (3/3B | 1/1M), ataxia (3/8B | 0/1M). Other findings included tremor (1/7B | 1/1M), abnormal brain imaging (2/6B / ?/1M), kyphosis/scoliosis (4/8B | 0/1M), respiratory distress (1/8B | 0/1M).

NEMF (Rqc2 in yeast) encodes the nuclear export mediator factor, a component of the Ribosome-associated Quality Control (RCQ) complex which is involved in proteolytic targeting of incomplete polypeptides prodduced by ribosome stalling. NEMF facilitates the recruitment of E3 ligase Listerin (LTN1) which ubiquitinates nascent polypeptide chains for subsequent proteasomal degradation.

The author provide evidence that mice homozygous for Nemf missense mutations display progressive motor phenotypes, exhibit neurogenic atrophy and progressive axonal degeneration. A further NEMF-null mouse model displayed more severe phenotype (with heterozygous mice being unaffected).

Equivalent mutations (of those in the above mouse model) in yeast (Rqc2) were shown to interfere with its ability to modify aberrant translation products with C-terminal tails which assist RQC-mediated protein degradation.

Mutation of Ltn1 (belonging to the same protein control pathway) has been also shown to lead to neurodegeneration im mice.

Overall NEMF is thought to play a role in neuronal translational homeostasis and the disorder to be mediated by dysfunction of the RQC pathway (normally protecting neurons against degeneration).
Sources: Literature
Intellectual disability v3.369 NEMF Konstantinos Varvagiannis gene: NEMF was added
gene: NEMF was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: NEMF was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: NEMF were set to 32934225
Phenotypes for gene: NEMF were set to Hypotonia; Global developmental delay; Intellectual disability; Axonal neuropathy; Ataxia; Abnormal brain imaging; Kyphosis; Scoliosis; Tremor; Respiratory distress
Penetrance for gene: NEMF were set to Complete
Review for gene: NEMF was set to GREEN
Added comment: Martin et al (2020 - PMID:32934225) report on 8 individuals from 6 families with a juvenile neuromuscular disease due to biallelic NEMF variants. A ninth individual with similar presentation was found to harbor a single NEMF missense SNV as de novo event (due to a speculated dominant-negative effect). This individual had a similar presentation.

Features incl. hypotonia (4/8 with biallelic variant (B) | 1/1 monoallelic (M) ), DD/ID (7/8B | 0/1M) with speech delay as universal feature (8/8B | 1/1M), axonal neuropathy (3/3B | 1/1M), ataxia (3/8B | 0/1M). Other findings included tremor (1/7B | 1/1M), abnormal brain imaging (2/6B / ?/1M), kyphosis/scoliosis (4/8B | 0/1M), respiratory distress (1/8B | 0/1M).

NEMF (Rqc2 in yeast) encodes the nuclear export mediator factor, a component of the Ribosome-associated Quality Control (RCQ) complex which is involved in proteolytic targeting of incomplete polypeptides prodduced by ribosome stalling. NEMF facilitates the recruitment of E3 ligase Listerin (LTN1) which ubiquitinates nascent polypeptide chains for subsequent proteasomal degradation.

The author provide evidence that mice homozygous for Nemf missense mutations display progressive motor phenotypes, exhibit neurogenic atrophy and progressive axonal degeneration. A further NEMF-null mouse model displayed more severe phenotype (with heterozygous mice being unaffected).

Equivalent mutations (of those in the above mouse model) in yeast (Rqc2) were shown to interfere with its ability to modify aberrant translation products with C-terminal tails which assist RQC-mediated protein degradation.

Mutation of Ltn1 (belonging to the same protein control pathway) has been also shown to lead to neurodegeneration im mice.

Overall NEMF is thought to play a role in neuronal translational homeostasis and the disorder to be mediated by dysfunction of the RQC pathway (normally protecting neurons against degeneration).
Sources: Literature
Intellectual disability v3.369 PRKD1 Arina Puzriakova changed review comment from: Gene included previously in context of publication by Sifrim et al. (2016) (PMID: 27479907).
However, re-evaluation of this paper showed that only two of the three patients had ID, which may possibly be associated with microcephaly. The two individuals carried a c.1774G>A and c.896T>G variant, respectively; however, a third patient also harbouring the c.1774G>A variant did not display any neuropsychological signs (or microcephaly) at 4.86 years (see supplementary table 12).

A recent report (PMID: 32817298, 2020) describes two additional unrelated cases with de novo variants, c.1774G>C and c.1808G>A, respectively. These patients shared cardiac and ectodermal abnormalities, as with the previously described patients; however, mental development was normal in both individuals.; to: Gene included previously in context of publication by Sifrim et al. (2016) (PMID: 27479907).
However, re-evaluation of this paper showed that only two of the three patients had ID, which may possibly be associated with microcephaly. The two individuals carried a c.1774G>A and c.896T>G variant, respectively; however, a third patient also harbouring the c.1774G>A variant did not display any neuropsychological signs (or microcephaly) at 4.86 years (see supplementary table 12, and figure 3).

A recent report (PMID: 32817298, 2020) describes two additional unrelated cases with de novo variants, c.1774G>C and c.1808G>A, respectively. These patients shared cardiac and ectodermal abnormalities, as with the previously described patients; however, mental development was normal in both individuals.
Intellectual disability v3.369 PRKD1 Arina Puzriakova Classified gene: PRKD1 as Green List (high evidence)
Intellectual disability v3.369 PRKD1 Arina Puzriakova Added comment: Comment on list classification: This gene has been flagged for review at the date of next GMS panel update (added 'for-review' tag).

Only 2/5 patients exhibit features of ID, both of whom were also the only microcephalic cases, indicating the possibility of additional contributing factors. Therefore, a rating downgrade from Green to Amber may be warranted.
Intellectual disability v3.369 PRKD1 Arina Puzriakova Gene: prkd1 has been classified as Green List (High Evidence).
Intellectual disability v3.368 PRKD1 Arina Puzriakova Publications for gene: PRKD1 were set to 27479907; 25529582
Intellectual disability v3.367 PRKD1 Arina Puzriakova Tag for-review tag was added to gene: PRKD1.
Intellectual disability v3.367 PRKD1 Arina Puzriakova reviewed gene: PRKD1: Rating: AMBER; Mode of pathogenicity: None; Publications: 27479907, 32817298; Phenotypes: Congenital heart defects and ectodermal dysplasia, 617364; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.367 CUL3 Arina Puzriakova Phenotypes for gene: CUL3 were changed from to Global developmental delay; Intellectual disability; Autism Spectrum Disorder; Seizures; Abnormality of cardiovascular system morphology; Abnormality of the palate; Pseudohypoaldosteronism, type IIE, 614496
Intellectual disability v3.366 CUL3 Arina Puzriakova Publications for gene: CUL3 were set to
Intellectual disability v3.365 CUL3 Arina Puzriakova Mode of inheritance for gene: CUL3 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.364 CUL3 Arina Puzriakova Classified gene: CUL3 as Amber List (moderate evidence)
Intellectual disability v3.364 CUL3 Arina Puzriakova Added comment: Comment on list classification: Upgraded from Red to Amber, as some cases reported with severe features of ID but not yet reaching the threshold for inclusion. Additional cases/publications would also enable clarification regarding the contribution of seizures to this phenotype.
Intellectual disability v3.364 CUL3 Arina Puzriakova Gene: cul3 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.363 CUL3 Arina Puzriakova commented on gene: CUL3: Literature search showed that CUL3 variants are often found in ASD patients, however the association with ID is much less discernible. Only two cases reported to date with severe ID features, but the same two individuals were also the only ones to present early-onset seizures. Therefore, it is difficult to distinguish whether these findings were independent of one another.
Intellectual disability v3.363 CUL3 Arina Puzriakova changed review comment from: - PMID: 25969726 (2015) - Determined as a candidate gene following discovery of a de novo missense variant (c.2156A>G, p.H719R) in an autistic patient with mild ID, sleep disturbances and ADHD.; to: - PMID: 25969726 (2015) - Determined as a candidate gene following discovery of a de novo missense variant (c.2156A>G, p.H719R) in an autistic patient with mild ID, sleep disturbances, ADHD, and no seizures. No functional analysis was undertaken.
Intellectual disability v3.363 CUL3 Arina Puzriakova reviewed gene: CUL3: Rating: ; Mode of pathogenicity: None; Publications: 25969726; Phenotypes: Autism spectrum disorder, Intellectual disability; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.363 NHP2 Arina Puzriakova Classified gene: NHP2 as Amber List (moderate evidence)
Intellectual disability v3.363 NHP2 Arina Puzriakova Added comment: Comment on list classification: Rating upgraded from Red to Amber as 2/3 cases described in literature present cognitive impairment. This does not yet meet the threshold for inclusion with a Green rating, but may be reviewed if further cases are published.
Intellectual disability v3.363 NHP2 Arina Puzriakova Gene: nhp2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.362 NHP2 Arina Puzriakova Phenotypes for gene: NHP2 were changed from Dyskeratosis congenita, autosomal recessive 2, 613987 to Dyskeratosis congenita, autosomal recessive 2, 613987; Høyeraal-Hreidarsson syndrome
Intellectual disability v3.361 NHP2 Arina Puzriakova Publications for gene: NHP2 were set to 25182133; 18523010; 25907943; 20301779
Intellectual disability v3.360 SETD1A Zerin Hyder reviewed gene: SETD1A: Rating: GREEN; Mode of pathogenicity: None; Publications: 32346159; Phenotypes: Epilepsy, early-onset, with or without developmental delay, craniofacial dysmorphisms, behavioural/psychiatric abnormalities; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.360 CYP2U1 Eleanor Williams Tag for-review tag was added to gene: CYP2U1.
Intellectual disability v3.360 CYP2U1 Eleanor Williams Classified gene: CYP2U1 as Green List (high evidence)
Intellectual disability v3.360 CYP2U1 Eleanor Williams Added comment: Comment on list classification: Leaving this gene as green for now, but after consultation with the Genomics England clinical team it was felt that it should be considered for downgrade to amber at the next GMS review. It is a spastic paraplegia gene and seems to mainly present in that manner. Amber rating would be appropriate as cognitive impairment is a feature and new cases may emerge which support that as a primary presentation.
Intellectual disability v3.360 CYP2U1 Eleanor Williams Gene: cyp2u1 has been classified as Green List (High Evidence).
Intellectual disability v3.359 NUP188 Arina Puzriakova Phenotypes for gene: NUP188 were changed from to Sandestig-Stefanova syndrome, 618804
Intellectual disability v3.358 NUP188 Arina Puzriakova Publications for gene: NUP188 were set to
Intellectual disability v3.357 NUP188 Arina Puzriakova Mode of inheritance for gene: NUP188 was changed from to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.356 NUP188 Arina Puzriakova Classified gene: NUP188 as Amber List (moderate evidence)
Intellectual disability v3.356 NUP188 Arina Puzriakova Added comment: Comment on list classification: At least six unrelated families exhibiting a strikingly similar phenotype due to biallelic truncating variants in the NUP188 gene. Only 1/8 individuals survived beyond the first year of life and exhibited severe ID.

It is anticipated that other surviving patients would likely present the same phenotype; however, for now NUP188 will be rated Amber on the ID panel, awaiting further publications to corroborate the relevance of this manifestation.
Intellectual disability v3.356 NUP188 Arina Puzriakova Gene: nup188 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.355 NUP188 Arina Puzriakova reviewed gene: NUP188: Rating: GREEN; Mode of pathogenicity: None; Publications: 32021605, 32275884; Phenotypes: Sandestig-Stefanova syndrome, 618804; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.355 INTS6 Arina Puzriakova Classified gene: INTS6 as Red List (low evidence)
Intellectual disability v3.355 INTS6 Arina Puzriakova Added comment: Comment on list classification: The Red review by Konstantinos Varvagiannis supports the current Red rating of CPD. There is currently no evidence to support this gene-disease association, and therefore have kept rating as Red.
Intellectual disability v3.355 INTS6 Arina Puzriakova Gene: ints6 has been classified as Red List (Low Evidence).
Intellectual disability v3.354 CPD Arina Puzriakova Classified gene: CPD as Red List (low evidence)
Intellectual disability v3.354 CPD Arina Puzriakova Added comment: Comment on list classification: The Red review by Konstantinos Varvagiannis supports the current Red rating of CPD. There is currently no evidence to support this gene-disease association, and therefore have kept rating as Red.
Intellectual disability v3.354 CPD Arina Puzriakova Gene: cpd has been classified as Red List (Low Evidence).
Intellectual disability v3.353 KDM6B Arina Puzriakova Classified gene: KDM6B as Amber List (moderate evidence)
Intellectual disability v3.353 KDM6B Arina Puzriakova Added comment: Comment on list classification: Sufficient number of patients to rate this gene GREEN at the next major review - psychomotor delay was consistently reported and was the key indication for clinical investigation in several cases.
Intellectual disability v3.353 KDM6B Arina Puzriakova Gene: kdm6b has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.352 KDM6B Arina Puzriakova Phenotypes for gene: KDM6B were changed from Neurodevelopmental disorder with coarse facies and mild distal skeletal abnormalities, 618505 to Neurodevelopmental disorder with coarse facies and mild distal skeletal abnormalities, 618505
Intellectual disability v3.352 KDM6B Arina Puzriakova Phenotypes for gene: KDM6B were changed from AUTOSOMAL RECESSIVE MENTAL RETARDATION to Neurodevelopmental disorder with coarse facies and mild distal skeletal abnormalities, 618505
Intellectual disability v3.351 KDM6B Arina Puzriakova Publications for gene: KDM6B were set to 21937992
Intellectual disability v3.350 KDM6B Arina Puzriakova Mode of inheritance for gene: KDM6B was changed from BIALLELIC, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.349 KDM6B Arina Puzriakova Tag for-review tag was added to gene: KDM6B.
Intellectual disability v3.349 KDM6B Arina Puzriakova reviewed gene: KDM6B: Rating: GREEN; Mode of pathogenicity: None; Publications: 31124279; Phenotypes: Neurodevelopmental disorder with coarse facies and mild distal skeletal abnormalities, 618505; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.349 HADH Arina Puzriakova Classified gene: HADH as Green List (high evidence)
Intellectual disability v3.349 HADH Arina Puzriakova Added comment: Comment on list classification: As ID is a secondary finding, reported in only a subset of patients, this gene should be downgraded from Green to Amber/Red at the next major review.
Intellectual disability v3.349 HADH Arina Puzriakova Gene: hadh has been classified as Green List (High Evidence).
Intellectual disability v3.348 HADH Arina Puzriakova Phenotypes for gene: HADH were changed from 3-HYDROXYACYL-COENZYME A DEHYDROGENASE DEFICIENCY to Hyperinsulinemic hypoglycemia, familial, 4, 609975; 3-hydroxyacyl-CoA dehydrogenase deficiency, 231530
Intellectual disability v3.347 HADH Arina Puzriakova Tag for-review tag was added to gene: HADH.
Intellectual disability v3.347 HADH Arina Puzriakova reviewed gene: HADH: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Hyperinsulinemic hypoglycemia, familial, 4, 609975, 3-hydroxyacyl-CoA dehydrogenase deficiency, 231530; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.347 ADGRG6 Arina Puzriakova Phenotypes for gene: ADGRG6 were changed from LETHAL CONGENITAL CONTRACTURE SYNDROME 9 to Lethal congenital contracture syndrome 9, 616503
Intellectual disability v3.346 ADGRG6 Arina Puzriakova Classified gene: ADGRG6 as Red List (low evidence)
Intellectual disability v3.346 ADGRG6 Arina Puzriakova Gene: adgrg6 has been classified as Red List (Low Evidence).
Intellectual disability v3.345 AGL Arina Puzriakova Classified gene: AGL as Red List (low evidence)
Intellectual disability v3.345 AGL Arina Puzriakova Gene: agl has been classified as Red List (Low Evidence).
Intellectual disability v3.344 ALDOB Arina Puzriakova Classified gene: ALDOB as Red List (low evidence)
Intellectual disability v3.344 ALDOB Arina Puzriakova Gene: aldob has been classified as Red List (Low Evidence).
Intellectual disability v3.343 ADCY5 Arina Puzriakova Classified gene: ADCY5 as Red List (low evidence)
Intellectual disability v3.343 ADCY5 Arina Puzriakova Gene: adcy5 has been classified as Red List (Low Evidence).
Intellectual disability v3.342 ABAT Arina Puzriakova Classified gene: ABAT as Amber List (moderate evidence)
Intellectual disability v3.342 ABAT Arina Puzriakova Added comment: Comment on list classification: Following discussion with Helen Brittain (Genomics England Clinical Team), it has been agreed that this gene should be upgraded from Amber to Green at the next major review.
Intellectual disability v3.342 ABAT Arina Puzriakova Gene: abat has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.341 ABAT Arina Puzriakova Tag for-review tag was added to gene: ABAT.
Intellectual disability v3.341 ABAT Arina Puzriakova reviewed gene: ABAT: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: GABA-transaminase deficiency, 613163; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.341 ACADSB Arina Puzriakova Phenotypes for gene: ACADSB were changed from to 2-methylbutyrylglycinuria, 610006
Intellectual disability v3.340 ACADSB Arina Puzriakova Mode of inheritance for gene: ACADSB was changed from to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.339 ACADSB Arina Puzriakova Classified gene: ACADSB as Amber List (moderate evidence)
Intellectual disability v3.339 ACADSB Arina Puzriakova Added comment: Comment on list classification: Upgraded from Red to Amber as DD has been reported, but only in a subset of symptomatic cases.

Metabolic abnormalities should be a sufficient indication for testing, for which this gene is already rated Green.
Intellectual disability v3.339 ACADSB Arina Puzriakova Gene: acadsb has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.338 ACADSB Arina Puzriakova reviewed gene: ACADSB: Rating: ; Mode of pathogenicity: None; Publications: 30730842; Phenotypes: 2-methylbutyrylglycinuria, 610006; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.338 AHCY Arina Puzriakova Publications for gene: AHCY were set to 15024124
Intellectual disability v3.337 AHCY Arina Puzriakova Classified gene: AHCY as Amber List (moderate evidence)
Intellectual disability v3.337 AHCY Arina Puzriakova Added comment: Comment on list classification: DD may occasionally be mild, however is an early and consistent finding amongst surviving patients. Inclusion on this panel may benefit detection of patients who would otherwise not be considered for testing via other routes (e.g. where metabolic abnormalities become apparent later).

Therefore, recommending a GREEN rating at the next major review.
Intellectual disability v3.337 AHCY Arina Puzriakova Gene: ahcy has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.336 AHCY Arina Puzriakova Tag for-review tag was added to gene: AHCY.
Intellectual disability v3.336 AHCY Arina Puzriakova commented on gene: AHCY: Added 'treatable' tag as some patients have shown improvement following dietary management (particularly methionine restriction and supplementation with creatine and phosphatidylcholine)
Intellectual disability v3.336 AHCY Arina Puzriakova Tag treatable tag was added to gene: AHCY.
Intellectual disability v3.336 AHCY Arina Puzriakova reviewed gene: AHCY: Rating: GREEN; Mode of pathogenicity: None; Publications: 15024124, 16435181, 16736098, 20852937, 22959829, 26095522, 26527160, 28779239, 30121674, 31957987; Phenotypes: Hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase, 613752; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.336 DDOST Eleanor Williams Classified gene: DDOST as Green List (high evidence)
Intellectual disability v3.336 DDOST Eleanor Williams Added comment: Comment on list classification: Leaving Green until the next major review, but the evidence does not support a green rating; this gene should be demoted to amber or red.
Intellectual disability v3.336 DDOST Eleanor Williams Gene: ddost has been classified as Green List (High Evidence).
Intellectual disability v3.335 DDOST Eleanor Williams Tag for-review tag was added to gene: DDOST.
Intellectual disability v3.335 DDOST Eleanor Williams reviewed gene: DDOST: Rating: AMBER; Mode of pathogenicity: None; Publications: 22305527; Phenotypes: ?Congenital disorder of glycosylation, type Ir, 614507, CONGENITAL DISORDER OF GLYCOSYLATION, TYPE IR; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.335 CYP2U1 Eleanor Williams reviewed gene: CYP2U1: Rating: AMBER; Mode of pathogenicity: None; Publications: 23176821; Phenotypes: Spastic paraplegia 56, autosomal recessive, 615030; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.335 AGPS Arina Puzriakova Phenotypes for gene: AGPS were changed from RHIZOMELIC CHONDRODYSPLASIA PUNCTATA TYPE 3 (RCDP3) to Rhizomelic chondrodysplasia punctata, type 3, 600121
Intellectual disability v3.334 AGPS Arina Puzriakova Publications for gene: AGPS were set to 7807941; 11152660
Intellectual disability v3.333 AGPS Arina Puzriakova Classified gene: AGPS as Green List (high evidence)
Intellectual disability v3.333 AGPS Arina Puzriakova Added comment: Comment on list classification: Though some relevant phenotypic features have been reported, the relationship with ID is not clear from literature. Patients are more likely to be recognised in context of the skeletal phenotype.

Therefore, suggesting a rating downgrade from Green to Amber at the next major review.
Intellectual disability v3.333 AGPS Arina Puzriakova Gene: agps has been classified as Green List (High Evidence).
Intellectual disability v3.332 AGPS Arina Puzriakova Tag for-review tag was added to gene: AGPS.
Intellectual disability v3.332 AGPS Arina Puzriakova reviewed gene: AGPS: Rating: AMBER; Mode of pathogenicity: None; Publications: 7807941, 11152660, 11152660, 21990100; Phenotypes: Rhizomelic chondrodysplasia punctata, type 3, 600121; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.332 MECP2 Arina Puzriakova reviewed gene: MECP2: Rating: GREEN; Mode of pathogenicity: None; Publications: 32469049; Phenotypes: Rett syndrome, 312750; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Intellectual disability v3.332 UPF3B Arina Puzriakova reviewed gene: UPF3B: Rating: GREEN; Mode of pathogenicity: None; Publications: 32667670; Phenotypes: Mental retardation, X-linked, syndromic 14, 300676; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability v3.332 STAT1 Arina Puzriakova Classified gene: STAT1 as Red List (low evidence)
Intellectual disability v3.332 STAT1 Arina Puzriakova Gene: stat1 has been classified as Red List (Low Evidence).
Intellectual disability v3.331 STAT1 Arina Puzriakova changed review comment from: Following discussion with the clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark; to: Following discussion with the clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark and Konstantinos Varvagiannis
Intellectual disability v3.331 RASA1 Arina Puzriakova changed review comment from: Following discussion with the clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark; to: Following discussion with the clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark and Konstantinos Varvagiannis
Intellectual disability v3.331 ABCC6 Arina Puzriakova Classified gene: ABCC6 as Red List (low evidence)
Intellectual disability v3.331 ABCC6 Arina Puzriakova Gene: abcc6 has been classified as Red List (Low Evidence).
Intellectual disability v3.330 ABCC6 Arina Puzriakova changed review comment from: Following discussion with the clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark; to: Following discussion with the clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark and Konstantinos Varvagiannis
Intellectual disability v3.330 RAD50 Arina Puzriakova changed review comment from: Comment on list classification: Borderline ID in second patient (at age 15 estimated IQ: 85). Therefore, keeping rating Red awaiting further cases to clarify the relevance of ID to the overall phenotype. ; to: Comment on list classification: Note uncertainty regarding ID in the first patient - PMID:1887849 states 'lack of mental retardation', while a later report PMID:19409520 describes 'mild to moderate retardation of psychomotor development'. ID was borderline in the second patient (at age 15 estimated IQ: 85).

Therefore, keeping rating Red awaiting further cases to clarify the relevance of ID to the phenotype associated with RAD50 variants.
Intellectual disability v3.330 RAD50 Arina Puzriakova changed review comment from: Comment on list classification: Borderline ID in second patient (at age 15 estimated IQ: 85). Therefore, keeping rating Red awaiting further cases to ascertain the contribution of RAD50 variants to an ID phenotype.; to: Comment on list classification: Borderline ID in second patient (at age 15 estimated IQ: 85). Therefore, keeping rating Red awaiting further cases to clarify the relevance of ID to the overall phenotype.
Intellectual disability v3.330 RAD50 Arina Puzriakova Phenotypes for gene: RAD50 were changed from Nijmegen breakage syndrome-like disorder,613078; NBSLD to Nijmegen breakage syndrome-like disorder, 613078
Intellectual disability v3.329 RAD50 Arina Puzriakova Publications for gene: RAD50 were set to 1887849; 19409520
Intellectual disability v3.328 RAD50 Arina Puzriakova Classified gene: RAD50 as Red List (low evidence)
Intellectual disability v3.328 RAD50 Arina Puzriakova Added comment: Comment on list classification: Borderline ID in second patient (at age 15 estimated IQ: 85). Therefore, keeping rating Red awaiting further cases to ascertain the contribution of RAD50 variants to an ID phenotype.
Intellectual disability v3.328 RAD50 Arina Puzriakova Gene: rad50 has been classified as Red List (Low Evidence).
Intellectual disability v3.327 WASHC4 Arina Puzriakova Phenotypes for gene: WASHC4 were changed from Mental retardation, autosomal recessive 43, MIM #615817 to Mental retardation, autosomal recessive 43, 615817
Intellectual disability v3.326 WASHC4 Arina Puzriakova Classified gene: WASHC4 as Amber List (moderate evidence)
Intellectual disability v3.326 WASHC4 Arina Puzriakova Added comment: Comment on list classification: Rating Amber in view of mild/borderline ID in 2/3 families. Additional cases with a more significant manifestation of ID required before inclusion of WASHC4 on a diagnostic panel.
Intellectual disability v3.326 WASHC4 Arina Puzriakova Gene: washc4 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.325 WASHC4 Arina Puzriakova reviewed gene: WASHC4: Rating: ; Mode of pathogenicity: None; Publications: 21498477, 31953988; Phenotypes: Mental retardation, autosomal recessive 43, 615817; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.325 AFG3L2 Arina Puzriakova Phenotypes for gene: AFG3L2 were changed from SPINOCEREBELLAR ATAXIA 28 to Spastic ataxia 5, autosomal recessive, 614487
Intellectual disability v3.324 AFG3L2 Arina Puzriakova Classified gene: AFG3L2 as Green List (high evidence)
Intellectual disability v3.324 AFG3L2 Arina Puzriakova Added comment: Comment on list classification: This gene should be downgraded from Green to Red at the next major review, in accordance with the review by Zornitza Stark.
Intellectual disability v3.324 AFG3L2 Arina Puzriakova Gene: afg3l2 has been classified as Green List (High Evidence).
Intellectual disability v3.323 AFG3L2 Arina Puzriakova Publications for gene: AFG3L2 were set to 22022284
Intellectual disability v3.322 AFG3L2 Arina Puzriakova Tag for-review tag was added to gene: AFG3L2.
Intellectual disability v3.322 RASA1 Arina Puzriakova Classified gene: RASA1 as Red List (low evidence)
Intellectual disability v3.322 RASA1 Arina Puzriakova Gene: rasa1 has been classified as Red List (Low Evidence).
Intellectual disability v3.321 LRP5 Sarah Leigh Added comment: Comment on mode of inheritance: Other phenotypes associated with LRP5 variants (https://www.omim.org/entry/603506?search=LRP5&highlight=lrp5#geneMap) have monoallelic inheritance, however, these phenotypes are not relevant for this panel as ID has not been reported.
Intellectual disability v3.321 LRP5 Sarah Leigh Mode of inheritance for gene: LRP5 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.320 WDFY3 Arina Puzriakova Classified gene: WDFY3 as Amber List (moderate evidence)
Intellectual disability v3.320 WDFY3 Arina Puzriakova Added comment: Comment on list classification: There is a sufficient number of cases with moderate ID to meet the threshold for inclusion on a diagnostic ID panel. Furthermore, ID is currently the most applicable clinical indication for detecting these cases using PanelApp panels.

Therefore, recommending a rating upgrade from Amber to Green at the next major review.
Intellectual disability v3.320 WDFY3 Arina Puzriakova Gene: wdfy3 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.319 WDFY3 Arina Puzriakova Tag for-review tag was added to gene: WDFY3.
Intellectual disability v3.319 TRAK1 Arina Puzriakova Phenotypes for gene: TRAK1 were changed from to Epileptic encephalopathy, early infantile, 68, 618201
Intellectual disability v3.318 TRAK1 Arina Puzriakova Publications for gene: TRAK1 were set to
Intellectual disability v3.317 TRAK1 Arina Puzriakova Mode of inheritance for gene: TRAK1 was changed from to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.316 TRAK1 Arina Puzriakova changed review comment from: Comment on list classification: Rating Amber - with ID seemingly following seizures, and being in association with a single recurrent variant, there is currently insufficient evidence to say that variants in this gene cause ID. This may, however, be reviewed if new evidence emerges.

All cases have presented with seizures which should be an adequate indication for diagnostic testing (this gene is rated Green on the Genetic epilepsy syndromes (v2.152) panel).; to: Comment on list classification: Rating Amber - with ID seemingly following seizures, and being in association with a single recurrent variant, TRAK1 currently does not meet the threshold to say that variants cause ID. This may, however, be reviewed if new evidence emerges.

All cases have presented with seizures which should be an adequate indication for diagnostic testing (this gene is rated Green on the Genetic epilepsy syndromes (v2.152) panel).
Intellectual disability v3.316 TRAK1 Arina Puzriakova Classified gene: TRAK1 as Amber List (moderate evidence)
Intellectual disability v3.316 TRAK1 Arina Puzriakova Added comment: Comment on list classification: Rating Amber - with ID seemingly following seizures, and being in association with a single recurrent variant, there is currently insufficient evidence to say that variants in this gene cause ID. This may, however, be reviewed if new evidence emerges.

All cases have presented with seizures which should be an adequate indication for diagnostic testing (this gene is rated Green on the Genetic epilepsy syndromes (v2.152) panel).
Intellectual disability v3.316 TRAK1 Arina Puzriakova Gene: trak1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.315 TRAK1 Arina Puzriakova reviewed gene: TRAK1: Rating: ; Mode of pathogenicity: None; Publications: 28940097, 28364549, 29846532; Phenotypes: Epileptic encephalopathy, early infantile, 68, 618201; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.315 SLC12A2 Konstantinos Varvagiannis reviewed gene: SLC12A2: Rating: GREEN; Mode of pathogenicity: None; Publications: 28135719, 32658972, 27900370, 32294086, 29288388, 30740830, 32754646; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.315 ZMYM2 Konstantinos Varvagiannis gene: ZMYM2 was added
gene: ZMYM2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: ZMYM2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ZMYM2 were set to 32891193
Phenotypes for gene: ZMYM2 were set to Abnormality of the urinary system; Global developmental delay; Intellectual disability; Microcephaly; Abnormality of the cardiovascular system; Autism; Seizures; Abnormality of the head or neck; Abnormality of the nail; Small hand; Short foot; Clinodactyly
Penetrance for gene: ZMYM2 were set to unknown
Review for gene: ZMYM2 was set to AMBER
Added comment: Heterozygous pathogenic (pLoF) ZMYM2 variants have been reported in individuals with syndromic presentation including CAKUT (in several cases) and variable neurological manifestations among extra-renal features. DD and ID were reported in some of the families described to date as summarized below. You might consider inclusion with green/amber rating in the ID panel and green in the panel for CAKUT.

--

Connaughton et al (2020 - PMID: 32891193) report on 19 individuals (from 15 unrelated families) with heterozygous pathogenic ZMYM2 variants. [Article not reviewed in detail].

Affected individuals from 7 families presented with CAKUT while all of them displayed extra-renal features. Neurological manifestations were reported in 16 individuals from 14 families (data not available for 1 fam), among others hypotonia (3/14 fam), speech delay (4/14 fam), global DD (9/14 fam), ID (4/14 fam), microcephaly (4/14 fam). ASD was reported in 4 fam (4 indiv). Seizures were reported in 2 fam (2 indiv). Variable other features included cardiac defects, facial dysmorphisms, small hands and feet with dys-/hypo-plastic nails and clinodactyly.

14 pLoF variants were identified, in most cases as de novo events (8 fam). In 2 families the variant was inherited from an affected parent. Germline mosaicism occurred in 1 family.

The human disease features were recapitulated in a X. tropicalis morpholino knockdown, with expression of truncating variants failing to rescue renal and craniofacial defects. Heterozygous Zmym2-deficient mice also recapitulated the features of CAKUT.

ZMYM2 (previously ZNF198) encodes a nuclear zinc finger protein localizing to the nucleus (and PML nuclear body).

It has previously been identified as transcriptional corepressor interacting with nuclear receptors and the LSD1-CoREST-HDAC1 complex. It has also been shown to interact with FOXP transcription factors.

The authors provide evidence for loss of interaction of the truncated ZMYM2 with FOXP1 (mutations in the latter having recently been reported in syndromic CAKUT).
Sources: Literature
Intellectual disability v3.315 DHX37 Arina Puzriakova changed review comment from: Comment on list classification: There is enough evidence to rate this gene GREEN at the next major review - at least 6 unrelated cases with ID associated with variants in this gene.; to: Comment on list classification: There is enough evidence to rate this gene GREEN at the next major review - at least 6 unrelated cases with ID associated with variants in this gene (albeit association with monoallelic variants in 2 cases warrants further investigation).
Intellectual disability v3.315 DHX37 Arina Puzriakova Classified gene: DHX37 as Amber List (moderate evidence)
Intellectual disability v3.315 DHX37 Arina Puzriakova Added comment: Comment on list classification: There is enough evidence to rate this gene GREEN at the next major review - at least 6 unrelated cases with ID associated with variants in this gene.
Intellectual disability v3.315 DHX37 Arina Puzriakova Gene: dhx37 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.314 DHX37 Arina Puzriakova Tag for-review tag was added to gene: DHX37.
Intellectual disability v3.314 DHX37 Arina Puzriakova reviewed gene: DHX37: Rating: GREEN; Mode of pathogenicity: None; Publications: 26539891, 31256877; Phenotypes: Neurodevelopmental disorder with brain anomalies and with or without vertebral or cardiac anomalies, 618731; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.314 LMNB1 Konstantinos Varvagiannis gene: LMNB1 was added
gene: LMNB1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: LMNB1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: LMNB1 were set to 32910914
Phenotypes for gene: LMNB1 were set to Global developmental delay; Intellectual disability; Microcephaly; Short stature; Seizures; Abnormality of the corpus callosum; Cortical gyral simplification; Feeding difficulties; Scoliosis
Penetrance for gene: LMNB1 were set to unknown
Mode of pathogenicity for gene: LMNB1 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: LMNB1 was set to GREEN
Added comment: Cristofoli et al (2020 - PMID: 32910914) report 7 individuals (from 5 families) harboring mostly de novo LMNB1 variants.

The common phenotype consisted of primary microcephaly (7/7 ranging from -4.4 to -10 SD), DD/ID (7/7), relative short stature in most (+0.7 to -4 SD). Additional features included brain MRI abnormalities (abnormal CC in 3, simplified gyral pattern in 3, small structurally normal brain, etc), seizures (4 individuals from 2 families), limb spasticity (1/7), cortical visual impairment (in 3), feeding difficulties (5/7), scoliosis (4/7). Non-overlapping dysmorphic features were reported in some.

Variants were identified by WES or custom-designed gene panel and included 3 missense variants, 1 in-frame deletion and a splice variant. The in-frame deletion was inherited from a similarly affected parent in whom the variant occurred as a dn event. The splice SNV(NM_005573.3:c.939+1G>A) occurred in 3 sibs and was present as mosaic variant (15%) in the parent. This variant was predicted to result to extension of exon 5 by 6 amino-acids (samples were unavailable for mRNA studies).

LMNB1 encodes a B-type lamin (the other being encoded by LMNB2). A- and B- type lamins are major components of the nuclear lamina. As the authors comment, LMNB1 is expressed in almost all cell types beginning at the earliest stages of development.

Lamin-deficient mouse models support an essential role of B-type lamins in organogenesis, neuronal migration, patterning during brain development.

Functional studies performed, demonstrated impaired formation of LMNB1 nuclear lamina in LMNB1-null HeLa cells transfected with cDNAs for 3 missense variants.

Two variants (Lys33Glu/Arg42Trp) were shown to result in decreased nuclear localization with increased abundance in the cytosolic fraction. In patient derived LCLs these variants led to abnormal nuclear morphology. A missense variant in another domain (Ala152Gly - 1st coil domain) resulted also in lower abundance of lamin B1, irregular lamin A/C nuclear lamina, as well as more condensed nuclei (HeLa cells).

LMNB1 duplications or missense mutations increasing LMNB1 expression are associated with a different presentation of AD leuodystrophy. A variant previously associated with leukodystrophy (Arg29Trp) was shown to behave differently (present in the nuclear extract but not in the cytosol, lamin B1 to A/C ratio in nuclear extract was not significantly altered compared to wt as was the case for Arg42Trp, Lys33Glu).

Given the pLI score of 0.55 as well as the phenotype of individuals with deletions (not presenting microcephaly) the authors predict that a dominant-negative effect applies (rather than haploinsufficiency).

Consider inclusion in the following panels : DD/ID (green), epilepsy (amber - 4 of 7 patients belonging to 2 families), primary microcephaly (green), callosome (amber/green - 3 individuals belonging to 3 families), mendeliome (green), etc.
Sources: Literature
Intellectual disability v3.314 SPTBN4 Konstantinos Varvagiannis edited their review of gene: SPTBN4: Added comment: ** Consider also the GeneReview on this disorder - PMID : 32672909; Changed publications: 28540413, 28940097, 29861105, 31230720, 31857255, 32672909
Intellectual disability v3.314 CAMK2G Arina Puzriakova Publications for gene: CAMK2G were set to 26350204; 24896178; 23033978
Intellectual disability v3.313 CAMK2G Arina Puzriakova Phenotypes for gene: CAMK2G were changed from to Mental retardation, autosomal dominant 59, 618522
Intellectual disability v3.312 CAMK2G Arina Puzriakova Mode of pathogenicity for gene: CAMK2G was changed from to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Intellectual disability v3.311 CAMK2G Arina Puzriakova Classified gene: CAMK2G as Amber List (moderate evidence)
Intellectual disability v3.311 CAMK2G Arina Puzriakova Added comment: Comment on list classification: Rating has been upgraded from Red to Amber based on the review by Konstantinos Varvagiannis - two unrelated individuals with severe ID, associated with de novo CAMK2G variants, with addition of functional data.
Intellectual disability v3.311 CAMK2G Arina Puzriakova Gene: camk2g has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.310 FIBP Arina Puzriakova Classified gene: FIBP as Amber List (moderate evidence)
Intellectual disability v3.310 FIBP Arina Puzriakova Added comment: Comment on list classification: Rating upgraded from Red to Amber based on review by Zornitza Stark.
Intellectual disability v3.310 FIBP Arina Puzriakova Gene: fibp has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.309 FIBP Arina Puzriakova Phenotypes for gene: FIBP were changed from Thauvin-Robinet-Faivre syndrome to Thauvin-Robinet-Faivre syndrome, 617107
Intellectual disability v3.308 FIBP Arina Puzriakova Added comment: Comment on publications: Two publications (PMID: 26660953; 27183861) describing four individuals from two unrelated families.
Intellectual disability v3.308 FIBP Arina Puzriakova Publications for gene: FIBP were set to 26660953
Intellectual disability v3.307 TANC2 Arina Puzriakova Tag watchlist tag was added to gene: TANC2.
Intellectual disability v3.307 TANC2 Arina Puzriakova Phenotypes for gene: TANC2 were changed from NDD syndrome; Neurodevelopmental Disorder; Intellectual disability; Childhood speech delay; Childhood motor delay to Intellectual developmental disorder with autistic features and language delay, with or without seizures, 618906
Intellectual disability v3.306 VAMP1 Arina Puzriakova Tag watchlist tag was added to gene: VAMP1.
Intellectual disability v3.306 VAMP1 Arina Puzriakova Phenotypes for gene: VAMP1 were changed from congenital myasthenic syndrome (CMS) and delayed development to Myasthenic syndrome, congenital, 25, 618323
Intellectual disability v3.305 VAMP1 Arina Puzriakova Publications for gene: VAMP1 were set to 28253535
Intellectual disability v3.304 VAMP1 Arina Puzriakova Classified gene: VAMP1 as Green List (high evidence)
Intellectual disability v3.304 VAMP1 Arina Puzriakova Added comment: Comment on list classification: Literature search revealed that developmental delay primarily affects motor function, and it is unclear whether patients exhibit any cognitive deficit. Additional cases would help delineate the association with this phenotype.

Therefore, recommending a rating downgrade from Green to Amber/Red at the next major review, awaiting further publications/clinical evidence.
Intellectual disability v3.304 VAMP1 Arina Puzriakova Gene: vamp1 has been classified as Green List (High Evidence).
Intellectual disability v3.303 VAMP1 Arina Puzriakova Tag for-review tag was added to gene: VAMP1.
Intellectual disability v3.303 TRIM32 Arina Puzriakova Tag for-review tag was added to gene: TRIM32.
Intellectual disability v3.303 TRIM32 Arina Puzriakova Phenotypes for gene: TRIM32 were changed from BARDET-BIEDL SYNDROME TYPE 11 (BBS11) to Bardet-Biedl syndrome 11, 615988
Intellectual disability v3.302 TRIM32 Arina Puzriakova Publications for gene: TRIM32 were set to 0
Intellectual disability v3.301 TRIM32 Arina Puzriakova Classified gene: TRIM32 as Green List (high evidence)
Intellectual disability v3.301 TRIM32 Arina Puzriakova Added comment: Comment on list classification: Recommended Green-to-Red rating downgrade on the next major review - only one family reported to date for association with BBS. Currently also Red on the Bardet-Biedl Syndrome (Version 1.5) gene panel.
Intellectual disability v3.301 TRIM32 Arina Puzriakova Gene: trim32 has been classified as Green List (High Evidence).
Intellectual disability v3.300 VARS2 Arina Puzriakova Classified gene: VARS2 as Amber List (moderate evidence)
Intellectual disability v3.300 VARS2 Arina Puzriakova Added comment: Comment on list classification: There is enough evidence to rate this gene GREEN at the next major review - >3 unrelated families with different variants. Severe psychomotor delay was an early and significant manifestation on clinical evaluation.
Intellectual disability v3.300 VARS2 Arina Puzriakova Gene: vars2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.299 VARS2 Arina Puzriakova Tag for-review tag was added to gene: VARS2.
Intellectual disability v3.299 SUCLA2 Arina Puzriakova Classified gene: SUCLA2 as Amber List (moderate evidence)
Intellectual disability v3.299 SUCLA2 Arina Puzriakova Added comment: Comment on list classification: Although sufficient number of cases with relevant clinical presentation, psychomotor delay is a component of a broader phenotype. Patients are more likely to be recognised via other routes (Metabolic/White Matter Disorders/Mitochondrial) - SUCLA2 is already Green on these PanelApp panels.

Therefore, rating Amber on the ID panel.
Intellectual disability v3.299 SUCLA2 Arina Puzriakova Gene: sucla2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.298 FRY Arina Puzriakova Publications for gene: FRY were set to 21937992
Intellectual disability v3.297 FRY Arina Puzriakova Classified gene: FRY as Amber List (moderate evidence)
Intellectual disability v3.297 FRY Arina Puzriakova Gene: fry has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.296 ELN Arina Puzriakova Classified gene: ELN as Red List (low evidence)
Intellectual disability v3.296 ELN Arina Puzriakova Gene: eln has been classified as Red List (Low Evidence).
Intellectual disability v3.295 ELN Arina Puzriakova changed review comment from: Following discussion with the clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark; to: Following discussion with the clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark and Konstantinos Varvagiannis.
Intellectual disability v3.295 ATP1A3 Zornitza Stark edited their review of gene: ATP1A3: Added comment: Four additional individuals with dystonia, dysmorphism, encephalopathy with developmental delay, brain MRI abnormalities always including cerebellar hypoplasia, no hemiplegia, and neonatal onset. All had de novo missense variants. All are described to have global developmental delay, hence supporting upgrade in rating on this panel.; Changed rating: GREEN; Changed publications: https://doi.org/10.1212/NXG.0000000000000466; Changed phenotypes: Alternating hemiplegia of childhood 2, MIM#614820, Neurodevelopmental disorder; Set current diagnostic: yes
Intellectual disability v3.295 WASHC4 Zornitza Stark gene: WASHC4 was added
gene: WASHC4 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: WASHC4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: WASHC4 were set to 31953988; 21498477
Phenotypes for gene: WASHC4 were set to Mental retardation, autosomal recessive 43, MIM #615817
Review for gene: WASHC4 was set to GREEN
gene: WASHC4 was marked as current diagnostic
Added comment: Three unrelated families reported.
Sources: Literature
Intellectual disability v3.295 RAD50 Zornitza Stark reviewed gene: RAD50: Rating: AMBER; Mode of pathogenicity: None; Publications: 32212377; Phenotypes: Nijmegen breakage syndrome-like disorder, MIM# 613078; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.295 ATP1A2 Sarah Leigh commented on gene: ATP1A2: There is enough evidence for this gene to be rated GREEN at the next major review.
Intellectual disability v3.295 ATP1A2 Sarah Leigh Tag for-review tag was added to gene: ATP1A2.
Intellectual disability v3.295 ATP1A2 Sarah Leigh edited their review of gene: ATP1A2: Added comment: Associated with phenotype in OMIM and in G2P for MIGRAINE, FAMILIAL HEMIPLEGIC, ATP1A2-related. Three variants associated with congnitive impairment in 2/7 and 1/5 members of two families with Migraine, familial hemiplegic, 2 602481. At least 12 variants have been reported in Migraine, familial hemiplegic, 2 602481 families (PMID 15159495). An additional variant was reported in a case of Alternating hemiplegia of childhood 1, 104290 with impared cognitive function (PMID 29610157).; Changed rating: GREEN
Intellectual disability v3.295 ANKH Sarah Leigh commented on gene: ANKH: There is no evidence for this gene to be rated GREEN, it should be rated RED at the next major review.
Intellectual disability v3.295 ANKH Sarah Leigh reviewed gene: ANKH: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.295 ANKH Sarah Leigh Publications for gene: ANKH were set to
Intellectual disability v3.294 ANKH Sarah Leigh Tag for-review tag was added to gene: ANKH.
Intellectual disability v3.294 TNR Arina Puzriakova Classified gene: TNR as Amber List (moderate evidence)
Intellectual disability v3.294 TNR Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to rate this gene GREEN at the next major review - at least 7 unrelated cases with cognitive impairment associated with variants in this gene.
Intellectual disability v3.294 TNR Arina Puzriakova Gene: tnr has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.293 TNR Arina Puzriakova reviewed gene: TNR: Rating: GREEN; Mode of pathogenicity: None; Publications: 22730557, 32099069; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.293 EARS2 Sarah Leigh Tag for-review tag was added to gene: EARS2.
Intellectual disability v3.293 EARS2 Sarah Leigh edited their review of gene: EARS2: Added comment: There is enough evidence for this gene to be rated GREEN at the next major review.; Changed rating: GREEN
Intellectual disability v3.293 EARS2 Sarah Leigh changed review comment from: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 15 variants reported in at least 12 unrelated cases, with variable degrees of psycomotor motor delay or regression and little or no language.; to: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 14 variants reported in at least 11 unrelated cases, with variable degrees of psycomotor motor delay or regression and little or no language.
Intellectual disability v3.293 EARS2 Sarah Leigh Publications for gene: EARS2 were set to 22492562
Intellectual disability v3.292 EARS2 Sarah Leigh changed review comment from: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 14 variants reported in at least 11 unrelated cases, with variable degrees of psycomotor motor delay or regression and little or no language.; to: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 15 variants reported in at least 12 unrelated cases, with variable degrees of psycomotor motor delay or regression and little or no language.
Intellectual disability v3.292 EARS2 Sarah Leigh Classified gene: EARS2 as Amber List (moderate evidence)
Intellectual disability v3.292 EARS2 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 14 variants reported in at least 11 unrelated cases, with variable degrees of psycomotor motor delay or regression and little or no language.
Intellectual disability v3.292 EARS2 Sarah Leigh Gene: ears2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.291 SLC12A2 Arina Puzriakova Publications for gene: SLC12A2 were set to 28940097; 30740830; 32754646
Intellectual disability v3.290 SLC12A2 Arina Puzriakova Mode of inheritance for gene: SLC12A2 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.289 SLC12A2 Arina Puzriakova changed review comment from: Comment on list classification: There is sufficient evidence to rate this gene GREEN at the next major review - at least three unrelated cases presenting a relevant phenotype in association with biallelic variants in SLC12A2.; to: Comment on list classification: There is sufficient evidence to rate this gene GREEN at the next major review - at least nine unrelated cases presenting a relevant phenotype in association with variants in SLC12A2.
Intellectual disability v3.289 SLC12A2 Arina Puzriakova edited their review of gene: SLC12A2: Changed publications: 28940097, 30740830, 32754646, 32658972; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.289 SLC12A2 Arina Puzriakova changed review comment from: - PMID: 28940097 (2017) - SLC12A2 first identified as a novel candidate gene in a 3.3-year-old male with GDD, failure to thrive, hypotonia, microcephaly, neonatal respiratory distress, recurrent aspiration pneumonia, and osteopenia. Sequencing revealed a homozygous variant (c.2617-2A>G) that segregated within the family.

- PMID: 30740830 (2019) - Homozygous 22kb deletion identified in a 5-year-old male with GDD, sensorineural hearing loss, gastrointestinal abnormalities, early postnatal respiratory distress, generalised hypotonia, and absent salivation. Neuropsychological testing demonstrated profound delays in all developmental areas, with skills ranging from 1 to 6 months. The deletion was the result of uniparental paternal isodisomy.

Functional studies using patient-derived fibroblasts showed truncated SLC12A2 transcripts and markedly reduced protein levels compared to control. Knockout mouse model recapitulated phenotypic features such as deafness, abnormal neuronal growth and migration, gastrointestinal abnormalities, and absent salivation.

- PMID: 32754646 (2020) - Compound heterozygous variants (c.1431delT and c.2006-1G>A) were identified in two sibs. The proband, an 8-year-old girl, presented a severe neurodevelopmental disorder (including severe ID), hearing impairment, gastrointestinal problems, hypotonia, and absent tear fluid, saliva, and sweat. Phenotypic overlap was noted in an affected older sister, who died at 22 days of age.; to: - PMID: 28940097 (2017) - SLC12A2 first identified as a novel candidate gene in a 3.3-year-old male with GDD, failure to thrive, hypotonia, microcephaly, neonatal respiratory distress, recurrent aspiration pneumonia, and osteopenia. Sequencing revealed a homozygous variant (c.2617-2A>G) that segregated within the family.

- PMID: 30740830 (2019) - Homozygous 22kb deletion identified in a 5-year-old male with GDD, sensorineural hearing loss, gastrointestinal abnormalities, early postnatal respiratory distress, generalised hypotonia, and absent salivation. Neuropsychological testing demonstrated profound delays in all developmental areas, with skills ranging from 1 to 6 months. The deletion was the result of uniparental paternal isodisomy.

Functional studies using patient-derived fibroblasts showed truncated SLC12A2 transcripts and markedly reduced protein levels compared to control. Knockout mouse model recapitulated phenotypic features such as deafness, abnormal neuronal growth and migration, gastrointestinal abnormalities, and absent salivation.

- PMID: 32754646 (2020) - Compound heterozygous variants (c.1431delT and c.2006-1G>A) were identified in two sibs. The proband, an 8-year-old girl, presented a severe neurodevelopmental disorder (including severe ID), hearing impairment, gastrointestinal problems, hypotonia, and absent tear fluid, saliva, and sweat. Phenotypic overlap was noted in an affected older sister, who died at 22 days of age.

- PMID: 32658972 (2020) - Six unrelated children, all with mild-severe ID/DD, associated with de novo variants in SLC12A2. Additional clinical features included bilateral sensorineural hearing loss (2/6), abnormalities on brain MRI (2/4), and cerebral palsy (2/6). Some functional data in Xenopus laevis oocytes, indicating a role of SLC12A2 in neurogenesis.
Intellectual disability v3.289 DHX37 Zornitza Stark gene: DHX37 was added
gene: DHX37 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: DHX37 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: DHX37 were set to 26539891; 31256877
Phenotypes for gene: DHX37 were set to Neurodevelopmental disorder with brain anomalies and with or without vertebral or cardiac anomalies, MIM#618731
Review for gene: DHX37 was set to GREEN
gene: DHX37 was marked as current diagnostic
Added comment: Overall, 5 unrelated families with bi-allelic variants, all with ID as part of the phenotype. Green for bi-allelic disease

Much less clear association between mono-allelic variants and ID, two missense variants reported. Note one was mosaic, and for the other, paternal sample was not available, so not confirmed to be de novo. No mechanism for mono-allelic vs bi-allelic disease proposed. Overall, Red for mono-allelic variants causing a neurodevelopmental phenotype at this stage. Note there is a separate association between mono allelic variants and DSD.
Sources: Literature
Intellectual disability v3.289 SLC12A2 Arina Puzriakova Publications for gene: SLC12A2 were set to 30740830
Intellectual disability v3.288 SLC12A2 Arina Puzriakova Classified gene: SLC12A2 as Amber List (moderate evidence)
Intellectual disability v3.288 SLC12A2 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to rate this gene GREEN at the next major review - at least three unrelated cases presenting a relevant phenotype in association with biallelic variants in SLC12A2.
Intellectual disability v3.288 SLC12A2 Arina Puzriakova Gene: slc12a2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.287 SLC12A2 Arina Puzriakova Tag for-review tag was added to gene: SLC12A2.
Intellectual disability v3.287 SLC12A2 Arina Puzriakova reviewed gene: SLC12A2: Rating: GREEN; Mode of pathogenicity: None; Publications: 28940097, 30740830, 32754646; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.287 EXOC7 Arina Puzriakova Classified gene: EXOC7 as Amber List (moderate evidence)
Intellectual disability v3.287 EXOC7 Arina Puzriakova Added comment: Comment on list classification: Though mild-severe DD is reported in all surviving patients to date (4 individuals from 2 families), additional unrelated cases required before inclusion on a diagnostic panel.

Therefore, rating Amber in anticipation of further publications (added to watchlist).
Intellectual disability v3.287 EXOC7 Arina Puzriakova Gene: exoc7 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.286 EXOC7 Arina Puzriakova Tag watchlist tag was added to gene: EXOC7.
Intellectual disability v3.286 HNRNPH1 Arina Puzriakova Tag for-review tag was added to gene: HNRNPH1.
Intellectual disability v3.286 HNRNPH1 Arina Puzriakova changed review comment from: Comment on list classification: Two studies report de novo variants in at least 7 unrelated cases with moderate-severe GDD/ID.; to: Comment on list classification: There is enough evidence to rate this gene GREEN at the next major review - two studies report de novo variants in at least 7 unrelated cases with moderate-severe GDD/ID.
Intellectual disability v3.286 HNRNPH1 Arina Puzriakova Classified gene: HNRNPH1 as Amber List (moderate evidence)
Intellectual disability v3.286 HNRNPH1 Arina Puzriakova Added comment: Comment on list classification: Two studies report de novo variants in at least 7 unrelated cases with moderate-severe GDD/ID.
Intellectual disability v3.286 HNRNPH1 Arina Puzriakova Gene: hnrnph1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.285 HARS Arina Puzriakova commented on gene: HARS: Added new-gene-name tag, new approved HGNC gene symbol for HARS is HARS1
Intellectual disability v3.285 HARS Arina Puzriakova Tag new-gene-name tag was added to gene: HARS.
Intellectual disability v3.285 HARS Arina Puzriakova Classified gene: HARS as Amber List (moderate evidence)
Intellectual disability v3.285 HARS Arina Puzriakova Added comment: Comment on list classification: Relevant phenotype for this panel but additional cases required. Therefore, rating Amber in anticipation of further publications.
Intellectual disability v3.285 HARS Arina Puzriakova Gene: hars has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.284 CCDC88A Arina Puzriakova Classified gene: CCDC88A as Amber List (moderate evidence)
Intellectual disability v3.284 CCDC88A Arina Puzriakova Added comment: Comment on list classification: This gene has been upgraded from Red to Amber based on the external reviews by Konstantinos Varvagiannis and Zornitza Stark.
Intellectual disability v3.284 CCDC88A Arina Puzriakova Gene: ccdc88a has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.283 CCDC174 Arina Puzriakova Classified gene: CCDC174 as Red List (low evidence)
Intellectual disability v3.283 CCDC174 Arina Puzriakova Added comment: Comment on list classification: Rating Red as only one founder variant reported to-date in a single publication - currently no evidence that other variants in this gene are disease-causing.

Added 'founder-effect' tag
Intellectual disability v3.283 CCDC174 Arina Puzriakova Gene: ccdc174 has been classified as Red List (Low Evidence).
Intellectual disability v3.282 CCDC174 Arina Puzriakova Tag founder-effect tag was added to gene: CCDC174.
Intellectual disability v3.282 TAF1C Arina Puzriakova Classified gene: TAF1C as Amber List (moderate evidence)
Intellectual disability v3.282 TAF1C Arina Puzriakova Gene: taf1c has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.281 PAK3 Arina Puzriakova reviewed gene: PAK3: Rating: ; Mode of pathogenicity: None; Publications: 31943058; Phenotypes: Intellectual disability; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability v3.281 TRAPPC2L Arina Puzriakova Classified gene: TRAPPC2L as Amber List (moderate evidence)
Intellectual disability v3.281 TRAPPC2L Arina Puzriakova Added comment: Comment on list classification: Rating Amber as additional cases required to delineate the genotype-phenotype relationship. Total of three families, but two share a founder variant, and there are some disparities between the clinical presentations reported in the two publications.
Intellectual disability v3.281 TRAPPC2L Arina Puzriakova Gene: trappc2l has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.280 TRAPPC2L Arina Puzriakova gene: TRAPPC2L was added
gene: TRAPPC2L was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: TRAPPC2L was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TRAPPC2L were set to 30120216; 32843486
Phenotypes for gene: TRAPPC2L were set to Encephalopathy, progressive, early-onset, with episodic rhabdomyolysis, 618331
Review for gene: TRAPPC2L was set to AMBER
Added comment: Gene is associated with Encephalopathy, progressive, early-onset, with episodic rhabdomyolysis in OMIM, but not in G2P.

PMID: 30120216 (2018) - Two unrelated probands with an identical homozygous missense (c.109G>T, p.Asp37Tyr) variant in TRAPPC2L. Both individuals presented neurodevelopmental delay, febrile illness-induced encephalopathy, and episodic rhabdomyolysis, followed by developmental arrest, seizures and tetraplegia. The variant segregated with the phenotype in each family, and haplotype analysis suggested a founder effect.

The mutant protein was expressed in patient fibroblasts, but displayed membrane trafficking delays. Studies in yeast showed that the variant impaired interaction with TRAPPC10, and increased levels of the active RAB11.


PMID: 32843486 (2020) - In an Ashkenazi Jewish family with three affected sibs with GDD/ID, WGS revealed a segregating homozygous missense variant (c.5G>C, p.Ala2Gly) in the TRAPPC2L gene. No seizures, brain MRI abnormalities, or illness provoked regression were documented in this family.

Comparable to the previous study, the variant resulted in delayed ER-to-Golgi trafficking and elevated levels of active RAB11. Studies using yeast and in vitro binding, showed that the variant disrupted interaction with another core TRAPP protein, TRAPPC6a.
Sources: Literature
Intellectual disability v3.279 LMBRD2 Arina Puzriakova Classified gene: LMBRD2 as Amber List (moderate evidence)
Intellectual disability v3.279 LMBRD2 Arina Puzriakova Added comment: Comment on list classification: There is a sufficient number of unrelated cases to rate this gene GREEN at the next major review.
Intellectual disability v3.279 LMBRD2 Arina Puzriakova Gene: lmbrd2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.278 LMBRD2 Arina Puzriakova Tag for-review tag was added to gene: LMBRD2.
Intellectual disability v3.278 SUPT16H Arina Puzriakova Publications for gene: SUPT16H were set to http://dx.doi.org/10.1136/jmedgenet-2019-106193
Intellectual disability v3.277 SUPT16H Arina Puzriakova Classified gene: SUPT16H as Amber List (moderate evidence)
Intellectual disability v3.277 SUPT16H Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence for this gene to be rated GREEN at the next major review - at least four unrelated individuals with GDD/ID (plus another additional patient with a deletion, albeit encompassing other potentially clinically relevant genes).
Intellectual disability v3.277 SUPT16H Arina Puzriakova Gene: supt16h has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.276 SUPT16H Arina Puzriakova Tag for-review tag was added to gene: SUPT16H.
Intellectual disability v3.276 ADARB1 Arina Puzriakova Publications for gene: ADARB1 were set to 32220291
Intellectual disability v3.275 ADARB1 Arina Puzriakova Phenotypes for gene: ADARB1 were changed from Intellectual disability; microcephaly; seizures to Neurodevelopmental disorder with hypotonia, microcephaly, and seizures, 618862
Intellectual disability v3.274 ADARB1 Arina Puzriakova edited their review of gene: ADARB1: Added comment: PMID: 32719099 (2020) - Three additional patients from two consanguineous families with novel biallelic variants in the ADARB1 gene. All affected individuals presented global DD, severe-profound ID, intractable early infantile-onset seizures, severe microcephaly, axial hypotonia and progressive appendicular spasticity. In vitro RNA editing assays showed that both variants resulted in severe impairment or loss of ADAR2 enzymatic activity.; Changed publications: 32220291, 32719099
Intellectual disability v3.274 HARS Zornitza Stark edited their review of gene: HARS: Changed publications: 32333447
Intellectual disability v3.274 TKFC Arina Puzriakova Classified gene: TKFC as Amber List (moderate evidence)
Intellectual disability v3.274 TKFC Arina Puzriakova Added comment: Comment on list classification: Additional cases required before inclusion on a diagnostic panel (added to watchlist).
Intellectual disability v3.274 TKFC Arina Puzriakova Gene: tkfc has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.273 TKFC Arina Puzriakova Phenotypes for gene: TKFC were changed from Developmental delay; cataracts; liver dysfunction to Triokinase and FMN cyclase deficiency syndrome, 618805
Intellectual disability v3.272 TKFC Arina Puzriakova Tag watchlist tag was added to gene: TKFC.
Intellectual disability v3.272 TKFC Arina Puzriakova reviewed gene: TKFC: Rating: AMBER; Mode of pathogenicity: None; Publications: 32004446; Phenotypes: Triokinase and FMN cyclase deficiency syndrome, 618805; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.272 TP73 Arina Puzriakova Classified gene: TP73 as Red List (low evidence)
Intellectual disability v3.272 TP73 Arina Puzriakova Added comment: Comment on list classification: Rating Red as gene only distinguished due to multiple hits in same candidate gene - patients display discordant phenotype and DD only reported in one patient.
Intellectual disability v3.272 TP73 Arina Puzriakova Gene: tp73 has been classified as Red List (Low Evidence).
Intellectual disability v3.271 TP73 Arina Puzriakova reviewed gene: TP73: Rating: RED; Mode of pathogenicity: None; Publications: 31130284; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.271 SMG8 Arina Puzriakova Classified gene: SMG8 as Red List (low evidence)
Intellectual disability v3.271 SMG8 Arina Puzriakova Added comment: Comment on list classification: Rating Red as gene only distinguished due to multiple hits in same candidate gene; however, patients display discordant phenotype and ID only reported in one patient.
Intellectual disability v3.271 SMG8 Arina Puzriakova Gene: smg8 has been classified as Red List (Low Evidence).
Intellectual disability v3.270 SMG8 Arina Puzriakova reviewed gene: SMG8: Rating: RED; Mode of pathogenicity: None; Publications: 31130284; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.270 RAP1GDS1 Arina Puzriakova Tag founder-effect tag was added to gene: RAP1GDS1.
Intellectual disability v3.270 RAP1GDS1 Arina Puzriakova Classified gene: RAP1GDS1 as Red List (low evidence)
Intellectual disability v3.270 RAP1GDS1 Arina Puzriakova Added comment: Comment on list classification: The same variant identified in two families from the region, indicating a possible founder effect. Therefore rated Red as there is not currently enough evidence that other variants in the RAP1GDS1 gene are disease causing.
Intellectual disability v3.270 RAP1GDS1 Arina Puzriakova Gene: rap1gds1 has been classified as Red List (Low Evidence).
Intellectual disability v3.269 RAP1GDS1 Arina Puzriakova reviewed gene: RAP1GDS1: Rating: ; Mode of pathogenicity: None; Publications: 32431071; Phenotypes: Intellectual disability, Global developmental delay, Hypotonia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.269 PDCD6IP Arina Puzriakova Classified gene: PDCD6IP as Amber List (moderate evidence)
Intellectual disability v3.269 PDCD6IP Arina Puzriakova Added comment: Comment on list classification: Phenotype is relevant to this panel but additional cases required to validate pathogenicity of variants in this gene.
Intellectual disability v3.269 PDCD6IP Arina Puzriakova Gene: pdcd6ip has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.268 TUBGCP2 Arina Puzriakova changed review comment from: Comment on list classification: Although the phenotype is relevant for this panel, additional cases would help determine the aetiology of the ID presentation. This gene has been added to other panels (Malformations of cortical development/Epilepsy), in view of which these patients are more likely to be recognised.

Rating Amber, awaiting further publications (added to watchlist).; to: Comment on list classification: Although the phenotype is relevant for this panel, additional cases would help determine the aetiology of the ID presentation. This gene has been added to other panels (Malformations of cortical development/Epilepsy/Microcephaly), in view of which these patients are more likely to be recognised.

Rating Amber, awaiting further publications (added to watchlist).
Intellectual disability v3.268 TUBGCP2 Arina Puzriakova Deleted their comment
Intellectual disability v3.268 TUBGCP2 Arina Puzriakova Classified gene: TUBGCP2 as Amber List (moderate evidence)
Intellectual disability v3.268 TUBGCP2 Arina Puzriakova Added comment: Comment on list classification: Although the phenotype is relevant for this panel, additional cases would help determine the aetiology of the ID presentation. This gene has been added to other panels (Malformations of cortical development/Epilepsy), in view of which these patients are more likely to be recognised.

Rating Amber, awaiting further publications (added to watchlist).
Intellectual disability v3.268 TUBGCP2 Arina Puzriakova Gene: tubgcp2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.268 TUBGCP2 Arina Puzriakova Classified gene: TUBGCP2 as No list
Intellectual disability v3.268 TUBGCP2 Arina Puzriakova Added comment: Comment on list classification: Although the phenotype is relevant for this panel, additional cases would help determine the aetiology of the ID presentation. This gene has been added to other panels (Malformations of cortical development/Epilepsy), in view of which these patients are more likely to be recognised.

Rating Amber, awaiting further publications (added to watchlist).
Intellectual disability v3.268 TUBGCP2 Arina Puzriakova Gene: tubgcp2 has been removed from the panel.
Intellectual disability v3.267 TUBGCP2 Arina Puzriakova Tag watchlist tag was added to gene: TUBGCP2.
Intellectual disability v3.267 TUBGCP2 Arina Puzriakova reviewed gene: TUBGCP2: Rating: AMBER; Mode of pathogenicity: None; Publications: 31630790; Phenotypes: Pachygyria, microcephaly, developmental delay, and dysmorphic facies, with or without seizures, 618737; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.267 PPP1R12A Arina Puzriakova Phenotypes for gene: PPP1R12A were changed from Intellectual disability; holoprosencephaly; disorder of sex development to Genitourinary and/or/brain malformation syndrome, 618820
Intellectual disability v3.266 PPP1R12A Arina Puzriakova Classified gene: PPP1R12A as Amber List (moderate evidence)
Intellectual disability v3.266 PPP1R12A Arina Puzriakova Added comment: Comment on list classification: There is enough evidence to rate this gene GREEN at the next major review - DD reported in at least 7 unrelated patients with PPP1R12A variants.
Intellectual disability v3.266 PPP1R12A Arina Puzriakova Gene: ppp1r12a has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.265 PPP1R12A Arina Puzriakova Tag for-review tag was added to gene: PPP1R12A.
Intellectual disability v3.265 PPP1R12A Arina Puzriakova changed review comment from: PMID: 31883643 (2020) - Screening cohorts of patients with holoprosencephaly and patients with disorders of sex development revealed 12 unrelated individuals with de novo LoF variants in the PPP1R12A gene. Variants were associated with a broad spectrum of manifestations, and a clear genotype-phenotype correlation was not observed - most commonly presentation included either malformations of the brain or the genitourinary tract (two individuals exhibited both brain and genitourinary anomalies). 7/12 individuals exhibited developmental delay, which warrants inclusion on this panel.; to: Associated with phenotype in OMIM, and a probable gene for PPP1R12A-related Holoprosencephaly Spectrum and Urogenital Malformations in G2P.

PMID: 31883643 (2020) - Screening cohorts of patients with holoprosencephaly and patients with disorders of sex development revealed 12 unrelated individuals with de novo LoF variants in the PPP1R12A gene. Variants were associated with a broad spectrum of manifestations, and a clear genotype-phenotype correlation was not observed - most commonly presentation included either malformations of the brain or the genitourinary tract (two individuals exhibited both brain and genitourinary anomalies). 7/12 individuals exhibited developmental delay, which warrants inclusion on this panel.
Intellectual disability v3.265 PPP1R12A Arina Puzriakova reviewed gene: PPP1R12A: Rating: GREEN; Mode of pathogenicity: None; Publications: 31883643; Phenotypes: Genitourinary and/or/brain malformation syndrome, 618820; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.265 TRNT1 Arina Puzriakova Tag for-review tag was added to gene: TRNT1.
Intellectual disability v3.265 TRNT1 Arina Puzriakova Publications for gene: TRNT1 were set to 25193871; 23553769; 29170023; 27389523
Intellectual disability v3.264 TRNT1 Arina Puzriakova Classified gene: TRNT1 as Amber List (moderate evidence)
Intellectual disability v3.264 TRNT1 Arina Puzriakova Added comment: Comment on list classification: There is enough evidence to rate this gene GREEN at the next major review - sufficient number of cases with (mild-profound) developmental delay, associated with biallelic variants in TRNT1.
Intellectual disability v3.264 TRNT1 Arina Puzriakova Gene: trnt1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.263 TENM3 Arina Puzriakova Classified gene: TENM3 as Amber List (moderate evidence)
Intellectual disability v3.263 TENM3 Arina Puzriakova Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review - sufficient unrelated cases with an ID phenotype.
Intellectual disability v3.263 TENM3 Arina Puzriakova Gene: tenm3 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.262 TENM3 Arina Puzriakova Tag for-review tag was added to gene: TENM3.
Intellectual disability v3.262 TENM3 Arina Puzriakova reviewed gene: TENM3: Rating: ; Mode of pathogenicity: None; Publications: 22766609, 27103084, 30513139, 29753094; Phenotypes: Microphthalmia, syndromic 15, 615145, ?Microphthalmia, isolated, with coloboma 9, 615145; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.262 KAT5 Konstantinos Varvagiannis reviewed gene: KAT5: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: 32822602; Phenotypes: Severe global developmental delay, Intellectual disability, Seizures, Microcephaly, Behavioral abnormality, Sleep disturbance, Morphological abnormality of the central nervous system, Short stature, Oral cleft, Abnormality of the face; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.262 LMBRD2 Konstantinos Varvagiannis gene: LMBRD2 was added
gene: LMBRD2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: LMBRD2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: LMBRD2 were set to 32820033; https://doi.org/10.1101/797787
Phenotypes for gene: LMBRD2 were set to Global developmental delay; Intellectual disability; Microcephaly; Seizures; Abnormality of nervous system morphology; Abnormality of the eye
Penetrance for gene: LMBRD2 were set to unknown
Review for gene: LMBRD2 was set to AMBER
Added comment: You may consider inclusion with green (13 individuals with dn missense SNVs overall, overlapping features for 10 with available phenotype / a recurring variant has been identified in 2 different studies) or amber rating (role of the gene not known, no variant studies, animal model probably not available).

► Malhotra et al (2020 - PMID: 32820033) report on 10 unrelated individuals with de novo missense LMBRD2 variants.

Features included DD (9/10), ID (6/8 of relevant age), microcephaly (7/10), seizures (5/10 - >=3 different variants), structural brain abnormalities (e.g. thin CC in 6/9), highly variable ocular abnormalities (5/10) and dysmorphic features in some (7/10 - nonspecific).

All had variable prior non-diagnostic genetic tests (CMA, gene panel, mendeliome, karyotype). WES/WGS revealed LMBRD2 missense variants, in all cases de novo. A single individual had additional variants with weaker evidence of pathogenicity.

5 unique missense SNVs and 2 recurrent ones (NM_001007527:c.367T>C - p.Trp123Arg / c.1448G>A - p.Arg483His) were identified. These occurred in different exons. Variants were not present in gnomAD and all had several in silico predictions in favor of a deleterious effect.

There was phenotypic variability among individuals with the same variant (e.g. seizures in 1/3 and microchephaly in 2/3 of those harboring R483H).

The gene has a pLI of 0 (although o/e ranges from 0.23 to 0.55), %HI of 15.13 and z-score of 2.27. The authors presume that haploinsufficiency may not apply, and consider a gain-of-function/dominant-negative effect more likely.

As the authors comment LMBRD2 (LMBR1 domain containing 2) encodes a membrane bound protein with poorly described function. It is widely expressed across tissues with notable expression in human brain (also in Drosophila, or Xenopus laevis). It displays high interspecies conservation.

It has been suggested (Paek et al - PMID: 28388415) that LMBRD2 is a potential regulator of β2 adrenoreceptor signalling through involvement in GPCR signalling.

► Kaplanis et al (2020 - https://doi.org/10.1101/797787) in a dataset of 31058 parent-offspring trios (WES) previously identified 3 individuals with developmental disorder, harboring c.1448G>A - p.Arg483His. These individuals (1 from the DDD study, and 2 GeneDx patients) appear in Decipher. [ https://decipher.sanger.ac.uk/ddd/research-variant/40e17c78cc9655a6721006fc1e0c98db/overview ]. The preprint by Kaplanis et al is cited by Malhotra et al, with Arg483His reported in 6 patients overall in both studies.
Sources: Literature
Intellectual disability v3.262 SPOP Arina Puzriakova changed review comment from: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.

Associated with Nabais Sa-de Vries syndrome in OMIM, and a probable gene for SPOP-related Neurodevelopmental Disorder in G2P.

At least 7 unrelated individuals with mild-severe ID, associated with de novo missense variants in the SPOP gene. Additional variable features include craniofacial dysmorphisms, cardiovascular abnormalities, hearing impairment, and endocrine abnormalities. Functional studies show differing effects of the variants (gain-of-function or dominant-negative) that correspond to the different clinical manifestations.; to: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.

Associated with Nabais Sa-de Vries syndrome in OMIM, and a probable gene for SPOP-related Neurodevelopmental Disorder in G2P.

At least 7 unrelated individuals with mild-severe ID, associated with de novo missense variants in the SPOP gene. Additional variable features include craniofacial dysmorphisms, cardiovascular abnormalities, hearing impairment, and endocrine abnormalities. Functional studies show differing effects of the variants (gain-of-function or dominant-negative) that correspond to differences in additional clinical manifestations.
Intellectual disability v3.262 TASP1 Arina Puzriakova Tag for-review tag was added to gene: TASP1.
Intellectual disability v3.262 TASP1 Arina Puzriakova Classified gene: TASP1 as Amber List (moderate evidence)
Intellectual disability v3.262 TASP1 Arina Puzriakova Added comment: Comment on list classification: Sufficient cases for a GREEN rating at the next major review.

Associated with phenotype in OMIM, and a possible gene for Developmental delay, happy demeanor, distinctive facial features, and congenital anomalies in G2P.

Four unrelated patients with homozygous LOF variants in this gene all exhibited a consistent phenotype which included global developmental delay. All variants segregated with disease, but no functional studies of the variants or patient cells were not performed.
Intellectual disability v3.262 TASP1 Arina Puzriakova Gene: tasp1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.261 SPOP Arina Puzriakova Phenotypes for gene: SPOP were changed from Intellectual disability; dysmorphism; microcephaly; macrocephaly to Nabais Sa-de Vries syndrome, type 1, 618828; Nabais Sa-de Vries syndrome, type 2, 618829
Intellectual disability v3.260 SPOP Arina Puzriakova Tag for-review tag was added to gene: SPOP.
Intellectual disability v3.260 SPOP Arina Puzriakova Classified gene: SPOP as Amber List (moderate evidence)
Intellectual disability v3.260 SPOP Arina Puzriakova Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.

Associated with Nabais Sa-de Vries syndrome in OMIM, and a probable gene for SPOP-related Neurodevelopmental Disorder in G2P.

At least 7 unrelated individuals with mild-severe ID, associated with de novo missense variants in the SPOP gene. Additional variable features include craniofacial dysmorphisms, cardiovascular abnormalities, hearing impairment, and endocrine abnormalities. Functional studies show differing effects of the variants (gain-of-function or dominant-negative) that correspond to the different clinical manifestations.
Intellectual disability v3.260 SPOP Arina Puzriakova Gene: spop has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.259 POMK Arina Puzriakova Publications for gene: POMK were set to
Intellectual disability v3.258 POMK Arina Puzriakova Classified gene: POMK as Amber List (moderate evidence)
Intellectual disability v3.258 POMK Arina Puzriakova Added comment: Comment on list classification: Sufficient cases to support causation; however, ID is unlikely to be the main presenting feature of this phenotype - therefore, rating Amber on this panel.

POMK is rated Green on other relevant panels including Congenital muscular dystrophy, Hydrocephalus, and Arthrogryposis.
Intellectual disability v3.258 POMK Arina Puzriakova Gene: pomk has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.257 PISD Arina Puzriakova Classified gene: PISD as Amber List (moderate evidence)
Intellectual disability v3.257 PISD Arina Puzriakova Added comment: Comment on list classification: Four families presenting a DD/ID phenotype, but three share the same founder variant - Rating Amber until further cases are reported (added to watchlist).
Intellectual disability v3.257 PISD Arina Puzriakova Gene: pisd has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.256 PISD Arina Puzriakova Tag watchlist tag was added to gene: PISD.
Intellectual disability v3.256 PISD Arina Puzriakova reviewed gene: PISD: Rating: ; Mode of pathogenicity: None; Publications: 31263216, 30858161, 30488656, 3561949; Phenotypes: Liberfarb syndrome, 618889; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.256 PIBF1 Arina Puzriakova Tag for-review tag was added to gene: PIBF1.
Intellectual disability v3.256 PIBF1 Arina Puzriakova Classified gene: PIBF1 as Amber List (moderate evidence)
Intellectual disability v3.256 PIBF1 Arina Puzriakova Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review - at least 7 families (4 with same founder variant) with Joubert syndrome, which is associated with global DD/ID.
Intellectual disability v3.256 PIBF1 Arina Puzriakova Gene: pibf1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.255 PIBF1 Arina Puzriakova reviewed gene: PIBF1: Rating: GREEN; Mode of pathogenicity: None; Publications: 26167768, 29695797, 30858804; Phenotypes: Joubert syndrome 33, 617767; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.255 TAF1C Konstantinos Varvagiannis gene: TAF1C was added
gene: TAF1C was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: TAF1C was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TAF1C were set to 32779182
Phenotypes for gene: TAF1C were set to Global developmental delay; Intellectual disability; Spasticity; Strabismus; Seizures; Abnormality of nervous system morphology
Penetrance for gene: TAF1C were set to Complete
Review for gene: TAF1C was set to AMBER
Added comment: Knuutinen et al (2020 - PMID: 32779182) report on 2 individuals from 2 consanguineous families, homozygous for TAF1C missense variants.

Both presented with an early onset neurological phenotype with severe global DD, ID (2/2 - moderate and profound), spasticity (2/2), ophthalmic findings (strabismus 2/2, nystagmus 1/2). Epilepsy, abnormal brain MRI (cerebral and cerebellar atrophy and white matter hyperintensities) as well and additional findings were reported in one (always the same individual).

Following a normal CMA, exome in the first case revealed a homozygous missense SNV (NM_005679.3:c.1165C>T / p.Arg389Cys) supported by in silico predictions. mRNA and protein levels were substantially reduced in fibroblasts from this subject. Only the patient and parents were tested for the variant but not 3 unaffected sibs (fig1).

The second individual was homozygous for another missense variant (p.Arg405Cys) also supported by in silico predictions. The girl was the single affected person within the family with an unaffected sib and parents heterozygous for the variant. Several other unaffected relatives in the extended pedigree were either carriers for this variant or homozygous for the wt allele.

TAF1C encodes the TATA-box binding protein associated factor (TAF) RNA polymerase I subunit.

RNA polymerase I (Pol I) transcribes genes to produce rRNA. For Pol I to initiate transcription, two transcription factors are required : UBF (upstream binding factor encoded by UBTF) and SL1 (selectivity factor 1). The latter is formed by TBP (TATA-binding protein) and 3 Pol I-specific TBP-associated factors (TAFs).

A recurrent de novo missense variant in UBTF (encoding the other Pol I transcription factor) causes a disorder with highly similar features. The specific variant acts through a gain-of-function mechanism (and not by LoF which appears to apply for TAF1C based on expression data).

The authors hypothesize that altered Pol I activity and resulting ribosomal stress could cause the microcephaly and leukodystrophy (both reported in 1 - the same - individual).

As a result, TAF1C may be considered for inclusion in the ID panel with amber rating pending further evidence.
Sources: Literature
Intellectual disability v3.255 ZMPSTE24 Arina Puzriakova commented on gene: ZMPSTE24
Intellectual disability v3.255 ZIC3 Arina Puzriakova commented on gene: ZIC3
Intellectual disability v3.255 XPC Arina Puzriakova commented on gene: XPC
Intellectual disability v3.255 WRAP53 Arina Puzriakova commented on gene: WRAP53
Intellectual disability v3.255 WNT7A Arina Puzriakova commented on gene: WNT7A
Intellectual disability v3.255 WNT3 Arina Puzriakova commented on gene: WNT3
Intellectual disability v3.255 WNT10B Arina Puzriakova commented on gene: WNT10B
Intellectual disability v3.255 WDR35 Arina Puzriakova commented on gene: WDR35
Intellectual disability v3.254 WDR34 Arina Puzriakova commented on gene: WDR34
Intellectual disability v3.254 WDR19 Arina Puzriakova commented on gene: WDR19
Intellectual disability v3.254 VSX2 Arina Puzriakova commented on gene: VSX2
Intellectual disability v3.254 UVSSA Arina Puzriakova commented on gene: UVSSA
Intellectual disability v3.254 USB1 Arina Puzriakova commented on gene: USB1
Intellectual disability v3.254 UROS Arina Puzriakova commented on gene: UROS
Intellectual disability v3.254 UGT1A1 Arina Puzriakova commented on gene: UGT1A1
Intellectual disability v3.254 TYRP1 Arina Puzriakova commented on gene: TYRP1
Intellectual disability v3.254 TYR Arina Puzriakova commented on gene: TYR
Intellectual disability v3.254 TXNL4A Arina Puzriakova commented on gene: TXNL4A
Intellectual disability v3.254 TUBA8 Arina Puzriakova commented on gene: TUBA8
Intellectual disability v3.254 TSHR Arina Puzriakova commented on gene: TSHR
Intellectual disability v3.254 TRPV4 Arina Puzriakova commented on gene: TRPV4
Intellectual disability v3.254 TRPS1 Arina Puzriakova commented on gene: TRPS1
Intellectual disability v3.254 TRPM1 Arina Puzriakova commented on gene: TRPM1
Intellectual disability v3.254 TRIP11 Arina Puzriakova commented on gene: TRIP11
Intellectual disability v3.254 TRAPPC2 Arina Puzriakova commented on gene: TRAPPC2
Intellectual disability v3.254 TP63 Arina Puzriakova commented on gene: TP63
Intellectual disability v3.254 TMPRSS6 Arina Puzriakova commented on gene: TMPRSS6
Intellectual disability v3.254 TMEM126B Arina Puzriakova commented on gene: TMEM126B
Intellectual disability v3.254 TGFB3 Arina Puzriakova commented on gene: TGFB3
Intellectual disability v3.254 TGFB2 Arina Puzriakova commented on gene: TGFB2
Intellectual disability v3.254 TEK Arina Puzriakova commented on gene: TEK
Intellectual disability v3.254 TCF12 Arina Puzriakova commented on gene: TCF12
Intellectual disability v3.254 TBXAS1 Arina Puzriakova commented on gene: TBXAS1
Intellectual disability v3.254 TBX5 Arina Puzriakova commented on gene: TBX5
Intellectual disability v3.254 TBX4 Arina Puzriakova commented on gene: TBX4
Intellectual disability v3.254 TBX3 Arina Puzriakova commented on gene: TBX3
Intellectual disability v3.254 TBX22 Arina Puzriakova commented on gene: TBX22
Intellectual disability v3.254 TBX20 Arina Puzriakova commented on gene: TBX20
Intellectual disability v3.254 TBX15 Arina Puzriakova commented on gene: TBX15
Intellectual disability v3.254 TAB2 Arina Puzriakova commented on gene: TAB2
Intellectual disability v3.254 STS Arina Puzriakova commented on gene: STS
Intellectual disability v3.254 STAT1 Arina Puzriakova commented on gene: STAT1
Intellectual disability v3.254 STAR Arina Puzriakova commented on gene: STAR
Intellectual disability v3.254 SRY Arina Puzriakova commented on gene: SRY
Intellectual disability v3.254 SPEG Arina Puzriakova commented on gene: SPEG
Intellectual disability v3.254 SPAG1 Arina Puzriakova commented on gene: SPAG1
Intellectual disability v3.254 SOX17 Arina Puzriakova commented on gene: SOX17
Intellectual disability v3.254 SMCHD1 Arina Puzriakova commented on gene: SMCHD1
Intellectual disability v3.254 SCN4A Arina Puzriakova commented on gene: SCN4A
Intellectual disability v3.254 RUNX2 Arina Puzriakova commented on gene: RUNX2
Intellectual disability v3.254 RSPO4 Arina Puzriakova commented on gene: RSPO4
Intellectual disability v3.254 RSPH3 Arina Puzriakova commented on gene: RSPH3
Intellectual disability v3.254 RSPH1 Arina Puzriakova commented on gene: RSPH1
Intellectual disability v3.254 RPS19 Arina Puzriakova commented on gene: RPS19
Intellectual disability v3.254 RPGRIP1 Arina Puzriakova commented on gene: RPGRIP1
Intellectual disability v3.254 RPE65 Arina Puzriakova commented on gene: RPE65
Intellectual disability v3.254 ROBO3 Arina Puzriakova commented on gene: ROBO3
Intellectual disability v3.254 RETREG1 Arina Puzriakova commented on gene: RETREG1
Intellectual disability v3.253 RASA1 Arina Puzriakova commented on gene: RASA1
Intellectual disability v3.253 PGM1 Arina Puzriakova commented on gene: PGM1
Intellectual disability v3.253 PDE6G Arina Puzriakova commented on gene: PDE6G
Intellectual disability v3.253 PAX9 Arina Puzriakova commented on gene: PAX9
Intellectual disability v3.253 PAX3 Arina Puzriakova commented on gene: PAX3
Intellectual disability v3.253 PAPSS2 Arina Puzriakova commented on gene: PAPSS2
Intellectual disability v3.253 OTULIN Arina Puzriakova commented on gene: OTULIN
Intellectual disability v3.253 OTOGL Arina Puzriakova commented on gene: OTOGL
Intellectual disability v3.253 ORC6 Arina Puzriakova commented on gene: ORC6
Intellectual disability v3.253 NRXN2 Arina Puzriakova commented on gene: NRXN2
Intellectual disability v3.253 NR5A1 Arina Puzriakova commented on gene: NR5A1
Intellectual disability v3.253 NR2F2 Arina Puzriakova commented on gene: NR2F2
Intellectual disability v3.253 NPR2 Arina Puzriakova commented on gene: NPR2
Intellectual disability v3.253 NPHS1 Arina Puzriakova commented on gene: NPHS1
Intellectual disability v3.253 NPHP4 Arina Puzriakova commented on gene: NPHP4
Intellectual disability v3.253 NOTCH2 Arina Puzriakova commented on gene: NOTCH2
Intellectual disability v3.253 NOG Arina Puzriakova commented on gene: NOG
Intellectual disability v3.253 NODAL Arina Puzriakova commented on gene: NODAL
Intellectual disability v3.253 NMNAT1 Arina Puzriakova commented on gene: NMNAT1
Intellectual disability v3.253 NKX3-2 Arina Puzriakova commented on gene: NKX3-2
Intellectual disability v3.253 NEK1 Arina Puzriakova commented on gene: NEK1
Intellectual disability v3.253 MYO5B Arina Puzriakova commented on gene: MYO5B
Intellectual disability v3.253 MYH9 Arina Puzriakova commented on gene: MYH9
Intellectual disability v3.253 MYH8 Arina Puzriakova commented on gene: MYH8
Intellectual disability v3.253 MYH6 Arina Puzriakova commented on gene: MYH6
Intellectual disability v3.253 MSX2 Arina Puzriakova commented on gene: MSX2
Intellectual disability v3.253 MSX1 Arina Puzriakova commented on gene: MSX1
Intellectual disability v3.253 MNX1 Arina Puzriakova commented on gene: MNX1
Intellectual disability v3.253 MMP13 Arina Puzriakova commented on gene: MMP13
Intellectual disability v3.253 MFRP Arina Puzriakova commented on gene: MFRP
Intellectual disability v3.253 MESP2 Arina Puzriakova commented on gene: MESP2
Intellectual disability v3.253 MC2R Arina Puzriakova commented on gene: MC2R
Intellectual disability v3.253 MATN3 Arina Puzriakova commented on gene: MATN3
Intellectual disability v3.253 MAPK10 Arina Puzriakova commented on gene: MAPK10
Intellectual disability v3.253 MAP3K1 Arina Puzriakova commented on gene: MAP3K1
Intellectual disability v3.253 LTBP3 Arina Puzriakova commented on gene: LTBP3
Intellectual disability v3.253 LTBP2 Arina Puzriakova commented on gene: LTBP2
Intellectual disability v3.253 LRRC6 Arina Puzriakova commented on gene: LRRC6
Intellectual disability v3.253 LRP4 Arina Puzriakova commented on gene: LRP4
Intellectual disability v3.253 LMX1B Arina Puzriakova commented on gene: LMX1B
Intellectual disability v3.253 LMNA Arina Puzriakova commented on gene: LMNA
Intellectual disability v3.253 LHX4 Arina Puzriakova commented on gene: LHX4
Intellectual disability v3.253 LHX3 Arina Puzriakova commented on gene: LHX3
Intellectual disability v3.253 LFNG Arina Puzriakova commented on gene: LFNG
Intellectual disability v3.253 LEMD3 Arina Puzriakova commented on gene: LEMD3