PanelApp

Activity

Filter

Cancel
Date Panel Item Activity
3000 actions
Intellectual disability syndromic and non-syndromic v0.5168 JPH3 Zornitza Stark reviewed gene: JPH3: Rating: AMBER; Mode of pathogenicity: None; Publications: 36273396; Phenotypes: Neurodevelopmental disorder, MONDO:0700092, JPH3-related; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.5168 ATP9A Zornitza Stark Phenotypes for gene: ATP9A were changed from Neurodevelopmental delay; Postnatal microcephaly; Failure to thrive; Gastrointestinal symptoms to Neurodevelopmental disorder with poor growth and behavioural abnormalities, MIM# 620242
Intellectual disability syndromic and non-syndromic v0.5167 ATP9A Zornitza Stark edited their review of gene: ATP9A: Changed phenotypes: Neurodevelopmental disorder with poor growth and behavioural abnormalities, MIM# 620242
Intellectual disability syndromic and non-syndromic v0.5167 GOLGA2 Zornitza Stark Phenotypes for gene: GOLGA2 were changed from Neuromuscular disorder to Developmental delay with hypotonia, myopathy, and brain abnormalities, MIM 620240
Intellectual disability syndromic and non-syndromic v0.5166 GOLGA2 Zornitza Stark Publications for gene: GOLGA2 were set to PMID: 30237576; 26742501
Intellectual disability syndromic and non-syndromic v0.5165 GOLGA2 Zornitza Stark edited their review of gene: GOLGA2: Added comment: Third family reported.; Changed publications: 34424553; Changed phenotypes: Developmental delay with hypotonia, myopathy, and brain abnormalities, MIM 620240; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.5165 RAB39B Achchuthan Shanmugasundram reviewed gene: RAB39B: Rating: GREEN; Mode of pathogenicity: None; Publications: 20159109, 25434005, 11050621, 29152164, 32873259, 34761259; Phenotypes: Intellectual developmental disorder, X-linked 72, OMIM:300271, Waisman syndrome, OMIM:311510; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability syndromic and non-syndromic v0.5165 WDR11 Zornitza Stark reviewed gene: WDR11: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Intellectual developmental disorder, autosomal recessive 78, MIM# 620237; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.5165 TRPM3 Zornitza Stark Phenotypes for gene: TRPM3 were changed from Neurodevelopmental disorder, MONDO:0700092, TRPM3-related to Neurodevelopmental disorder with hypotonia, dysmorphic facies, and skeletal anomalies, with or without seizures, MIM# 620224
Intellectual disability syndromic and non-syndromic v0.5164 TRPM3 Zornitza Stark edited their review of gene: TRPM3: Changed phenotypes: Neurodevelopmental disorder with hypotonia, dysmorphic facies, and skeletal anomalies, with or without seizures, MIM# 620224
Intellectual disability syndromic and non-syndromic v0.5164 WDR5 Bryony Thompson Publications for gene: WDR5 were set to DOI:https://doi.org/10.1016/j.xhgg.2022.100157
Intellectual disability syndromic and non-syndromic v0.5163 WDR5 Bryony Thompson edited their review of gene: WDR5: Changed publications: 36408368
Intellectual disability syndromic and non-syndromic v0.5163 CCDC84 Zornitza Stark Marked gene: CCDC84 as ready
Intellectual disability syndromic and non-syndromic v0.5163 CCDC84 Zornitza Stark Gene: ccdc84 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.5163 CCDC84 Zornitza Stark Classified gene: CCDC84 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.5163 CCDC84 Zornitza Stark Gene: ccdc84 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.5162 TTI1 Zornitza Stark Phenotypes for gene: TTI1 were changed from Neurodevelopmental disorder, MONDO:0700092, TTI1-related to Neurodevelopmental disorder, MONDO:0700092, TTI1-related
Intellectual disability syndromic and non-syndromic v0.5162 TTI1 Zornitza Stark Phenotypes for gene: TTI1 were changed from Intellectual disability to Neurodevelopmental disorder, MONDO:0700092, TTI1-related
Intellectual disability syndromic and non-syndromic v0.5161 OGDH Zornitza Stark Classified gene: OGDH as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.5161 OGDH Zornitza Stark Gene: ogdh has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5162 OGDH Zornitza Stark Marked gene: OGDH as ready
Intellectual disability syndromic and non-syndromic v0.5162 OGDH Zornitza Stark Gene: ogdh has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5162 FICD Elena Savva Classified gene: FICD as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.5162 FICD Elena Savva Gene: ficd has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.5161 FICD Elena Savva Classified gene: FICD as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.5161 FICD Elena Savva Gene: ficd has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.5161 FICD Elena Savva Classified gene: FICD as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.5161 FICD Elena Savva Gene: ficd has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.5161 TTI1 Zornitza Stark Classified gene: TTI1 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.5161 TTI1 Zornitza Stark Gene: tti1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5160 FICD Elena Savva Marked gene: FICD as ready
Intellectual disability syndromic and non-syndromic v0.5160 FICD Elena Savva Gene: ficd has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v0.5160 FICD Elena Savva gene: FICD was added
gene: FICD was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: FICD was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FICD were set to 36704923
Phenotypes for gene: FICD were set to Neurodevelopmental disorder, FICD-related (MONDO#0700092)
Review for gene: FICD was set to AMBER
Added comment: PMID: 36704923:
- five individuals (3 families) w/ infancy onset diabetes mellitus (5/5) and severe neurodevelopmental delay (4/5)
- all homozygous for p.R371S
- variant expression in E. coli showed loss of affinity, deregulates BiP-AMP and affects secretion
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.5160 OGDH Zornitza Stark Classified gene: OGDH as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.5160 OGDH Zornitza Stark Gene: ogdh has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5159 OGDH Zornitza Stark gene: OGDH was added
gene: OGDH was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: OGDH was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: OGDH were set to 36520152; 32383294
Phenotypes for gene: OGDH were set to Oxoglutarate dehydrogenase deficiency, MIM# 203740
Review for gene: OGDH was set to GREEN
Added comment: 6 individuals reported with bi-allelic variants in this gene and DD.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.5158 CCDC84 Lucy Spencer gene: CCDC84 was added
gene: CCDC84 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: CCDC84 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CCDC84 were set to 34009673
Phenotypes for gene: CCDC84 were set to Mosaic variegated aneuploidy syndrome 4 (MIM#620153)
Review for gene: CCDC84 was set to AMBER
Added comment: PMID: 34009673- patients with constitutional mosaic aneuploidy were found to have biallelic mutations in CENATAC(CCDC84). 2 adult siblings with mosaic aneuploidies, microcephaly, dev delay, and maculopathy. Both chet for a missense and a splice site deletion- but the paper days these both result in the creation of a novel splice site that leads to frameshifts and loss of the c-terminal 64 amino acids.

Gene is shown to be part of a spliceosome. CENATAC depletion or expression of disease mutants resulted in retention of introns in ~100 genes enriched for nucleocytoplasmic transport and cell cycle regulation, and caused chromosome segregation errors.

Functional analysis in CENATAC-depleted HeLa cells demonstrated chromosome congression defects and subsequent mitotic arrest, which could be fully rescued by wildtype but not mutant CENATAC. Expression of the MVA-associated mutants exacerbated the phenotype, suggesting that the mutant proteins dominantly repress the function of any residual wildtype protein.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.5158 TTI1 Ee Ming Wong reviewed gene: TTI1: Rating: GREEN; Mode of pathogenicity: None; Publications: DOI:https://doi.org/10.1016/j.ajhg.2023.01.006; Phenotypes: Neurodevelopmental disorder, MONDO:0700092, TTI1-related to; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability syndromic and non-syndromic v0.5158 NAE1 Zornitza Stark Phenotypes for gene: NAE1 were changed from Neurodevelopmental disorder, MONDO:0700092, NAE1-related to Neurodevelopmental disorder with dysmorphic facies and ischiopubic hypoplasia, MIM# 620210
Intellectual disability syndromic and non-syndromic v0.5157 NAE1 Zornitza Stark edited their review of gene: NAE1: Changed phenotypes: Neurodevelopmental disorder with dysmorphic facies and ischiopubic hypoplasia, MIM# 620210
Intellectual disability syndromic and non-syndromic v0.5157 TCEAL1 Zornitza Stark Phenotypes for gene: TCEAL1 were changed from Neurodevelopmental disorder, MONDO:0700092, TCEAL1-related; hypotonia; abnormal gait; developmental delay; intellectual disability; autism; dysmorphic facial features to Neurodevelopmental disorder with gait disturbance, dysmorphic facies and behavioral abnormalities, X-linked, MIM# 301094
Intellectual disability syndromic and non-syndromic v0.5156 TCEAL1 Zornitza Stark reviewed gene: TCEAL1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with gait disturbance, dysmorphic facies and behavioral abnormalities, X-linked, MIM# 301094; 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 syndromic and non-syndromic v0.5156 FGF13 Zornitza Stark Phenotypes for gene: FGF13 were changed from Developmental and epileptic encephalopathy 90, MIM# 301058; Intellectual disability; epilepsy to Developmental and epileptic encephalopathy 90, MIM# 301058; Intellectual developmental disorder, X-linked 110, MIM# 301095
Intellectual disability syndromic and non-syndromic v0.5155 FGF13 Zornitza Stark Publications for gene: FGF13 were set to 33245860
Intellectual disability syndromic and non-syndromic v0.5154 FGF13 Zornitza Stark Tag 5'UTR tag was added to gene: FGF13.
Intellectual disability syndromic and non-syndromic v0.5154 FGF13 Zornitza Stark edited their review of gene: FGF13: Added comment: PMID 34184986: 3 individuals reported with moderate to severe ID and maternally inherited 5' variant c.-32C-G; Changed publications: 33245860, 34184986; Changed phenotypes: Developmental and epileptic encephalopathy 90, MIM# 301058, Intellectual developmental disorder, X-linked 110, MIM# 301095
Intellectual disability syndromic and non-syndromic v0.5154 ZNF668 Zornitza Stark Phenotypes for gene: ZNF668 were changed from DNA damage repair defect; microcephaly; growth deficiency; severe global developmental delay; brain malformation; facial dysmorphism to Neurodevelopmental disorder with poor growth, large ears, and dysmorphic facies, MIM# 620194
Intellectual disability syndromic and non-syndromic v0.5153 SMC5 Zornitza Stark Phenotypes for gene: SMC5 were changed from Multiple congenital anomalies/dysmorphic syndrome, MONDO:0019042, SLF2-related; Atelis syndrome; microcephaly; short stature; ID to Atelis syndrome 2, MIM# 620185
Intellectual disability syndromic and non-syndromic v0.5152 SMC5 Zornitza Stark edited their review of gene: SMC5: Changed phenotypes: Atelis syndrome 2, MIM# 620185
Intellectual disability syndromic and non-syndromic v0.5152 SLF2 Zornitza Stark Phenotypes for gene: SLF2 were changed from Multiple congenital anomalies/dysmorphic syndrome, MONDO:0019042, SLF2-related; Atelis syndrome; microcephaly; short stature; ID to Atelis syndrome 1, MIM# 620184
Intellectual disability syndromic and non-syndromic v0.5151 SLF2 Zornitza Stark edited their review of gene: SLF2: Changed phenotypes: Atelis syndrome 1, MIM# 620184
Intellectual disability syndromic and non-syndromic v0.5151 NAE1 Zornitza Stark Marked gene: NAE1 as ready
Intellectual disability syndromic and non-syndromic v0.5151 NAE1 Zornitza Stark Gene: nae1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5151 NAE1 Zornitza Stark Classified gene: NAE1 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.5151 NAE1 Zornitza Stark Gene: nae1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5150 NAE1 Zornitza Stark gene: NAE1 was added
gene: NAE1 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: NAE1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NAE1 were set to 36608681
Phenotypes for gene: NAE1 were set to Neurodevelopmental disorder, MONDO:0700092, NAE1-related
Review for gene: NAE1 was set to GREEN
Added comment: Four individuals reported with bi-allelic variants and intellectual disability, ischiopubic hypoplasia, stress-mediated lymphopenia and neurodegeneration.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.5149 TRPC5 Zornitza Stark Marked gene: TRPC5 as ready
Intellectual disability syndromic and non-syndromic v0.5149 TRPC5 Zornitza Stark Gene: trpc5 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.5149 TRPC5 Zornitza Stark Classified gene: TRPC5 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.5149 TRPC5 Zornitza Stark Gene: trpc5 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.5148 TRPC5 Zornitza Stark gene: TRPC5 was added
gene: TRPC5 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: TRPC5 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: TRPC5 were set to 36323681; 24817631; 23033978; 33504798; 28191890
Phenotypes for gene: TRPC5 were set to Neurodevelopmental disorder, MONDO:0700092, TRPC5-related
Review for gene: TRPC5 was set to AMBER
Added comment: PMID: 36323681; Leitão E. et al. (2022) Nat Commun.13(1):6570:
Missense variant NM_012471.2:c.523C>T, p.(Arg175Cys in three brothers with intellectual disability (ID) and autistic spectrum disorder (ASD), inherited from an asymptomatic mother and absent in the maternal grandparents.
Whole cell patch clamp studies of HEK293 created by site-directed mutagenesis showed increased current of this calcium channel (constitutively opened).
(This variant is absent in gnomAD v2.1.1).

Also, the nonsense variant, c.965G> A, p.(Trp322*) was found in a high functioning ASD male (maternally inherited), NMD-predicted.

Other papers and TRPC5 variants that were cited to associate this gene with X-linked ID and/or ASD include:
PMID: 24817631; Mignon-Ravix, C. et al. (2014) Am. J.Med. Genet. A 164A: 1991–1997: A hemizygous 47-kb deletion in Xq23 including exon 1 of the TRPC5 gene. He had macrocephaly, delayed psychomotor development, speech delay, behavioural problems, and autistic features. Maternally inherited, and a family history compatible with X-linked inheritance (i.e., maternal great uncle was also affected, although not tested).

In addition, PMID: 36323681; Leitão E. et al. (2022) cites papers with the variants p.(Pro667Thr), p.(Arg71Gln) and p.(Trp225*).
NB. p.(Pro667Thr) is absent in gnomAD (v2.1.1), p.(Arg71Gln) is also absent (the alternative variant p.(Arg71Trp) is present once as heterozygous only). p.(Trp225*) is absent, and it should be noted that PTCs / LoF variants are very rare (pLI = 1).

However, looking further into the three references, the evidence is not as clear or as accurate as was stated.

The missense variant c.1999C>A, p.(Pro667Thr), was stated as de novo, but was actually maternally inherited but was still considered a candidate for severe intellectual disability (shown in the Appendix, Patient 93, with severe speech delay, autism spectrum disorder and Gilles de la Tourette). This patient also has a de novo MTF1 variant. Reference: PMID: 23033978; de Ligt, J. et al. (2012) N. Engl. J. Med. 367: 1921–1929).

Missense variant (de novo): c.212G>A, p.(Arg71Gln), was found as part of the Deciphering Developmental Disorders (DDD) study and is shown in individual 164 in Supplementary Table 2 of PMID: 33504798; Martin, HC. et al. (2021) Nat. Commun.12: 627. Also displayed in DECIPHER (DDD research variant) with several phenotype traits, but ID and ASD are not specifically mentioned.

Nonsense variant: c.674G>A. p.(Trp225*) was stated as de novo but was inherited (reference PMID: 28191890; Kosmicki, JA. et al. (2017) Nat. Genet. 49: 504–510. Supplement Table 7). This was a study of severe intellectual delay, developmental delay / autism. (NB. The de novo p.(Arg71Gln) variant from the DDD study is also listed (subject DDD 342 in Supplement 4 / Table 2).
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.5147 CRLS1 Zornitza Stark Phenotypes for gene: CRLS1 were changed from Mitochondrial disease MONDO:0044970 CRLS1-related to Combined oxidative phosphorylation deficiency 57, MIM# 620167
Intellectual disability syndromic and non-syndromic v0.5146 SLC31A1 Zornitza Stark Publications for gene: SLC31A1 were set to PMID: 35913762
Intellectual disability syndromic and non-syndromic v0.5145 SLC31A1 Zornitza Stark reviewed gene: SLC31A1: Rating: RED; Mode of pathogenicity: None; Publications: 36562171; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.5145 CDK16 Zornitza Stark Publications for gene: CDK16 were set to 25644381
Intellectual disability syndromic and non-syndromic v0.5144 ZMYM3 Zornitza Stark Mode of inheritance for gene: ZMYM3 was changed from Unknown to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability syndromic and non-syndromic v0.5143 CDK16 Alison Yeung Phenotypes for gene: CDK16 were changed from Neurodevelopmental disorder (MONDO#0700092) CDK16-related to Neurodevelopmental disorder (MONDO#0700092) CDK16-related
Intellectual disability syndromic and non-syndromic v0.5142 CDK16 Alison Yeung Phenotypes for gene: CDK16 were changed from Intellectual disability to Neurodevelopmental disorder (MONDO#0700092) CDK16-related
Intellectual disability syndromic and non-syndromic v0.5141 CDK16 Alison Yeung Classified gene: CDK16 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.5141 CDK16 Alison Yeung Gene: cdk16 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5140 TRA2B Seb Lunke Phenotypes for gene: TRA2B were changed from Neurodevelopmental disorder, TRA2B-related, MONDO# 0700092 to Neurodevelopmental disorder, TRA2B-related, MONDO# 0700092
Intellectual disability syndromic and non-syndromic v0.5140 EIF4A2 Zornitza Stark Classified gene: EIF4A2 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.5140 EIF4A2 Zornitza Stark Gene: eif4a2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5139 TRA2B Seb Lunke Phenotypes for gene: TRA2B were changed from Neurodevelopmental disorder, TRA2B-related (MONDO#0700092) to Neurodevelopmental disorder, TRA2B-related, MONDO# 0700092
Intellectual disability syndromic and non-syndromic v0.5139 EIF4A2 Zornitza Stark Classified gene: EIF4A2 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.5139 EIF4A2 Zornitza Stark Gene: eif4a2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5139 TRA2B Seb Lunke Marked gene: TRA2B as ready
Intellectual disability syndromic and non-syndromic v0.5139 TRA2B Seb Lunke Gene: tra2b has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5139 EIF4A2 Zornitza Stark Marked gene: EIF4A2 as ready
Intellectual disability syndromic and non-syndromic v0.5139 EIF4A2 Zornitza Stark Gene: eif4a2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5139 CDK16 Belinda Chong changed review comment from: Total of 3 families with ID 1 with ASD.
PMID 36323681:
Identified a nonsense variant (c.961 G > T, p.(Glu321*)) in a 42-year-old patient with ID and spasticity.
A missense variant (c.1039G > T, p.(Gly347Cys)) affecting a highly conserved amino acid of the kinase domain (CADD PHRED score: 32) was identified by genome sequencing in a male patient with ID, ASD, and epilepsy, whose family history was compatible with X-linked inheritance.

PMID 31981491:
In addition, a nonsense variant (c.46C > T, p.(Arg16*)) was recently reported in a patient with ASD.

PMID 25644381:
Single family described in this manuscript describing multiple candidate genes for XLID.; to: 3 families with ID 1 with ASD.
PMID 36323681:
Identified a nonsense variant (c.961 G > T, p.(Glu321*)) in a 42-year-old patient with ID and spasticity.
A missense variant (c.1039G > T, p.(Gly347Cys)) affecting a highly conserved amino acid of the kinase domain (CADD PHRED score: 32) was identified by genome sequencing in a male patient with ID, ASD, and epilepsy, whose family history was compatible with X-linked inheritance.

PMID 31981491:
In addition, a nonsense variant (c.46C > T, p.(Arg16*)) was recently reported in a patient with ASD.

PMID 25644381:
Single family described in this manuscript describing multiple candidate genes for XLID.
Intellectual disability syndromic and non-syndromic v0.5139 CDK16 Belinda Chong changed review comment from: Total of 3 families with ID i with ASD.
PMID 36323681:
Identified a nonsense variant (c.961 G > T, p.(Glu321*)) in a 42-year-old patient with ID and spasticity.
A missense variant (c.1039G > T, p.(Gly347Cys)) affecting a highly conserved amino acid of the kinase domain (CADD PHRED score: 32) was identified by genome sequencing in a male patient with ID, ASD, and epilepsy, whose family history was compatible with X-linked inheritance.

PMID 31981491:
In addition, a nonsense variant (c.46C > T, p.(Arg16*)) was recently reported in a patient with ASD.

PMID 25644381:
Single family described in this manuscript describing multiple candidate genes for XLID.; to: Total of 3 families with ID 1 with ASD.
PMID 36323681:
Identified a nonsense variant (c.961 G > T, p.(Glu321*)) in a 42-year-old patient with ID and spasticity.
A missense variant (c.1039G > T, p.(Gly347Cys)) affecting a highly conserved amino acid of the kinase domain (CADD PHRED score: 32) was identified by genome sequencing in a male patient with ID, ASD, and epilepsy, whose family history was compatible with X-linked inheritance.

PMID 31981491:
In addition, a nonsense variant (c.46C > T, p.(Arg16*)) was recently reported in a patient with ASD.

PMID 25644381:
Single family described in this manuscript describing multiple candidate genes for XLID.
Intellectual disability syndromic and non-syndromic v0.5139 EIF4A2 Zornitza Stark Classified gene: EIF4A2 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.5139 EIF4A2 Zornitza Stark Gene: eif4a2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5138 CDK16 Belinda Chong commented on gene: CDK16: Total of 3 families with ID i with ASD.
PMID 36323681:
Identified a nonsense variant (c.961 G > T, p.(Glu321*)) in a 42-year-old patient with ID and spasticity.
A missense variant (c.1039G > T, p.(Gly347Cys)) affecting a highly conserved amino acid of the kinase domain (CADD PHRED score: 32) was identified by genome sequencing in a male patient with ID, ASD, and epilepsy, whose family history was compatible with X-linked inheritance.

PMID 31981491:
In addition, a nonsense variant (c.46C > T, p.(Arg16*)) was recently reported in a patient with ASD.

PMID 25644381:
Single family described in this manuscript describing multiple candidate genes for XLID.
Intellectual disability syndromic and non-syndromic v0.5138 TRA2B Seb Lunke Classified gene: TRA2B as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.5138 TRA2B Seb Lunke Gene: tra2b has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5138 CDK16 Belinda Chong reviewed gene: CDK16: Rating: GREEN; Mode of pathogenicity: None; Publications: 36323681, 31981491, 25644381; Phenotypes: Neurodevelopmental disorder (MONDO#0700092) CDK16-related; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability syndromic and non-syndromic v0.5138 TRA2B Seb Lunke Classified gene: TRA2B as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.5138 TRA2B Seb Lunke Gene: tra2b has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5137 ZMYM3 Zornitza Stark Publications for gene: ZMYM3 were set to 24721225
Intellectual disability syndromic and non-syndromic v0.5136 ZMYM3 Zornitza Stark Phenotypes for gene: ZMYM3 were changed from to Neurodevelopmental disorder, MONDO:0700092, ZMYM3-related
Intellectual disability syndromic and non-syndromic v0.5135 ZMYM3 Zornitza Stark Classified gene: ZMYM3 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.5135 ZMYM3 Zornitza Stark Gene: zmym3 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5134 EIF4A2 Dean Phelan gene: EIF4A2 was added
gene: EIF4A2 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: EIF4A2 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: EIF4A2 were set to PMID: 36528028
Phenotypes for gene: EIF4A2 were set to Neurodevelopmental disorder (MONDO:0700092), EIF4A2-related
Mode of pathogenicity for gene: EIF4A2 was set to Other
Review for gene: EIF4A2 was set to GREEN
Added comment: PMID: 36528028
- EIF4A2 variants were observed in 15 individuals from 14 families. Affected individuals had a range of symptoms including global developmental delay (9/15), ID (7/15), epilepsy (11/15) and structural brain alterations (10/15). Monoallelic and biallelic variants were reported and functional studies showed both LOF and GOF disease mechanisms.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.5134 TRA2B Elena Savva gene: TRA2B was added
gene: TRA2B was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: TRA2B was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: TRA2B were set to PMID: 36549593
Phenotypes for gene: TRA2B were set to Neurodevelopmental disorder, TRA2B-related (MONDO#0700092)
Review for gene: TRA2B was set to GREEN
Added comment: PMID: 36549593
- 12 individuals with ID and dev delay. Additional features include infantile spams 6/12, hypotonia 12/12, dilated brain ventricles 6/12, microcephaly 5/12
- All variants result in the loss of 1/2 transcripts (start-losses or PTCs upstream of a second translation start position). Shorter transcript expression is increased, longer transcript expression is decreased.
- Apparently het mice K/O are normal, but complete K/O cannot develop embryonically.
- DN mechanism suggested
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.5133 ZMYM3 Belinda Chong reviewed gene: ZMYM3: Rating: GREEN; Mode of pathogenicity: None; Publications: 36586412, 24721225; Phenotypes: Neurodevelopmental disorders (NDDs); 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 syndromic and non-syndromic v0.5133 BUB1 Zornitza Stark Phenotypes for gene: BUB1 were changed from Neurodevelopmental disorder, BUB1-related MONDO:0700092; Intellectual disability and microcephaly to Primary microcephaly-30 (MCPH30), MIM#620183
Intellectual disability syndromic and non-syndromic v0.5132 BUB1 Zornitza Stark reviewed gene: BUB1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Primary microcephaly-30 (MCPH30), MIM#620183; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.5132 PTPN4 Zornitza Stark Phenotypes for gene: PTPN4 were changed from Intellectual disability; developmental delay to Neurodevelopmental disorder, MONDO:0700092, PTPN4-related
Intellectual disability syndromic and non-syndromic v0.5131 CLDN5 Zornitza Stark Marked gene: CLDN5 as ready
Intellectual disability syndromic and non-syndromic v0.5131 CLDN5 Zornitza Stark Gene: cldn5 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5131 CLDN5 Zornitza Stark Phenotypes for gene: CLDN5 were changed from seizures; developmental delay; microcephaly; brain calcifications to Syndromic disorder, MONDO:0002254, CLDN5-related
Intellectual disability syndromic and non-syndromic v0.5130 CLDN5 Zornitza Stark Classified gene: CLDN5 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.5130 CLDN5 Zornitza Stark Gene: cldn5 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5129 CLDN5 Zornitza Stark reviewed gene: CLDN5: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Syndromic disorder, MONDO:0002254, CLDN5-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.5129 SETD2 Zornitza Stark Phenotypes for gene: SETD2 were changed from Luscan-Lumish syndrome, MIM#616831 to Luscan-Lumish syndrome, MIM#616831; Rabin-Pappas syndrome,MIM# 620155; Intellectual developmental disorder, autosomal dominant 70, MIM# 620157
Intellectual disability syndromic and non-syndromic v0.5128 SETD2 Zornitza Stark Publications for gene: SETD2 were set to 29681085
Intellectual disability syndromic and non-syndromic v0.5127 SETD2 Zornitza Stark edited their review of gene: SETD2: Added comment: PMID 32710489: 12 unrelated patients, ranging from 1 month to 12 years of age, with a multisystemic neurodevelopmental disorder associated with a specific de novo heterozygous mutation in the SETD2 gene (R1740W).

Key clinical features: severely impaired global development apparent from infancy, feeding difficulties with failure to thrive, small head circumference, and dysmorphic facial features. Affected individuals have impaired intellectual development and hypotonia; they do not achieve walking or meaningful speech. Other neurologic findings may include seizures, hearing loss, ophthalmologic defects, and brain imaging abnormalities. There is variable involvement of other organ systems, including skeletal, genitourinary, cardiac, and possibly endocrine.

Further 3 unrelated patients identified with mild to moderately impaired intellectual development associated with a specific de novo heterozygous mutation in the SETD2 gene (R1740Q).

These are distinct clinically from Luscan-Lumish syndrome, which is characterised by overgrowth.; Changed publications: 29681085, 32710489; Changed phenotypes: Luscan-Lumish syndrome, MIM#616831, Rabin-Pappas syndrome,MIM# 620155, Intellectual developmental disorder, autosomal dominant 70, MIM# 620157
Intellectual disability syndromic and non-syndromic v0.5127 CLDN5 Suliman Khan gene: CLDN5 was added
gene: CLDN5 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: CLDN5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CLDN5 were set to PMID: 36477332
Phenotypes for gene: CLDN5 were set to seizures; developmental delay; microcephaly; brain calcifications
Penetrance for gene: CLDN5 were set to Complete
Mode of pathogenicity for gene: CLDN5 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: CLDN5 was set to GREEN
Added comment: PMID: 36477332 identified de novo heterozygous missense variants in CLDN5 in fifteen unrelated patients who presented with a shared constellation of features including developmental delay, seizures (primarily infantile onset focal epilepsy), microcephaly and a recognizable pattern of pontine atrophy and brain calcifications.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.5127 BUB1B Zornitza Stark Marked gene: BUB1B as ready
Intellectual disability syndromic and non-syndromic v0.5127 BUB1B Zornitza Stark Gene: bub1b has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5127 BUB1B Zornitza Stark Phenotypes for gene: BUB1B were changed from to Mosaic variegated aneuploidy syndrome 1, MIM# 257300
Intellectual disability syndromic and non-syndromic v0.5126 BUB1B Zornitza Stark Publications for gene: BUB1B were set to
Intellectual disability syndromic and non-syndromic v0.5125 BUB1B Zornitza Stark Mode of inheritance for gene: BUB1B was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.5124 BUB1B Zornitza Stark reviewed gene: BUB1B: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Mosaic variegated aneuploidy syndrome 1, MIM# 257300; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.5124 BUB1B Liyan Song reviewed gene: BUB1B: Rating: AMBER; Mode of pathogenicity: None; Publications: 21190457, 15475955, 15098245; Phenotypes: Mosaic variegated aneuploidy syndrome 1, MIM: #257300, Premature chromatid separation trait, MIM: #176430; Mode of inheritance: Other
Intellectual disability syndromic and non-syndromic v0.5124 KIF26A Zornitza Stark Phenotypes for gene: KIF26A were changed from Cortical dysplasia, complex, with other brain malformations 11, MIM# 620156 to Cortical dysplasia, complex, with other brain malformations 11, MIM# 620156
Intellectual disability syndromic and non-syndromic v0.5124 KIF26A Zornitza Stark Phenotypes for gene: KIF26A were changed from Cerebral malformation MONDO:0016054, KIF26-related to Cortical dysplasia, complex, with other brain malformations 11, MIM# 620156
Intellectual disability syndromic and non-syndromic v0.5123 KIF26A Zornitza Stark edited their review of gene: KIF26A: Changed phenotypes: Cortical dysplasia, complex, with other brain malformations 11, MIM# 620156
Intellectual disability syndromic and non-syndromic v0.5123 CACNA2D1 Zornitza Stark Phenotypes for gene: CACNA2D1 were changed from Developmental and epileptic encephalopathy disorder MONDO:0100062 CACNA2D1-related to Developmental and epileptic encephalopathy 110, MIM# 620149
Intellectual disability syndromic and non-syndromic v0.5122 CACNA2D1 Zornitza Stark reviewed gene: CACNA2D1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Developmental and epileptic encephalopathy 110, MIM# 620149; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.5122 FZR1 Zornitza Stark Marked gene: FZR1 as ready
Intellectual disability syndromic and non-syndromic v0.5122 FZR1 Zornitza Stark Gene: fzr1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5122 FZR1 Zornitza Stark Classified gene: FZR1 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.5122 FZR1 Zornitza Stark Gene: fzr1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5121 FZR1 Zornitza Stark gene: FZR1 was added
gene: FZR1 was added to Intellectual disability syndromic and non-syndromic. Sources: Expert Review
Mode of inheritance for gene: FZR1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FZR1 were set to 34788397
Phenotypes for gene: FZR1 were set to Developmental and epileptic encephalopathy 109, MIM# 620145
Review for gene: FZR1 was set to GREEN
Added comment: Four unrelated individuals reported with de novo missense variants in this gene. Affected individuals had developmental delay before and concurrent with the onset of seizures. Features included impaired intellectual development with poor speech, ataxic gait, coordination problems, and behavioral abnormalities. Drosophila model supports gene-disease association.
Sources: Expert Review
Intellectual disability syndromic and non-syndromic v0.5120 ELP2 Zornitza Stark Marked gene: ELP2 as ready
Intellectual disability syndromic and non-syndromic v0.5120 ELP2 Zornitza Stark Gene: elp2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5120 ELP2 Zornitza Stark Phenotypes for gene: ELP2 were changed from to intellectual disability, autosomal recessive 58 MONDO:0014996
Intellectual disability syndromic and non-syndromic v0.5119 ELP2 Zornitza Stark Publications for gene: ELP2 were set to
Intellectual disability syndromic and non-syndromic v0.5118 ELP2 Zornitza Stark Mode of inheritance for gene: ELP2 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.5117 ELP2 Zornitza Stark reviewed gene: ELP2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: intellectual disability, autosomal recessive 58 MONDO:0014996; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.5117 AMER1 Zornitza Stark Marked gene: AMER1 as ready
Intellectual disability syndromic and non-syndromic v0.5117 AMER1 Zornitza Stark Gene: amer1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5117 AMER1 Zornitza Stark Phenotypes for gene: AMER1 were changed from to Osteopathia striata with cranial sclerosis, OMIM:300373
Intellectual disability syndromic and non-syndromic v0.5116 AMER1 Zornitza Stark Publications for gene: AMER1 were set to
Intellectual disability syndromic and non-syndromic v0.5115 AMER1 Zornitza Stark Mode of inheritance for gene: AMER1 was changed from Unknown to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Intellectual disability syndromic and non-syndromic v0.5114 DLD Zornitza Stark Marked gene: DLD as ready
Intellectual disability syndromic and non-syndromic v0.5114 DLD Zornitza Stark Gene: dld has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5114 DLD Zornitza Stark Phenotypes for gene: DLD were changed from to Dihydrolipoamide dehydrogenase deficiency MIM#246900
Intellectual disability syndromic and non-syndromic v0.5113 DLD Zornitza Stark Publications for gene: DLD were set to
Intellectual disability syndromic and non-syndromic v0.5112 DLD Zornitza Stark Mode of inheritance for gene: DLD was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.5111 DLD Zornitza Stark reviewed gene: DLD: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Dihydrolipoamide dehydrogenase deficiency MIM#246900; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.5111 DHCR24 Zornitza Stark Marked gene: DHCR24 as ready
Intellectual disability syndromic and non-syndromic v0.5111 DHCR24 Zornitza Stark Gene: dhcr24 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5111 DHCR24 Zornitza Stark Phenotypes for gene: DHCR24 were changed from to Desmosterolosis, MIM# 602398
Intellectual disability syndromic and non-syndromic v0.5110 DHCR24 Zornitza Stark Publications for gene: DHCR24 were set to
Intellectual disability syndromic and non-syndromic v0.5109 DHCR24 Zornitza Stark Mode of inheritance for gene: DHCR24 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.5108 DOCK8 Zornitza Stark Marked gene: DOCK8 as ready
Intellectual disability syndromic and non-syndromic v0.5108 DOCK8 Zornitza Stark Gene: dock8 has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v0.5108 DOCK8 Zornitza Stark Phenotypes for gene: DOCK8 were changed from to intellectual developmental disorder, autosomal dominant 2, MIM#614113
Intellectual disability syndromic and non-syndromic v0.5107 DOCK8 Zornitza Stark Publications for gene: DOCK8 were set to
Intellectual disability syndromic and non-syndromic v0.5106 DOCK8 Zornitza Stark Mode of inheritance for gene: DOCK8 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.5105 CDC42 Zornitza Stark Marked gene: CDC42 as ready
Intellectual disability syndromic and non-syndromic v0.5105 CDC42 Zornitza Stark Gene: cdc42 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5105 CDC42 Zornitza Stark Publications for gene: CDC42 were set to
Intellectual disability syndromic and non-syndromic v0.5104 CDC42 Zornitza Stark Phenotypes for gene: CDC42 were changed from to Takenouchi-Kosaki syndrome, MIM#616737
Intellectual disability syndromic and non-syndromic v0.5103 CDC42 Zornitza Stark Mode of inheritance for gene: CDC42 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.5102 ALMS1 Zornitza Stark Marked gene: ALMS1 as ready
Intellectual disability syndromic and non-syndromic v0.5102 ALMS1 Zornitza Stark Gene: alms1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5102 ALMS1 Zornitza Stark Phenotypes for gene: ALMS1 were changed from to Alstrom syndrome, MIM# 203800
Intellectual disability syndromic and non-syndromic v0.5101 ALMS1 Zornitza Stark Publications for gene: ALMS1 were set to
Intellectual disability syndromic and non-syndromic v0.5100 ALMS1 Zornitza Stark Mode of inheritance for gene: ALMS1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.5099 ALMS1 Zornitza Stark reviewed gene: ALMS1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Alstrom syndrome, MIM# 203800; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.5099 BLM Zornitza Stark Marked gene: BLM as ready
Intellectual disability syndromic and non-syndromic v0.5099 BLM Zornitza Stark Gene: blm has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v0.5099 BLM Zornitza Stark Phenotypes for gene: BLM were changed from to Bloom syndrome, MIM# 210900
Intellectual disability syndromic and non-syndromic v0.5098 BLM Zornitza Stark Mode of inheritance for gene: BLM was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.5097 BLM Zornitza Stark Classified gene: BLM as Red List (low evidence)
Intellectual disability syndromic and non-syndromic v0.5097 BLM Zornitza Stark Gene: blm has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v0.5096 B3GLCT Zornitza Stark Marked gene: B3GLCT as ready
Intellectual disability syndromic and non-syndromic v0.5096 B3GLCT Zornitza Stark Gene: b3glct has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5096 B3GLCT Zornitza Stark Phenotypes for gene: B3GLCT were changed from to Peters Plus Syndrome (MIM 261540); Peters anomaly; Growth retardation; Brachydactyly; ID
Intellectual disability syndromic and non-syndromic v0.5095 B3GLCT Zornitza Stark Publications for gene: B3GLCT were set to
Intellectual disability syndromic and non-syndromic v0.5094 B3GLCT Zornitza Stark Mode of inheritance for gene: B3GLCT was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.5093 AP1S1 Zornitza Stark Marked gene: AP1S1 as ready
Intellectual disability syndromic and non-syndromic v0.5093 AP1S1 Zornitza Stark Gene: ap1s1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5093 AP1S1 Zornitza Stark Phenotypes for gene: AP1S1 were changed from to MEDNIK syndrome, MIM# 609313
Intellectual disability syndromic and non-syndromic v0.5092 AP1S1 Zornitza Stark Publications for gene: AP1S1 were set to 30244301; 24754424; 19057675; 23423674
Intellectual disability syndromic and non-syndromic v0.5091 AP1S1 Zornitza Stark Publications for gene: AP1S1 were set to
Intellectual disability syndromic and non-syndromic v0.5090 AP1S1 Zornitza Stark Mode of inheritance for gene: AP1S1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.5089 ASAH1 Zornitza Stark Marked gene: ASAH1 as ready
Intellectual disability syndromic and non-syndromic v0.5089 ASAH1 Zornitza Stark Gene: asah1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5089 ASAH1 Zornitza Stark Phenotypes for gene: ASAH1 were changed from to Farber lipogranulomatosis MIM #228000
Intellectual disability syndromic and non-syndromic v0.5088 ASAH1 Zornitza Stark Publications for gene: ASAH1 were set to
Intellectual disability syndromic and non-syndromic v0.5087 ASAH1 Zornitza Stark Mode of inheritance for gene: ASAH1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.5086 DPM1 Zornitza Stark Marked gene: DPM1 as ready
Intellectual disability syndromic and non-syndromic v0.5086 DPM1 Zornitza Stark Gene: dpm1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5086 DPM1 Zornitza Stark Phenotypes for gene: DPM1 were changed from to Congenital disorder of glycosylation, type Ie, MIM# 608799
Intellectual disability syndromic and non-syndromic v0.5085 DPM1 Zornitza Stark Publications for gene: DPM1 were set to 10642602; 23856421; 16641202; 15669674; 10642597
Intellectual disability syndromic and non-syndromic v0.5085 DPM1 Zornitza Stark Publications for gene: DPM1 were set to
Intellectual disability syndromic and non-syndromic v0.5084 DPM1 Zornitza Stark Mode of inheritance for gene: DPM1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.5083 CENPF Zornitza Stark Marked gene: CENPF as ready
Intellectual disability syndromic and non-syndromic v0.5083 CENPF Zornitza Stark Gene: cenpf has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5083 CENPF Zornitza Stark Phenotypes for gene: CENPF were changed from to Stromme syndrome (MIM#243605)
Intellectual disability syndromic and non-syndromic v0.5082 CENPF Zornitza Stark Publications for gene: CENPF were set to
Intellectual disability syndromic and non-syndromic v0.5081 CENPF Zornitza Stark Mode of inheritance for gene: CENPF was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.5080 NLGN4X Zornitza Stark Classified gene: NLGN4X as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.5080 NLGN4X Zornitza Stark Gene: nlgn4x has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.5079 NLGN4X Krithika Murali reviewed gene: NLGN4X: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID:26350204, PMID:14963808, PMID:12669065, PMID:23352163, PMID:28263302, PMID:16648374; Phenotypes: Intellectual developmental disorder, X-linked - MIM#300495; 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 syndromic and non-syndromic v0.5079 CENPF Mark Williams reviewed gene: CENPF: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 35488810, 31953238, 26820108; Phenotypes: Stromme syndrome; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.5079 ELP2 Renee Crooks changed review comment from: Phenotype of Intellectual Disability has been observed in the PMIDs listed above in the following forms;
-spastic diplegia
-cortico-cerebullar
-nodular heterotopia
-epilepsy
-severe motor development delay
-short stature
-neuropsychiatric problems
-choreoathetosis
-nystagmus; to: Phenotype of Intellectual Disability has been observed in the PMIDs listed above in the following forms;
-spastic diplegia
-cortico-cerebullar
-nodular heterotopia
-epilepsy
-severe motor development delay
-short stature
-neuropsychiatric problems
-choreoathetosis
-nystagmus

NB - review submit by Renée Crooks ( aka using google account as Lee Ren)
Intellectual disability syndromic and non-syndromic v0.5079 ELP2 Renee Crooks reviewed gene: ELP2: Rating: GREEN; Mode of pathogenicity: None; Publications: 33510603: 33976153: 33393008: 34653680: 25847581; Phenotypes: Intellectual Diability; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.5079 AMER1 Deepak Subramanian reviewed gene: AMER1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 19079258, 22987541, 23401208, 28497491, 32879452, 35186393, 20950377, 22043478; Phenotypes: Osteopathia striata with cranial sclerosis, OMIM:300373, Osteopathia striata-cranial sclerosis syndrome, ORPHA:2780, Intellectual disability, HP:0001249; 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 syndromic and non-syndromic v0.5079 DLD Philip Adam Harraka reviewed gene: DLD: Rating: GREEN; Mode of pathogenicity: None; Publications: 34745891, 33092611, 8968745; Phenotypes: Dihydrolipoamide dehydrogenase deficiency, hepatic and neurological disease; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.5079 DHCR24 Nicolle Hua reviewed gene: DHCR24: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: PMID: 11519011, 24961299, 29175559, 21559050, 12457401, 21671375; Phenotypes: Desmosterolosis, MIM# 602398; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.5079 DOCK8 Shannon Nicolson reviewed gene: DOCK8: Rating: RED; Mode of pathogenicity: None; Publications: 18060736, 29930340, 29191242, 33455084, 32978894, 25435912; Phenotypes: MIM#614113 intellectual developmental disorder, autosomal dominant 2; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.5079 CDC42 Lorraine Skalicka reviewed gene: CDC42: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 29925821, 26708094, 26386261, 29394990; Phenotypes: Takenouchi-Kosaki syndrome, Intellectual disability; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.5079 ALMS1 Christa Whelan reviewed gene: ALMS1: Rating: RED; Mode of pathogenicity: None; Publications: MIM # 203800, 27142762, 25846608, 18154657, 25296579, 17146208, 17940554, 22043170, 31889847, 2231654, 8418611, 8181924, 8556827, 9663233, 25864795, 8556827, 11941369.; Phenotypes: Alström Syndrome (multisystemic), characterized by progressive cone-rod dystrophy leading to blindness, sensorineural hearing loss, childhood obesity associated with hyperinsulinemia, and type 2 diabetes mellitus, Dilated cardiomyopathy occurs in approximately 70% of patients during infancy or adolescence, Renal failure, pulmonary, hepatic, and urologic dysfunction are often observed, and systemic fibrosis develops with age MIM# 203800; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.5079 BLM Ken Lee Wan reviewed gene: BLM: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability syndromic and non-syndromic v0.5079 B3GLCT Jessica Wright reviewed gene: B3GLCT: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 20301637, 16909395, 17032646, 18199743, 25544610; Phenotypes: Peters Plus Syndrome (MIM 261540), Peters anomaly, Growth retardation, Brachydactyly, ID; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.5079 AP1S1 Gemma O'Farrell changed review comment from: Publications support gene-disease association. AP1S1 associated with MENDIK syndrome of which intellectual disability and global developmental delay are part of the phenotype. Functional data available.

OMIM: 603531

AP1S1 variant described in French-Canadian (Quebec) families with MENDIK (founder variant; splice variant, leading to PTC) different AS1P1 variant (insertion) described in Sephardic-Jewish child with mental retardation and a Turkish child with intellectual disability and MENDIK.; to: Publications support gene-disease association. AP1S1 associated with MENDIK syndrome of which intellectual disability and global developmental delay are part of the phenotype. Functional data available.

OMIM: 603531

AP1S1 variant described in French-Canadian (Quebec) families with MENDIK (founder variant; splice variant, leading to PTC) different AS1P1 variant (insertion) described in Sephardic-Jewish child with mental retardation and a Turkish child with intellectual disability and MENDIK.
Intellectual disability syndromic and non-syndromic v0.5079 AP1S1 Gemma O'Farrell reviewed gene: AP1S1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 30244301, 24754424, 19057675, 23423674; Phenotypes: MENDIK syndrome, mental retardation, enteropathy, deafness, peripheral neuropathy, ichthyosis and keratoderma; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.5079 ASAH1 Jacqueline Montgomery reviewed gene: ASAH1: Rating: GREEN; Mode of pathogenicity: None; Publications: 32875576; Phenotypes: Farber lipogranulomatosis MIM #228000; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.5079 DPM1 Sindhu V changed review comment from: More than 3 unrelated families with consistent phenotype of developmental delay, hypotonia , seizures, (acquired) microcephaly, vision impairment with/without elevated CK and cerebellar signs. Molecular evidence of biallelic involvement with missense, deletion and splice site variants as contributory mechanisms. Quantification of isoform consistent with CDG 1E pattern.; to: More than 3 unrelated families with consistent phenotype of developmental delay, hypotonia , seizures, (acquired) microcephaly, vision impairment with/without elevated CK and cerebellar signs. Molecular evidence of biallelic involvement with missense, deletion and splice site variants as contributory mechanisms. Quantification of isoform consistent with CDG 1E pattern.
Intellectual disability syndromic and non-syndromic v0.5079 DPM1 Sindhu V reviewed gene: DPM1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 10642602, 23856421, 16641202, 15669674, 10642597; Phenotypes: Acquired microcephaly, developmental delay, epilepsy, strabismus, hypotonia, cortical vision impairment, elevated creatine kinase, growth failure; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.5079 BCKDK Zornitza Stark Marked gene: BCKDK as ready
Intellectual disability syndromic and non-syndromic v0.5079 BCKDK Zornitza Stark Gene: bckdk has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5079 BCKDK Zornitza Stark Phenotypes for gene: BCKDK were changed from to Branched-chain ketoacid dehydrogenase kinase deficiency MIM#614923
Intellectual disability syndromic and non-syndromic v0.5078 BCKDK Zornitza Stark Publications for gene: BCKDK were set to
Intellectual disability syndromic and non-syndromic v0.5077 BCKDK Zornitza Stark Mode of inheritance for gene: BCKDK was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.5076 BCKDK Zornitza Stark changed review comment from: At least 5 unrelated families reported. ID if untreated. Treatment available.; to: At least 5 unrelated families reported. ID/autism/seizures are part of the phenotype.

Treatment available: Branched-chain amino acid supplementation: improves psychomotor/cognitive development/IQ; improves behavioural/psychiatric disturbance(s); improves systemic manifestations
Intellectual disability syndromic and non-syndromic v0.5076 BCKDK Zornitza Stark reviewed gene: BCKDK: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Branched-chain ketoacid dehydrogenase kinase deficiency MIM#614923; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.5076 AHI1 Zornitza Stark Marked gene: AHI1 as ready
Intellectual disability syndromic and non-syndromic v0.5076 AHI1 Zornitza Stark Gene: ahi1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5076 AHI1 Zornitza Stark Phenotypes for gene: AHI1 were changed from to Joubert Syndrome 3 OMIM #608629
Intellectual disability syndromic and non-syndromic v0.5075 AHI1 Zornitza Stark Publications for gene: AHI1 were set to
Intellectual disability syndromic and non-syndromic v0.5074 AHI1 Zornitza Stark Mode of inheritance for gene: AHI1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.5073 CEP41 Zornitza Stark Marked gene: CEP41 as ready
Intellectual disability syndromic and non-syndromic v0.5073 CEP41 Zornitza Stark Gene: cep41 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5073 CEP41 Zornitza Stark Phenotypes for gene: CEP41 were changed from to Joubert syndrome 15, MIM# 614464
Intellectual disability syndromic and non-syndromic v0.5072 CEP41 Zornitza Stark Publications for gene: CEP41 were set to
Intellectual disability syndromic and non-syndromic v0.5071 CEP41 Zornitza Stark Mode of inheritance for gene: CEP41 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.5070 DAG1 Zornitza Stark Marked gene: DAG1 as ready
Intellectual disability syndromic and non-syndromic v0.5070 DAG1 Zornitza Stark Gene: dag1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5070 DAG1 Zornitza Stark Phenotypes for gene: DAG1 were changed from to Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 9
Intellectual disability syndromic and non-syndromic v0.5069 DAG1 Zornitza Stark Publications for gene: DAG1 were set to
Intellectual disability syndromic and non-syndromic v0.5068 DAG1 Zornitza Stark Mode of inheritance for gene: DAG1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.5067 DAG1 Zornitza Stark reviewed gene: DAG1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 9; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.5067 BCKDK Savige Judy reviewed gene: BCKDK: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID:16875466, PMID: 22956686; Phenotypes: Intellectual disability, autism, epilepsy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability syndromic and non-syndromic v0.5067 AHI1 Caleb Cartagena reviewed gene: AHI1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 15322546, 16453322, 21937992; Phenotypes: Joubert Syndrome 3 OMIM #608629; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.5067 CEP41 Mitchell O'Brien reviewed gene: CEP41: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 22246503; Phenotypes: Joubert syndrome 15, MIM# 614464; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.5067 DAG1 Nicholas Clark reviewed gene: DAG1: Rating: AMBER; Mode of pathogenicity: None; Publications: (PMID: 25934851, 29337005, 24052401, 21388311, 25503980, 30450679, 12140559, 21388311); Phenotypes: Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 9, Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 9; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.5067 BOLA3 Zornitza Stark Marked gene: BOLA3 as ready
Intellectual disability syndromic and non-syndromic v0.5067 BOLA3 Zornitza Stark Gene: bola3 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5067 BOLA3 Zornitza Stark Phenotypes for gene: BOLA3 were changed from to Multiple mitochondrial dysfunctions syndrome 2 with hyperglycinemia (MMDS2, OMIM #614299)
Intellectual disability syndromic and non-syndromic v0.5066 BOLA3 Zornitza Stark Publications for gene: BOLA3 were set to
Intellectual disability syndromic and non-syndromic v0.5065 BOLA3 Zornitza Stark Mode of inheritance for gene: BOLA3 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.5064 BOLA3 Zornitza Stark reviewed gene: BOLA3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Multiple mitochondrial dysfunctions syndrome 2 with hyperglycinemia (MMDS2, OMIM #614299); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.5064 BOLA3 Layla Zhu reviewed gene: BOLA3: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 24334290, PMID: 29654549, PMID: 21944046, PMID: 22562699, PMID: 26741492, PMID: 24334290; Phenotypes: multiple mitochondrial dysfunctions syndrome 2 with hyperglycinemia (MMDS2, OMIM #614299); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.5064 CBS Zornitza Stark Marked gene: CBS as ready
Intellectual disability syndromic and non-syndromic v0.5064 CBS Zornitza Stark Gene: cbs has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5064 CBS Zornitza Stark Phenotypes for gene: CBS were changed from to Homocystinuria (MIM# 236200)
Intellectual disability syndromic and non-syndromic v0.5063 CBS Zornitza Stark Mode of inheritance for gene: CBS was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.5062 CBS Zornitza Stark reviewed gene: CBS: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Homocystinuria (MIM# 236200); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.5062 BOLA3 Layla Zhu Deleted their review
Intellectual disability syndromic and non-syndromic v0.5062 BOLA3 Layla Zhu reviewed gene: BOLA3: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 29654549; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.5062 EPRS Zornitza Stark Marked gene: EPRS as ready
Intellectual disability syndromic and non-syndromic v0.5062 EPRS Zornitza Stark Gene: eprs has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5062 TCEAL1 Zornitza Stark Marked gene: TCEAL1 as ready
Intellectual disability syndromic and non-syndromic v0.5062 TCEAL1 Zornitza Stark Gene: tceal1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5062 TCEAL1 Zornitza Stark Phenotypes for gene: TCEAL1 were changed from hypotonia; abnormal gait; developmental delay; intellectual disability; autism; dysmorphic facial features. to Neurodevelopmental disorder, MONDO:0700092, TCEAL1-related; hypotonia; abnormal gait; developmental delay; intellectual disability; autism; dysmorphic facial features
Intellectual disability syndromic and non-syndromic v0.5061 TCEAL1 Zornitza Stark Classified gene: TCEAL1 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.5061 TCEAL1 Zornitza Stark Gene: tceal1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5060 CBS Lloyd Pereira changed review comment from: Listed in OMIM with a strong disease association (MIM #236200 homocysteinuria).

Multiple experimental and clinical studies demonstrate link between CBS and homocysteinuria (see below):

Multiple LOF variants classified as pathogenic or likely pathogenic in ClinVar and reported in the literature in multiple homozygote and compound heterozygote individuals affected with homocystinuria, e.g. c.19dup p.(Gln7fs) (PMID: 25218699; 12124992) and c.919G>A p.(Gly307Ser) (PMID: 7506602, 7581402, 8744616, 9889017, 23733603).

Multiple CBS variants reported in CBS deficiency (PMID: 12124992).

ClinGen classify as definitive for Homocysteinuria. Clingen states- Twenty-one unique variants were curated (missense, nonsense, frameshift, and splice site) in 15 probands from 8 publications, and three of these probands each had two affected siblings in whom CBS variants were identified (PMID 1301198, 10408774, 7762555, 12815602, 16307898, 25455305, 26667307, 29508359). Gene-disease relationship is supported by the biochemical function of CBS, which is consistent with the biochemical features in patients with homocystinuria (including elevated plasma total homocysteine and methionine) (PMID 13654400, 15890029), functional studies in yeast, bacteria, and cultured cells, including chaperone studies in fibroblasts from patients with homocystinuria (PMID 9590298, 25331909), as well as the biochemical and clinical features of mouse models (PMID 18987302) and enzyme replacement studies in mice (PMID 29398487).

Recent review reports on role of CBS in down syndrome (PMID: 31955501). However, caveat that multiple genes are associated with down syndrome. Not a strong body of research available linking CBS variants and down syndrome.; to: Listed in OMIM with a strong disease association (MIM #236200 homocysteinuria).

Multiple experimental and clinical studies demonstrate link between CBS and homocysteinuria (see below):

Multiple LOF variants classified as pathogenic or likely pathogenic in ClinVar and reported in the literature in multiple homozygote and compound heterozygote individuals affected with homocystinuria, e.g. c.19dup p.(Gln7fs) (PMID: 25218699; 12124992) and c.919G>A p.(Gly307Ser) (PMID: 7506602, 7581402, 8744616, 9889017, 23733603).

Multiple CBS variants reported in CBS deficiency (PMID: 12124992).

ClinGen classify as definitive for Homocysteinuria. Clingen states- Twenty-one unique variants were curated (missense, nonsense, frameshift, and splice site) in 15 probands from 8 publications, and three of these probands each had two affected siblings in whom CBS variants were identified (PMID 1301198, 10408774, 7762555, 12815602, 16307898, 25455305, 26667307, 29508359). Gene-disease relationship is supported by the biochemical function of CBS, which is consistent with the biochemical features in patients with homocystinuria (including elevated plasma total homocysteine and methionine) (PMID 13654400, 15890029), functional studies in yeast, bacteria, and cultured cells, including chaperone studies in fibroblasts from patients with homocystinuria (PMID 9590298, 25331909), as well as the biochemical and clinical features of mouse models (PMID 18987302) and enzyme replacement studies in mice (PMID 29398487).

Recent review reports on role of CBS in down syndrome (PMID: 31955501). However, caveat that multiple genes are associated with down syndrome. Not a strong body of research available linking CBS variants and down syndrome.
Intellectual disability syndromic and non-syndromic v0.5060 TCEAL1 Melanie Marty edited their review of gene: TCEAL1: Changed phenotypes: Neurodevelopmental disorder, MONDO:0700092, TCEAL1-related, hypotonia, abnormal gait, developmental delay, intellectual disability, autism, dysmorphic facial features
Intellectual disability syndromic and non-syndromic v0.5060 CBS Lloyd Pereira reviewed gene: CBS: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Homocysteinuria B6-responsive and nonresponsive types, Thrombosis hyperhomocysteinemic.; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.5060 GABRA3 Zornitza Stark Marked gene: GABRA3 as ready
Intellectual disability syndromic and non-syndromic v0.5060 GABRA3 Zornitza Stark Gene: gabra3 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5060 GABRA3 Zornitza Stark Phenotypes for gene: GABRA3 were changed from Epilepsy, intellectual disability, dysmorphic features, to Epilepsy, X-linked 2, with or without impaired intellectual development and dysmorphic features, MIM# 301091
Intellectual disability syndromic and non-syndromic v0.5059 GABRA3 Alison Yeung Classified gene: GABRA3 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.5059 GABRA3 Alison Yeung Gene: gabra3 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5058 ARF3 Zornitza Stark Marked gene: ARF3 as ready
Intellectual disability syndromic and non-syndromic v0.5058 ARF3 Zornitza Stark Gene: arf3 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5058 ARF3 Zornitza Stark Phenotypes for gene: ARF3 were changed from Neurodevelopmental disorder (MONDO:0700092), ARF3-related; Global developmental delay; Intellectual disability; Seizures; Morphological abnormality of the central nervous system to Neurodevelopmental disorder (MONDO:0700092), ARF3-related; Global developmental delay; Intellectual disability; Seizures; Morphological abnormality of the central nervous system
Intellectual disability syndromic and non-syndromic v0.5057 ARF3 Zornitza Stark Phenotypes for gene: ARF3 were changed from Global developmental delay; Intellectual disability; Seizures; Morphological abnormality of the central nervous system to Neurodevelopmental disorder (MONDO:0700092), ARF3-related; Global developmental delay; Intellectual disability; Seizures; Morphological abnormality of the central nervous system
Intellectual disability syndromic and non-syndromic v0.5057 EPRS Alison Yeung Classified gene: EPRS as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.5057 EPRS Alison Yeung Gene: eprs has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5056 ARF3 Zornitza Stark Publications for gene: ARF3 were set to 34346499
Intellectual disability syndromic and non-syndromic v0.5055 ARF3 Zornitza Stark Classified gene: ARF3 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.5055 ARF3 Zornitza Stark Gene: arf3 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5054 ARF3 Zornitza Stark Classified gene: ARF3 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.5054 ARF3 Zornitza Stark Gene: arf3 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5053 TCEAL1 Melanie Marty gene: TCEAL1 was added
gene: TCEAL1 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: TCEAL1 was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Publications for gene: TCEAL1 were set to PMID: 36368327
Phenotypes for gene: TCEAL1 were set to hypotonia; abnormal gait; developmental delay; intellectual disability; autism; dysmorphic facial features.
Review for gene: TCEAL1 was set to GREEN
Added comment: 7 individuals (males and females) with de novo variants involving TCEAL1 with an X-linked
dominant neurodevelopmental syndrome. Individuals had hypotonia, abnormal gait, developmental delay/intellectual disability especially affecting expressive language, autistic-like behavior, and mildly dysmorphic facial features. Additional features included strabismus, refractive errors, variable nystagmus, gastroesophageal reflux, constipation, dysmotility, recurrent infections, seizures, and structural brain anomalies.

1 additional male individual with a maternally inherited missense variant (unaffected mother), which was considered a VUS. This individual had hypertonia and spasticity without syndromic features.

4 PTCs, 2 CNVs, 2 missense reported.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.5053 ARF3 Dean Phelan reviewed gene: ARF3: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 36369169, 34346499; Phenotypes: Neurodevelopmental disorder (MONDO:0700092), ARF3-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.5053 EPRS Lucy Spencer gene: EPRS was added
gene: EPRS was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: EPRS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EPRS were set to 29576217, 36411955
Phenotypes for gene: EPRS were set to Leukodystrophy, hypomyelinating, 15 (MIM#617951)
Review for gene: EPRS was set to GREEN
Added comment: 5 patients across 2 papers, with delayed development (3/5) and/or regression, ataxia, dystonia, hypomyelinating leukodystrophy or periventricular white matter, 2 with epilepsy, 3 with optic atrophy, 2 with deafness, 2 with micrcephaly, 1 noted to have some facial dysmorphism.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.5053 GABRA3 Sarah Pantaleo gene: GABRA3 was added
gene: GABRA3 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: GABRA3 was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Publications for gene: GABRA3 were set to PMID: 29053855
Phenotypes for gene: GABRA3 were set to Epilepsy, intellectual disability, dysmorphic features,
Penetrance for gene: GABRA3 were set to Incomplete
Review for gene: GABRA3 was set to GREEN
Added comment: Six variants in GABRA3 encoding the alpha3-subunit of the GABA(A) receptor.
Five missense variants and one micro duplication were detected in four families and two sporadic cases presenting with a range of epileptic seizure types, a varying degree of intellectual disability and developmental delay, sometimes with dysmorphic features or nystagmus.
The variants co-segregated mostly but not completely with the phenotype in the families, indicating in some cases incomplete penetrance, involvement of other genes, or presence of phenocopies.
Overall, males were more severely affected and there were three asymptomatic female mutation carriers compared to only one male without a clinical phenotype.
Mechanism suggested - three detected missense variants are localised in the extracellular GABA-binding NH2-terminus, one in the M2-M3 linker and one in the M4 transmembrane segment of the alpha3-subunit. Functional studies in Xenopus leaves oocytes revealed a variable but significant reduction of GABA-evoked anion currents for all mutants compared to wild-type receptors. The degree of current reduction correlated partially with the phenotype.
Results reveal that rare loss-of-function variants in GABRA3 increase the risk for a varying combination of epilepsy, intellectual disability/developmental delay and dysmorphic features, presenting in some pedigrees with an X-linked inheritance pattern.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.5053 FEM1C Zornitza Stark Marked gene: FEM1C as ready
Intellectual disability syndromic and non-syndromic v0.5053 FEM1C Zornitza Stark Gene: fem1c has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5053 FEM1C Zornitza Stark Classified gene: FEM1C as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.5053 FEM1C Zornitza Stark Gene: fem1c has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5052 FEM1C Paul De Fazio gene: FEM1C was added
gene: FEM1C was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: FEM1C was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: FEM1C were set to 36336956; 28135719; 33398170; 33398168
Phenotypes for gene: FEM1C were set to Neurodevelopmental disorder, FEM1C-related MONDO:0700092
Review for gene: FEM1C was set to GREEN
gene: FEM1C was marked as current diagnostic
Added comment: PMID:36336956 describes a 9-year-old boy with severe DD, lack of speech, pyramidal signs, and limb ataxia who had a de novo missense variant Asp126His in FEM1C ascertained by WES. The equivalent variant introduced into the nematode C.elegans resulted in disabled locomotion caused by synaptic abnormalities and not muscle dysfunction.

An alternate change Asp126Val was reported in the DDD study de novo in a patient with uncharacterised developmental delay (PMID:28135719).

The Asp126 residue (but not either of the variants above specifically) was shown to be functionally important by in vitro studies (PMID:33398170;33398168). The residue is highly conserved and located in a region of missense constraint.

Borderline green, 2 patients and an animal model. Note all evidence points to the Asp126 residue being of specific importance.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.5052 KDM2B Ain Roesley Classified gene: KDM2B as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.5052 KDM2B Ain Roesley Gene: kdm2b has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5051 KDM2B Ain Roesley Marked gene: KDM2B as ready
Intellectual disability syndromic and non-syndromic v0.5051 KDM2B Ain Roesley Gene: kdm2b has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5051 KDM2B Ain Roesley Classified gene: KDM2B as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.5051 KDM2B Ain Roesley Gene: kdm2b has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5050 KDM2B Ain Roesley gene: KDM2B was added
gene: KDM2B was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: KDM2B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KDM2B were set to 36322151
Phenotypes for gene: KDM2B were set to neurodevelopmental disorder MONDO#070009, KDM2B-related
Review for gene: KDM2B was set to GREEN
gene: KDM2B was marked as current diagnostic
Added comment: 27 individuals from 22 families were recruited
13 SNV classified LP/P, all de novo except 2 familial cases
5 variants were classified as VUS if more than 1 het is present in gnomAD or does result in a KDM2B-specific episignature (therefore suggesting normal function)
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.5049 MAN2A2 Zornitza Stark Marked gene: MAN2A2 as ready
Intellectual disability syndromic and non-syndromic v0.5049 MAN2A2 Zornitza Stark Gene: man2a2 has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v0.5049 MAN2A2 Zornitza Stark gene: MAN2A2 was added
gene: MAN2A2 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: MAN2A2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MAN2A2 were set to 36357165
Phenotypes for gene: MAN2A2 were set to Congenital disorder of glycosylation, MONDO:0015286, MAN2A2-reated
Review for gene: MAN2A2 was set to RED
Added comment: Single consanguineous family reported with homozygous truncating variant in two brothers with ID. Supportive biochemical data only
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.5048 CDK10 Zornitza Stark Marked gene: CDK10 as ready
Intellectual disability syndromic and non-syndromic v0.5048 CDK10 Zornitza Stark Gene: cdk10 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5048 CDK10 Zornitza Stark Phenotypes for gene: CDK10 were changed from to Al Kaissi syndrome MIM#617694
Intellectual disability syndromic and non-syndromic v0.5047 CDK10 Zornitza Stark Publications for gene: CDK10 were set to
Intellectual disability syndromic and non-syndromic v0.5046 CDK10 Zornitza Stark Mode of inheritance for gene: CDK10 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.5045 CDK10 Zornitza Stark reviewed gene: CDK10: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Al Kaissi syndrome MIM#617694; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.5045 EXOSC3 Zornitza Stark Marked gene: EXOSC3 as ready
Intellectual disability syndromic and non-syndromic v0.5045 EXOSC3 Zornitza Stark Gene: exosc3 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5045 EXOSC3 Zornitza Stark Phenotypes for gene: EXOSC3 were changed from to Pontocerebellar hypoplasia, type 1B, MIM# 614678
Intellectual disability syndromic and non-syndromic v0.5044 EXOSC3 Zornitza Stark Publications for gene: EXOSC3 were set to
Intellectual disability syndromic and non-syndromic v0.5043 EXOSC3 Zornitza Stark Mode of inheritance for gene: EXOSC3 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.5042 EXOSC3 Zornitza Stark reviewed gene: EXOSC3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Pontocerebellar hypoplasia, type 1B, MIM# 614678; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.5042 ARPC4 Zornitza Stark Marked gene: ARPC4 as ready
Intellectual disability syndromic and non-syndromic v0.5042 ARPC4 Zornitza Stark Gene: arpc4 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5042 ARPC4 Zornitza Stark Classified gene: ARPC4 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.5042 ARPC4 Zornitza Stark Gene: arpc4 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5041 ARPC4 Zornitza Stark gene: ARPC4 was added
gene: ARPC4 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: ARPC4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ARPC4 were set to 35047857
Phenotypes for gene: ARPC4 were set to Developmental delay, language impairment, and ocular abnormalities, MIM# 620141
Review for gene: ARPC4 was set to GREEN
Added comment: 7 affected individuals from 6 families (gonadal mosaicism was confirmed in the mother of the 2 affected siblings) with a recurrent missense variant (NM_005718.4:c.472C>T; p.R158C). 6/7 affected individuals had microcephaly. The variant was associated with a decreased amount of F-actin in cells from two affected individuals.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.5040 EXOSC3 Michelle Dang changed review comment from: Association with global developmental delay, hypotonia, hyperreflexia, cerebellar (+/- pontine) atrophy with variable severity. Assessment of cognitive function/IQ limited by motor and speech impairments. Severe forms associated with early deaths during infancy periods. Intellectual impairment/psychomotor retardation (to varying degrees) reported in all cases across varying degrees of severity (23284067). Zanni et al (23975261) identified 2 individuals with compound heterozygous mutations resulting in intellectual impairment and early onset spasticity. Wan et al (22544365) described global developmental delay in addition to cerebellar features and spinal motor degeneration.; to: Association with global developmental delay, hypotonia, hyperreflexia, cerebellar (+/- pontine) atrophy with variable severity. Assessment of cognitive function/IQ limited by motor and speech impairments. Severe forms associated with early deaths during infancy periods.
Intellectual impairment/psychomotor retardation (to varying degrees) reported in all cases across varying degrees of severity (23284067). Zanni et al (23975261) identified 2 individuals with compound heterozygous mutations resulting in intellectual impairment and early onset spasticity. Wan et al (22544365) described global developmental delay in addition to cerebellar features and spinal motor degeneration, with functional effects of the mutation reproduced with knocked down endogenous expression of exosc3 in zebrafish embryos and subsequent rescue of the phenotype by co-injection with wild-type zebrafish exosc3 mRNA.
Intellectual disability syndromic and non-syndromic v0.5040 EXOSC3 Michelle Dang changed review comment from: Association with global developmental delay, hypotonia, hyperreflexia, cerebellar (+/- pontine) atrophy with variable severity. Assessment of cognitive function/IQ limited by motor and speech impairments. Severe forms associated with early deaths during infancy periods. Intellectual impairment/psychomotor retardation (to varying degrees) reported in all cases across various severity (23284067). Zanni et al (23975261) identified 2 individuals with compound heterozygous mutations resulting in intellectual impairment and early onset spasticity. Wan et al (22544365) described global developmental delay in addition to cerebellar features and spinal motor degeneration.; to: Association with global developmental delay, hypotonia, hyperreflexia, cerebellar (+/- pontine) atrophy with variable severity. Assessment of cognitive function/IQ limited by motor and speech impairments. Severe forms associated with early deaths during infancy periods. Intellectual impairment/psychomotor retardation (to varying degrees) reported in all cases across varying degrees of severity (23284067). Zanni et al (23975261) identified 2 individuals with compound heterozygous mutations resulting in intellectual impairment and early onset spasticity. Wan et al (22544365) described global developmental delay in addition to cerebellar features and spinal motor degeneration.
Intellectual disability syndromic and non-syndromic v0.5040 EXOSC3 Michelle Dang Deleted their comment
Intellectual disability syndromic and non-syndromic v0.5040 EXOSC3 Michelle Dang edited their review of gene: EXOSC3: Added comment: Association with global developmental delay, hypotonia, hyperreflexia, cerebellar (+/- pontine) atrophy with variable severity. Assessment of cognitive function/IQ limited by motor and speech impairments. Severe forms associated with early deaths during infancy periods. Intellectual impairment/psychomotor retardation (to varying degrees) reported in all cases across various severity (23284067). Zanni et al (23975261) identified 2 individuals with compound heterozygous mutations resulting in intellectual impairment and early onset spasticity. Wan et al (22544365) described global developmental delay in addition to cerebellar features and spinal motor degeneration.; Changed phenotypes: Cerebellar atrophy, Developmental delay, Lower motor neuron degeneration, Upper motor neuron features, Spasticity/hyperreflexia (+/-)
Intellectual disability syndromic and non-syndromic v0.5040 EXOSC3 Michelle Dang changed review comment from: Association with global developmental delay, hypotonia, hyperreflexia, cerebellar (+/- pontine) atrophy. Variable severity. Assessment of cognitive function/IQ limited by motor and speech impairments. Severe forms associated with early deaths during infancy periods. Intellectual impairment (to varying degrees) reported in all cases across various severity.; to: Association with global developmental delay, hypotonia, hyperreflexia, cerebellar (+/- pontine) atrophy with variable severity. Assessment of cognitive function/IQ limited by motor and speech impairments. Severe forms associated with early deaths during infancy periods. Intellectual impairment/psychomotor retardation (to varying degrees) reported in all cases across various severity (23284067). Zanni et al (23975261) identified 2 individuals with compound heterozygous mutations resulting in intellectual impairment and early onset spasticity. Wan et al (22544365) described global developmental delay in addition to cerebellar features and spinal motor degeneration.
Intellectual disability syndromic and non-syndromic v0.5040 EXOSC3 Michelle Dang reviewed gene: EXOSC3: Rating: GREEN; Mode of pathogenicity: None; Publications: 22544365, 23975261, 25149867, 23284067; Phenotypes: 23284067, 25149867; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.5040 CDK10 Lyndon Gallacher reviewed gene: CDK10: Rating: ; Mode of pathogenicity: None; Publications: 28886341; Phenotypes: Severe growth retardation, spine malformation, facial dysmorphisms, developmental delay, intellectual disability; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.5040 DOCK8 Chirag Patel Classified gene: DOCK8 as Red List (low evidence)
Intellectual disability syndromic and non-syndromic v0.5040 DOCK8 Chirag Patel Gene: dock8 has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v0.5039 DOCK8 Chirag Patel reviewed gene: DOCK8: Rating: RED; Mode of pathogenicity: None; Publications: PMID: 29930340; Phenotypes: ; Mode of inheritance: None
Intellectual disability syndromic and non-syndromic v0.5039 HECTD4 Zornitza Stark Phenotypes for gene: HECTD4 were changed from Neurodevelopmental disorder, MONDO:0700092, HECTD4-related to Neurodevelopmental disorder, MONDO:0700092, HECTD4-related
Intellectual disability syndromic and non-syndromic v0.5039 HECTD4 Zornitza Stark Marked gene: HECTD4 as ready
Intellectual disability syndromic and non-syndromic v0.5039 HECTD4 Zornitza Stark Gene: hectd4 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5039 HECTD4 Zornitza Stark Phenotypes for gene: HECTD4 were changed from Neurodevelopmental disorder overlapping Angelman syndrome, no OMIM# to Neurodevelopmental disorder, MONDO:0700092, HECTD4-related
Intellectual disability syndromic and non-syndromic v0.5038 HECTD4 Zornitza Stark reviewed gene: HECTD4: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder, MONDO:0700092, HECTD4-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.5038 UBE3C Zornitza Stark Marked gene: UBE3C as ready
Intellectual disability syndromic and non-syndromic v0.5038 UBE3C Zornitza Stark Gene: ube3c has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5038 UBE3C Zornitza Stark Phenotypes for gene: UBE3C were changed from Neurodevelopmental disorder overlapping Angelman syndrome, no OMIM# to Neurodevelopmental disorder, MONDO:0700092, UBE3C-related
Intellectual disability syndromic and non-syndromic v0.5037 UBE3C Zornitza Stark reviewed gene: UBE3C: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder, MONDO:0700092, UBE3C-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.5037 KIF26A Zornitza Stark Marked gene: KIF26A as ready
Intellectual disability syndromic and non-syndromic v0.5037 KIF26A Zornitza Stark Gene: kif26a has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5037 KIF26A Zornitza Stark Phenotypes for gene: KIF26A were changed from Congenital brain malformations, no OMIM # to Cerebral malformation MONDO:0016054, KIF26-related
Intellectual disability syndromic and non-syndromic v0.5036 KIF26A Zornitza Stark reviewed gene: KIF26A: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Cerebral malformation MONDO:0016054, KIF26-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.5036 UBE3C Chirag Patel Classified gene: UBE3C as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.5036 UBE3C Chirag Patel Gene: ube3c has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5035 UBE3C Chirag Patel gene: UBE3C was added
gene: UBE3C was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: UBE3C was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: UBE3C were set to PMID: 36401616
Phenotypes for gene: UBE3C were set to Neurodevelopmental disorder overlapping Angelman syndrome, no OMIM#
Review for gene: UBE3C was set to GREEN
Added comment: 3 patients/2 families with syndromic neurodevelopmental, seizure, and movement disorders and neurobehavioral phenotypes. WES found bi-allelic variants in UBE3C. The RNA studies in some patients with LoF variants provided evidence for the LoF effect.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.5034 HECTD4 Chirag Patel Classified gene: HECTD4 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.5034 HECTD4 Chirag Patel Gene: hectd4 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5033 HECTD4 Chirag Patel gene: HECTD4 was added
gene: HECTD4 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: HECTD4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HECTD4 were set to PMID: 36401616
Phenotypes for gene: HECTD4 were set to Neurodevelopmental disorder overlapping Angelman syndrome, no OMIM#
Review for gene: HECTD4 was set to GREEN
Added comment: 7 patients/5 families with syndromic neurodevelopmental, seizure, and movement disorders and neurobehavioral phenotypes. WES found bi-allelic variants in HECTD4. The RNA studies in some patients with LoF variants provided evidence for the LoF effect.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.5032 KIF26A Chirag Patel Classified gene: KIF26A as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.5032 KIF26A Chirag Patel Gene: kif26a has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5031 KIF26A Chirag Patel gene: KIF26A was added
gene: KIF26A was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: KIF26A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KIF26A were set to PMID: 36228617
Phenotypes for gene: KIF26A were set to Congenital brain malformations, no OMIM #
Review for gene: KIF26A was set to GREEN
Added comment: 5 unrelated patients with biallelic loss-of-function variants in KIF26A (found through WES), exhibiting a spectrum of congenital brain malformations (schizencephaly, corpus callosum anomalies, polymicrgyria, and ventriculomegaly). Combining mice and human iPSC-derived organoid models, they discovered that loss of KIF26A causes excitatory neuron-specific defects in radial migration, localization, dendritic and axonal growth, and apoptosis, offering a convincing explanation of the disease etiology in patients. Single-cell RNA sequencing in KIF26A knockout organoids revealed transcriptional changes in MAPK, MYC, and E2F pathways.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.5030 SPTAN1 Zornitza Stark Publications for gene: SPTAN1 were set to 20493457; 22258530; 32811770
Intellectual disability syndromic and non-syndromic v0.5029 SPTAN1 Zornitza Stark edited their review of gene: SPTAN1: Added comment: Another 21 individuals reported in PMID 36331550; some had DEE and others had isolated ID.; Changed publications: 20493457, 22258530, 32811770, 36331550
Intellectual disability syndromic and non-syndromic v0.5029 TBC1D2B Chirag Patel Classified gene: TBC1D2B as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.5029 TBC1D2B Chirag Patel Gene: tbc1d2b has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5028 TBC1D2B Chirag Patel reviewed gene: TBC1D2B: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 36029130; Phenotypes: Neurodevelopmental disorder with seizures and gingival overgrowth, OMIM #619323; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.5028 SPTBN5 Zornitza Stark Publications for gene: SPTBN5 were set to 35782384
Intellectual disability syndromic and non-syndromic v0.5027 SPTBN5 Zornitza Stark Tag disputed tag was added to gene: SPTBN5.
Intellectual disability syndromic and non-syndromic v0.5027 SPTBN5 Zornitza Stark Classified gene: SPTBN5 as Red List (low evidence)
Intellectual disability syndromic and non-syndromic v0.5027 SPTBN5 Zornitza Stark Gene: sptbn5 has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v0.5026 SPTBN5 Zornitza Stark reviewed gene: SPTBN5: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder, MONDO:0700092, SPTBN5-related; Mode of inheritance: None
Intellectual disability syndromic and non-syndromic v0.5026 MTSS1 Zornitza Stark Marked gene: MTSS1 as ready
Intellectual disability syndromic and non-syndromic v0.5026 MTSS1 Zornitza Stark Gene: mtss1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5026 MTSS1 Zornitza Stark Classified gene: MTSS1 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.5026 MTSS1 Zornitza Stark Gene: mtss1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5025 MTSS1 Zornitza Stark reviewed gene: MTSS1: Rating: GREEN; Mode of pathogenicity: None; Publications: 36067766; Phenotypes: Intellectual disability, MTSS1-related (MONDO#0001071); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.5025 TPR Zornitza Stark Marked gene: TPR as ready
Intellectual disability syndromic and non-syndromic v0.5025 TPR Zornitza Stark Gene: tpr has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v0.5025 TPR Zornitza Stark gene: TPR was added
gene: TPR was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: TPR was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TPR were set to 34494102
Phenotypes for gene: TPR were set to Multiple congenital anomalies/dysmorphic syndrome, MONDO:0019042, TPR-related
Review for gene: TPR was set to RED
Added comment: Two siblings harbouring variants c.6625C>T/ p.Arg2209Ter (identified in heterozygous state in both siblings and father) and c.2610 + 5G > A (identified in heterozygous state in both siblings and mother) were reported with ataxia, microcephaly and severe intellectual disability. Functional analyses in patient fibroblasts provide evidence that the variants affect TPR splicing, reduce steady-state TPR levels, abnormal nuclear pore composition and density, and altered global RNA distribution.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.5024 SMC5 Zornitza Stark Marked gene: SMC5 as ready
Intellectual disability syndromic and non-syndromic v0.5024 SMC5 Zornitza Stark Gene: smc5 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5024 SMC5 Zornitza Stark Classified gene: SMC5 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.5024 SMC5 Zornitza Stark Gene: smc5 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5023 SMC5 Zornitza Stark gene: SMC5 was added
gene: SMC5 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: SMC5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SMC5 were set to 36333305
Phenotypes for gene: SMC5 were set to Multiple congenital anomalies/dysmorphic syndrome, MONDO:0019042, SLF2-related; Atelis syndrome; microcephaly; short stature; ID
Review for gene: SMC5 was set to GREEN
Added comment: Four individuals from three families with a chromosome breakage disorder and bi-allelic variants in this gene. However, three of the individuals had the same homozygous missense variant. Evidence for functional impact of the variant was limited. However, zebrafish model recapitulated the phenotype and was not rescued by the introduction of this variant, arguing for functional effect. Borderline Amber/Green.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.5022 SLF2 Zornitza Stark Marked gene: SLF2 as ready
Intellectual disability syndromic and non-syndromic v0.5022 SLF2 Zornitza Stark Gene: slf2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5022 SLF2 Zornitza Stark Classified gene: SLF2 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.5022 SLF2 Zornitza Stark Gene: slf2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5021 SLF2 Zornitza Stark gene: SLF2 was added
gene: SLF2 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: SLF2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLF2 were set to 36333305
Phenotypes for gene: SLF2 were set to Multiple congenital anomalies/dysmorphic syndrome, MONDO:0019042, SLF2-related; Atelis syndrome; microcephaly; short stature; ID
Review for gene: SLF2 was set to GREEN
Added comment: Seven individuals from 6 families with a chromosome breakage disorder and bi-allelic variants in this gene (LoF). Functional data including zebrafish model.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.5020 SPTBN5 Chern Lim reviewed gene: SPTBN5: Rating: ; Mode of pathogenicity: Other; Publications: 36117916, 36238261; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.5020 MAST3 Zornitza Stark Phenotypes for gene: MAST3 were changed from Developmental and epileptic encephalopathy to Developmental and epileptic encephalopathy 108, MIM#620115
Intellectual disability syndromic and non-syndromic v0.5019 MAST3 Zornitza Stark edited their review of gene: MAST3: Changed phenotypes: Developmental and epileptic encephalopathy 108, MIM#620115
Intellectual disability syndromic and non-syndromic v0.5019 CACNA1I Zornitza Stark Phenotypes for gene: CACNA1I were changed from Neurodevelopmental disorder to Neurodevelopmental disorder with variable intellectual disability and speech impairment, with or without seizures (NEDISS), MIM#620114
Intellectual disability syndromic and non-syndromic v0.5018 FRA10AC1 Zornitza Stark Phenotypes for gene: FRA10AC1 were changed from Neurodevelopmental disorder, MONDO:0700092, FRA10AC1-related to Neurodevelopmental disorder with growth retardation, dysmorphic facies, and corpus callosum abnormalities, MIM# 620113
Intellectual disability syndromic and non-syndromic v0.5017 FRA10AC1 Zornitza Stark edited their review of gene: FRA10AC1: Changed phenotypes: Neurodevelopmental disorder with growth retardation, dysmorphic facies, and corpus callosum abnormalities, MIM# 620113
Intellectual disability syndromic and non-syndromic v0.5017 WDR5 Bryony Thompson Marked gene: WDR5 as ready
Intellectual disability syndromic and non-syndromic v0.5017 WDR5 Bryony Thompson Gene: wdr5 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5017 WDR5 Bryony Thompson Classified gene: WDR5 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.5017 WDR5 Bryony Thompson Gene: wdr5 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5016 WDR5 Bryony Thompson gene: WDR5 was added
gene: WDR5 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: WDR5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: WDR5 were set to DOI:https://doi.org/10.1016/j.xhgg.2022.100157
Phenotypes for gene: WDR5 were set to Neurodevelopmental disorder MONDO:0700092, WDR5-related
Mode of pathogenicity for gene: WDR5 was set to Other
Review for gene: WDR5 was set to GREEN
Added comment: Six different missense variants were identified (de novo) in 11 affected individuals with neurodevelopmental disorders, with a broad spectrum of additional features, including epilepsy, aberrant growth parameters, skeletal and cardiac abnormalities. 9/11 probands have ID. In vivo and in vitro functional suggest that loss-of-function is not the mechanism of disease. The mechanism of disease is yet to be established.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.5015 JARID2 Zornitza Stark Phenotypes for gene: JARID2 were changed from Intellectual disability to Developmental delay with variable intellectual disability and dysmorphic facies (DIDDF), MIM#620098
Intellectual disability syndromic and non-syndromic v0.5014 JARID2 Zornitza Stark edited their review of gene: JARID2: Changed phenotypes: Developmental delay with variable intellectual disability and dysmorphic facies (DIDDF), MIM#620098
Intellectual disability syndromic and non-syndromic v0.5014 PI4K2A Seb Lunke Marked gene: PI4K2A as ready
Intellectual disability syndromic and non-syndromic v0.5014 PI4K2A Seb Lunke Gene: pi4k2a has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5014 PI4K2A Seb Lunke Classified gene: PI4K2A as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.5014 PI4K2A Seb Lunke Gene: pi4k2a has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5013 PI4K2A Seb Lunke gene: PI4K2A was added
gene: PI4K2A was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: PI4K2A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PI4K2A were set to 30564627; 35880319; 19581584
Phenotypes for gene: PI4K2A were set to complex neurodevelopmental disorder with motor features, PI4K2A-related, MONDO:0100516
Review for gene: PI4K2A was set to GREEN
Added comment: Two reportedly unrelated, consanguine families with the same hom stop mutation in PI4K2A, p.(Arg309Ter). Probands with seizures, developmental delay, hypotonia/dystonia, myoclonus and developmental delay. MRI showed extensive brain abnormalities including dysgenesis of the corpus callosum, ventriculomegaly, and white matter volume loss.

Functional studies showed cellular mislocalisation of the Arg309Ter truncated protein construct compared to WT and an missense control.

An earlier paper from 2018 described two additional probands with a different stop mutation, p.(Ser22Ter), and overlapping phenotypic presentation.

in 2011, a Pi4k2a knock-out mouse model was described. "Knock-out animals initially appeared normal but later develop a progressive neurological dis-ease characterized by tremor, limb weakness, urinary incontinence and premature mortality. Histological analysis revealed massive axonal degeneration in the spinal cord in the descending corticospinal tracts."
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.5012 CAMSAP1 Zornitza Stark Marked gene: CAMSAP1 as ready
Intellectual disability syndromic and non-syndromic v0.5012 CAMSAP1 Zornitza Stark Gene: camsap1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5012 CAMSAP1 Zornitza Stark Classified gene: CAMSAP1 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.5012 CAMSAP1 Zornitza Stark Gene: camsap1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5011 CAMSAP1 Naomi Baker gene: CAMSAP1 was added
gene: CAMSAP1 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: CAMSAP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CAMSAP1 were set to 36283405
Phenotypes for gene: CAMSAP1 were set to lissencephaly spectrum disorders (MONDO:0018838), CAMSAP1-related
Review for gene: CAMSAP1 was set to GREEN
Added comment: Five unrelated families with bi-allelic loss-of-function variants. Clinical features of the syndrome include a characteristic craniofacial appearance, primary microcephaly, lissencephaly, agenesis or severe hypogenesis of the corpus callosum, severe neurodevelopmental delay, cortical visual impairment, and seizures.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.5011 KLHL20 Zornitza Stark Marked gene: KLHL20 as ready
Intellectual disability syndromic and non-syndromic v0.5011 KLHL20 Zornitza Stark Gene: klhl20 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5011 KLHL20 Zornitza Stark Classified gene: KLHL20 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.5011 KLHL20 Zornitza Stark Gene: klhl20 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5010 MYCBP2 Zornitza Stark Marked gene: MYCBP2 as ready
Intellectual disability syndromic and non-syndromic v0.5010 MYCBP2 Zornitza Stark Gene: mycbp2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5010 MYCBP2 Zornitza Stark Phenotypes for gene: MYCBP2 were changed from neurodevelopmental spectrum disorder with corpus callosum defects to Neurodevelopmental disorder, MONDO:0700092, MYCBP2-related; corpus callosum abnormalities
Intellectual disability syndromic and non-syndromic v0.5009 MYCBP2 Zornitza Stark Classified gene: MYCBP2 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.5009 MYCBP2 Zornitza Stark Gene: mycbp2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5008 MYCBP2 Suliman Khan edited their review of gene: MYCBP2: Changed phenotypes: intellectual disability, epilepsy, autistic features and callosum abnormalities,
Intellectual disability syndromic and non-syndromic v0.5008 MYCBP2 Zornitza Stark edited their review of gene: MYCBP2: Changed phenotypes: Neurodevelopmental disorder, MONDO:0700092, MYCBP2-related, corpus callosum abnormalities
Intellectual disability syndromic and non-syndromic v0.5008 MYCBP2 Zornitza Stark reviewed gene: MYCBP2: Rating: GREEN; Mode of pathogenicity: None; Publications: 36200388; Phenotypes: Neurodevelopmental disorder, MONDO:0700092, MYCBP2-related, corpus callosum abnormalitie; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.5008 KLHL20 Dean Phelan gene: KLHL20 was added
gene: KLHL20 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: KLHL20 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KLHL20 were set to PMID: 36214804
Phenotypes for gene: KLHL20 were set to Neurodevelopmental disorder (MONDO:0700092), KLHL20-related
Review for gene: KLHL20 was set to GREEN
Added comment: PMID: 36214804
- 14 patients with de novo missense variants in KLHL20. The patients had mild to severe ID, febrile seizures or epilepsy, autism spectrum disorder, hyperactivity and subtle dysmorphic facial features.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.5008 MYCBP2 Suliman Khan gene: MYCBP2 was added
gene: MYCBP2 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: MYCBP2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MYCBP2 were set to PMID: 36200388
Phenotypes for gene: MYCBP2 were set to neurodevelopmental spectrum disorder with corpus callosum defects
Penetrance for gene: MYCBP2 were set to Complete
Review for gene: MYCBP2 was set to GREEN
Added comment: Sources: Literature
Intellectual disability syndromic and non-syndromic v0.5008 FRMD5 Zornitza Stark Phenotypes for gene: FRMD5 were changed from Neurodevelopmental disorder MONDO:0700092, FRMD5-related to Neurodevelopmental disorder with eye movement abnormalities and ataxia, MIM# 620094
Intellectual disability syndromic and non-syndromic v0.5007 FRMD5 Zornitza Stark edited their review of gene: FRMD5: Changed phenotypes: Neurodevelopmental disorder with eye movement abnormalities and ataxia, MIM# 620094
Intellectual disability syndromic and non-syndromic v0.5007 OTC Zornitza Stark Marked gene: OTC as ready
Intellectual disability syndromic and non-syndromic v0.5007 OTC Zornitza Stark Gene: otc has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5007 OTC Zornitza Stark Phenotypes for gene: OTC were changed from to Ornithine transcarbamylase deficiency, MIM#311250
Intellectual disability syndromic and non-syndromic v0.5006 OTC Zornitza Stark Mode of inheritance for gene: OTC was changed from Unknown to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability syndromic and non-syndromic v0.5005 OTC Zornitza Stark reviewed gene: OTC: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Ornithine transcarbamylase deficiency, MIM#311250; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability syndromic and non-syndromic v0.5005 OTC Zornitza Stark Tag treatable tag was added to gene: OTC.
Intellectual disability syndromic and non-syndromic v0.5005 LETM1 Zornitza Stark Phenotypes for gene: LETM1 were changed from Mitochondrial disease MONDO#0044970, LETM1-related to Childhood-onset neurodegeneration with multisystem involvement due to mitochondrial dysfunction (CONDMIM), MIM#620089
Intellectual disability syndromic and non-syndromic v0.5004 LETM1 Zornitza Stark reviewed gene: LETM1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Childhood-onset neurodegeneration with multisystem involvement due to mitochondrial dysfunction (CONDMIM), MIM#620089; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.5004 HNRNPH1 Zornitza Stark Phenotypes for gene: HNRNPH1 were changed from HNRNPH1 ‐related syndromic intellectual disability to Neurodevelopmental disorder with craniofacial dysmorphism and skeletal defects, MIM# 620083
Intellectual disability syndromic and non-syndromic v0.5003 HNRNPH1 Zornitza Stark reviewed gene: HNRNPH1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with craniofacial dysmorphism and skeletal defects, MIM# 620083; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.5003 AKT3 Zornitza Stark Marked gene: AKT3 as ready
Intellectual disability syndromic and non-syndromic v0.5003 AKT3 Zornitza Stark Gene: akt3 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5003 AKT3 Zornitza Stark Phenotypes for gene: AKT3 were changed from to Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 2, MIM# 615937
Intellectual disability syndromic and non-syndromic v0.5002 AKT3 Zornitza Stark Publications for gene: AKT3 were set to
Intellectual disability syndromic and non-syndromic v0.5001 AKT3 Zornitza Stark Mode of inheritance for gene: AKT3 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.5000 AKT3 Zornitza Stark reviewed gene: AKT3: Rating: GREEN; Mode of pathogenicity: None; Publications: 22729224, 22729223, 35665751, 34354878, 32446860, 31441589; Phenotypes: Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 2, MIM# 615937; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.5000 TMEM147 Zornitza Stark Phenotypes for gene: TMEM147 were changed from Neurodevelopmental disorder (MONDO:0700092), TMEM147-related to Neurodevelopmental disorder with facial dysmorphism, absent language, and pseudo-Pelger-Huet anomaly, MIM# 620075
Intellectual disability syndromic and non-syndromic v0.4999 TMEM147 Zornitza Stark reviewed gene: TMEM147: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with facial dysmorphism, absent language, and pseudo-Pelger-Huet anomaly, MIM# 620075; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4999 PSMC1 Zornitza Stark Phenotypes for gene: PSMC1 were changed from spastic paraplegia; severe developmental delay; severe intellectual disability; hearing loss; micropenis; undescended testes; Syndromic disease MONDO:0002254, PSMC1-related to Neurodevelopmental disorder with poor growth, spastic tetraplegia, and hearing loss , MIM# 620071
Intellectual disability syndromic and non-syndromic v0.4998 PSMC1 Zornitza Stark reviewed gene: PSMC1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with poor growth, spastic tetraplegia, and hearing loss , MIM# 620071; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4998 HNRNPR Zornitza Stark Phenotypes for gene: HNRNPR were changed from Intellectual disability; seizures; dysmorphic features to Neurodevelopmental disorder with dysmorphic facies and skeletal and brain abnormalities, MIM# 620073
Intellectual disability syndromic and non-syndromic v0.4997 HNRNPR Zornitza Stark edited their review of gene: HNRNPR: Changed phenotypes: Neurodevelopmental disorder with dysmorphic facies and skeletal and brain abnormalities, MIM# 620073
Intellectual disability syndromic and non-syndromic v0.4997 FGF14 Zornitza Stark Marked gene: FGF14 as ready
Intellectual disability syndromic and non-syndromic v0.4997 FGF14 Zornitza Stark Gene: fgf14 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4997 FGF14 Zornitza Stark Phenotypes for gene: FGF14 were changed from to Spinocerebellar ataxia 27, MIM# 609307; Vestibulocerebellar disorder with predominant ocular signs, MIM# 193003
Intellectual disability syndromic and non-syndromic v0.4996 FGF14 Zornitza Stark Mode of inheritance for gene: FGF14 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.4995 FGF14 Zornitza Stark edited their review of gene: FGF14: Changed phenotypes: Spinocerebellar ataxia 27, MIM# 609307, Vestibulocerebellar disorder with predominant ocular signs, MIM# 193003
Intellectual disability syndromic and non-syndromic v0.4995 GAMT Zornitza Stark Tag treatable tag was added to gene: GAMT.
Intellectual disability syndromic and non-syndromic v0.4995 HEATR3 Zornitza Stark Phenotypes for gene: HEATR3 were changed from Bone marrow failure, short stature, facial and acromelic dysmorphic features, and mild intellectual disability; Diamond Blackfan anaemia MONDO:0015253, HEATR3 related to Bone marrow failure, short stature, facial and acromelic dysmorphic features, and mild intellectual disability; Diamond-Blackfan anaemia 21, MIM# 620072
Intellectual disability syndromic and non-syndromic v0.4994 HEATR3 Zornitza Stark reviewed gene: HEATR3: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Diamond-Blackfan anaemia 21, MIM# 620072; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4994 ETHE1 Zornitza Stark Tag treatable tag was added to gene: ETHE1.
Intellectual disability syndromic and non-syndromic v0.4994 FRMD5 Zornitza Stark Marked gene: FRMD5 as ready
Intellectual disability syndromic and non-syndromic v0.4994 FRMD5 Zornitza Stark Gene: frmd5 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4994 FRMD5 Zornitza Stark Phenotypes for gene: FRMD5 were changed from to Neurodevelopmental disorder MONDO:0700092, FRMD5-related
Intellectual disability syndromic and non-syndromic v0.4993 FRMD5 Zornitza Stark Publications for gene: FRMD5 were set to
Intellectual disability syndromic and non-syndromic v0.4992 FRMD5 Zornitza Stark edited their review of gene: FRMD5: Changed phenotypes: Neurodevelopmental disorder MONDO:0700092, FRMD5-related
Intellectual disability syndromic and non-syndromic v0.4992 FRMD5 Zornitza Stark edited their review of gene: FRMD5: Changed publications: 36206744
Intellectual disability syndromic and non-syndromic v0.4992 FRMD5 Zornitza Stark Classified gene: FRMD5 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4992 FRMD5 Zornitza Stark Gene: frmd5 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4991 FRMD5 Zornitza Stark gene: FRMD5 was added
gene: FRMD5 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: FRMD5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Review for gene: FRMD5 was set to GREEN
Added comment: Eight individuals reported with missense variants in this gene, de novo in 6 where parents were available. Clinical presentation was with ID, seizures, ataxia. Fly model.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4990 GIGYF1 Elena Savva Phenotypes for gene: GIGYF1 were changed from Developmental disorder to Autism, Intellectual disability, GIGYF1-related (MONDO#0001071)
Intellectual disability syndromic and non-syndromic v0.4990 GIGYF1 Elena Savva Publications for gene: GIGYF1 were set to 33057194
Intellectual disability syndromic and non-syndromic v0.4989 GIGYF1 Elena Savva Classified gene: GIGYF1 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4989 GIGYF1 Elena Savva Gene: gigyf1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4988 GIGYF1 Elena Savva reviewed gene: GIGYF1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 35917186; Phenotypes: Autism, Intellectual disability, GIGYF1-related (MONDO#0001071); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability syndromic and non-syndromic v0.4988 HECW2 Zornitza Stark Mode of inheritance for gene: HECW2 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4987 HECW2 Zornitza Stark changed review comment from: Two probands reported with biallelic variants and putative loss of function mechanism of disease (compared to the established gain of function monoallelic disease)
PMID: 35753050 - Caucasian girl who presented a severe neurodevelopmental disorder with drug-resistant epilepsy, hypotonia, severe gastro-esophageal reflux and brain magnetic resonance imaging anomalies with a homozygous splice variant that causes in-frame elimination of exon 22 (c.3917+2_3917+12delinsG r.3766_3917+1del p.Leu1256_Trp1306del). Protein expression level was reduced by 60%, suggesting a partial loss-of-function mechanism of disease.
PMID: 35487419 - homozygous nonsense variant (c.736C>T; p.Arg246*) identified in a proband from a Moroccan consanguineous family, with developmental delay, intellectual disability, hypotonia, generalized tonico-clonic seizures and a persistent tilted head.; to: Two probands reported with biallelic variants and putative loss of function mechanism of disease (compared to the established gain of function monoallelic disease)
PMID: 35753050 - Caucasian girl who presented a severe neurodevelopmental disorder with drug-resistant epilepsy, hypotonia, severe gastro-esophageal reflux and brain magnetic resonance imaging anomalies with a homozygous splice variant that causes in-frame elimination of exon 22 (c.3917+2_3917+12delinsG r.3766_3917+1del p.Leu1256_Trp1306del). Protein expression level was reduced by 60%, suggesting a partial loss-of-function mechanism of disease.
PMID: 35487419 - homozygous nonsense variant (c.736C>T; p.Arg246*) identified in a proband from a Moroccan consanguineous family, with developmental delay, intellectual disability, hypotonia, generalized tonico-clonic seizures and a persistent tilted head.

Association with bi-allelic variants is AMBER.
Intellectual disability syndromic and non-syndromic v0.4987 HECW2 Zornitza Stark edited their review of gene: HECW2: Added comment: Two probands reported with biallelic variants and putative loss of function mechanism of disease (compared to the established gain of function monoallelic disease)
PMID: 35753050 - Caucasian girl who presented a severe neurodevelopmental disorder with drug-resistant epilepsy, hypotonia, severe gastro-esophageal reflux and brain magnetic resonance imaging anomalies with a homozygous splice variant that causes in-frame elimination of exon 22 (c.3917+2_3917+12delinsG r.3766_3917+1del p.Leu1256_Trp1306del). Protein expression level was reduced by 60%, suggesting a partial loss-of-function mechanism of disease.
PMID: 35487419 - homozygous nonsense variant (c.736C>T; p.Arg246*) identified in a proband from a Moroccan consanguineous family, with developmental delay, intellectual disability, hypotonia, generalized tonico-clonic seizures and a persistent tilted head.; Changed publications: 29807643, 29395664, 27334371, 27389779, 35753050, 35487419; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4987 CPS1 Zornitza Stark Tag treatable tag was added to gene: CPS1.
Intellectual disability syndromic and non-syndromic v0.4987 DPH5 Zornitza Stark Marked gene: DPH5 as ready
Intellectual disability syndromic and non-syndromic v0.4987 DPH5 Zornitza Stark Gene: dph5 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4987 DPH5 Zornitza Stark edited their review of gene: DPH5: Changed publications: 35482014
Intellectual disability syndromic and non-syndromic v0.4987 DPH5 Zornitza Stark Classified gene: DPH5 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4987 DPH5 Zornitza Stark Gene: dph5 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4986 DPH5 Zornitza Stark gene: DPH5 was added
gene: DPH5 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: DPH5 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: DPH5 were set to Neurodevelopmental disorder with short stature, prominent forehead, and feeding difficulties 620070
Review for gene: DPH5 was set to GREEN
Added comment: 5 individuals from 3 unrelated families reported with severe ID, feeding difficulties, dysmorphic features and congenital anomalies, though there was no consistent pattern to these.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4985 ADGRL1 Zornitza Stark Phenotypes for gene: ADGRL1 were changed from Neurodevelopmental disorder, ADGRL1-related (MONDO#0700092) to Developmental delay, behavioral abnormalities, and neuropsychiatric disorders, MIM# 620065
Intellectual disability syndromic and non-syndromic v0.4984 ADGRL1 Zornitza Stark Mode of inheritance for gene: ADGRL1 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.4983 ADGRL1 Zornitza Stark reviewed gene: ADGRL1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Developmental delay, behavioral abnormalities, and neuropsychiatric disorders, MIM# 620065; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.4983 BRIP1 Zornitza Stark Marked gene: BRIP1 as ready
Intellectual disability syndromic and non-syndromic v0.4983 BRIP1 Zornitza Stark Gene: brip1 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.4983 BRIP1 Zornitza Stark Phenotypes for gene: BRIP1 were changed from to Fanconi anaemia, complementation group J, MIM# 609054
Intellectual disability syndromic and non-syndromic v0.4982 BRIP1 Zornitza Stark Mode of inheritance for gene: BRIP1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4981 BRIP1 Zornitza Stark Classified gene: BRIP1 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.4981 BRIP1 Zornitza Stark Gene: brip1 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.4980 ACAD9 Zornitza Stark Tag treatable tag was added to gene: ACAD9.
Intellectual disability syndromic and non-syndromic v0.4980 GABRG1 Zornitza Stark Phenotypes for gene: GABRG1 were changed from to Developmental and epileptic encephalopathy MONDO:0100062
Intellectual disability syndromic and non-syndromic v0.4979 GABRG1 Zornitza Stark Publications for gene: GABRG1 were set to
Intellectual disability syndromic and non-syndromic v0.4978 GABRG1 Zornitza Stark Mode of inheritance for gene: GABRG1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.4977 LETM1 Zornitza Stark Marked gene: LETM1 as ready
Intellectual disability syndromic and non-syndromic v0.4977 LETM1 Zornitza Stark Gene: letm1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4977 LETM1 Zornitza Stark Classified gene: LETM1 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4977 LETM1 Zornitza Stark Gene: letm1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4976 DEPDC5 Dean Phelan reviewed gene: DEPDC5: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 36067010, 32848577; Phenotypes: Neurodevelopmental disorder, DEPDC5-related, MONDO:0700092; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4976 GABBR1 Zornitza Stark Marked gene: GABBR1 as ready
Intellectual disability syndromic and non-syndromic v0.4976 GABBR1 Zornitza Stark Gene: gabbr1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4976 GABBR1 Zornitza Stark Classified gene: GABBR1 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4976 GABBR1 Zornitza Stark Gene: gabbr1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4975 GABBR1 Zornitza Stark gene: GABBR1 was added
gene: GABBR1 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: GABBR1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: GABBR1 were set to 36103875
Phenotypes for gene: GABBR1 were set to Neurodevelopmental disorder, GABBR1-related, MONDO:0700092
Review for gene: GABBR1 was set to GREEN
Added comment: Four individuals with de novo variants in this gene and varying severity of DD/ID, seizures and hypotonia.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4974 LETM1 Ee Ming Wong gene: LETM1 was added
gene: LETM1 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: LETM1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LETM1 were set to 36055214
Phenotypes for gene: LETM1 were set to Mitochondrial disease MONDO#0044970, LETM1-related
Review for gene: LETM1 was set to GREEN
gene: LETM1 was marked as current diagnostic
Added comment: -18 affected individuals from 11 unrelated families harbouring ultra-rare bi-allelic missense and loss-of-function LETM1 variants
-Most of the affected individuals (14/18, 78%) had an infantile-onset disease manifestation,
and 4/18 (22%) presented first symptoms between the ages of 1.5 and 2 years
-Variant types included missense, frameshift, stop loss, in-frame deletion and splice defect
-From biochemical and morphological studies, bi-allelic LETM1 variants are associated with defective mitochondrial K efflux, swollen mitochondrial matrix structures, and loss of important mitochondrial oxidative phosphorylation protein components
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4974 MED11 Ain Roesley Classified gene: MED11 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4974 MED11 Ain Roesley Gene: med11 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4974 MED11 Ain Roesley Classified gene: MED11 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4974 MED11 Ain Roesley Gene: med11 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4973 MED11 Ain Roesley Marked gene: MED11 as ready
Intellectual disability syndromic and non-syndromic v0.4973 MED11 Ain Roesley Gene: med11 has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v0.4973 MED11 Ain Roesley gene: MED11 was added
gene: MED11 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: MED11 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MED11 were set to 36001086
Phenotypes for gene: MED11 were set to neurodevelopmental disorder MONDO#0700092, MED11-related
Review for gene: MED11 was set to GREEN
gene: MED11 was marked as current diagnostic
Added comment: 7 affected from 5 families (3x consang) with the same recurrent variant of p.(Arg109*).

Protein truncating, NOT NMD as proven by RT-PCR and western blot. Zebrafish knockout model recapitulates key clinical phenotypes

NO evidence of founder effect from haplotype analysis

7/7 cerebral dysgyria, cortical atrophy
5/7 limb contracture
4/7 epilepsy
3/7 families with IUGR
3/7 GDD
3/7 hearing loss
3/7 undescended testis
2/7 nystagmus
1/7 congenital cataract
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4973 MED11 Ain Roesley gene: MED11 was added
gene: MED11 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: MED11 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MED11 were set to 36001086
Phenotypes for gene: MED11 were set to neurodevelopmental disorder MONDO#0700092, MED11-related
Review for gene: MED11 was set to GREEN
gene: MED11 was marked as current diagnostic
Added comment: 7 affected from 5 families (3x consang) with the same recurrent variant of p.(Arg109*).

Protein truncating, NOT NMD as proven by RT-PCR and western blot. Zebrafish knockout model recapitulates key clinical phenotypes

NO evidence of founder effect from haplotype analysis

7/7 cerebral dysgyria, cortical atrophy
5/7 limb contracture
4/7 epilepsy
3/7 families with IUGR
3/7 GDD
3/7 hearing loss
3/7 undescended testis
2/7 nystagmus
1/7 congenital cataract
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4972 SLC32A1 Zornitza Stark Marked gene: SLC32A1 as ready
Intellectual disability syndromic and non-syndromic v0.4972 SLC32A1 Zornitza Stark Gene: slc32a1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4972 SLC32A1 Zornitza Stark Classified gene: SLC32A1 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4972 SLC32A1 Zornitza Stark Gene: slc32a1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4971 ATP6V0C Alison Yeung Classified gene: ATP6V0C as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4971 ATP6V0C Alison Yeung Gene: atp6v0c has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4970 GABRG1 Anna Ritchie reviewed gene: GABRG1: Rating: RED; Mode of pathogenicity: None; Publications: PMID: 36121006; Phenotypes: Developmental and epileptic encephalopathy MONDO:0100062; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.4970 NAPB Alison Yeung Marked gene: NAPB as ready
Intellectual disability syndromic and non-syndromic v0.4970 NAPB Alison Yeung Gene: napb has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4970 NAPB Alison Yeung Classified gene: NAPB as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4970 NAPB Alison Yeung Gene: napb has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4969 ATP6V0C Naomi Baker reviewed gene: ATP6V0C: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID:36074901; Phenotypes: neurodevelopmental disorder (MONDO:0700092), ATP6V0C-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.4969 FOSL2 Zornitza Stark Marked gene: FOSL2 as ready
Intellectual disability syndromic and non-syndromic v0.4969 FOSL2 Zornitza Stark Gene: fosl2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4969 FOSL2 Zornitza Stark Classified gene: FOSL2 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4969 FOSL2 Zornitza Stark Gene: fosl2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4968 SLC32A1 Lucy Spencer gene: SLC32A1 was added
gene: SLC32A1 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: SLC32A1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SLC32A1 were set to 36073542
Phenotypes for gene: SLC32A1 were set to developmental and epileptic encephalopathy MONDO:0100062, SLC32A1-related
Review for gene: SLC32A1 was set to GREEN
Added comment: PMID: 36073542- 4 patients with de novo missense. All have moderate to severe ID or developmental delay and seizures. 3 have a movement disorder. Developmental delay appears to be a new association for this gene described in this paper.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4968 MTSS1L Elena Savva Classified gene: MTSS1L as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4968 MTSS1L Elena Savva Gene: mtss1l has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4967 MTSS1L Elena Savva Classified gene: MTSS1L as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4967 MTSS1L Elena Savva Gene: mtss1l has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4966 MTSS1L Elena Savva Marked gene: MTSS1L as ready
Intellectual disability syndromic and non-syndromic v0.4966 MTSS1L Elena Savva Gene: mtss1l has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v0.4966 GCSH Ain Roesley Phenotypes for gene: GCSH were changed from Glycine encephalopathy, MIM#605899 to Glycine encephalopathy MIM#605899; neurodevelopmental disorder MONDO#0700092, GCHS-related
Intellectual disability syndromic and non-syndromic v0.4966 GCSH Ain Roesley Publications for gene: GCSH were set to 1671321
Intellectual disability syndromic and non-syndromic v0.4966 GCSH Ain Roesley Mode of inheritance for gene: GCSH was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4966 MTSS1 Elena Savva Deleted their review
Intellectual disability syndromic and non-syndromic v0.4966 GCSH Ain Roesley Classified gene: GCSH as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4966 GCSH Ain Roesley Gene: gcsh has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4965 GCSH Ain Roesley reviewed gene: GCSH: Rating: GREEN; Mode of pathogenicity: None; Publications: 36190515; Phenotypes: Glycine encephalopathy MIM#605899, neurodevelopmental disorder MONDO#0700092, GCHS-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability syndromic and non-syndromic v0.4965 MTSS1 Elena Savva gene: MTSS1 was added
gene: MTSS1 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: MTSS1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MTSS1 were set to PMID: 36067766
Phenotypes for gene: MTSS1 were set to Intellectual disability, MTSS1-related (MONDO#0001071)
Review for gene: MTSS1 was set to GREEN
Added comment: Alt gene name: MTSS2

Huang (2022): recurring de novo missense variant (p.R671W) causing syndromic intellectual disability in 5 unrelated individuals.
- Individuals present with GDD, mild ID (5/5), nystagmus (3/5), optic atrophy (1/5), ptosis (2/5), sensorineural hearing loss (2/4), microcephaly or relative microcephaly (5/5), and shared mild facial dysmorphisms.
- Overexpression supports a DN mechanism
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4964 MTSS1L Elena Savva gene: MTSS1L was added
gene: MTSS1L was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: MTSS1L was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MTSS1L were set to PMID: 36067766
Phenotypes for gene: MTSS1L were set to Intellectual disability, MTSS2-related (MONDO#0001071)
Review for gene: MTSS1L was set to GREEN
Added comment: Alt gene name: MTSS2

Huang (2022): recurring de novo missense variant (p.R671W) causing syndromic intellectual disability in 5 unrelated individuals.
- Individuals present with GDD, mild ID (5/5), nystagmus (3/5), optic atrophy (1/5), ptosis (2/5), sensorineural hearing loss (2/4), microcephaly or relative microcephaly (5/5), and shared mild facial dysmorphisms.
- Overexpression supports a DN mechanism
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4963 NAPB Paul De Fazio gene: NAPB was added
gene: NAPB was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: NAPB was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NAPB were set to 26235277; 28097321; 33189936
Phenotypes for gene: NAPB were set to Developmental and epileptic encephalopathy 107 MIM#620033
Review for gene: NAPB was set to GREEN
gene: NAPB was marked as current diagnostic
Added comment: PMID 26235277: homozygous nonsense variant identified in a 6 year old girl by trio WES with early-onset epileptic encephalopathy characterised by multifocal seizures and profound GDD

PMID 28097321: exome sequencing in 152 consanguineous families with at least one member affected with ID. Homozygous nonsense variant identified in a patient with profound ID, seizures, feeding difficulties in infancy, muscularhypotonia, microcephaly, and impaired vision

PMID 33189936: homozygous canonical splice variant identified by trio exome sequencing in two siblings with seizures, intellectual disability and global developmental delay, microcephaly (<-3SD), and muscular hypotonia.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4963 RABGAP1 Zornitza Stark Marked gene: RABGAP1 as ready
Intellectual disability syndromic and non-syndromic v0.4963 RABGAP1 Zornitza Stark Gene: rabgap1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4963 RABGAP1 Zornitza Stark Classified gene: RABGAP1 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4963 RABGAP1 Zornitza Stark Gene: rabgap1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4962 RABGAP1 Zornitza Stark gene: RABGAP1 was added
gene: RABGAP1 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: RABGAP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RABGAP1 were set to 36083289
Phenotypes for gene: RABGAP1 were set to Neurodevelopmental disorder, RABGAP1-related,MONDO:0700092
Review for gene: RABGAP1 was set to GREEN
Added comment: 5 individuals from three families reported with ID, microcephaly, SNHL and seizures. Mouse model recapitulated the phenotype.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4961 NSD2 Zornitza Stark Phenotypes for gene: NSD2 were changed from Rauch-Steindl syndrome, MIM# 619695; Microcephaly; intellectual disability to Rauch-Steindl syndrome, MIM# 619695; Microcephaly; intellectual disability; Neurodevelopmental disorder, NSD2-associated, GoF, MONDO:0700092
Intellectual disability syndromic and non-syndromic v0.4960 NSD2 Zornitza Stark Publications for gene: NSD2 were set to 30345613; 31171569
Intellectual disability syndromic and non-syndromic v0.4959 NSD2 Zornitza Stark edited their review of gene: NSD2: Added comment: PMID 36189577: two individuals reported with a GoF variant, p.Glu1099Lys, and a distinct phenotype: intellectual disability, coarse/ square facial gestalt, abnormalities of the hands, and organomegaly.; Changed publications: 30345613, 31171569, 36189577; Changed phenotypes: Rauch-Steindl syndrome, MIM# 619695, Microcephaly, intellectual disability, Neurodevelopmental disorder, NSD2-associated, GoF, MONDO:0700092
Intellectual disability syndromic and non-syndromic v0.4959 FOSL2 Krithika Murali gene: FOSL2 was added
gene: FOSL2 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: FOSL2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FOSL2 were set to 36197437
Phenotypes for gene: FOSL2 were set to Neurodevelopmental disorder, MONDO:0700092, FOSL2-related
Review for gene: FOSL2 was set to GREEN
Added comment: PMID 36197437 Cospain et al 2022 report 11 individuals from 10 families with heterozygous PTC variants in exon 4/4 of the FOSL2 gene. All variants were predicted to escape NMD resulting in a truncated protein, with the truncation occurring proximal to the C-terminal domain (supportive functional studies).

In 10/11 families the variant occurred de novo in a single affected proband. In one family with 2 affected siblings, the variant was present in the siblings but absent in the unaffected parent likely due to gonadal mosaicism.

Clinical features included:
- Cutis aplasia congenital of the scalp (10/11)
- Tooth enamel hypoplasia and discolouration (8/9)
- Multiple other ectodermal features also noted e.g. small brittle nails, hypotrichosis/hypertrichosis, lichen sclerosis
- 5 individuals had cataracts (mostly bilateral, congenital/early childhood onset)
- 6/9 IUGR
- 5/9 postnatal growth restriction
- 7/9 developmental delay/ID (mild to severe)
- 5/7 ADHD/ASD
- 2/9 seizures
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4959 KCNK3 Krithika Murali reviewed gene: KCNK3: Rating: GREEN; Mode of pathogenicity: None; Publications: 36195757; Phenotypes: Neurodevelopmental disorder, MONDO:0700092, KCNK3-related, developmental delay with sleep apnoea (DDSA); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.4959 MOCS1 Zornitza Stark Tag treatable tag was added to gene: MOCS1.
Intellectual disability syndromic and non-syndromic v0.4959 MLYCD Zornitza Stark Tag treatable tag was added to gene: MLYCD.
Intellectual disability syndromic and non-syndromic v0.4959 COQ8A Zornitza Stark Tag treatable tag was added to gene: COQ8A.
Intellectual disability syndromic and non-syndromic v0.4959 COQ4 Zornitza Stark Tag treatable tag was added to gene: COQ4.
Intellectual disability syndromic and non-syndromic v0.4959 DOHH Zornitza Stark Phenotypes for gene: DOHH were changed from Neurodevelopmental disorder, DOHH-related (MONDO#0700092) to Neurodevelopmental disorder with microcephaly, cerebral atrophy, and visual impairment, MIM# 620066
Intellectual disability syndromic and non-syndromic v0.4958 DOHH Zornitza Stark reviewed gene: DOHH: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with microcephaly, cerebral atrophy, and visual impairment, MIM# 620066; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4958 DPH2 Zornitza Stark Phenotypes for gene: DPH2 were changed from Diphthamide-deficiency syndrome to Developmental delay with short stature, dysmorphic facial features, and sparse hair 2, MIM# 620062; Diphthamide-deficiency syndrome
Intellectual disability syndromic and non-syndromic v0.4957 DPH2 Zornitza Stark reviewed gene: DPH2: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Developmental delay with short stature, dysmorphic facial features, and sparse hair 2, MIM# 620062; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4957 BCKDK Zornitza Stark Tag treatable tag was added to gene: BCKDK.
Intellectual disability syndromic and non-syndromic v0.4957 ASL Zornitza Stark Tag treatable tag was added to gene: ASL.
Intellectual disability syndromic and non-syndromic v0.4957 ARSB Zornitza Stark Tag treatable tag was added to gene: ARSB.
Tag clinical trial tag was added to gene: ARSB.
Intellectual disability syndromic and non-syndromic v0.4957 ARG1 Zornitza Stark Marked gene: ARG1 as ready
Intellectual disability syndromic and non-syndromic v0.4957 ARG1 Zornitza Stark Gene: arg1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4957 ARG1 Zornitza Stark Phenotypes for gene: ARG1 were changed from to Argininaemia MIM#207800
Intellectual disability syndromic and non-syndromic v0.4956 ARG1 Zornitza Stark Mode of inheritance for gene: ARG1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4955 ARG1 Zornitza Stark reviewed gene: ARG1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Argininaemia MIM#207800; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4955 ARG1 Zornitza Stark Tag treatable tag was added to gene: ARG1.
Intellectual disability syndromic and non-syndromic v0.4955 AHCY Zornitza Stark Tag treatable tag was added to gene: AHCY.
Intellectual disability syndromic and non-syndromic v0.4955 GALE Zornitza Stark Tag treatable tag was added to gene: GALE.
Intellectual disability syndromic and non-syndromic v0.4955 GALT Zornitza Stark Tag treatable tag was added to gene: GALT.
Intellectual disability syndromic and non-syndromic v0.4955 TAT Zornitza Stark Tag treatable tag was added to gene: TAT.
Intellectual disability syndromic and non-syndromic v0.4955 PCCB Zornitza Stark Tag treatable tag was added to gene: PCCB.
Intellectual disability syndromic and non-syndromic v0.4955 PCCA Zornitza Stark Tag treatable tag was added to gene: PCCA.
Intellectual disability syndromic and non-syndromic v0.4955 QDPR Zornitza Stark Tag treatable tag was added to gene: QDPR.
Intellectual disability syndromic and non-syndromic v0.4955 PTS Zornitza Stark Tag treatable tag was added to gene: PTS.
Intellectual disability syndromic and non-syndromic v0.4955 PAH Zornitza Stark Marked gene: PAH as ready
Intellectual disability syndromic and non-syndromic v0.4955 PAH Zornitza Stark Gene: pah has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4955 PAH Zornitza Stark Phenotypes for gene: PAH were changed from to Phenylketonuria, MIM#261600
Intellectual disability syndromic and non-syndromic v0.4954 PAH Zornitza Stark Mode of inheritance for gene: PAH was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4953 PAH Zornitza Stark reviewed gene: PAH: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Phenylketonuria, MIM#261600; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4953 PAH Zornitza Stark Tag treatable tag was added to gene: PAH.
Intellectual disability syndromic and non-syndromic v0.4953 ETFB Zornitza Stark Tag treatable tag was added to gene: ETFB.
Intellectual disability syndromic and non-syndromic v0.4953 ETFA Zornitza Stark Tag treatable tag was added to gene: ETFA.
Intellectual disability syndromic and non-syndromic v0.4953 ETFDH Zornitza Stark Tag treatable tag was added to gene: ETFDH.
Intellectual disability syndromic and non-syndromic v0.4953 HADHB Zornitza Stark Tag treatable tag was added to gene: HADHB.
Intellectual disability syndromic and non-syndromic v0.4953 HADHA Zornitza Stark Tag treatable tag was added to gene: HADHA.
Intellectual disability syndromic and non-syndromic v0.4953 MMAB Zornitza Stark Tag treatable tag was added to gene: MMAB.
Intellectual disability syndromic and non-syndromic v0.4953 MMAA Zornitza Stark Tag treatable tag was added to gene: MMAA.
Intellectual disability syndromic and non-syndromic v0.4953 MUT Zornitza Stark Tag treatable tag was added to gene: MUT.
Intellectual disability syndromic and non-syndromic v0.4953 ACADM Zornitza Stark Tag treatable tag was added to gene: ACADM.
Intellectual disability syndromic and non-syndromic v0.4953 IVD Zornitza Stark Tag treatable tag was added to gene: IVD.
Intellectual disability syndromic and non-syndromic v0.4953 BTD Zornitza Stark Tag treatable tag was added to gene: BTD.
Intellectual disability syndromic and non-syndromic v0.4953 HLCS Zornitza Stark Tag treatable tag was added to gene: HLCS.
Intellectual disability syndromic and non-syndromic v0.4953 GCDH Zornitza Stark Tag treatable tag was added to gene: GCDH.
Intellectual disability syndromic and non-syndromic v0.4953 CBS Zornitza Stark Tag treatable tag was added to gene: CBS.
Intellectual disability syndromic and non-syndromic v0.4953 MMADHC Zornitza Stark Tag treatable tag was added to gene: MMADHC.
Intellectual disability syndromic and non-syndromic v0.4953 MMACHC Zornitza Stark Marked gene: MMACHC as ready
Intellectual disability syndromic and non-syndromic v0.4953 MMACHC Zornitza Stark Gene: mmachc has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4953 MMACHC Zornitza Stark Phenotypes for gene: MMACHC were changed from to Methylmalonic aciduria and homocystinuria, cblC type, MIM#277400
Intellectual disability syndromic and non-syndromic v0.4952 MMACHC Zornitza Stark Mode of inheritance for gene: MMACHC was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4951 MMACHC Zornitza Stark reviewed gene: MMACHC: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Methylmalonic aciduria and homocystinuria, cblC type, MIM#277400; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4951 MMACHC Zornitza Stark Tag treatable tag was added to gene: MMACHC.
Intellectual disability syndromic and non-syndromic v0.4951 MAN2B1 Zornitza Stark Tag treatable tag was added to gene: MAN2B1.
Intellectual disability syndromic and non-syndromic v0.4951 LMBRD1 Zornitza Stark Tag treatable tag was added to gene: LMBRD1.
Intellectual disability syndromic and non-syndromic v0.4951 BCKDHB Zornitza Stark Tag treatable tag was added to gene: BCKDHB.
Intellectual disability syndromic and non-syndromic v0.4951 BCKDHA Zornitza Stark Tag treatable tag was added to gene: BCKDHA.
Intellectual disability syndromic and non-syndromic v0.4951 DBT Zornitza Stark Marked gene: DBT as ready
Intellectual disability syndromic and non-syndromic v0.4951 DBT Zornitza Stark Gene: dbt has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4951 DBT Zornitza Stark Phenotypes for gene: DBT were changed from to Maple syrup urine disease, type II (MIM#248600)
Intellectual disability syndromic and non-syndromic v0.4950 DBT Zornitza Stark Mode of inheritance for gene: DBT was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4949 DBT Zornitza Stark Tag treatable tag was added to gene: DBT.
Intellectual disability syndromic and non-syndromic v0.4949 DBT Zornitza Stark reviewed gene: DBT: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Maple syrup urine disease, type II (MIM#248600); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4949 HMGCL Zornitza Stark Tag treatable tag was added to gene: HMGCL.
Intellectual disability syndromic and non-syndromic v0.4949 ASS1 Zornitza Stark Tag treatable tag was added to gene: ASS1.
Intellectual disability syndromic and non-syndromic v0.4949 ATP7A Zornitza Stark Marked gene: ATP7A as ready
Intellectual disability syndromic and non-syndromic v0.4949 ATP7A Zornitza Stark Gene: atp7a has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4949 ATP7A Zornitza Stark Phenotypes for gene: ATP7A were changed from to Menkes disease MIM#309400
Intellectual disability syndromic and non-syndromic v0.4948 ATP7A Zornitza Stark Mode of inheritance for gene: ATP7A was changed from Unknown to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability syndromic and non-syndromic v0.4947 ATP7A Zornitza Stark Tag treatable tag was added to gene: ATP7A.
Intellectual disability syndromic and non-syndromic v0.4947 ATP7A Zornitza Stark reviewed gene: ATP7A: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Menkes disease MIM#309400; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability syndromic and non-syndromic v0.4947 PDCD6IP Zornitza Stark Phenotypes for gene: PDCD6IP were changed from Primary microcephaly to Microcephaly 29, primary, autosomal recessive, MIM# 620047
Intellectual disability syndromic and non-syndromic v0.4946 PDCD6IP Zornitza Stark reviewed gene: PDCD6IP: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Microcephaly 29, primary, autosomal recessive, MIM# 620047; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4946 ARSA Zornitza Stark Marked gene: ARSA as ready
Intellectual disability syndromic and non-syndromic v0.4946 ARSA Zornitza Stark Gene: arsa has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4946 ARSA Zornitza Stark Phenotypes for gene: ARSA were changed from to Metachromatic leukodystrophy, MIM# 250100
Intellectual disability syndromic and non-syndromic v0.4945 ARSA Zornitza Stark Mode of inheritance for gene: ARSA was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4944 ARSA Zornitza Stark Tag treatable tag was added to gene: ARSA.
Tag clinical trial tag was added to gene: ARSA.
Intellectual disability syndromic and non-syndromic v0.4944 ARSA Zornitza Stark reviewed gene: ARSA: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Metachromatic leukodystrophy, MIM# 250100; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4944 AP3B1 Zornitza Stark Tag treatable tag was added to gene: AP3B1.
Tag clinical trial tag was added to gene: AP3B1.
Intellectual disability syndromic and non-syndromic v0.4944 ALDH7A1 Zornitza Stark Marked gene: ALDH7A1 as ready
Intellectual disability syndromic and non-syndromic v0.4944 ALDH7A1 Zornitza Stark Gene: aldh7a1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4944 ALDH7A1 Zornitza Stark Phenotypes for gene: ALDH7A1 were changed from to Epilepsy, pyridoxine-dependent, MIM# 266100
Intellectual disability syndromic and non-syndromic v0.4943 ALDH7A1 Zornitza Stark Publications for gene: ALDH7A1 were set to
Intellectual disability syndromic and non-syndromic v0.4942 ALDH7A1 Zornitza Stark Mode of inheritance for gene: ALDH7A1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4941 ALDH7A1 Zornitza Stark Tag treatable tag was added to gene: ALDH7A1.
Intellectual disability syndromic and non-syndromic v0.4941 ALDH7A1 Zornitza Stark reviewed gene: ALDH7A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 33200442; Phenotypes: Epilepsy, pyridoxine-dependent, MIM# 266100; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4941 PTPA Zornitza Stark Marked gene: PTPA as ready
Intellectual disability syndromic and non-syndromic v0.4941 PTPA Zornitza Stark Gene: ptpa has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.4941 PTPA Zornitza Stark Classified gene: PTPA as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.4941 PTPA Zornitza Stark Gene: ptpa has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.4940 PTPA Zornitza Stark Classified gene: PTPA as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.4940 PTPA Zornitza Stark Gene: ptpa has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.4939 PTPA Konstantinos Varvagiannis changed review comment from: Biallelic PTPA pathogenic variants lead to a form of ID with later-onset parkinsonism based on 4 individuals from 2 families in the literature. Affected individuals were homozygous for missense variants demonstrated to result to reduced mRNA and protein levels as well as PP2A complex activation. Drosophila studies support an age-dependent locomotor dysfunction. Variants in other PP2A-complex-related genes also lead to NDDs. Summary provided below.

There is currently no associated phenotype in OMIM, G2P, PanelApp Australia or SysID.

Consider inclusion in relevant panels (ID, Parkinsonism/movement disorders, etc) with amber rating pending further reports.

------

Fevga, Tesson et al (2022 - PMID: 36073231) describe the features of 4 individuals, from 2 unrelated families, with biallelic pathogenic PTPA variants.

These presented with normal or delayed early milestones, learning disability and ID (mild to moderate) followed by progressive signs of parkinsonism (at the age of 11 yrs in 2 sibs, 15 yrs in another individual). Motor symptoms were responsive to levodopa and later to deep brain stimulation.

Linkage analysis in one consanguineous family followed by exome revealed homozygosity for a missense PTPA variant (NM_178001:c.893T>G/p.Met298Arg). Exome sequencing in affected subjects from the 2nd family revealed homozygosity for a further missense variant (c.512C>A/p.Ala171Asp). There were no other candidate variants for the phenotype following parental / segregation studies.

Role of the gene:
As the authors discuss, PTPA (or PPP2R4) is ubiquitously expressed in all tissues incl. brain and encodes a phosphotyrosyl phosphatase activator of the dimeric form of protein phosphatase-2A (PP2A). PP2A in turn, is the major Ser/Thr phosphatase in brain targeting a large number of proteins involved in diverse functions. Activation of PP2A is dependent on its methylation, which is negatively regulated by the PP2A-specific methylesterase (PME-1). By binding to PME-1, PTPA counteracts the negative influence of the former on PP2A. Pathogenic variants in genes encoding subunits/regulators of the PP2A complex (e.g. PPP2R1A or PPP2CA) are associated with neurodevelopmental disorders.

Variant studies:
Upon overexpression of wt and both variants in a HEK-293 cell line the authors demonstrated that both variants resulted in significantly reduced mRNA and protein levels (which for Ala171Asp were attributed to increased proteasomal degradation). Both variants were shown to result in impaired PP2A complex activation compared to wt.

Drosophila / animal models:
Pan-neuronal RNAi-mediated knockdown of ptpa in Drosophila resulted in an age-dependent locomotor dysfunction, reversible with L-DOPA treatment.
Previous studies in mice suggest cognitive/electrophysiological impairments upon downregulation of PP2A activity in transgenic mice.
Sources: Literature; to: Biallelic PTPA pathogenic variants lead to a form of ID with later-onset parkinsonism based on 4 individuals from 2 families in the literature. Affected individuals were homozygous for missense variants demonstrated to result to reduced mRNA and protein levels as well as PP2A complex activation. Drosophila studies support an age-dependent locomotor dysfunction. Variants in other PP2A-complex-related genes also lead to NDDs. Summary provided below.

There is currently no associated phenotype in OMIM, G2P, PanelApp UK or SysID.

Consider inclusion in relevant panels (ID, Parkinsonism/movement disorders, etc) with amber rating pending further reports.

------

Fevga, Tesson et al (2022 - PMID: 36073231) describe the features of 4 individuals, from 2 unrelated families, with biallelic pathogenic PTPA variants.

These presented with normal or delayed early milestones, learning disability and ID (mild to moderate) followed by progressive signs of parkinsonism (at the age of 11 yrs in 2 sibs, 15 yrs in another individual). Motor symptoms were responsive to levodopa and later to deep brain stimulation.

Linkage analysis in one consanguineous family followed by exome revealed homozygosity for a missense PTPA variant (NM_178001:c.893T>G/p.Met298Arg). Exome sequencing in affected subjects from the 2nd family revealed homozygosity for a further missense variant (c.512C>A/p.Ala171Asp). There were no other candidate variants for the phenotype following parental / segregation studies.

Role of the gene:
As the authors discuss, PTPA (or PPP2R4) is ubiquitously expressed in all tissues incl. brain and encodes a phosphotyrosyl phosphatase activator of the dimeric form of protein phosphatase-2A (PP2A). PP2A in turn, is the major Ser/Thr phosphatase in brain targeting a large number of proteins involved in diverse functions. Activation of PP2A is dependent on its methylation, which is negatively regulated by the PP2A-specific methylesterase (PME-1). By binding to PME-1, PTPA counteracts the negative influence of the former on PP2A. Pathogenic variants in genes encoding subunits/regulators of the PP2A complex (e.g. PPP2R1A or PPP2CA) are associated with neurodevelopmental disorders.

Variant studies:
Upon overexpression of wt and both variants in a HEK-293 cell line the authors demonstrated that both variants resulted in significantly reduced mRNA and protein levels (which for Ala171Asp were attributed to increased proteasomal degradation). Both variants were shown to result in impaired PP2A complex activation compared to wt.

Drosophila / animal models:
Pan-neuronal RNAi-mediated knockdown of ptpa in Drosophila resulted in an age-dependent locomotor dysfunction, reversible with L-DOPA treatment.
Previous studies in mice suggest cognitive/electrophysiological impairments upon downregulation of PP2A activity in transgenic mice.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4939 PTPA Konstantinos Varvagiannis gene: PTPA was added
gene: PTPA was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: PTPA was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PTPA were set to 36073231
Phenotypes for gene: PTPA were set to Intellectual disability; Parkinsonism
Penetrance for gene: PTPA were set to Complete
Review for gene: PTPA was set to AMBER
Added comment: Biallelic PTPA pathogenic variants lead to a form of ID with later-onset parkinsonism based on 4 individuals from 2 families in the literature. Affected individuals were homozygous for missense variants demonstrated to result to reduced mRNA and protein levels as well as PP2A complex activation. Drosophila studies support an age-dependent locomotor dysfunction. Variants in other PP2A-complex-related genes also lead to NDDs. Summary provided below.

There is currently no associated phenotype in OMIM, G2P, PanelApp Australia or SysID.

Consider inclusion in relevant panels (ID, Parkinsonism/movement disorders, etc) with amber rating pending further reports.

------

Fevga, Tesson et al (2022 - PMID: 36073231) describe the features of 4 individuals, from 2 unrelated families, with biallelic pathogenic PTPA variants.

These presented with normal or delayed early milestones, learning disability and ID (mild to moderate) followed by progressive signs of parkinsonism (at the age of 11 yrs in 2 sibs, 15 yrs in another individual). Motor symptoms were responsive to levodopa and later to deep brain stimulation.

Linkage analysis in one consanguineous family followed by exome revealed homozygosity for a missense PTPA variant (NM_178001:c.893T>G/p.Met298Arg). Exome sequencing in affected subjects from the 2nd family revealed homozygosity for a further missense variant (c.512C>A/p.Ala171Asp). There were no other candidate variants for the phenotype following parental / segregation studies.

Role of the gene:
As the authors discuss, PTPA (or PPP2R4) is ubiquitously expressed in all tissues incl. brain and encodes a phosphotyrosyl phosphatase activator of the dimeric form of protein phosphatase-2A (PP2A). PP2A in turn, is the major Ser/Thr phosphatase in brain targeting a large number of proteins involved in diverse functions. Activation of PP2A is dependent on its methylation, which is negatively regulated by the PP2A-specific methylesterase (PME-1). By binding to PME-1, PTPA counteracts the negative influence of the former on PP2A. Pathogenic variants in genes encoding subunits/regulators of the PP2A complex (e.g. PPP2R1A or PPP2CA) are associated with neurodevelopmental disorders.

Variant studies:
Upon overexpression of wt and both variants in a HEK-293 cell line the authors demonstrated that both variants resulted in significantly reduced mRNA and protein levels (which for Ala171Asp were attributed to increased proteasomal degradation). Both variants were shown to result in impaired PP2A complex activation compared to wt.

Drosophila / animal models:
Pan-neuronal RNAi-mediated knockdown of ptpa in Drosophila resulted in an age-dependent locomotor dysfunction, reversible with L-DOPA treatment.
Previous studies in mice suggest cognitive/electrophysiological impairments upon downregulation of PP2A activity in transgenic mice.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4939 PPP2R5C Zornitza Stark Phenotypes for gene: PPP2R5C were changed from macrocephaly; intellectual disability to Neurodevelopmental disorder, PPP2R5C-related (MONDO:070092); macrocephaly; intellectual disability
Intellectual disability syndromic and non-syndromic v0.4938 PPP2R5C Zornitza Stark Publications for gene: PPP2R5C were set to
Intellectual disability syndromic and non-syndromic v0.4937 PPP2R5C Zornitza Stark Classified gene: PPP2R5C as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4937 PPP2R5C Zornitza Stark Gene: ppp2r5c has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4936 PPP2R5C Teresa Zhao reviewed gene: PPP2R5C: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID: 25972378; Phenotypes: Neurodevelopmental disorder, PPP2R5C-related (MONDO:070092); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability syndromic and non-syndromic v0.4936 CACNA1C Zornitza Stark Marked gene: CACNA1C as ready
Intellectual disability syndromic and non-syndromic v0.4936 CACNA1C Zornitza Stark Gene: cacna1c has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4936 CACNA1C Zornitza Stark Phenotypes for gene: CACNA1C were changed from to Neurodevelopmental disorder with hypotonia, language delay, and skeletal defects with or without seizures, MIM# 620029
Intellectual disability syndromic and non-syndromic v0.4935 CACNA1C Zornitza Stark reviewed gene: CACNA1C: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with hypotonia, language delay, and skeletal defects with or without seizures, MIM# 620029; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.4935 UFSP2 Zornitza Stark Phenotypes for gene: UFSP2 were changed from Abnormal muscle tone; Seizures; Global developmental delay; Delayed speech and language development; Intellectual disability; Strabismus to Developmental and epileptic encephalopathy 106, MIM# 620028; Abnormal muscle tone; Seizures; Global developmental delay; Delayed speech and language development; Intellectual disability; Strabismus
Intellectual disability syndromic and non-syndromic v0.4934 UFSP2 Zornitza Stark edited their review of gene: UFSP2: Changed phenotypes: Developmental and epileptic encephalopathy 106, MIM# 620028, Abnormal muscle tone, Seizures, Global developmental delay, Delayed speech and language development, Intellectual disability, Strabismus
Intellectual disability syndromic and non-syndromic v0.4934 TRAPPC10 Zornitza Stark Phenotypes for gene: TRAPPC10 were changed from neurodevelopmental disorder (MONDO:0700092), TRAPPC10-related to Neurodevelopmental disorder with microcephaly, short stature, and speech delay, MIM# 620027
Intellectual disability syndromic and non-syndromic v0.4933 TRAPPC10 Zornitza Stark reviewed gene: TRAPPC10: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with microcephaly, short stature, and speech delay, MIM# 620027; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4933 CAPRIN1 Zornitza Stark Publications for gene: CAPRIN1 were set to 35979925
Intellectual disability syndromic and non-syndromic v0.4932 UBAP2L Zornitza Stark Marked gene: UBAP2L as ready
Intellectual disability syndromic and non-syndromic v0.4932 UBAP2L Zornitza Stark Gene: ubap2l has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4932 UBAP2L Zornitza Stark Phenotypes for gene: UBAP2L were changed from Delayed speech and language development; Motor delay; Intellectual disability; Autistic behavior; Seizures; Microcephaly; Abnormality of head or neck; Short stature; Abnormality of the skeletal system to Neurodevelopmental disorder, MONDO:0700092, UBAP2L-related; Delayed speech and language development; Motor delay; Intellectual disability; Autistic behavior; Seizures; Microcephaly; Abnormality of head or neck; Short stature; Abnormality of the skeletal system
Intellectual disability syndromic and non-syndromic v0.4931 UBAP2L Zornitza Stark Mode of inheritance for gene: UBAP2L was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.4930 UBAP2L Zornitza Stark Classified gene: UBAP2L as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4930 UBAP2L Zornitza Stark Gene: ubap2l has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4929 UBAP2L Zornitza Stark reviewed gene: UBAP2L: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder, MONDO:0700092, UBAP2L-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.4929 CHKA Zornitza Stark Phenotypes for gene: CHKA were changed from Neurodevelopmental disorder, MONDO:0700092; Abnormal muscle tone; Global developmental delay; Intellectual disability; Seizures; Microcephaly; Abnormality of movement; Abnormality of nervous system morphology; Short stature to Neurodevelopmental disorder with microcephaly, movement abnormalities, and seizures, MIM#620023
Intellectual disability syndromic and non-syndromic v0.4928 CHKA Zornitza Stark reviewed gene: CHKA: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with microcephaly, movement abnormalities, and seizures, MIM#620023; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4928 CAPRIN1 Konstantinos Varvagiannis reviewed gene: CAPRIN1: Rating: GREEN; Mode of pathogenicity: None; Publications: 35979925, 35977029, 28135719, 31398340, https://doi.org/10.1101/2021.12.20.21267194; Phenotypes: Global developmental delay, Delayed speech and language development, Intellectual disability, Autistic behavior, Seizures; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability syndromic and non-syndromic v0.4928 UBAP2L Konstantinos Varvagiannis gene: UBAP2L was added
gene: UBAP2L was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: UBAP2L was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: UBAP2L were set to 35977029
Phenotypes for gene: UBAP2L were set to Delayed speech and language development; Motor delay; Intellectual disability; Autistic behavior; Seizures; Microcephaly; Abnormality of head or neck; Short stature; Abnormality of the skeletal system
Penetrance for gene: UBAP2L were set to unknown
Review for gene: UBAP2L was set to GREEN
Added comment: Based on Jia et al (2022 - PMID: 35977029) speech, motor delay as well as ID are observed in individuals harboring de novo pLoF variants in UBAP2L. The gene encodes a regulator of the stress granule (SG) assembly. Extensive evidence is provided on the effect of variants as well as the role of UBAP2L and other genes for components and/or regulation of SG in pathogenesis of NDDs. Among others a Ubap2l htz deletion mouse model (behavioral and cognitive impairment, abnormal cortical development due to impaired SG assembly, etc). Data from 26 previous studies, aggregating 40,853 probands with NDDs (mostly DD/ID, also ASD) suggest enrichment for DNMs in UBAP2L or other genes previously known and further shown to be important for SG formation (incl. G3BP1/G3BP2, CAPRIN1).

Details provided below.

Not associated with any phenotype in OMIM, G2P or SysNDD.

--------

Jia et al (2022 - PMID: 35977029) describe 12 affected individuals with heterozygous de novo pLoF variants in UBAP2L.

Phenotype: Features included hypotonia, speech (11/11) and motor delay (8/12), ID (8/10 with formal evaluation), variable behavioral concerns (ADHD 5/11, ASD in 4/10, etc). Seizures were reported in 7/12 with 3/10 having a formal diagnosis of epilepsy. Few had microcephaly (3/10). Facial dysmorphisms were common (9/9) and included abnormal palpebral fissures, deep prominent concha, high broad forehead, hypertelorism, thin upper lip and mild synophrys (each in 4 or less individuals). Short stature or skeletal alterations were described in some (4/10 each).

Role of the gene: UBAP2L encodes an essential regulator of stress granule assembly. Stress granules are membraneless cytoplasmic compartments in eukaryotic cells, induced upon a variety of stressors and playing a role in regulation of gene expression.

Variants identified : 9 nonsense/frameshift UBAP2L variants and 3 splicing ones were reported, in all cases as de novo events, upon trio/quad exome sequencing. All were absent from gnomAD. There were no other causative variants.

Variant effect/studies (NM_014847.4 / NP_055662.3) :
- Minigene assays revealed that the 3 splice variants all resulted in out-of-frame exon skipping.
- In patient fibroblasts one of these splice variants was demonstrated to result to reduced protein levels.
- 8 of the 9 nonsense/frameshift variants were predicted to result to NMD.
- 1 nonsense variant (c.88C>T/p.Q30*) was shown to result to decreased protein expression in patient fibroblasts, with detection of the protein using an antibody for the C terminus but not the N terminus. Protein N-terminal sequencing confirmed that the protein lacked the N terminus, with utilization of an alternative start site (11 codons downstream).
- Generation of HeLa UBAP2L KO cell lines resulted in significant reduction of SG numbers which was also the case for 4 variants studied, under stress conditions.
- The protein has a DUF domain (aa 495-526) known to mediate interaction of UBAP2L with G3BP1 (a stress granule marker) with deletions of this domain leading to shuttling of UBAP2L from the cytoplasm to the nucleus. Truncating variants upstream of the DUF domain were shown to result in nuclear localization.

Mouse model :
- The authors generated Ubap2l KO model with hmz deletion of Ubap2l resulting in a lethal phenotype (2.6% survived) and htz deletion leading to behavioral issues (low preference for social novelty, anxious-like behaviors) and cognitive impairment.
- Ubap2l haploinsufficiency resulted in abnormal cortical development and lamination with reduction of neural progenitor proliferation.
- Ubap2l deficiency was shown to impair SG assembly during cortical development both under physiological stress conditions or upon utilization of an oxidative stress inducer.

Additional evidence of UBAP2L and SG overall in pathogenesis of NDDs:
- Based on DNMs from 40,853 individuals with NDDs from 26 studies (9,228 with ASD, 31,625 with DD/ID) the authors demonstrate significant excess of DNM in 31 genes encoding SG components, regulators or both, the latter being the case for UBAP2L and 2 further genes (G3BP1 and G3BP2 - both with crucial roles in SG assembly).
- Excess dn splice-site (N=3) and missense (N=5) variants in G3BP1 were observed in the above cohort [c.95+1G>A, c.353+1G>T, c.539+1G>A / p.S208C, R320C, V366M].
- Excess dn missense (N=7) variants in G3BP2 were observed in the above cohort [p.R13W, D151N, E158K, L209P, E399D, K408E, R438C].
- Generation of G3BP1 or G3BP2 KO HeLa cell lines and immunofluorescence upon use of oxidative stress inducer revealed significant reduction of stress granules.
- Generation of HeLa cell lines for 5 G3BP1 mutants (R78C*, R132I*, S208C*, R320C*, V366M) and 7 G3BP2 mutants (p.R13W*, D151N*, E158K, L209P*, E399D, K408E, R438C) revealed that several (those in asterisk) resulted in significantly fewer SG formation under oxidative stress compared to WT while the subcellular distribution of the proteins under stress was identical to WT.
- Among the identified genes for SG enriched for DNMs, CAPRIN1 was implicated in previous publications as a NDD risk gene with 3 dn missense SNVs reported (p.I373K, p.Q446H, p.L484P). CAPRIN1 binding to G3BP1/2 has been shown to promote SG formation. Significant reduction of SG was observed in CAPRIN1 KO HeLa lines. p.I373K abolished interaction with G3BP1/2 and disrupted SG formation.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4928 SLC31A1 Zornitza Stark Marked gene: SLC31A1 as ready
Intellectual disability syndromic and non-syndromic v0.4928 SLC31A1 Zornitza Stark Gene: slc31a1 has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v0.4928 SLC31A1 Zornitza Stark Classified gene: SLC31A1 as Red List (low evidence)
Intellectual disability syndromic and non-syndromic v0.4928 SLC31A1 Zornitza Stark Gene: slc31a1 has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v0.4927 PPFIBP1 Zornitza Stark Phenotypes for gene: PPFIBP1 were changed from Neurodevelopmental disorder, MONDO:0700092, PPFIBP1-related to Neurodevelopmental disorder with seizures, microcephaly, and brain abnormalities, MIM# 620024
Intellectual disability syndromic and non-syndromic v0.4926 PPFIBP1 Zornitza Stark edited their review of gene: PPFIBP1: Changed phenotypes: Neurodevelopmental disorder with seizures, microcephaly, and brain abnormalities, MIM# 620024
Intellectual disability syndromic and non-syndromic v0.4926 PDZD8 Zornitza Stark Marked gene: PDZD8 as ready
Intellectual disability syndromic and non-syndromic v0.4926 PDZD8 Zornitza Stark Gene: pdzd8 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4926 PDZD8 Zornitza Stark Classified gene: PDZD8 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4926 PDZD8 Zornitza Stark Gene: pdzd8 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4925 PDZD8 Zornitza Stark gene: PDZD8 was added
gene: PDZD8 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: PDZD8 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PDZD8 were set to 35227461
Phenotypes for gene: PDZD8 were set to Intellectual developmental disorder with autism and dysmorphic facies, MIM# 620021
Review for gene: PDZD8 was set to GREEN
Added comment: Four individuals from two unrelated families, Drosophila and mouse models support gene-disease association.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4924 SLC31A1 Daniel Flanagan gene: SLC31A1 was added
gene: SLC31A1 was added to Intellectual disability syndromic and non-syndromic. Sources: Expert list
Mode of inheritance for gene: SLC31A1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC31A1 were set to PMID: 35913762
Phenotypes for gene: SLC31A1 were set to Neurodevelopmental disorder, SLC31A1-related (MONDO#0700092)
Review for gene: SLC31A1 was set to RED
Added comment: SLC31A1 is also referred to as CTR1.
Monozygotic twins with hypotonia, global developmental delay, seizures, and rapid brain atrophy, consistent with profound central nervous system copper deficiency. Homozygous for a novel missense variant (p.(Arg95His)) in copper transporter CTR1, both parents heterozygous. A mouse knock-out model of CTR1 deficiency resulted in prenatal lethality.
Sources: Expert list
Intellectual disability syndromic and non-syndromic v0.4924 TMEM163 Zornitza Stark Marked gene: TMEM163 as ready
Intellectual disability syndromic and non-syndromic v0.4924 TMEM163 Zornitza Stark Gene: tmem163 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4924 TMEM163 Zornitza Stark Classified gene: TMEM163 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4924 TMEM163 Zornitza Stark Gene: tmem163 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4923 TMEM163 Zornitza Stark Phenotypes for gene: TMEM163 were changed from Hypomyelinating leukodystrophy to Hypomyelinating leukodystrophy, MONDO:0019046
Intellectual disability syndromic and non-syndromic v0.4922 COX11 Zornitza Stark Marked gene: COX11 as ready
Intellectual disability syndromic and non-syndromic v0.4922 COX11 Zornitza Stark Gene: cox11 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4922 COX11 Zornitza Stark Classified gene: COX11 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4922 COX11 Zornitza Stark Gene: cox11 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4921 TMEM147 Zornitza Stark Marked gene: TMEM147 as ready
Intellectual disability syndromic and non-syndromic v0.4921 TMEM147 Zornitza Stark Gene: tmem147 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4921 TMEM147 Zornitza Stark Classified gene: TMEM147 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4921 TMEM147 Zornitza Stark Gene: tmem147 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4920 CEP104 Zornitza Stark Phenotypes for gene: CEP104 were changed from Joubert syndrome 25, MIM# 616781; MONDO:0014770 to Joubert syndrome 25, MIM# 616781; MONDO:0014770; Neurodevelopmental disorder; MONDO:0014770, CEP104-related
Intellectual disability syndromic and non-syndromic v0.4919 CEP104 Zornitza Stark Publications for gene: CEP104 were set to 26477546
Intellectual disability syndromic and non-syndromic v0.4918 NOTCH1 Zornitza Stark Marked gene: NOTCH1 as ready
Intellectual disability syndromic and non-syndromic v0.4918 NOTCH1 Zornitza Stark Gene: notch1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4918 NOTCH1 Zornitza Stark Classified gene: NOTCH1 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4918 NOTCH1 Zornitza Stark Gene: notch1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4917 LGI3 Zornitza Stark Marked gene: LGI3 as ready
Intellectual disability syndromic and non-syndromic v0.4917 LGI3 Zornitza Stark Gene: lgi3 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4917 LGI3 Zornitza Stark Phenotypes for gene: LGI3 were changed from Global developmental delay; Intellectual disability; Distal deformities; Diminished reflexes; Facial myokymia; Hyporeflexia/areflexi to Neurodevelopmental disorder, MONDO:0700092, LGI3-related; Global developmental delay; Intellectual disability; Distal deformities; Diminished reflexes; Facial myokymia; Hyporeflexia/areflexi
Intellectual disability syndromic and non-syndromic v0.4916 LGI3 Zornitza Stark Classified gene: LGI3 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4916 LGI3 Zornitza Stark Gene: lgi3 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4915 LGI3 Zornitza Stark reviewed gene: LGI3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder, MONDO:0700092, LGI3-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4915 TMEM147 Naomi Baker gene: TMEM147 was added
gene: TMEM147 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: TMEM147 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TMEM147 were set to PMID: 36044892
Phenotypes for gene: TMEM147 were set to Neurodevelopmental disorder (MONDO:0700092), TMEM147-related
Review for gene: TMEM147 was set to GREEN
Added comment: PMID: 36044892; Twelve different variants reported in 23 affected individuals from 15 unrelated families with biallelic variants. All individuals had global developmental delay and intellectual disability. Consistent facial dysmorphisms included coarse facies, prominent forehead, board depressed nasal root, tented mouth, long smooth philtrum, and low-set ears. In vitro studies of missense variants demonstrated accelerated protein degradation via the autophagy-lysosomal pathway, while analysis of primary fibroblasts and granulocytes provided functional evidence of ER and nuclear envelope dysfunction.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4915 SARS Ee Ming Wong reviewed gene: SARS: Rating: RED; Mode of pathogenicity: Other; Publications: 36041817; Phenotypes: neurodevelopmental disorder MONDO#070009, SARS1-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Intellectual disability syndromic and non-syndromic v0.4915 COX11 Chern Lim gene: COX11 was added
gene: COX11 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: COX11 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COX11 were set to 36030551
Phenotypes for gene: COX11 were set to Mitochondrial disease (MONDO:0044970), COX11-related
Review for gene: COX11 was set to GREEN
gene: COX11 was marked as current diagnostic
Added comment: PMID: 36030551
- Biallelic variants in COX11 associated with infantile-onset mitochondrial encephalopathies in two unrelated consanguineous families, one with homozygous missense variant, another with homozygous frameshift variant.
- Functional studies supported pathogenicity of the missense variant, and showed that mutant COX11 fibroblasts had decreased ATP levels which could be rescued by CoQ10.
- RNA studies suggested the mutant transcript with p.(Val12Glyfs*21) is not degraded by nonsense mediated decay.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4915 LGI3 Melanie Marty edited their review of gene: LGI3: Changed phenotypes: Global developmental delay, Intellectual disability, Distal deformities, Diminished reflexes, Facial myokymia, Hyporeflexia/areflexia
Intellectual disability syndromic and non-syndromic v0.4915 CAPRIN1 Zornitza Stark Marked gene: CAPRIN1 as ready
Intellectual disability syndromic and non-syndromic v0.4915 CAPRIN1 Zornitza Stark Gene: caprin1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4915 TMEM163 Teresa Zhao gene: TMEM163 was added
gene: TMEM163 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: TMEM163 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: TMEM163 were set to PMID: 35953447
Phenotypes for gene: TMEM163 were set to Hypomyelinating leukodystrophy
Review for gene: TMEM163 was set to GREEN
Added comment: Four unrelated families with a hypomyelinating leukodystrophy phenotype. Genomic testing identified three distinct heterozygous missense variants in TMEM163 with two unrelated individuals sharing the same de novo variant.

All have global developmental delay, three of them have seizures.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4915 CAPRIN1 Zornitza Stark Classified gene: CAPRIN1 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4915 CAPRIN1 Zornitza Stark Gene: caprin1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4914 GRIN2A Zornitza Stark Publications for gene: GRIN2A were set to 30544257
Intellectual disability syndromic and non-syndromic v0.4913 GRIN2A Zornitza Stark Mode of inheritance for gene: GRIN2A was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4912 NOTCH1 Chern Lim changed review comment from: PMID: 35947102:
- Seven unrelated patients with leukoencephalopathy and calcifications, germline heterozygous de novo gain-of-function variants in NOTCH1.
- Missense and small inframe insertion variants in the negative regulatory region.
Sources: Literature; to: PMID: 35947102:
- Seven unrelated patients with leukoencephalopathy and calcifications, germline heterozygous de novo gain-of-function variants in NOTCH1.
- Other clinical features include intellectual disability, spasticity and etc. Childhood onset in most individuals however 15y and 40y reported in two individuals.
- Missense and small inframe insertion variants in the negative regulatory region.
Intellectual disability syndromic and non-syndromic v0.4912 CEP104 Belinda Chong reviewed gene: CEP104: Rating: GREEN; Mode of pathogenicity: None; Publications: 34196201, 35359234; Phenotypes: CEP104 Neurodevelopmental disorder, MONDO:0014770; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability syndromic and non-syndromic v0.4912 NOTCH1 Chern Lim gene: NOTCH1 was added
gene: NOTCH1 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: NOTCH1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: NOTCH1 were set to 35947102
Phenotypes for gene: NOTCH1 were set to Genetic cerebral small vessel disease (MONDO:0018787), NOTCH1-related
Mode of pathogenicity for gene: NOTCH1 was set to Other
Review for gene: NOTCH1 was set to GREEN
gene: NOTCH1 was marked as current diagnostic
Added comment: PMID: 35947102:
- Seven unrelated patients with leukoencephalopathy and calcifications, germline heterozygous de novo gain-of-function variants in NOTCH1.
- Missense and small inframe insertion variants in the negative regulatory region.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4912 LGI3 Melanie Marty changed review comment from: Six individuals from eight unrelated families with loss-of-function (LoF) bi-allelic variants in LGI3.
Lgi3-null mice showed reduced and mis-local-ized Kv1 channel complexes in myelinated peripheral axons.
Sources: Literature; to: Sixteen individuals from eight unrelated families with loss-of-function (LoF) bi-allelic variants in LGI3.
Lgi3-null mice showed reduced and mis-local-ized Kv1 channel complexes in myelinated peripheral axons.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4912 LGI3 Melanie Marty gene: LGI3 was added
gene: LGI3 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: LGI3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LGI3 were set to PMID: 35948005
Phenotypes for gene: LGI3 were set to Global developmental delay; Intellectual disability; Distal deformities; Diminished reflexes; Facial myokymia; Hyporeflexia/areflexi
Review for gene: LGI3 was set to GREEN
Added comment: Six individuals from eight unrelated families with loss-of-function (LoF) bi-allelic variants in LGI3.
Lgi3-null mice showed reduced and mis-local-ized Kv1 channel complexes in myelinated peripheral axons.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4912 GRIN2A Teresa Zhao reviewed gene: GRIN2A: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 35983985; Phenotypes: Epilepsy, focal, with speech disorder and with or without mental retardation (MIM#245570); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4912 CAPRIN1 Paul De Fazio gene: CAPRIN1 was added
gene: CAPRIN1 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: CAPRIN1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CAPRIN1 were set to 35979925
Phenotypes for gene: CAPRIN1 were set to Neurodevelopmental disorder, CAPRIN1-related MONDO:0700092
Review for gene: CAPRIN1 was set to GREEN
gene: CAPRIN1 was marked as current diagnostic
Added comment: 12 individuals reported with ID and language impairment. Other features included seizures (4 individuals), hands and feet malformations (5 individuals), breathing problems (6 individuals), ocular problems (4 individuals) and hearing problems (3 individuals).

All of the variants were nonsense (NMD-predicted) or splicing variants. 10 were de novo, 1 was inherited from an affected father. Functional studies supported pathogenicity.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4911 Zornitza Stark List of related panels changed from to Intellectual disability; HP:0001249; Neurodevelopmental delay; HP:0012758
Intellectual disability syndromic and non-syndromic v0.4910 Zornitza Stark HPO terms changed from to Intellectual disability, HP:0001249; Neurodevelopmental delay, HP:0012758
Intellectual disability syndromic and non-syndromic v0.4909 LNPK Zornitza Stark Publications for gene: LNPK were set to 30032983
Intellectual disability syndromic and non-syndromic v0.4908 CCDC82 Zornitza Stark Marked gene: CCDC82 as ready
Intellectual disability syndromic and non-syndromic v0.4908 CCDC82 Zornitza Stark Gene: ccdc82 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4908 CCDC82 Zornitza Stark Phenotypes for gene: CCDC82 were changed from Intellectual disability and spastic paraparesis, no OMIM # to Neurodevelopmental disorder, MONDO:0700092, CCDC82-related
Intellectual disability syndromic and non-syndromic v0.4907 CCDC82 Zornitza Stark Publications for gene: CCDC82 were set to PMID: 35373332, 35118659, 27457812
Intellectual disability syndromic and non-syndromic v0.4906 CCDC82 Zornitza Stark reviewed gene: CCDC82: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder, MONDO:0700092, CCDC82-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4906 LNPK Chirag Patel Classified gene: LNPK as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4906 LNPK Chirag Patel Gene: lnpk has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4905 LNPK Chirag Patel reviewed gene: LNPK: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 35599435; Phenotypes: Neurodevelopmental disorder with epilepsy and hypoplasia of the corpus callosum, MIM# 618090; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4905 CCDC82 Chirag Patel Classified gene: CCDC82 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4905 CCDC82 Chirag Patel Gene: ccdc82 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4905 CCDC82 Chirag Patel Classified gene: CCDC82 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4905 CCDC82 Chirag Patel Gene: ccdc82 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4904 CCDC82 Chirag Patel gene: CCDC82 was added
gene: CCDC82 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: CCDC82 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CCDC82 were set to PMID: 35373332, 35118659, 27457812
Phenotypes for gene: CCDC82 were set to Intellectual disability and spastic paraparesis, no OMIM #
Review for gene: CCDC82 was set to GREEN
Added comment: 4 consanguineous families with 9 affected individuals with developmental delay/intellectual disability, and 2 families had spasticity and 1 had epilepsy. WES identified 3 homozgyous truncating variants, segregating with disease and parents as carriers. No functional studies.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4903 FBXW7 Zornitza Stark Phenotypes for gene: FBXW7 were changed from FBXW7-related neurodevelopmental syndrome to Developmental delay, hypotonia, and impaired language, MIM# 620012
Intellectual disability syndromic and non-syndromic v0.4902 FBXW7 Zornitza Stark edited their review of gene: FBXW7: Changed phenotypes: Developmental delay, hypotonia, and impaired language, MIM# 620012
Intellectual disability syndromic and non-syndromic v0.4902 ACADS Zornitza Stark Classified gene: ACADS as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.4902 ACADS Zornitza Stark Gene: acads has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.4901 ACADS Zornitza Stark changed review comment from: Definitive by ClinGen. Metabolic decompensation. DD/ID is a feature.; to: Definitive by ClinGen. However, largely just causes a biochemical abnormality, and association with clinical disease is debated. DD/ID reported.
Intellectual disability syndromic and non-syndromic v0.4901 ACADS Zornitza Stark edited their review of gene: ACADS: Changed rating: AMBER
Intellectual disability syndromic and non-syndromic v0.4901 TAF4 Zornitza Stark Phenotypes for gene: TAF4 were changed from Neurodevelopmental disorder to Neurodevelopmental disorder, MONDO:0700092, TAF4-related
Intellectual disability syndromic and non-syndromic v0.4900 TAF4 Zornitza Stark Publications for gene: TAF4 were set to 33875846; 28191890
Intellectual disability syndromic and non-syndromic v0.4899 TAF4 Zornitza Stark Classified gene: TAF4 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4899 TAF4 Zornitza Stark Gene: taf4 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4898 ZMYND8 Zornitza Stark Marked gene: ZMYND8 as ready
Intellectual disability syndromic and non-syndromic v0.4898 ZMYND8 Zornitza Stark Gene: zmynd8 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4898 ZMYND8 Zornitza Stark Phenotypes for gene: ZMYND8 were changed from Delayed speech and language development; Motor delay; Intellectual disability; Abnormality of cardiovascular system morphology; Hearing abnormality; Abnormality of vision; Abnormality of the face; Seizures to Neurodevelopmental disorder, MONDO:0700092, ZMYND8-related; Delayed speech and language development; Motor delay; Intellectual disability; Abnormality of cardiovascular system morphology; Hearing abnormality; Abnormality of vision; Abnormality of the face; Seizures
Intellectual disability syndromic and non-syndromic v0.4897 ZMYND8 Zornitza Stark Mode of inheritance for gene: ZMYND8 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.4896 ZMYND8 Zornitza Stark Classified gene: ZMYND8 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4896 ZMYND8 Zornitza Stark Gene: zmynd8 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4895 TAF4 Konstantinos Varvagiannis reviewed gene: TAF4: Rating: GREEN; Mode of pathogenicity: None; Publications: 35904126; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability syndromic and non-syndromic v0.4895 ZMYND8 Konstantinos Varvagiannis gene: ZMYND8 was added
gene: ZMYND8 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: ZMYND8 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ZMYND8 were set to 35916866; 32530565
Phenotypes for gene: ZMYND8 were set to Delayed speech and language development; Motor delay; Intellectual disability; Abnormality of cardiovascular system morphology; Hearing abnormality; Abnormality of vision; Abnormality of the face; Seizures
Penetrance for gene: ZMYND8 were set to unknown
Review for gene: ZMYND8 was set to GREEN
Added comment: Dias et al (2022 - PMID: 35916866) describe the phenotype of 11 unrelated individuals with monoallelic de novo (or suspected de novo) missense (N=9) or truncating (N=2) ZMYND8 variants. One of these subjects was previously reported by Suzuki et al (2020 - PMID: 32530565).

Features included speech delay/language difficulties (9/11), motor delay (9/11), ID (in 10/11 - profound in 1, moderate in 2), CHD (7/11 - PDA, VSD, ASD, pulmonary stenosis, etc), hearing or vision impairment (7/11). Seizures were reported in few (in text 5/11, table 2/11). Variable non-familial facial features were present in (9/11).

As the authors discuss, ZMYND8 encodes a multidomain protein playing a role in transcription regulation, chromatin remodeling, regulation of super enhancers, DNA damage response/tumor suppression.

The protein is broadly expressed in brain and shows highest expression in early development.

Molecular modeling and/or a yeast two-hybrid system were suggestive of disrupted interaction of ZMYND8 with Drebrin (missense variants in PWWP domain) or GATAD2A (variants in MYND domain).

Neuronal Zmynd8 knockdown in Drosophila resulted in deficits in habituation learning.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4895 ADAR Zornitza Stark Marked gene: ADAR as ready
Intellectual disability syndromic and non-syndromic v0.4895 ADAR Zornitza Stark Gene: adar has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4895 ADAR Zornitza Stark Phenotypes for gene: ADAR were changed from to Aicardi-Goutieres syndrome 6, MIM# 615010
Intellectual disability syndromic and non-syndromic v0.4894 ADAR Zornitza Stark Mode of inheritance for gene: ADAR was changed from Unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4893 ADAR Zornitza Stark reviewed gene: ADAR: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Aicardi-Goutieres syndrome 6, MIM# 615010; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4893 ACTG1 Zornitza Stark Marked gene: ACTG1 as ready
Intellectual disability syndromic and non-syndromic v0.4893 ACTG1 Zornitza Stark Gene: actg1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4893 ACTG1 Zornitza Stark Phenotypes for gene: ACTG1 were changed from to Baraitser-Winter syndrome 2, MIM#614583
Intellectual disability syndromic and non-syndromic v0.4892 ACTG1 Zornitza Stark Mode of inheritance for gene: ACTG1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.4891 ACTG1 Zornitza Stark reviewed gene: ACTG1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Baraitser-Winter syndrome 2, MIM#614583; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.4891 ACTB Zornitza Stark Marked gene: ACTB as ready
Intellectual disability syndromic and non-syndromic v0.4891 ACTB Zornitza Stark Gene: actb has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4891 ACTB Zornitza Stark Phenotypes for gene: ACTB were changed from to Baraitser-Winter syndrome 1, MIM# 243310; ACTB-related neurodevelopment disorder
Intellectual disability syndromic and non-syndromic v0.4890 ACTB Zornitza Stark Publications for gene: ACTB were set to
Intellectual disability syndromic and non-syndromic v0.4889 ACTB Zornitza Stark Mode of inheritance for gene: ACTB was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.4888 ACTB Zornitza Stark reviewed gene: ACTB: Rating: GREEN; Mode of pathogenicity: None; Publications: 29220674; Phenotypes: Baraitser-Winter syndrome 1 243310, ACTB-related neurodevelopment disorder; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.4888 ACO2 Zornitza Stark Marked gene: ACO2 as ready
Intellectual disability syndromic and non-syndromic v0.4888 ACO2 Zornitza Stark Gene: aco2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4888 ACO2 Zornitza Stark Phenotypes for gene: ACO2 were changed from to Infantile cerebellar-retinal degeneration, MIM#614559
Intellectual disability syndromic and non-syndromic v0.4887 ACO2 Zornitza Stark Publications for gene: ACO2 were set to
Intellectual disability syndromic and non-syndromic v0.4886 ACO2 Zornitza Stark Mode of inheritance for gene: ACO2 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4885 ACO2 Zornitza Stark reviewed gene: ACO2: Rating: GREEN; Mode of pathogenicity: None; Publications: 22405087, 25351951, 30689204, 32519519, 25351951; Phenotypes: Infantile cerebellar-retinal degeneration, MIM#614559; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4885 ABCD1 Zornitza Stark Marked gene: ABCD1 as ready
Intellectual disability syndromic and non-syndromic v0.4885 ABCD1 Zornitza Stark Gene: abcd1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4885 ABCD1 Zornitza Stark Phenotypes for gene: ABCD1 were changed from to Adrenoleukodystrophy, MIM# 300100
Intellectual disability syndromic and non-syndromic v0.4884 ABCD1 Zornitza Stark Mode of inheritance for gene: ABCD1 was changed from Unknown to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability syndromic and non-syndromic v0.4883 ABCD1 Zornitza Stark reviewed gene: ABCD1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Adrenoleukodystrophy, MIM# 300100; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability syndromic and non-syndromic v0.4883 ACADS Zornitza Stark Marked gene: ACADS as ready
Intellectual disability syndromic and non-syndromic v0.4883 ACADS Zornitza Stark Gene: acads has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4883 ACADS Zornitza Stark Phenotypes for gene: ACADS were changed from to Acyl-CoA dehydrogenase, short-chain, deficiency of, MIM# 201470
Intellectual disability syndromic and non-syndromic v0.4882 ACADS Zornitza Stark Mode of inheritance for gene: ACADS was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4881 ACADS Zornitza Stark reviewed gene: ACADS: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Acyl-CoA dehydrogenase, short-chain, deficiency of, MIM# 201470; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4881 ACADM Zornitza Stark Marked gene: ACADM as ready
Intellectual disability syndromic and non-syndromic v0.4881 ACADM Zornitza Stark Gene: acadm has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4881 ACADM Zornitza Stark Phenotypes for gene: ACADM were changed from to Acyl-CoA dehydrogenase, medium chain, deficiency of, MIM# 201450
Intellectual disability syndromic and non-syndromic v0.4880 ACADM Zornitza Stark Mode of inheritance for gene: ACADM was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4879 ACADM Zornitza Stark reviewed gene: ACADM: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Acyl-CoA dehydrogenase, medium chain, deficiency of, MIM# 201450; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4879 PAX5 Zornitza Stark Phenotypes for gene: PAX5 were changed from neurodevelopmental disorder MONDO:0700092 to Neurodevelopmental disorder MONDO:0700092, PAX5-related; Hypogammaglobulinaemia
Intellectual disability syndromic and non-syndromic v0.4878 PAX5 Zornitza Stark Publications for gene: PAX5 were set to 35094443; 31452935; 28263302; 25418537; 8001127; 27626380
Intellectual disability syndromic and non-syndromic v0.4877 PAX5 Zornitza Stark Mode of inheritance for gene: PAX5 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4876 PAX5 Zornitza Stark reviewed gene: PAX5: Rating: AMBER; Mode of pathogenicity: None; Publications: 35947077; Phenotypes: Neurodevelopmental disorder MONDO:0700092, PAX5-related, Hypogammaglobulinaemia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4876 SMG9 Zornitza Stark Phenotypes for gene: SMG9 were changed from Heart and brain malformation syndrome, MIM# 616920 to Heart and brain malformation syndrome, MIM# 616920; Neurodevelopmental disorder with intention tremor, pyramidal signs, dyspraxia, and ocular anomalies, MIM# 619995
Intellectual disability syndromic and non-syndromic v0.4875 SMG9 Zornitza Stark Publications for gene: SMG9 were set to 27018474; 31390136
Intellectual disability syndromic and non-syndromic v0.4874 SMG9 Zornitza Stark edited their review of gene: SMG9: Added comment: PMID 35087184: 5 individuals from 3 unrelated Finnish families reported with same homozygous missense variant (founder effect) and predominantly neurological phenotype. Uncertain if this is a distinct disorder or part of a spectrum with the previously reported cases.; Changed publications: 27018474, 31390136, 35087184; Changed phenotypes: Heart and brain malformation syndrome, MIM# 616920, Neurodevelopmental disorder with intention tremor, pyramidal signs, dyspraxia, and ocular anomalies, MIM# 619995
Intellectual disability syndromic and non-syndromic v0.4874 THUMPD1 Zornitza Stark edited their review of gene: THUMPD1: Changed phenotypes: Neurodevelopmental disorder with speech delay and variable ocular anomalies, MIM# 619989; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4874 TAF4 Ee Ming Wong reviewed gene: TAF4: Rating: GREEN; Mode of pathogenicity: None; Publications: 33875846, 28191890, 35904126; Phenotypes: Neurodevelopmental disorder, MONDO:0700092, TAF4-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Intellectual disability syndromic and non-syndromic v0.4874 SPTBN5 Zornitza Stark Marked gene: SPTBN5 as ready
Intellectual disability syndromic and non-syndromic v0.4874 SPTBN5 Zornitza Stark Gene: sptbn5 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4874 SPTBN5 Zornitza Stark Classified gene: SPTBN5 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4874 SPTBN5 Zornitza Stark Gene: sptbn5 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4873 SPTBN5 Ee Ming Wong gene: SPTBN5 was added
gene: SPTBN5 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: SPTBN5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SPTBN5 were set to 35782384
Phenotypes for gene: SPTBN5 were set to Neurodevelopmental disorder, MONDO:0700092, SPTBN5-related
Review for gene: SPTBN5 was set to GREEN
gene: SPTBN5 was marked as current diagnostic
Added comment: - Four probands from unrelated families (1x Pakistani and 3x Italian) with de novo heterozygous SPTBN5 variants
- 3x missense variants and 1x LoF variant were reported
- Phenotypes include intellectual disability (mild to severe), aggressive tendencies and variable features such as craniofacial and physical dysmorphisms, autistic behavior, and
gastroesophageal reflux
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4873 PSMC1 Zornitza Stark Marked gene: PSMC1 as ready
Intellectual disability syndromic and non-syndromic v0.4873 PSMC1 Zornitza Stark Gene: psmc1 has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v0.4873 PSMC1 Zornitza Stark Classified gene: PSMC1 as Red List (low evidence)
Intellectual disability syndromic and non-syndromic v0.4873 PSMC1 Zornitza Stark Gene: psmc1 has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v0.4872 PSMC1 Hazel Phillimore gene: PSMC1 was added
gene: PSMC1 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: PSMC1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PSMC1 were set to PMID: 35861243
Phenotypes for gene: PSMC1 were set to spastic paraplegia; severe developmental delay; severe intellectual disability; hearing loss; micropenis; undescended testes; Syndromic disease MONDO:0002254, PSMC1-related
Review for gene: PSMC1 was set to RED
Added comment: Homozygosity mapping on one large consanguineous Bedouin kindred showed three affected children (out of the ten) to be homozygous for NM_002802.3:c.983T>C; p.(Ile328Thr).

Drosophila rescue experiments were carried out. Transgenic studies using drosophila with the silenced ortholog Rpt2 gene were rescued by the human wild-type PSMC1.

Three of the ten offspring of healthy consanguineous parents of Bedouin Israeli ancestry were affected with a similar phenotype of failure to thrive, developmental delay and severe intellectual disability, spastic tetraplegia with central hypotonia, chorea, as well as hearing loss. None of the three achieved verbal communication or ambulation (sitting / standing) at any age. They had mild dysmorphism of borderline dolichocephaly and microcephaly, prominent bushy eyebrows, flat midface, long nasal bridge and micrognathia. All three had micropenis with undescended testes. One of the affected (as a toddler) underwent thorough endocrinological analysis: testosterone and gonadotropin levels were low.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4872 SARS Ain Roesley Phenotypes for gene: SARS were changed from Intellectual disability to neurodevelopmental disorder MONDO#070009, SARS1-related
Intellectual disability syndromic and non-syndromic v0.4872 SARS Ain Roesley Publications for gene: SARS were set to 28236339; 34570399
Intellectual disability syndromic and non-syndromic v0.4872 SARS Ain Roesley Classified gene: SARS as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4872 SARS Ain Roesley Gene: sars has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4871 SARS Ain Roesley reviewed gene: SARS: Rating: GREEN; Mode of pathogenicity: None; Publications: 35790048; Phenotypes: neurodevelopmental disorder MONDO#070009, SARS1-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability syndromic and non-syndromic v0.4871 WARS Seb Lunke Marked gene: WARS as ready
Intellectual disability syndromic and non-syndromic v0.4871 WARS Seb Lunke Gene: wars has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4871 WARS Seb Lunke Classified gene: WARS as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4871 WARS Seb Lunke Gene: wars has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4870 BICD2 Lucy Spencer reviewed gene: BICD2: Rating: GREEN; Mode of pathogenicity: None; Publications: 35896821; Phenotypes: Neurodevelopmental disorder (MONDO#0700092), BICD2-related; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4870 PPFIBP1 Zornitza Stark Publications for gene: PPFIBP1 were set to https://www.medrxiv.org/content/10.1101/2022.04.04.22273309v1
Intellectual disability syndromic and non-syndromic v0.4869 C18orf32 Alison Yeung Marked gene: C18orf32 as ready
Intellectual disability syndromic and non-syndromic v0.4869 C18orf32 Alison Yeung Gene: c18orf32 has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v0.4869 C18orf32 Alison Yeung Classified gene: C18orf32 as Red List (low evidence)
Intellectual disability syndromic and non-syndromic v0.4869 C18orf32 Alison Yeung Gene: c18orf32 has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v0.4868 C18orf32 Naomi Baker gene: C18orf32 was added
gene: C18orf32 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: C18orf32 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: C18orf32 were set to PMID:35107634
Phenotypes for gene: C18orf32 were set to Neurodevelopmental disorder (MONDO:0700092), C18orf32-related
Review for gene: C18orf32 was set to RED
Added comment: Two siblings reported as affected, although sequencing only performed in one sibling, with homozygous loss-of-function variant identified. Clinical presentation included developmental delay, recurrent lower respiratory tract infections, sparse rough hair, roving eye movements, hypotonia, bilateral ankle contractures and inverted nipples.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4868 SLITRK2 Zornitza Stark Marked gene: SLITRK2 as ready
Intellectual disability syndromic and non-syndromic v0.4868 SLITRK2 Zornitza Stark Gene: slitrk2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4868 SLITRK2 Zornitza Stark Classified gene: SLITRK2 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4868 SLITRK2 Zornitza Stark Gene: slitrk2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4867 WARS Anna Ritchie gene: WARS was added
gene: WARS was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: WARS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: WARS were set to PMID: 35815345; 35790048
Phenotypes for gene: WARS were set to Neurodevelopmental disorder (MONDO:0700092), WARS-related
Review for gene: WARS was set to GREEN
Added comment: At least seven affected individuals from four families with biallelic variants, showing varying
severities of developmental delay, intellectual disability and microcephaly. Hearing impairment and, as well as brain anomalies, skeletal system, movement/gait, and behaviour were variable features.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4867 PPFIBP1 Ee Ming Wong reviewed gene: PPFIBP1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 35830857; Phenotypes: Neurodevelopmental disorder, MONDO:0700092, PPFIBP1-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability syndromic and non-syndromic v0.4867 DOHH Zornitza Stark Marked gene: DOHH as ready
Intellectual disability syndromic and non-syndromic v0.4867 DOHH Zornitza Stark Gene: dohh has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4867 ADGRL1 Zornitza Stark Marked gene: ADGRL1 as ready
Intellectual disability syndromic and non-syndromic v0.4867 ADGRL1 Zornitza Stark Gene: adgrl1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4867 DOHH Zornitza Stark Classified gene: DOHH as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4867 DOHH Zornitza Stark Gene: dohh has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4867 SLITRK2 Paul De Fazio gene: SLITRK2 was added
gene: SLITRK2 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: SLITRK2 was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Publications for gene: SLITRK2 were set to 35840571
Phenotypes for gene: SLITRK2 were set to Neurodevelopmental disorder, SLITRK2-related MONDO:0700092
Review for gene: SLITRK2 was set to GREEN
gene: SLITRK2 was marked as current diagnostic
Added comment: 6 missense variants and 1 nonsense variant (NOT NMD-predicted, single-exon gene) reported in 7 males and 1 female with neurodevelopmental disorders. Phenotypes included dev delay, mild to severe ID, delayed or absent speech, seizures and brain MRI anomalies (in some patients).

The nonsense variant was identified in two affected brothers but not in the mother, suggesting it was de novo in the maternal germline. The variant in the one affected female was de novo. All other variants in hemizygous males were inherited from an unaffected mother. In one case, the variant was also identified in the unaffected grandmother.

Functional studies showed some but not all variants displayed impaired membrane transport and impaired excitatory synapse-promoting effects. Conditional knockout mice exhibited impaired long-term memory and abnormal gait.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4867 ADGRL1 Zornitza Stark Classified gene: ADGRL1 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4867 ADGRL1 Zornitza Stark Gene: adgrl1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4866 ADGRL1 Elena Savva Marked gene: ADGRL1 as ready
Intellectual disability syndromic and non-syndromic v0.4866 ADGRL1 Elena Savva Gene: adgrl1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4866 ADGRL1 Zornitza Stark Classified gene: ADGRL1 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4866 ADGRL1 Zornitza Stark Gene: adgrl1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4866 ADGRL1 Elena Savva Classified gene: ADGRL1 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4866 ADGRL1 Elena Savva Gene: adgrl1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4865 DOHH Daniel Flanagan gene: DOHH was added
gene: DOHH was added to Intellectual disability syndromic and non-syndromic. Sources: Expert list
Mode of inheritance for gene: DOHH was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DOHH were set to PMID: 35858628
Phenotypes for gene: DOHH were set to Neurodevelopmental disorder, DOHH-related (MONDO#0700092)
Review for gene: DOHH was set to GREEN
Added comment: Bi-allelic missense and truncating DOHH variants segregating with disease in five affected individuals from four unrelated families. Clinical features were developmental delay and/or intellectual disability (5/5), microcephaly (5/5), visual impairment (nystagmus (3/5), strabismus (3/5), and cortical visual impairment (1/5)) and congenital heart malformations (3/5 individuals).
Sources: Expert list
Intellectual disability syndromic and non-syndromic v0.4865 ADGRL1 Elena Savva gene: ADGRL1 was added
gene: ADGRL1 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: ADGRL1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ADGRL1 were set to PMID: 35907405
Phenotypes for gene: ADGRL1 were set to Neurodevelopmental disorder, ADGRL1-related (MONDO#0700092)
Review for gene: ADGRL1 was set to GREEN
Added comment: PMID: 35907405 - 9 patients w/ ADHD (3/9), autism (4/9), mild-moderate ID (5/9) and epilepsy (2/9) and facial dysmorphism (7/9). Variants include missense (4) and PTCs (5), and were either de novo (7/9) or inherited from parents with learning difficulties/ID (2/9).

Functional studies on both PTCs and missense variants show significant reductions in calcium signalling and surface protein.

Het null mouse model shows neurological and developmental abnormalities, with hom null mice non-viable.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4864 TAF8 Zornitza Stark Phenotypes for gene: TAF8 were changed from Neurodevelopmental disorder, MONDO:0700092, TAF8-related to Neurodevelopmental disorder with severe motor impairment, absent language, cerebral hypomyelination, and brain atrophy, MIM# 619972
Intellectual disability syndromic and non-syndromic v0.4863 TAF8 Zornitza Stark edited their review of gene: TAF8: Changed phenotypes: Neurodevelopmental disorder with severe motor impairment, absent language, cerebral hypomyelination, and brain atrophy, MIM# 619972
Intellectual disability syndromic and non-syndromic v0.4863 POU3F3 Zornitza Stark Phenotypes for gene: POU3F3 were changed from Snijders Blok-Fisher syndrome MIM#618604 to Snijders Blok-Fisher syndrome MIM#618604
Intellectual disability syndromic and non-syndromic v0.4862 POU3F3 Zornitza Stark Phenotypes for gene: POU3F3 were changed from no OMIM number yet. to Snijders Blok-Fisher syndrome MIM#618604
Intellectual disability syndromic and non-syndromic v0.4861 POU3F3 Zornitza Stark reviewed gene: POU3F3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Snijders Blok-Fisher syndrome MIM#618604; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.4861 TMEM63C Zornitza Stark Phenotypes for gene: TMEM63C were changed from Hereditary spastic paraplegia, MONDO:0019064, TMEM63C-related to Spastic paraplegia 87, autosomal recessive, MIM# 619966
Intellectual disability syndromic and non-syndromic v0.4860 TMEM63C Zornitza Stark reviewed gene: TMEM63C: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Spastic paraplegia 87, autosomal recessive, MIM# 619966; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4860 ARFGEF1 Zornitza Stark Phenotypes for gene: ARFGEF1 were changed from Intellectual disability; Epilepsy to Developmental delay, impaired speech, and behavioral abnormalities, MIM# 619964
Intellectual disability syndromic and non-syndromic v0.4859 ARFGEF1 Zornitza Stark edited their review of gene: ARFGEF1: Changed phenotypes: Developmental delay, impaired speech, and behavioral abnormalities, MIM# 619964
Intellectual disability syndromic and non-syndromic v0.4859 C20orf24 Zornitza Stark Marked gene: C20orf24 as ready
Intellectual disability syndromic and non-syndromic v0.4859 C20orf24 Zornitza Stark Gene: c20orf24 has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v0.4859 C20orf24 Zornitza Stark gene: C20orf24 was added
gene: C20orf24 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
new gene name tags were added to gene: C20orf24.
Mode of inheritance for gene: C20orf24 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: C20orf24 were set to 35614220; 24194475
Phenotypes for gene: C20orf24 were set to Craniofacial dysmorphism, skeletal anomalies, and impaired intellectual development syndrome 2, MIM# 616994
Review for gene: C20orf24 was set to RED
Added comment: Bi-allelic LoF variant identified in patient originally reported in PMID 24194475. HGNC approved name is RAB5IF.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4858 HIST1H4E Zornitza Stark Phenotypes for gene: HIST1H4E were changed from Neurodevelopmental disorder, HIST1H4E-related MONDO:0700092 to Tessadori-van Haaften neurodevelopmental syndrome 3, MIM# 619950
Intellectual disability syndromic and non-syndromic v0.4857 HIST1H4E Zornitza Stark Mode of inheritance for gene: HIST1H4E was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.4856 HIST1H4E Zornitza Stark reviewed gene: HIST1H4E: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Tessadori-van Haaften neurodevelopmental syndrome 3, MIM# 619950; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.4856 KMT2B Zornitza Stark Phenotypes for gene: KMT2B were changed from Dystonia 28, childhood-onset, MIM#617284 to Dystonia 28, childhood-onset 617284; MONDO:0015004; Intellectual developmental disorder, autosomal dominant 68, MIM# 619934
Intellectual disability syndromic and non-syndromic v0.4855 KMT2B Zornitza Stark Publications for gene: KMT2B were set to
Intellectual disability syndromic and non-syndromic v0.4854 KMT2B Zornitza Stark changed review comment from: ID described as part of the phenotype in some patients.; to: Childhood-onset dystonia: ID described as part of the phenotype in some patients.
Intellectual disability syndromic and non-syndromic v0.4854 KMT2B Zornitza Stark edited their review of gene: KMT2B: Added comment: Nine individuals reported in PMID 33150406 with heterozygous variants in this gene and intellectual disability, speech delay, microcephaly, growth delay, feeding problems, and dysmorphic features, including epicanthic folds, posteriorly rotated ears, syndactyly/clinodactyly of toes, and fifth finger clinodactyly, normal MRIs and NO dystonia.; Changed publications: 33150406; Changed phenotypes: Dystonia 28, childhood-onset 617284, MONDO:0015004, Intellectual developmental disorder, autosomal dominant 68, MIM# 619934
Intellectual disability syndromic and non-syndromic v0.4854 LMAN2L Zornitza Stark Phenotypes for gene: LMAN2L were changed from ?Mental retardation, autosomal recessive, 52; OMIM #616887 to Mental retardation, autosomal recessive, 52 OMIM #616887; Intellectual developmental disorder, autosomal dominant 69 , MIM# 617863
Intellectual disability syndromic and non-syndromic v0.4853 LMAN2L Zornitza Stark reviewed gene: LMAN2L: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Mental retardation, autosomal recessive, 52 OMIM #616887, Intellectual developmental disorder, autosomal dominant 69 , MIM# 617863; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4853 PLXNA1 Zornitza Stark reviewed gene: PLXNA1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Dworschak-Punetha neurodevelopmental syndrome, MIM# 619955; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4853 PLXNA1 Zornitza Stark Phenotypes for gene: PLXNA1 were changed from Neurodevelopmental disorder with cerebral and eye anomalies to Dworschak-Punetha neurodevelopmental syndrome, MIM# 619955
Intellectual disability syndromic and non-syndromic v0.4852 CHMP3 Zornitza Stark Marked gene: CHMP3 as ready
Intellectual disability syndromic and non-syndromic v0.4852 CHMP3 Zornitza Stark Gene: chmp3 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.4852 CHMP3 Zornitza Stark Classified gene: CHMP3 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.4852 CHMP3 Zornitza Stark Gene: chmp3 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.4851 PABPC1 Elena Savva Classified gene: PABPC1 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4851 PABPC1 Elena Savva Gene: pabpc1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4850 PABPC1 Elena Savva Classified gene: PABPC1 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4850 PABPC1 Elena Savva Gene: pabpc1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4850 PABPC1 Elena Savva Classified gene: PABPC1 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4850 PABPC1 Elena Savva Gene: pabpc1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4849 PABPC1 Elena Savva Marked gene: PABPC1 as ready
Intellectual disability syndromic and non-syndromic v0.4849 PABPC1 Elena Savva Gene: pabpc1 has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v0.4849 PABPC1 Elena Savva gene: PABPC1 was added
gene: PABPC1 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: PABPC1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: PABPC1 were set to PMID: 35511136
Phenotypes for gene: PABPC1 were set to Neurodevelopmental disorder, PABPC1-related (MONDO#0700092)
Review for gene: PABPC1 was set to GREEN
Added comment: PMID: 35511136 - 4 probands with an overlapping phenotype of DD, expressive speech delay, and autistic features and heterozygous de novo variants that cluster in the PABP domain of PABPC1.
Electroporation of mouse embryo brains showed that Pabpc1 knockdown decreases the proliferation of neural progenitor cells. Wild-type Pabpc1 could rescue this disturbance, whereas 3 of the 4 variants did not.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4848 WNK3 Zornitza Stark Marked gene: WNK3 as ready
Intellectual disability syndromic and non-syndromic v0.4848 WNK3 Zornitza Stark Gene: wnk3 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4848 WNK3 Zornitza Stark Classified gene: WNK3 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4848 WNK3 Zornitza Stark Gene: wnk3 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4847 ACOX1 Alison Yeung Phenotypes for gene: ACOX1 were changed from Peroxisomal acyl-CoA oxidase deficiency, MIM# 264470; Mitchell syndrome, MIM# 618960 to Peroxisomal acyl-CoA oxidase deficiency, MIM# 264470; Mitchell syndrome, MIM# 618960
Intellectual disability syndromic and non-syndromic v0.4847 ACOX1 Alison Yeung Phenotypes for gene: ACOX1 were changed from Peroxisomal acyl-CoA oxidase deficiency, MIM# 264470; Mitchell syndrome, MIM# 618960 to Peroxisomal acyl-CoA oxidase deficiency, MIM# 264470; Mitchell syndrome, MIM# 618960
Intellectual disability syndromic and non-syndromic v0.4846 ACOX1 Alison Yeung Phenotypes for gene: ACOX1 were changed from Peroxisomal acyl-CoA oxidase deficiency, MIM# 264470; Mitchell syndrome, MIM# 618960 to Peroxisomal acyl-CoA oxidase deficiency, MIM# 264470; Mitchell syndrome, MIM# 618960
Intellectual disability syndromic and non-syndromic v0.4846 CHMP3 Chern Lim gene: CHMP3 was added
gene: CHMP3 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: CHMP3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CHMP3 were set to PMID: 35710109
Phenotypes for gene: CHMP3 were set to Hereditary spastic paraplegia (MONDO:0019064), CHMP3-related
Review for gene: CHMP3 was set to AMBER
gene: CHMP3 was marked as current diagnostic
Added comment: PMID: 35710109
- Single large family with consanguinity, homozygous missense variant in 5 affected individuals with intellectual and progressive motor disabilities, seizures and spastic quadriplegia.
- Functional studies showed reduced CHMP3 protein in patient's fibroblasts, lenti-rescue study showed improved cellular phenotypes associated with impaired autophagy.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4846 ACOX1 Alison Yeung Publications for gene: ACOX1 were set to 32169171; 17458872
Intellectual disability syndromic and non-syndromic v0.4845 ACOX1 Alison Yeung Phenotypes for gene: ACOX1 were changed from to Peroxisomal acyl-CoA oxidase deficiency, MIM# 264470; Mitchell syndrome, MIM# 618960
Intellectual disability syndromic and non-syndromic v0.4845 ACOX1 Alison Yeung Marked gene: ACOX1 as ready
Intellectual disability syndromic and non-syndromic v0.4845 ACOX1 Alison Yeung Gene: acox1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4845 ACOX1 Alison Yeung Publications for gene: ACOX1 were set to
Intellectual disability syndromic and non-syndromic v0.4844 ACOX1 Alison Yeung Mode of inheritance for gene: ACOX1 was changed from Unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4843 ACOX1 Alison Yeung reviewed gene: ACOX1: Rating: GREEN; Mode of pathogenicity: None; Publications: 32169171, 17458872; Phenotypes: Peroxisomal acyl-CoA oxidase deficiency, MIM# 264470, Mitchell syndrome, MIM# 618960; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4843 WNK3 Lucy Spencer gene: WNK3 was added
gene: WNK3 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: WNK3 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: WNK3 were set to 35678782
Phenotypes for gene: WNK3 were set to Neurodevelopmental disorder, WNK3-related (MONDO#0700092)
Review for gene: WNK3 was set to GREEN
Added comment: 6 maternally inherited hemizygous variants, 3 missense, 2 canonical splice, and a nonsense. Seen in 14 individuals from 6 families, all 14 are male who inherited hemizygous variants from their unaffected heterozygous mothers. The variants cosegregated with disease in 3 families with multiple affected individuals. All 14 patients have ID, 11 have speech delay, 10 have facial abnormalities, 5 have seizures, 6 with microcephaly and 7 with anomalies in brain imaging.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4843 MAL Zornitza Stark Marked gene: MAL as ready
Intellectual disability syndromic and non-syndromic v0.4843 MAL Zornitza Stark Gene: mal has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.4843 TMEM63C Elena Savva Classified gene: TMEM63C as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4843 TMEM63C Elena Savva Gene: tmem63c has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4843 MAL Zornitza Stark Classified gene: MAL as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.4843 MAL Zornitza Stark Gene: mal has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.4842 TMEM63C Elena Savva Classified gene: TMEM63C as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4842 TMEM63C Elena Savva Gene: tmem63c has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4842 TMEM63C Elena Savva Classified gene: TMEM63C as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4842 TMEM63C Elena Savva Gene: tmem63c has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4841 TMEM63C Elena Savva Marked gene: TMEM63C as ready
Intellectual disability syndromic and non-syndromic v0.4841 TMEM63C Elena Savva Gene: tmem63c has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v0.4841 TMEM63C Elena Savva gene: TMEM63C was added
gene: TMEM63C was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: TMEM63C was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TMEM63C were set to PMID: 35718349
Phenotypes for gene: TMEM63C were set to Hereditary spastic paraplegia, MONDO:0019064, TMEM63C-related
Review for gene: TMEM63C was set to GREEN
Added comment: PMID: 35718349 - Four NMD PTCs observed in at least 3 unrelated patients. Two segregated strongly in highly consanguineous families.
Common clinical details include mild ID, spastic paraplegia, hypereflexia, spasticity, delayed motor development.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4840 MAL Zornitza Stark gene: MAL was added
gene: MAL was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: MAL was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MAL were set to 35217805
Phenotypes for gene: MAL were set to Leukodystrophy MONDO:0019046, MAL-related
Review for gene: MAL was set to AMBER
Added comment: Single family with two affected siblings reported, with homozygous missense variant, some functional data.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4839 TAF8 Zornitza Stark changed review comment from: Further 7 individuals reported from 4 families, three of which were consanguineous.

Clinical features included severe psychomotor retardation with almost absent development, feeding problems, microcephaly, growth retardation, spasticity and epilepsy.

Five had the previously reported c.781-1G > A variant in homozygous state. This is likely to be a founder variant.

One family with different compound heterozygous variants.; to: Further 7 individuals reported from 4 families, three of which were consanguineous.

Clinical features included severe psychomotor retardation with almost absent development, feeding problems, microcephaly, growth retardation, spasticity and epilepsy.

Five had the previously reported c.781-1G > A variant in homozygous state. Unclear if this is a founder variant, families of different ethnicities.

One family with different compound heterozygous variants.
Intellectual disability syndromic and non-syndromic v0.4839 TAF8 Zornitza Stark Tag founder was removed from gene: TAF8.
Intellectual disability syndromic and non-syndromic v0.4839 TAF8 Zornitza Stark Tag founder tag was added to gene: TAF8.
Intellectual disability syndromic and non-syndromic v0.4839 TAF8 Zornitza Stark Phenotypes for gene: TAF8 were changed from Neurodevelopmental disorder, MONDO:0700092, TAF8-related to Neurodevelopmental disorder, MONDO:0700092, TAF8-related
Intellectual disability syndromic and non-syndromic v0.4838 TAF8 Zornitza Stark Phenotypes for gene: TAF8 were changed from to Neurodevelopmental disorder, MONDO:0700092, TAF8-related
Intellectual disability syndromic and non-syndromic v0.4837 TAF8 Zornitza Stark Publications for gene: TAF8 were set to PMID: 29648665
Intellectual disability syndromic and non-syndromic v0.4836 TAF8 Zornitza Stark Classified gene: TAF8 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4836 TAF8 Zornitza Stark Gene: taf8 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4835 TAF8 Zornitza Stark edited their review of gene: TAF8: Changed publications: 35759269
Intellectual disability syndromic and non-syndromic v0.4835 TAF8 Zornitza Stark reviewed gene: TAF8: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder, MONDO:0700092, TAF8-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4835 KCNK9 Zornitza Stark Publications for gene: KCNK9 were set to 28333430; 27151206; 24980697; 18678320
Intellectual disability syndromic and non-syndromic v0.4834 KCNK9 Zornitza Stark edited their review of gene: KCNK9: Added comment: Additional 47 individuals reported with 15 variants, including another hotspot at p.Arg131.; Changed publications: 28333430, 27151206, 24980697, 18678320, 35698242
Intellectual disability syndromic and non-syndromic v0.4834 TSPAN7 Zornitza Stark Classified gene: TSPAN7 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.4834 TSPAN7 Zornitza Stark Gene: tspan7 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.4833 TSPAN7 Zornitza Stark Tag disputed was removed from gene: TSPAN7.
Intellectual disability syndromic and non-syndromic v0.4833 TSPAN7 Zornitza Stark edited their review of gene: TSPAN7: Added comment: Two families reported with LoF variants and ID: Abidi FE et al. 2002 Jun (PMID:12070254); Zemni R et al. 2000 Feb (PMID:10655063) Assessed as MODERATE by ClinGen.; Changed rating: AMBER
Intellectual disability syndromic and non-syndromic v0.4833 TSPAN7 Zornitza Stark Classified gene: TSPAN7 as Red List (low evidence)
Intellectual disability syndromic and non-syndromic v0.4833 TSPAN7 Zornitza Stark Gene: tspan7 has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v0.4832 TSPAN7 Zornitza Stark Tag disputed tag was added to gene: TSPAN7.
Intellectual disability syndromic and non-syndromic v0.4832 TSPAN7 Zornitza Stark edited their review of gene: TSPAN7: Changed rating: RED
Intellectual disability syndromic and non-syndromic v0.4832 TRPM3 Zornitza Stark Phenotypes for gene: TRPM3 were changed from Intellectual disability; epilepsy to Neurodevelopmental disorder, MONDO:0700092, TRPM3-related
Intellectual disability syndromic and non-syndromic v0.4831 GRIA1 Zornitza Stark changed review comment from: Single individual reported with bi-allelic LoF variant.; to: Single individual reported with bi-allelic LoF variant. RED/AMBER for bi-allelic variants.
Intellectual disability syndromic and non-syndromic v0.4831 GRIA1 Zornitza Stark Mode of inheritance for gene: GRIA1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4830 GRIA1 Zornitza Stark Phenotypes for gene: GRIA1 were changed from Intellectual developmental disorder, autosomal dominant 67, MIM# 619927 to Intellectual developmental disorder, autosomal dominant 67, MIM# 619927; Intellectual developmental disorder, autosomal recessive 76, MIM# 619931
Intellectual disability syndromic and non-syndromic v0.4829 GRIA1 Zornitza Stark edited their review of gene: GRIA1: Added comment: Single individual reported with bi-allelic LoF variant.; Changed publications: 35675825; Changed phenotypes: Intellectual developmental disorder, autosomal recessive 76, MIM# 619931
Intellectual disability syndromic and non-syndromic v0.4829 GRIA1 Zornitza Stark Phenotypes for gene: GRIA1 were changed from Intellectual disability; autism to Intellectual developmental disorder, autosomal dominant 67, MIM# 619927
Intellectual disability syndromic and non-syndromic v0.4828 GRIA1 Zornitza Stark edited their review of gene: GRIA1: Changed phenotypes: Intellectual developmental disorder, autosomal dominant 67, MIM# 619927
Intellectual disability syndromic and non-syndromic v0.4828 NR4A2 Zornitza Stark Phenotypes for gene: NR4A2 were changed from Intellectual disability; rolandic epilepsy; autism to Intellectual developmental disorder with language impairment and early-onset DOPA-responsive dystonia-parkinsonism, MIM# 619911
Intellectual disability syndromic and non-syndromic v0.4827 KCNC2 Zornitza Stark Marked gene: KCNC2 as ready
Intellectual disability syndromic and non-syndromic v0.4827 KCNC2 Zornitza Stark Gene: kcnc2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4827 KCNC2 Zornitza Stark Classified gene: KCNC2 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4827 KCNC2 Zornitza Stark Gene: kcnc2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4826 KCNC2 Zornitza Stark gene: KCNC2 was added
gene: KCNC2 was added to Intellectual disability syndromic and non-syndromic. Sources: Expert Review
Mode of inheritance for gene: KCNC2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KCNC2 were set to 32392612; 31972370; 35314505
Phenotypes for gene: KCNC2 were set to Developmental and epileptic encephalopathy 103, MIM# 619913
Review for gene: KCNC2 was set to GREEN
Added comment: More than 10 unrelated families reported. ID ranges from mild to severe.
Sources: Expert Review
Intellectual disability syndromic and non-syndromic v0.4825 ATP2B1 Zornitza Stark Phenotypes for gene: ATP2B1 were changed from Neurodevelopmental disorder, MONDO:0700092, ATP2B1-related to Intellectual developmental disorder, autosomal dominant 66, MIM# 619910
Intellectual disability syndromic and non-syndromic v0.4824 ATP2B1 Zornitza Stark reviewed gene: ATP2B1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Intellectual developmental disorder, autosomal dominant 66, MIM# 619910; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.4824 PRDM13 Zornitza Stark Phenotypes for gene: PRDM13 were changed from Cerebellar dysfunction, impaired intellectual development, and hypogonadotropic hypogonadism, MIM# 619761 to Pontocerebellar hypoplasia, type 17, MIM# 619909; Cerebellar dysfunction, impaired intellectual development, and hypogonadotropic hypogonadism, MIM# 619761
Intellectual disability syndromic and non-syndromic v0.4823 PRDM13 Zornitza Stark edited their review of gene: PRDM13: Added comment: Note only single family reported with MIM#619761. The two disorders likely represent a continuum of severity.; Changed phenotypes: Pontocerebellar hypoplasia, type 17, MIM# 619909, Cerebellar dysfunction, impaired intellectual development, and hypogonadotropic hypogonadism, MIM# 619761
Intellectual disability syndromic and non-syndromic v0.4823 TIAM1 Zornitza Stark Phenotypes for gene: TIAM1 were changed from Neurodevelopmental disorder, TIAM1-related, MONDO:0700092 to Neurodevelopmental disorder with language delay and seizures, MIM# 619908
Intellectual disability syndromic and non-syndromic v0.4822 SEMA6B Zornitza Stark Marked gene: SEMA6B as ready
Intellectual disability syndromic and non-syndromic v0.4822 SEMA6B Zornitza Stark Gene: sema6b has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4822 SEMA6B Zornitza Stark Classified gene: SEMA6B as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4822 SEMA6B Zornitza Stark Gene: sema6b has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4821 IREB2 Zornitza Stark Publications for gene: IREB2 were set to 30915432; 31243445; 11175792
Intellectual disability syndromic and non-syndromic v0.4820 IREB2 Zornitza Stark edited their review of gene: IREB2: Added comment: Additional individual reported in PMID 35602653; Changed publications: 30915432, 31243445, 11175792, 35602653
Intellectual disability syndromic and non-syndromic v0.4820 PAN2 Zornitza Stark Marked gene: PAN2 as ready
Intellectual disability syndromic and non-syndromic v0.4820 PAN2 Zornitza Stark Gene: pan2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4820 PAN2 Zornitza Stark Classified gene: PAN2 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4820 PAN2 Zornitza Stark Gene: pan2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4819 RMND1 Belinda Chong reviewed gene: RMND1: Rating: GREEN; Mode of pathogenicity: None; Publications: 26395190; Phenotypes: Combined oxidative phosphorylation deficiency 11 MIM#614922; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability syndromic and non-syndromic v0.4819 PRPF8 Zornitza Stark Marked gene: PRPF8 as ready
Intellectual disability syndromic and non-syndromic v0.4819 PRPF8 Zornitza Stark Gene: prpf8 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4819 PRPF8 Zornitza Stark Phenotypes for gene: PRPF8 were changed from Intellectual disability; epilepsy; Retinitis pigmentosa 13 - MIM#600059 to Neurodevelopmental disorder MONDO:0700092, PRPF8-related; Retinitis pigmentosa 13 - MIM#600059
Intellectual disability syndromic and non-syndromic v0.4818 BUB1 Zornitza Stark Marked gene: BUB1 as ready
Intellectual disability syndromic and non-syndromic v0.4818 BUB1 Zornitza Stark Gene: bub1 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.4818 PAN2 Naomi Baker gene: PAN2 was added
gene: PAN2 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: PAN2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PAN2 were set to PMID:35304602; 29620724
Phenotypes for gene: PAN2 were set to Syndromic disease MONDO:0002254
Review for gene: PAN2 was set to GREEN
Added comment: PMID:35304602 reports five individuals from 3 families with biallelic (homozygous) loss-of-function variants. Clinical presentation incudes mild-moderate intellectual disability, hypotonia, sensorineural hearing loss, EEG abnormalities, congenital heart defects (tetralogy of Fallot, septal defects, dilated aortic root), urinary tract malformations, ophthalmological anomalies, short stature with other skeletal anomalies, and craniofacial features including flat occiput, ptosis, long philtrum, and short neck.

PMID:29620724 reports one individual with biallelic (homozygous) loss-of-function variant who presented with global developmental delay, mild hypotonia, craniosynostosis, severe early-onset scoliosis, imperforate anus, and double urinary collecting system.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4818 PRPF8 Zornitza Stark Classified gene: PRPF8 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4818 PRPF8 Zornitza Stark Gene: prpf8 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4817 BUB1 Zornitza Stark Classified gene: BUB1 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.4817 BUB1 Zornitza Stark Gene: bub1 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.4816 BUB1 Zornitza Stark Classified gene: BUB1 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.4816 BUB1 Zornitza Stark Gene: bub1 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.4815 BUB1 Zornitza Stark Classified gene: BUB1 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.4815 BUB1 Zornitza Stark Gene: bub1 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.4814 PRPF8 Krithika Murali gene: PRPF8 was added
gene: PRPF8 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: PRPF8 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PRPF8 were set to 35543142
Phenotypes for gene: PRPF8 were set to Intellectual disability; epilepsy; Retinitis pigmentosa 13 - MIM#600059
Review for gene: PRPF8 was set to GREEN
Added comment: PMID 35543142 O'Grady et al 2022 report 14 unrelated individuals with heterozygous PRPF8 variants and ID, dymorphic features and epilepsy (7/14). Short stature, abnormal gait and cardiac anomalies also reported. 11 variants identified were de novo, 1 variant - maternal mosaicism, 1 variant - duo sequencing (not identified in mother, father could not be sequenced). 1 individual did not have parental testing. Cardiac anomalies varied and included benign cardiac tumour, dilated cardiomyopathy, dilated aortic root (COL5A2 VUS also identified), bicuspid aortic valve, cardiac arrest, self-resolving ASD/VSD.

Heterozygous PRPF8 variants previously associated with retinitis pigmentosa. 1 out of the 14 individuals in this cohort had a diagnosis of RP. RP variants noted to cluster in the C'terminal MPN domain. The individual with RP in this paper had a variant in the preceding RNAase H homology domain near the C-terminus. Not all of the individuals in this paper had formal ophthalmological examination
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4814 BUB1 Paul De Fazio gene: BUB1 was added
gene: BUB1 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: BUB1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BUB1 were set to 35044816; 19772675; 19117986; 23209306
Phenotypes for gene: BUB1 were set to Neurodevelopmental disorder, BUB1-related MONDO:0700092; Intellectual disability and microcephaly
Review for gene: BUB1 was set to GREEN
gene: BUB1 was marked as current diagnostic
Added comment: 2 unrelated patients with ID, microcephaly, short stature, dysmorphic features reported with biallelic variants:

P1 (3yo male): homozygous start-loss variant (2 hets and 0 hom in gnomAD). Functional testing showed a small amount of full-length protein was translated, and BUB1 recruitment to kinetochores was nearly undetectable.
P2 (16yo female): compound heterozygous for a canonical splice variant (1 het and no hom in gnomAD) and an NMD-predicted frameshift variant (absent from gnomAD). The splice variant was shown to result in an in-frame deletion of 54 amino acids in the kinase domain. P2 cells have reduced protein levels but essentially no kinase activity.

BUB1 patient cells have impaired mitotic fidelity.

Homozygous Bub1 disruption in mice is embryonic lethal (PMID:19772675). A hypomorphic mouse is viable with increased tumourigenesis with ageing and aneuploidy (PMID:19117986). A kinase-dead mouse does not show increased tumourigenesis but does have a high frequency of aneuploid cells (PMID:23209306)
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4814 SEMA6B Dean Phelan gene: SEMA6B was added
gene: SEMA6B was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: SEMA6B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SEMA6B were set to PMID: 35604360
Phenotypes for gene: SEMA6B were set to Intellectual disability, MONDO:0001071, SEMA6B related
Penetrance for gene: SEMA6B were set to Complete
Review for gene: SEMA6B was set to GREEN
Added comment: PMID: 35604360
- 14 heterozygous variants were observed in 16 unrelated individuals referred for intellectual disability. Majority of the variants 9/14 were PTCs in the last exon and predicted to escape NMD. Functional studies of selected variants and shRNA knock down studies showed mislocalisation and abnormal protein function.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4814 HEATR3 Zornitza Stark Marked gene: HEATR3 as ready
Intellectual disability syndromic and non-syndromic v0.4814 HEATR3 Zornitza Stark Gene: heatr3 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.4814 HEATR3 Zornitza Stark Classified gene: HEATR3 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.4814 HEATR3 Zornitza Stark Gene: heatr3 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.4813 HEATR3 Chern Lim gene: HEATR3 was added
gene: HEATR3 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: HEATR3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HEATR3 were set to PMID: 35213692
Phenotypes for gene: HEATR3 were set to Bone marrow failure, short stature, facial and acromelic dysmorphic features, and mild intellectual disability; Diamond Blackfan anaemia MONDO:0015253, HEATR3 related
Review for gene: HEATR3 was set to AMBER
gene: HEATR3 was marked as current diagnostic
Added comment: PMID: 35213692:
- 4 unrelated individuals with biallelic HEATR3 variants (missense and splice site variants), exhibiting bone marrow failure, short stature, facial and acromelic dysmorphic features, and mild intellectual disability.
- Functional analysis showed HEATR3 variants destabilised the protein, resulting in a reduction of nuclear uL18 and impaired ribosome biogenesis.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4813 SRRM2 Zornitza Stark Phenotypes for gene: SRRM2 were changed from Developmental disorders to neurodevelopmental disorder MONDO:0700092 SRRM2-related
Intellectual disability syndromic and non-syndromic v0.4812 SRRM2 Zornitza Stark Classified gene: SRRM2 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4812 SRRM2 Zornitza Stark Gene: srrm2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4811 SRRM2 Michelle Torres reviewed gene: SRRM2: Rating: GREEN; Mode of pathogenicity: None; Publications: 35567594; Phenotypes: neurodevelopmental disorder MONDO:0700092 SRRM2-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.4811 TCTN2 Zornitza Stark Marked gene: TCTN2 as ready
Intellectual disability syndromic and non-syndromic v0.4811 TCTN2 Zornitza Stark Gene: tctn2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4811 TCTN2 Zornitza Stark Phenotypes for gene: TCTN2 were changed from to Joubert syndrome 24, MIM# 616654 MONDO:0014724
Intellectual disability syndromic and non-syndromic v0.4810 TCTN2 Zornitza Stark Publications for gene: TCTN2 were set to
Intellectual disability syndromic and non-syndromic v0.4809 TCTN2 Zornitza Stark Mode of inheritance for gene: TCTN2 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4808 TCTN2 Zornitza Stark reviewed gene: TCTN2: Rating: GREEN; Mode of pathogenicity: None; Publications: 21565611, 25118024; Phenotypes: Joubert syndrome 24, MIM# 616654 MONDO:0014724; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4808 PRDM13 Zornitza Stark Phenotypes for gene: PRDM13 were changed from intellectual disability, MONDO:0001071, PRDM13-associated; Pontocerebellar hypoplasia (MONDO:0020135), PRDM13 related; congenital hypogonadotropic hypogonadism, MONDO:0015770 to Cerebellar dysfunction, impaired intellectual development, and hypogonadotropic hypogonadism, MIM# 619761
Intellectual disability syndromic and non-syndromic v0.4807 PRDM13 Zornitza Stark reviewed gene: PRDM13: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Cerebellar dysfunction, impaired intellectual development, and hypogonadotropic hypogonadism, MIM# 619761; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4807 HIST1H4J Zornitza Stark Phenotypes for gene: HIST1H4J were changed from microcephaly; intellectual disability; dysmorphic features to Tessadori-van Haaften neurodevelopmental syndrome 2 , MIM# 619759
Intellectual disability syndromic and non-syndromic v0.4806 HIST1H4J Zornitza Stark reviewed gene: HIST1H4J: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Tessadori-van Haaften neurodevelopmental syndrome 2 , MIM# 619759; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.4806 U2AF2 Zornitza Stark Phenotypes for gene: U2AF2 were changed from Developmental disorders to Neurodevelopmental disorder MONDO:0700092, MMGT1-related
Intellectual disability syndromic and non-syndromic v0.4805 MMGT1 Zornitza Stark Phenotypes for gene: MMGT1 were changed from Developmental disorders to Neurodevelopmental disorder MONDO:0700092, MMGT1-related
Intellectual disability syndromic and non-syndromic v0.4804 MMGT1 Zornitza Stark edited their review of gene: MMGT1: Changed phenotypes: Neurodevelopmental disorder MONDO:0700092, MMGT1-related
Intellectual disability syndromic and non-syndromic v0.4804 LRP2 Zornitza Stark Marked gene: LRP2 as ready
Intellectual disability syndromic and non-syndromic v0.4804 LRP2 Zornitza Stark Gene: lrp2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4804 LRP2 Zornitza Stark Phenotypes for gene: LRP2 were changed from to Donnai-Barrow syndrome, MIM#222448
Intellectual disability syndromic and non-syndromic v0.4803 LRP2 Zornitza Stark Publications for gene: LRP2 were set to
Intellectual disability syndromic and non-syndromic v0.4802 LRP2 Zornitza Stark Mode of inheritance for gene: LRP2 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4801 GEMIN4 Zornitza Stark Publications for gene: GEMIN4 were set to 25558065; 30237576
Intellectual disability syndromic and non-syndromic v0.4800 GFM2 Zornitza Stark Marked gene: GFM2 as ready
Intellectual disability syndromic and non-syndromic v0.4800 GFM2 Zornitza Stark Gene: gfm2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4800 GFM2 Zornitza Stark Publications for gene: GFM2 were set to PMID: 22700954, 26016410, 29075935
Intellectual disability syndromic and non-syndromic v0.4799 PLCH1 Zornitza Stark Phenotypes for gene: PLCH1 were changed from Holoprosencephaly spectrum; Severe developmental delay; Brain malformations to Holoprosencephaly 14, MIM# 619895
Intellectual disability syndromic and non-syndromic v0.4798 PLCH1 Zornitza Stark edited their review of gene: PLCH1: Changed phenotypes: Holoprosencephaly 14, MIM# 619895
Intellectual disability syndromic and non-syndromic v0.4798 SLC38A3 Zornitza Stark Phenotypes for gene: SLC38A3 were changed from developmental epileptic encephalopathy, SLC38A3-related MONDO:0100062 to Developmental and epileptic encephalopathy 102, MIM# 619881
Intellectual disability syndromic and non-syndromic v0.4797 SLC38A3 Zornitza Stark reviewed gene: SLC38A3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Developmental and epileptic encephalopathy 102, MIM# 619881; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4797 COPB2 Zornitza Stark Phenotypes for gene: COPB2 were changed from Osteoporosis and developmental delay to Osteoporosis, childhood- or juvenile-onset, with developmental delay, MIM# 619884
Intellectual disability syndromic and non-syndromic v0.4796 COPB2 Zornitza Stark edited their review of gene: COPB2: Changed phenotypes: Osteoporosis, childhood- or juvenile-onset, with developmental delay, MIM# 619884
Intellectual disability syndromic and non-syndromic v0.4796 ADD1 Zornitza Stark Marked gene: ADD1 as ready
Intellectual disability syndromic and non-syndromic v0.4796 ADD1 Zornitza Stark Gene: add1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4796 ADD1 Zornitza Stark Phenotypes for gene: ADD1 were changed from Intellectual disability, corpus callosum dysgenesis, and ventriculomegaly; no OMIM # to Neurodevelopmental disorder MONDO:0700092, ADD1-related; Intellectual disability, corpus callosum dysgenesis, and ventriculomegaly; no OMIM #
Intellectual disability syndromic and non-syndromic v0.4795 PROSER1 Zornitza Stark Phenotypes for gene: PROSER1 were changed from Developmental delay, hypotonia, seizures, failure-to-thrive, strabismus, drooling, recurrent otitis media, hearing impairment, and genitourinary malformations, no OMIM # to Syndromic disease MONDO:0002254, PROSER1-related; Developmental delay, hypotonia, seizures, failure-to-thrive, strabismus, drooling, recurrent otitis media, hearing impairment, and genitourinary malformations, no OMIM #
Intellectual disability syndromic and non-syndromic v0.4794 PROSER1 Zornitza Stark Marked gene: PROSER1 as ready
Intellectual disability syndromic and non-syndromic v0.4794 PROSER1 Zornitza Stark Gene: proser1 has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v0.4794 PROSER1 Zornitza Stark Tag founder tag was added to gene: PROSER1.
Intellectual disability syndromic and non-syndromic v0.4794 PCDHGC4 Zornitza Stark Phenotypes for gene: PCDHGC4 were changed from Intellectual disability; Seizures to Neurodevelopmental disorder with poor growth and skeletal anomalies, MIM# 619880
Intellectual disability syndromic and non-syndromic v0.4793 PCDHGC4 Zornitza Stark edited their review of gene: PCDHGC4: Changed phenotypes: Neurodevelopmental disorder with poor growth and skeletal anomalies, MIM# 619880
Intellectual disability syndromic and non-syndromic v0.4793 ZNF526 Zornitza Stark Phenotypes for gene: ZNF526 were changed from Intellectual disability; Microcephaly; Cataracts; Epilepsy; Hypertonia; Dystonia to Dentici-Novelli neurodevelopmental syndrome, MIM# 619877
Intellectual disability syndromic and non-syndromic v0.4792 ZNF526 Zornitza Stark edited their review of gene: ZNF526: Changed phenotypes: Dentici-Novelli neurodevelopmental syndrome, MIM# 619877
Intellectual disability syndromic and non-syndromic v0.4792 LRP2 Chirag Patel reviewed gene: LRP2: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 17632512; Phenotypes: Donnai-Barrow syndrome, MIM#222448; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4792 GEMIN4 Chirag Patel Classified gene: GEMIN4 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4792 GEMIN4 Chirag Patel Gene: gemin4 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4791 GEMIN4 Chirag Patel reviewed gene: GEMIN4: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 25558065, 30237576, 27878435; Phenotypes: Neurodevelopmental disorder with microcephaly, cataracts, and renal abnormalities, MIM# 617913; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4791 GFM2 Chirag Patel Classified gene: GFM2 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4791 GFM2 Chirag Patel Gene: gfm2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4790 GFM2 Chirag Patel gene: GFM2 was added
gene: GFM2 was added to Intellectual disability syndromic and non-syndromic. Sources: Expert list
Mode of inheritance for gene: GFM2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GFM2 were set to PMID: 22700954, 26016410, 29075935
Phenotypes for gene: GFM2 were set to Combined oxidative phosphorylation deficiency 39, OMIM #618397
Review for gene: GFM2 was set to GREEN
Added comment: Combined oxidative phosphorylation deficiency-39 (COXPD39) is an autosomal recessive multisystem disorder resulting from a defect in mitochondrial energy metabolism. Affected individuals show global developmental delay, sometimes with regression after normal early development, axial hypotonia with limb spasticity or abnormal involuntary movements, and impaired intellectual development with poor speech. More variable features may include hypotonia, seizures, and features of Leigh syndrome on brain imaging. There are variable deficiencies of the mitochondrial respiratory chain enzyme complexes in patient tissues.

4 families reported with biallelic variants with functional evidence in 1 family.
Sources: Expert list
Intellectual disability syndromic and non-syndromic v0.4789 MOCS3 Zornitza Stark Marked gene: MOCS3 as ready
Intellectual disability syndromic and non-syndromic v0.4789 MOCS3 Zornitza Stark Gene: mocs3 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.4789 MOCS3 Zornitza Stark Classified gene: MOCS3 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.4789 MOCS3 Zornitza Stark Gene: mocs3 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.4788 MOCS3 Zornitza Stark gene: MOCS3 was added
gene: MOCS3 was added to Intellectual disability syndromic and non-syndromic. Sources: Expert Review
Mode of inheritance for gene: MOCS3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MOCS3 were set to 33897766; 28544736
Phenotypes for gene: MOCS3 were set to Molybdenum cofactor deficiency MONDO:0020480
Review for gene: MOCS3 was set to AMBER
Added comment: Two unrelated families reported.
Sources: Expert Review
Intellectual disability syndromic and non-syndromic v0.4787 CPSF3 Zornitza Stark Phenotypes for gene: CPSF3 were changed from Neurodevelopmental disorder, CPSF3-related, MONDO:0700092 to Neurodevelopmental disorder with microcephaly, hypotonia, and seizures (NEDMHS), MIM#619876
Intellectual disability syndromic and non-syndromic v0.4786 CPSF3 Zornitza Stark reviewed gene: CPSF3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with microcephaly, hypotonia, and seizures (NEDMHS), MIM#619876; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4786 MFF Zornitza Stark Marked gene: MFF as ready
Intellectual disability syndromic and non-syndromic v0.4786 MFF Zornitza Stark Gene: mff has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4786 MFF Zornitza Stark Phenotypes for gene: MFF were changed from to Encephalopathy due to defective mitochondrial and peroxisomal fission 2, MIM# 617086
Intellectual disability syndromic and non-syndromic v0.4785 MFF Zornitza Stark Publications for gene: MFF were set to
Intellectual disability syndromic and non-syndromic v0.4784 MFF Zornitza Stark Mode of inheritance for gene: MFF was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4783 MFF Zornitza Stark reviewed gene: MFF: Rating: GREEN; Mode of pathogenicity: None; Publications: 22499341, 26783368, 32181496; Phenotypes: Encephalopathy due to defective mitochondrial and peroxisomal fission 2, MIM# 617086; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4783 OPHN1 Zornitza Stark Marked gene: OPHN1 as ready
Intellectual disability syndromic and non-syndromic v0.4783 OPHN1 Zornitza Stark Gene: ophn1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4783 OPHN1 Zornitza Stark Phenotypes for gene: OPHN1 were changed from to Mental retardation, X-linked, with cerebellar hypoplasia and distinctive facial appearance, MIM#300486
Intellectual disability syndromic and non-syndromic v0.4782 OPHN1 Zornitza Stark Publications for gene: OPHN1 were set to
Intellectual disability syndromic and non-syndromic v0.4781 OPHN1 Zornitza Stark Mode of inheritance for gene: OPHN1 was changed from Unknown to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability syndromic and non-syndromic v0.4780 OPHN1 Zornitza Stark reviewed gene: OPHN1: Rating: GREEN; Mode of pathogenicity: None; Publications: 20528889, 9582072, 12807966, 16221952; Phenotypes: Mental retardation, X-linked, with cerebellar hypoplasia and distinctive facial appearance, MIM#300486; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability syndromic and non-syndromic v0.4780 GRIA4 Ain Roesley Phenotypes for gene: GRIA4 were changed from Neurodevelopmental disorder with or without seizures and gait abnormalities MIM#617864 to Neurodevelopmental disorder with or without seizures and gait abnormalities MIM#617864
Intellectual disability syndromic and non-syndromic v0.4780 GRIA4 Ain Roesley Mode of inheritance for gene: GRIA4 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.4780 GRIA4 Ain Roesley Publications for gene: GRIA4 were set to 35518358; 29220673
Intellectual disability syndromic and non-syndromic v0.4779 GRIA4 Ain Roesley Marked gene: GRIA4 as ready
Intellectual disability syndromic and non-syndromic v0.4779 GRIA4 Ain Roesley Gene: gria4 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4779 GRIA4 Ain Roesley Phenotypes for gene: GRIA4 were changed from to Neurodevelopmental disorder with or without seizures and gait abnormalities MIM#617864
Intellectual disability syndromic and non-syndromic v0.4779 GRIA4 Ain Roesley Publications for gene: GRIA4 were set to
Intellectual disability syndromic and non-syndromic v0.4779 GRIA4 Ain Roesley Mode of inheritance for gene: GRIA4 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.4778 GRIA4 Ain Roesley reviewed gene: GRIA4: Rating: GREEN; Mode of pathogenicity: None; Publications: 35518358, 29220673; Phenotypes: Neurodevelopmental disorder with or without seizures and gait abnormalities MIM#617864; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Intellectual disability syndromic and non-syndromic v0.4778 GRID2 Ain Roesley Phenotypes for gene: GRID2 were changed from to Spinocerebellar ataxia, autosomal recessive 18 MIM#616204
Intellectual disability syndromic and non-syndromic v0.4778 GRID2 Ain Roesley Marked gene: GRID2 as ready
Intellectual disability syndromic and non-syndromic v0.4778 GRID2 Ain Roesley Gene: grid2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4778 GRID2 Ain Roesley Publications for gene: GRID2 were set to
Intellectual disability syndromic and non-syndromic v0.4778 GRID2 Ain Roesley Mode of inheritance for gene: GRID2 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4777 GRID2 Ain Roesley reviewed gene: GRID2: Rating: GREEN; Mode of pathogenicity: None; Publications: 32622959, 32170608; Phenotypes: Spinocerebellar ataxia, autosomal recessive 18 MIM#616204; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability syndromic and non-syndromic v0.4777 ADD1 Chirag Patel Classified gene: ADD1 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4777 ADD1 Chirag Patel Gene: add1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4777 ADD1 Chirag Patel Classified gene: ADD1 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4777 ADD1 Chirag Patel Gene: add1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4776 ADD1 Chirag Patel gene: ADD1 was added
gene: ADD1 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: ADD1 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Publications for gene: ADD1 were set to PMID: 34906466
Phenotypes for gene: ADD1 were set to Intellectual disability, corpus callosum dysgenesis, and ventriculomegaly; no OMIM #
Review for gene: ADD1 was set to GREEN
Added comment: 4 unrelated individuals affected by ID and/or complete or partial agenesis of corpus callosum, and enlarged lateral ventricles. WES found loss-of-function variants - 1 recessive missense variant and 3 de novo variants. The recessive variant is associated with ACC and enlarged lateral ventricles, and the de novo variants were associated with complete or partial agenesis of corpus callosum, mild ID and attention deficit. Human variants impair ADD1 protein expression and/or dimerization with ADD2. Add1 knockout mice recapitulate corpus callosum dysgenesis and ventriculomegaly phenotypes. Three adducin genes (ADD1, ADD2, and ADD3) encode cytoskeleton proteins that are critical for osmotic rigidity and cell shape. ADD1, ADD2, and ADD3 form heterodimers (ADD1/ADD2, ADD1/ADD3), which further form heterotetramers. Adducins interconnect spectrin and actin filaments to form polygonal scaffolds beneath the cell membranes and form ring-like structures in neuronal axons. Adducins regulate mouse neural development, but their function in the human brain is unknown.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4775 PROSER1 Chirag Patel gene: PROSER1 was added
gene: PROSER1 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: PROSER1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PROSER1 were set to PMID: 35229282
Phenotypes for gene: PROSER1 were set to Developmental delay, hypotonia, seizures, failure-to-thrive, strabismus, drooling, recurrent otitis media, hearing impairment, and genitourinary malformations, no OMIM #
Review for gene: PROSER1 was set to RED
Added comment: 4 children from 3 related families with developmental delay, hypotonia, seizures, failure-to-thrive, strabismus, drooling, recurrent otitis media, hearing impairment, genitourinary malformations, and common facial features (arched eyebrows, prominent eyes, broad nasal bridge, low-hanging columella, open mouth, thick lower lip, protruding tongue, large low-set ears, and parietal bossing). WES revealed a homozygous frame-shift variant (p.Thr612Glnfs*22) in PROSER1. This encodes the proline and serine rich protein 1, part of the histone methyltransferases KMT2C/KMT2D complexes. PROSER1 stabilizes TET2, a member of the TET family of DNA demethylases which is involved in recruiting the enhancer-associated KMT2C/KMT2D complexes and mediating DNA demethylation, activating gene expression. Therefore, PROSER1 may play vital and potentially general roles in gene regulation. No functional assays and 3 related families.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4774 MTOR Zornitza Stark Marked gene: MTOR as ready
Intellectual disability syndromic and non-syndromic v0.4774 MTOR Zornitza Stark Gene: mtor has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4774 MTOR Zornitza Stark Phenotypes for gene: MTOR were changed from to Smith-Kingsmore syndrome, MIM# 616638; Focal cortical dysplasia, type II, somatic, MIM# 607341; Overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes, MONDO:0100283
Intellectual disability syndromic and non-syndromic v0.4773 MTOR Zornitza Stark Publications for gene: MTOR were set to
Intellectual disability syndromic and non-syndromic v0.4772 MTOR Zornitza Stark Mode of pathogenicity for gene: MTOR was changed from to Other
Intellectual disability syndromic and non-syndromic v0.4771 MTOR Zornitza Stark Mode of inheritance for gene: MTOR was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.4770 MTOR Zornitza Stark reviewed gene: MTOR: Rating: GREEN; Mode of pathogenicity: Other; Publications: 28892148, 25878179, 26018084; Phenotypes: Smith-Kingsmore syndrome, MIM# 616638, Focal cortical dysplasia, type II, somatic, MIM# 607341, Overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes, MONDO:0100283; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.4770 WASF1 Zornitza Stark Phenotypes for gene: WASF1 were changed from to Neurodevelopmental disorder with absent language and variable seizures , MIM#618707
Intellectual disability syndromic and non-syndromic v0.4769 WASF1 Zornitza Stark Publications for gene: WASF1 were set to PMID: 29961568
Intellectual disability syndromic and non-syndromic v0.4768 WASF1 Zornitza Stark reviewed gene: WASF1: Rating: GREEN; Mode of pathogenicity: None; Publications: 29961568, 34845217, 34478686, 34356165; Phenotypes: Neurodevelopmental disorder with absent language and variable seizures , MIM#618707; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.4768 FTO Bryony Thompson Publications for gene: FTO were set to 19559399; 26378117
Intellectual disability syndromic and non-syndromic v0.4767 FTO Bryony Thompson Classified gene: FTO as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4767 FTO Bryony Thompson Gene: fto has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4766 FTO Bryony Thompson reviewed gene: FTO: Rating: GREEN; Mode of pathogenicity: None; Publications: 19559399, 26378117, 26697951, 26378117, 26740239; Phenotypes: Growth retardation, developmental delay, facial dysmorphism MIM#612938; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4766 RHEB Zornitza Stark Phenotypes for gene: RHEB were changed from Intellectual disability; Macrocephaly; Focal cortical dysplasia to Neurodevelopmental disorder MONDO:0700092, RHEB-related; Intellectual disability; Macrocephaly; Focal cortical dysplasia
Intellectual disability syndromic and non-syndromic v0.4765 RHEB Zornitza Stark edited their review of gene: RHEB: Changed phenotypes: Neurodevelopmental disorder MONDO:0700092, RHEB-related, Intellectual disability, Macrocephaly, Focal cortical dysplasia
Intellectual disability syndromic and non-syndromic v0.4765 RBM28 Zornitza Stark Publications for gene: RBM28 were set to 18439547
Intellectual disability syndromic and non-syndromic v0.4764 RBM28 Zornitza Stark Classified gene: RBM28 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.4764 RBM28 Zornitza Stark Gene: rbm28 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.4763 RBM28 Zornitza Stark edited their review of gene: RBM28: Added comment: PMID 33941690: second family reported, yeast functional studies.; Changed rating: AMBER; Changed publications: 18439547, 33941690
Intellectual disability syndromic and non-syndromic v0.4763 SLC1A1 Zornitza Stark changed review comment from: ID is part of the phenotype of this metabolic disorder.; to: ID is part of the phenotype of this metabolic disorder. However, only two families reported and rated as LIMITED by ClinGen.
Intellectual disability syndromic and non-syndromic v0.4763 SLC1A1 Zornitza Stark edited their review of gene: SLC1A1: Changed rating: AMBER; Changed publications: 21123949
Intellectual disability syndromic and non-syndromic v0.4763 GTF3C3 Zornitza Stark Phenotypes for gene: GTF3C3 were changed from Global developmental delay; Intellectual disability; Seizures to Neurodevelopmental disorder MONDO:0700092, GTF3C3-related
Intellectual disability syndromic and non-syndromic v0.4762 GTF3C3 Zornitza Stark edited their review of gene: GTF3C3: Changed phenotypes: Neurodevelopmental disorder MONDO:0700092, GTF3C3-related
Intellectual disability syndromic and non-syndromic v0.4762 DEPDC5 Zornitza Stark Marked gene: DEPDC5 as ready
Intellectual disability syndromic and non-syndromic v0.4762 DEPDC5 Zornitza Stark Gene: depdc5 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4762 DEPDC5 Zornitza Stark Phenotypes for gene: DEPDC5 were changed from to Epilepsy, familial focal, with variable foci 1, MIM#604364
Intellectual disability syndromic and non-syndromic v0.4761 DEPDC5 Zornitza Stark Publications for gene: DEPDC5 were set to
Intellectual disability syndromic and non-syndromic v0.4760 DEPDC5 Zornitza Stark Mode of inheritance for gene: DEPDC5 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.4759 DEPDC5 Zornitza Stark reviewed gene: DEPDC5: Rating: GREEN; Mode of pathogenicity: None; Publications: 31444548, 23542697, 23542701; Phenotypes: Epilepsy, familial focal, with variable foci 1, MIM#604364; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.4759 DCHS1 Zornitza Stark Marked gene: DCHS1 as ready
Intellectual disability syndromic and non-syndromic v0.4759 DCHS1 Zornitza Stark Gene: dchs1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4759 DCHS1 Zornitza Stark Phenotypes for gene: DCHS1 were changed from to Van Maldergem syndrome 1, MIM# 601390
Intellectual disability syndromic and non-syndromic v0.4758 DCHS1 Zornitza Stark Publications for gene: DCHS1 were set to
Intellectual disability syndromic and non-syndromic v0.4757 DCHS1 Zornitza Stark Mode of inheritance for gene: DCHS1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4756 DCHS1 Zornitza Stark reviewed gene: DCHS1: Rating: GREEN; Mode of pathogenicity: None; Publications: 27262615, 22473091, 24056717, 29046692; Phenotypes: Van Maldergem syndrome 1, MIM# 601390; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4756 ACTL6B Zornitza Stark Mode of inheritance for gene: ACTL6B was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4755 ACTL6B Zornitza Stark edited their review of gene: ACTL6B: Changed phenotypes: Epileptic encephalopathy, early infantile, 76, MIM# 618468, Intellectual developmental disorder with severe speech and ambulation defects, MIM# 618470; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4755 MAPKAPK5 Zornitza Stark Marked gene: MAPKAPK5 as ready
Intellectual disability syndromic and non-syndromic v0.4755 MAPKAPK5 Zornitza Stark Gene: mapkapk5 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4755 MAPKAPK5 Zornitza Stark Phenotypes for gene: MAPKAPK5 were changed from Developmental delay, variable brain anomalies, congenital heart defects, dysmorphic to Neurocardiofaciodigital syndrome, MIM# 619869
Intellectual disability syndromic and non-syndromic v0.4754 MAPKAPK5 Zornitza Stark reviewed gene: MAPKAPK5: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurocardiofaciodigital syndrome, MIM# 619869; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4754 DCAF17 Zornitza Stark Marked gene: DCAF17 as ready
Intellectual disability syndromic and non-syndromic v0.4754 DCAF17 Zornitza Stark Gene: dcaf17 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4754 DCAF17 Zornitza Stark Phenotypes for gene: DCAF17 were changed from to Woodhouse-Sakati syndrome, MIM# 241080
Intellectual disability syndromic and non-syndromic v0.4753 DCAF17 Zornitza Stark Publications for gene: DCAF17 were set to
Intellectual disability syndromic and non-syndromic v0.4752 DCAF17 Zornitza Stark Mode of inheritance for gene: DCAF17 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4751 DCAF17 Zornitza Stark reviewed gene: DCAF17: Rating: GREEN; Mode of pathogenicity: None; Publications: 19026396, 20507343, 35002959, 34877714, 34732557, 34590781; Phenotypes: Woodhouse-Sakati syndrome, MIM# 241080; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4751 CYC1 Ain Roesley Phenotypes for gene: CYC1 were changed from Mitochondrial complex III deficiency, nuclear type 6 MIM#615453 to Mitochondrial complex III deficiency, nuclear type 6 MIM#615453
Intellectual disability syndromic and non-syndromic v0.4749 CYC1 Ain Roesley Phenotypes for gene: CYC1 were changed from Mitochondrial complex III deficiency, nuclear type 6 MIM#615453 to Mitochondrial complex III deficiency, nuclear type 6 MIM#615453
Intellectual disability syndromic and non-syndromic v0.4750 CYC1 Ain Roesley Mode of inheritance for gene: CYC1 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4750 CYC1 Ain Roesley Marked gene: CYC1 as ready
Intellectual disability syndromic and non-syndromic v0.4750 CYC1 Ain Roesley Gene: cyc1 has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v0.4750 CYC1 Ain Roesley Phenotypes for gene: CYC1 were changed from to Mitochondrial complex III deficiency, nuclear type 6 MIM#615453
Intellectual disability syndromic and non-syndromic v0.4750 CYC1 Ain Roesley Publications for gene: CYC1 were set to 23910460; 34252606
Intellectual disability syndromic and non-syndromic v0.4749 CYC1 Ain Roesley Publications for gene: CYC1 were set to
Intellectual disability syndromic and non-syndromic v0.4749 CYC1 Ain Roesley Mode of inheritance for gene: CYC1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4749 CYC1 Ain Roesley Classified gene: CYC1 as Red List (low evidence)
Intellectual disability syndromic and non-syndromic v0.4749 CYC1 Ain Roesley Gene: cyc1 has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v0.4748 CYC1 Ain Roesley reviewed gene: CYC1: Rating: RED; Mode of pathogenicity: None; Publications: 23910460, 34252606; Phenotypes: Mitochondrial complex III deficiency, nuclear type 6 MIM#615453; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability syndromic and non-syndromic v0.4748 CTR9 Zornitza Stark Marked gene: CTR9 as ready
Intellectual disability syndromic and non-syndromic v0.4748 CTR9 Zornitza Stark Gene: ctr9 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4748 CTR9 Zornitza Stark Phenotypes for gene: CTR9 were changed from Neurodevelopmental disorder (MONDO:0700092), CTR9-related; Intellectual disability (MONDO:0001071); hypotonia (HP:0001252); joint hyperlaxity (HP:0001388); speech delay; coordination problems; tremor (HP:0001337); autism spectrum disorder (MONDO:0005258) to Neurodevelopmental disorder (MONDO:0700092), CTR9-related
Intellectual disability syndromic and non-syndromic v0.4747 CTR9 Zornitza Stark Classified gene: CTR9 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4747 CTR9 Zornitza Stark Gene: ctr9 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4746 DNAH14 Zornitza Stark Classified gene: DNAH14 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4746 DNAH14 Zornitza Stark Gene: dnah14 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4745 DNAH14 Zornitza Stark Phenotypes for gene: DNAH14 were changed from Neurodevelopmental disorder, DNAH14-related (MONDO#0700092) to Neurodevelopmental disorder (MONDO#0700092), DNAH14-related
Intellectual disability syndromic and non-syndromic v0.4744 DNAH14 Zornitza Stark Marked gene: DNAH14 as ready
Intellectual disability syndromic and non-syndromic v0.4744 DNAH14 Zornitza Stark Gene: dnah14 has been removed from the panel.
Intellectual disability syndromic and non-syndromic v0.4744 PRDM13 Zornitza Stark Phenotypes for gene: PRDM13 were changed from intellectual disability, MONDO:0001071, PRDM13-associated; ataxia with cerebellar hypoplasia, MONDO:0016054, PRDM13-associated; congenital hypogonadotropic hypogonadism, MONDO:0015770 to intellectual disability, MONDO:0001071, PRDM13-associated; Pontocerebellar hypoplasia (MONDO:0020135), PRDM13 related; congenital hypogonadotropic hypogonadism, MONDO:0015770
Intellectual disability syndromic and non-syndromic v0.4743 PRDM13 Zornitza Stark Publications for gene: PRDM13 were set to 34730112
Intellectual disability syndromic and non-syndromic v0.4742 PRDM13 Zornitza Stark Classified gene: PRDM13 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4742 PRDM13 Zornitza Stark Gene: prdm13 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4741 CTR9 Dean Phelan gene: CTR9 was added
gene: CTR9 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: CTR9 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CTR9 were set to PMID: 35499524
Phenotypes for gene: CTR9 were set to Neurodevelopmental disorder (MONDO:0700092), CTR9-related; Intellectual disability (MONDO:0001071); hypotonia (HP:0001252); joint hyperlaxity (HP:0001388); speech delay; coordination problems; tremor (HP:0001337); autism spectrum disorder (MONDO:0005258)
Review for gene: CTR9 was set to GREEN
Added comment: PMID: 35499524 - Thirteen individuals with variables degrees of intellectual disability, hypotonia, joint hyperlaxity, speech delay, coordination problems, tremor, autism spectrum disorder. Mild dysmorphism and cardiac anomalies were less frequent. Eleven of the variants were shown to be de novo.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4741 PRDM13 Dean Phelan reviewed gene: PRDM13: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 35390279; Phenotypes: Pontocerebellar hypoplasia (MONDO:0020135), PRDM13 related, Intellectual disability (MONDO:0001071); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4741 DNAH14 Chern Lim gene: DNAH14 was added
gene: DNAH14 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: DNAH14 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DNAH14 were set to PMID: 35438214
Phenotypes for gene: DNAH14 were set to Neurodevelopmental disorder, DNAH14-related (MONDO#0700092)
Review for gene: DNAH14 was set to GREEN
gene: DNAH14 was marked as current diagnostic
Added comment: PMID: 35438214:
- Three previously unreported patients with compound heterozygous DNAH14 variants, including one nonsense, one frameshift, and four missense variants. A spectrum of neurological and developmental phenotypes was observed, including seizures, global developmental delay, microcephaly, and hypotonia.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4741 DROSHA Zornitza Stark Marked gene: DROSHA as ready
Intellectual disability syndromic and non-syndromic v0.4741 DROSHA Zornitza Stark Gene: drosha has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.4741 DROSHA Zornitza Stark Classified gene: DROSHA as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.4741 DROSHA Zornitza Stark Gene: drosha has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.4740 DROSHA Lucy Spencer gene: DROSHA was added
gene: DROSHA was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: DROSHA was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: DROSHA were set to 35405010
Phenotypes for gene: DROSHA were set to Neurodevelopmental disorder (MONDO#0700092), DROSHA-related
Review for gene: DROSHA was set to AMBER
Added comment: 2 individuals with profound intellectual disability, epilepsy, white matter atrophy, microcephaly, and dysmorphic features, who carry damaging de novo heterozygous variants in DROSHA. Both variants are missense, absent from gnomad. Both individuals noted to have Rett-like features.

Functional studies in patient fibroblasts showed one of the missense altered the expression of mature miRNA. Fruit fly models with homozygous LOF variants die during larval stages. introduction of the missense seen in the patients was able to partially rescue this phenotype suggesting LOF is not the mechanism.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4740 KCNH5 Elena Savva Classified gene: KCNH5 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4740 KCNH5 Elena Savva Gene: kcnh5 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4740 KCNH5 Elena Savva Classified gene: KCNH5 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4740 KCNH5 Elena Savva Gene: kcnh5 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4740 KCNH5 Elena Savva Classified gene: KCNH5 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4740 KCNH5 Elena Savva Gene: kcnh5 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4739 KCNH5 Elena Savva Marked gene: KCNH5 as ready
Intellectual disability syndromic and non-syndromic v0.4739 KCNH5 Elena Savva Gene: kcnh5 has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v0.4739 DTYMK Zornitza Stark Phenotypes for gene: DTYMK were changed from Intellectual disability; microcephaly to Neurodegeneration, childhood-onset, with progressive microcephaly (MIM# 619847)
Intellectual disability syndromic and non-syndromic v0.4738 DTYMK Zornitza Stark Publications for gene: DTYMK were set to 31271740
Intellectual disability syndromic and non-syndromic v0.4737 DTYMK Zornitza Stark Classified gene: DTYMK as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4737 DTYMK Zornitza Stark Gene: dtymk has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4736 PPFIBP1 Zornitza Stark Marked gene: PPFIBP1 as ready
Intellectual disability syndromic and non-syndromic v0.4736 PPFIBP1 Zornitza Stark Gene: ppfibp1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4736 KCNH5 Elena Savva gene: KCNH5 was added
gene: KCNH5 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: KCNH5 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: KCNH5 were set to https://www.medrxiv.org/content/10.1101/2022.04.26.22274147v1
Phenotypes for gene: KCNH5 were set to Neurodevelopmental disorder MONDO#0700092, KCNH5-related
Mode of pathogenicity for gene: KCNH5 was set to Other
Review for gene: KCNH5 was set to GREEN
Added comment: Happ (2022), preprint: Screen of 893 patients with DEE found 17 patients with missense variants (16/17 de novo, 1/17 inherited). GOF mechanism suggested.
Patient phenotypes included focal/generalized seizures, Cognitive outcome for the ten individuals >5 years ranged from normal (3/10) to mild (3/10), moderate (2/10), severe (1/10) and profound (1/10) intellectual disability (ID)

p.Arg327His (7 probands), p.Arg333His (4 probands) were recurring
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4735 PPFIBP1 Zornitza Stark Classified gene: PPFIBP1 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4735 PPFIBP1 Zornitza Stark Gene: ppfibp1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4735 STX1A Ain Roesley Classified gene: STX1A as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4735 STX1A Ain Roesley Gene: stx1a has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4734 PPFIBP1 Zornitza Stark Classified gene: PPFIBP1 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4734 PPFIBP1 Zornitza Stark Gene: ppfibp1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4734 STX1A Ain Roesley Classified gene: STX1A as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4734 STX1A Ain Roesley Gene: stx1a has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4733 STX1A Ain Roesley Marked gene: STX1A as ready
Intellectual disability syndromic and non-syndromic v0.4733 STX1A Ain Roesley Gene: stx1a has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v0.4733 STX1A Ain Roesley gene: STX1A was added
gene: STX1A was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: STX1A was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Phenotypes for gene: STX1A were set to neurodevelopmental disorder MONDO#0700092, STX1A-related
Review for gene: STX1A was set to GREEN
gene: STX1A was marked as current diagnostic
Added comment: Preprint: https://www.medrxiv.org/content/10.1101/2022.04.20.22274073v1
8 individuals - 2x hom (related) and 6x hets (all de novo except 1x unknown)

7 unrelated since the 2 siblings share similar features:
7/7 ID, 7/7 motor delay, 4/7 epilepsy, 5/7 neonatal hypotonia 2/7 regression, 2/7 ASD excluding 1 with features but did not meet criteria
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4732 PPFIBP1 Zornitza Stark gene: PPFIBP1 was added
gene: PPFIBP1 was added to Intellectual disability syndromic and non-syndromic. Sources: Expert Review
Mode of inheritance for gene: PPFIBP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PPFIBP1 were set to https://www.medrxiv.org/content/10.1101/2022.04.04.22273309v1
Phenotypes for gene: PPFIBP1 were set to Neurodevelopmental disorder, MONDO:0700092, PPFIBP1-related
Review for gene: PPFIBP1 was set to GREEN
Added comment: 16 individuals from 10 unrelated families reported with moderate to profound developmental delay, often refractory early-onset epilepsy and progressive microcephaly. Drosophila model.
Sources: Expert Review
Intellectual disability syndromic and non-syndromic v0.4731 DTYMK Daniel Flanagan reviewed gene: DTYMK: Rating: GREEN; Mode of pathogenicity: None; Publications: 34918187; Phenotypes: Neurodegeneration, childhood-onset, with progressive microcephaly (MIM# 619847); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4731 CPS1 Ain Roesley Phenotypes for gene: CPS1 were changed from Carbamoylphosphate synthetase I deficiency MIM#237300 to Carbamoylphosphate synthetase I deficiency MIM#237300
Intellectual disability syndromic and non-syndromic v0.4731 CPS1 Ain Roesley Publications for gene: CPS1 were set to 8486760; 17310273; 21120950; 31268178
Intellectual disability syndromic and non-syndromic v0.4730 CPS1 Ain Roesley Publications for gene: CPS1 were set to
Intellectual disability syndromic and non-syndromic v0.4730 CPS1 Ain Roesley Phenotypes for gene: CPS1 were changed from to Carbamoylphosphate synthetase I deficiency MIM#237300
Intellectual disability syndromic and non-syndromic v0.4730 CPS1 Ain Roesley Marked gene: CPS1 as ready
Intellectual disability syndromic and non-syndromic v0.4730 CPS1 Ain Roesley Gene: cps1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4730 CPS1 Ain Roesley Mode of inheritance for gene: CPS1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4729 CPS1 Ain Roesley reviewed gene: CPS1: Rating: GREEN; Mode of pathogenicity: None; Publications: 8486760, 17310273, 21120950, 31268178; Phenotypes: Carbamoylphosphate synthetase I deficiency MIM#237300; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability syndromic and non-syndromic v0.4729 GNAI1 Zornitza Stark Phenotypes for gene: GNAI1 were changed from Intellectual disability; seizures; hypotonia to Neurodevelopmental disorder with hypotonia, impaired speech, and behavioral abnormalities, MIM# 619854
Intellectual disability syndromic and non-syndromic v0.4728 GNAI1 Zornitza Stark edited their review of gene: GNAI1: Changed phenotypes: Neurodevelopmental disorder with hypotonia, impaired speech, and behavioral abnormalities, MIM# 619854
Intellectual disability syndromic and non-syndromic v0.4728 MCCC2 Zornitza Stark Marked gene: MCCC2 as ready
Intellectual disability syndromic and non-syndromic v0.4728 MCCC2 Zornitza Stark Gene: mccc2 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.4728 MCCC2 Zornitza Stark Phenotypes for gene: MCCC2 were changed from to 3-Methylcrotonyl-CoA carboxylase 2 deficiency (MIM#210210)
Intellectual disability syndromic and non-syndromic v0.4727 MCCC2 Zornitza Stark Publications for gene: MCCC2 were set to
Intellectual disability syndromic and non-syndromic v0.4726 MCCC2 Zornitza Stark Mode of inheritance for gene: MCCC2 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4725 MCCC2 Zornitza Stark Classified gene: MCCC2 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.4725 MCCC2 Zornitza Stark Gene: mccc2 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.4724 MCCC2 Zornitza Stark reviewed gene: MCCC2: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: 3-Methylcrotonyl-CoA carboxylase 2 deficiency (MIM#210210); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4724 SIK1 Zornitza Stark Marked gene: SIK1 as ready
Intellectual disability syndromic and non-syndromic v0.4724 SIK1 Zornitza Stark Gene: sik1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4724 SIK1 Zornitza Stark Phenotypes for gene: SIK1 were changed from to Developmental and epileptic encephalopathy 30, MIM#616341; developmental and epileptic encephalopathy, MONDO#0100062
Intellectual disability syndromic and non-syndromic v0.4723 SIK1 Zornitza Stark Publications for gene: SIK1 were set to
Intellectual disability syndromic and non-syndromic v0.4722 SIK1 Zornitza Stark Mode of inheritance for gene: SIK1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.4721 SIK1 Zornitza Stark reviewed gene: SIK1: Rating: GREEN; Mode of pathogenicity: None; Publications: 25839329, 27966542, 35267137; Phenotypes: Developmental and epileptic encephalopathy 30, MIM#616341, developmental and epileptic encephalopathy, MONDO#0100062; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.4721 CHD8 Zornitza Stark Phenotypes for gene: CHD8 were changed from {Autism, susceptibility to, 18} 615032; CHD8-related neurodevelopmental syndrome to {Autism, susceptibility to, 18} 615032; Neurodevelopmental disorder, MONDO:0700092, CHD8-associated
Intellectual disability syndromic and non-syndromic v0.4720 CHD8 Zornitza Stark edited their review of gene: CHD8: Changed phenotypes: {Autism, susceptibility to, 18} 615032, Neurodevelopmental disorder, MONDO:0700092, CHD8-associated
Intellectual disability syndromic and non-syndromic v0.4720 HERC1 Zornitza Stark Marked gene: HERC1 as ready
Intellectual disability syndromic and non-syndromic v0.4720 HERC1 Zornitza Stark Gene: herc1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4720 HERC1 Zornitza Stark Phenotypes for gene: HERC1 were changed from to Macrocephaly, dysmorphic facies, and psychomotor retardation, MIM# 617011
Intellectual disability syndromic and non-syndromic v0.4719 HERC1 Zornitza Stark Publications for gene: HERC1 were set to
Intellectual disability syndromic and non-syndromic v0.4718 HERC1 Zornitza Stark Mode of inheritance for gene: HERC1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4717 HERC1 Zornitza Stark reviewed gene: HERC1: Rating: GREEN; Mode of pathogenicity: None; Publications: 28323226, 27108999, 26153217, 26138117, 20041218; Phenotypes: Macrocephaly, dysmorphic facies, and psychomotor retardation, MIM# 617011; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4717 LINS1 Alison Yeung Phenotypes for gene: LINS1 were changed from Intellectual developmental disorder, autosomal recessive 27, MIM# 614340 to Intellectual developmental disorder, autosomal recessive 27, MIM# 614340
Intellectual disability syndromic and non-syndromic v0.4716 LINS1 Alison Yeung Phenotypes for gene: LINS1 were changed from to Intellectual developmental disorder, autosomal recessive 27, MIM# 614340
Intellectual disability syndromic and non-syndromic v0.4715 LINS1 Alison Yeung Marked gene: LINS1 as ready
Intellectual disability syndromic and non-syndromic v0.4715 LINS1 Alison Yeung Gene: lins1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4715 LINS1 Alison Yeung Publications for gene: LINS1 were set to
Intellectual disability syndromic and non-syndromic v0.4714 LINS1 Alison Yeung Mode of inheritance for gene: LINS1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4713 LINS1 Alison Yeung reviewed gene: LINS1: Rating: GREEN; Mode of pathogenicity: None; Publications: 32802957, 34450347, 32499722, 31922598; Phenotypes: ntellectual developmental disorder, autosomal recessive 27, MIM# 614340; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4713 HCN1 Zornitza Stark Marked gene: HCN1 as ready
Intellectual disability syndromic and non-syndromic v0.4713 HCN1 Zornitza Stark Gene: hcn1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4713 HCN1 Zornitza Stark Phenotypes for gene: HCN1 were changed from to Developmental and epileptic encephalopathy 24, MIM# 615871; Generalized epilepsy with febrile seizures plus, type 10, MIM# 618482
Intellectual disability syndromic and non-syndromic v0.4712 HCN1 Zornitza Stark Publications for gene: HCN1 were set to
Intellectual disability syndromic and non-syndromic v0.4711 HCN1 Zornitza Stark Mode of inheritance for gene: HCN1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.4710 HCN1 Zornitza Stark reviewed gene: HCN1: Rating: GREEN; Mode of pathogenicity: None; Publications: 24747641, 30351409, 30351409; Phenotypes: Developmental and epileptic encephalopathy 24, MIM# 615871, Generalized epilepsy with febrile seizures plus, type 10, MIM# 618482; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.4710 MCCC2 Teresa Zhao reviewed gene: MCCC2: Rating: AMBER; Mode of pathogenicity: None; Publications: 34899149; Phenotypes: 3-Methylcrotonyl-CoA carboxylase 2 deficiency (MIM#210210); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4710 AP1S2 Zornitza Stark Marked gene: AP1S2 as ready
Intellectual disability syndromic and non-syndromic v0.4710 AP1S2 Zornitza Stark Gene: ap1s2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4710 AP1S2 Zornitza Stark Phenotypes for gene: AP1S2 were changed from to Pettigrew syndrome, MIM# 304340
Intellectual disability syndromic and non-syndromic v0.4709 AP1S2 Zornitza Stark Publications for gene: AP1S2 were set to
Intellectual disability syndromic and non-syndromic v0.4708 AP1S2 Zornitza Stark Mode of inheritance for gene: AP1S2 was changed from Unknown to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability syndromic and non-syndromic v0.4707 AP1S2 Zornitza Stark reviewed gene: AP1S2: Rating: GREEN; Mode of pathogenicity: None; Publications: 17186471, 17617514, 19377476, 30714330, 23756445; Phenotypes: Pettigrew syndrome, MIM# 304340; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability syndromic and non-syndromic v0.4707 ENTPD1 Zornitza Stark Marked gene: ENTPD1 as ready
Intellectual disability syndromic and non-syndromic v0.4707 ENTPD1 Zornitza Stark Gene: entpd1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4707 ENTPD1 Zornitza Stark Classified gene: ENTPD1 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4707 ENTPD1 Zornitza Stark Gene: entpd1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4706 ENTPD1 Zornitza Stark gene: ENTPD1 was added
gene: ENTPD1 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: ENTPD1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ENTPD1 were set to 35471564
Phenotypes for gene: ENTPD1 were set to Spastic paraplegia 64, autosomal recessive, MIM# 615683
Review for gene: ENTPD1 was set to GREEN
Added comment: 27 individuals from 17 families published, expanding the phenotype to a complex neurodevelopmental disorder characterised by ID, white matter abnormalities and spastic paraplegia.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4705 NRCAM Zornitza Stark Phenotypes for gene: NRCAM were changed from Neurodevelopmental disorder with neuromuscular and skeletal abnormalities, MIM# 619833 to Neurodevelopmental disorder with neuromuscular and skeletal abnormalities, MIM# 619833
Intellectual disability syndromic and non-syndromic v0.4705 NRCAM Zornitza Stark Phenotypes for gene: NRCAM were changed from neurodevelopmental disorder, MONDO:0700092 to Neurodevelopmental disorder with neuromuscular and skeletal abnormalities, MIM# 619833
Intellectual disability syndromic and non-syndromic v0.4704 NRCAM Zornitza Stark reviewed gene: NRCAM: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with neuromuscular and skeletal abnormalities, MIM# 619833; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4704 CDC42BPB Zornitza Stark Phenotypes for gene: CDC42BPB were changed from Central hypotonia; Global developmental delay; Intellectual disability; Seizures; Autistic behavior; Behavioral abnormality to Chilton-Okur-Chung neurodevelopmental syndrome, MIM# 619841
Intellectual disability syndromic and non-syndromic v0.4703 CDC42BPB Zornitza Stark reviewed gene: CDC42BPB: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Chilton-Okur-Chung neurodevelopmental syndrome, MIM# 619841; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.4703 CNNM2 Ain Roesley Marked gene: CNNM2 as ready
Intellectual disability syndromic and non-syndromic v0.4703 CNNM2 Ain Roesley Gene: cnnm2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4703 CNNM2 Ain Roesley Publications for gene: CNNM2 were set to
Intellectual disability syndromic and non-syndromic v0.4703 CNNM2 Ain Roesley Mode of inheritance for gene: CNNM2 was changed from Unknown to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4703 CNNM2 Ain Roesley Phenotypes for gene: CNNM2 were changed from to Hypomagnesemia 6, renal MIM#613882; Hypomagnesemia, seizures, and mental retardation MIM#616418
Intellectual disability syndromic and non-syndromic v0.4702 CNNM2 Ain Roesley reviewed gene: CNNM2: Rating: GREEN; Mode of pathogenicity: None; Publications: 34604137, 35170241; Phenotypes: Hypomagnesemia 6, renal MIM#613882, Hypomagnesemia, seizures, and mental retardation MIM#616418; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability syndromic and non-syndromic v0.4702 PIGC Zornitza Stark Publications for gene: PIGC were set to 27694521
Intellectual disability syndromic and non-syndromic v0.4701 PIGC Zornitza Stark edited their review of gene: PIGC: Added comment: Third family reported, pair of siblings, DD/seizures.; Changed publications: 27694521, 32707268
Intellectual disability syndromic and non-syndromic v0.4701 PIGW Zornitza Stark Marked gene: PIGW as ready
Intellectual disability syndromic and non-syndromic v0.4701 PIGW Zornitza Stark Gene: pigw has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4701 PIGW Zornitza Stark Phenotypes for gene: PIGW were changed from to Glycosylphosphatidylinositol biosynthesis defect 11, MIM# 616025
Intellectual disability syndromic and non-syndromic v0.4700 PIGW Zornitza Stark Publications for gene: PIGW were set to
Intellectual disability syndromic and non-syndromic v0.4699 PIGW Zornitza Stark Mode of inheritance for gene: PIGW was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4698 PIGW Zornitza Stark reviewed gene: PIGW: Rating: GREEN; Mode of pathogenicity: None; Publications: 24367057, 27626616, 30813920, 32198969; Phenotypes: Glycosylphosphatidylinositol biosynthesis defect 11, MIM# 616025; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4698 CIT Zornitza Stark Marked gene: CIT as ready
Intellectual disability syndromic and non-syndromic v0.4698 CIT Zornitza Stark Gene: cit has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4698 CIT Zornitza Stark Phenotypes for gene: CIT were changed from to Microcephaly 17, primary, autosomal recessive (MIM#617090)
Intellectual disability syndromic and non-syndromic v0.4697 CIT Zornitza Stark Publications for gene: CIT were set to
Intellectual disability syndromic and non-syndromic v0.4696 CIT Zornitza Stark Mode of inheritance for gene: CIT was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4695 CIT Zornitza Stark reviewed gene: CIT: Rating: GREEN; Mode of pathogenicity: None; Publications: 27453578, 27503289, 27453579; Phenotypes: Microcephaly 17, primary, autosomal recessive (MIM#617090); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4695 CIC Ain Roesley Marked gene: CIC as ready
Intellectual disability syndromic and non-syndromic v0.4695 CIC Ain Roesley Gene: cic has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4695 CIC Ain Roesley Phenotypes for gene: CIC were changed from to Intellectual developmental disorder, autosomal dominant 45 MIM#617600
Intellectual disability syndromic and non-syndromic v0.4695 CIC Ain Roesley Publications for gene: CIC were set to
Intellectual disability syndromic and non-syndromic v0.4695 CIC Ain Roesley Mode of inheritance for gene: CIC was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.4694 CIC Ain Roesley reviewed gene: CIC: Rating: GREEN; Mode of pathogenicity: None; Publications: 28288114, 21076407; Phenotypes: Intellectual developmental disorder, autosomal dominant 45 MIM#617600; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Intellectual disability syndromic and non-syndromic v0.4694 PDE4D Zornitza Stark Marked gene: PDE4D as ready
Intellectual disability syndromic and non-syndromic v0.4694 PDE4D Zornitza Stark Gene: pde4d has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4694 PDE4D Zornitza Stark Phenotypes for gene: PDE4D were changed from to Acrodysostosis 2, with or without hormone resistance, MIM# 614613
Intellectual disability syndromic and non-syndromic v0.4693 PDE4D Zornitza Stark Publications for gene: PDE4D were set to
Intellectual disability syndromic and non-syndromic v0.4692 PDE4D Zornitza Stark Mode of inheritance for gene: PDE4D was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.4691 PDE4D Zornitza Stark reviewed gene: PDE4D: Rating: GREEN; Mode of pathogenicity: None; Publications: 22464250, 22464252, 23033274, 24203977; Phenotypes: Acrodysostosis 2, with or without hormone resistance, MIM# 614613; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.4691 ATP11A Zornitza Stark Phenotypes for gene: ATP11A were changed from Neurological disorder to Leukodystrophy, hypomyelinating, 24 , MIM# 619851
Intellectual disability syndromic and non-syndromic v0.4690 ATP11A Zornitza Stark reviewed gene: ATP11A: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Leukodystrophy, hypomyelinating, 24 , MIM# 619851; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.4690 PIDD1 Zornitza Stark Phenotypes for gene: PIDD1 were changed from Global developmental delay; Intellectual disability; Seizures; Autism; Behavioral abnormality; Psychosis; Pachygyria; Lissencephaly; Abnormality of the corpus callosum to Intellectual developmental disorder, autosomal recessive 75, with neuropsychiatric features and variant lissencephaly, MIM# 619827
Intellectual disability syndromic and non-syndromic v0.4689 PIDD1 Zornitza Stark reviewed gene: PIDD1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Intellectual developmental disorder, autosomal recessive 75, with neuropsychiatric features and variant lissencephaly, MIM# 619827; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4689 CLPB Zornitza Stark Phenotypes for gene: CLPB were changed from 3-methylglutaconic aciduria, type VII, with cataracts, neurologic involvement and neutropaenia, MIM# 616271 to 3-methylglutaconic aciduria, type VII, with cataracts, neurologic involvement and neutropaenia, MIM# 616271; 3-methylglutaconic aciduria, type VIIA, autosomal dominant, MIM# 619835
Intellectual disability syndromic and non-syndromic v0.4688 CLPB Zornitza Stark edited their review of gene: CLPB: Changed phenotypes: 3-methylglutaconic aciduria, type VII, with cataracts, neurologic involvement and neutropaenia, MIM# 616271, 3-methylglutaconic aciduria, type VIIA, autosomal dominant, MIM# 619835
Intellectual disability syndromic and non-syndromic v0.4688 GLRA2 Zornitza Stark Marked gene: GLRA2 as ready
Intellectual disability syndromic and non-syndromic v0.4688 GLRA2 Zornitza Stark Gene: glra2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4688 GLRA2 Zornitza Stark Classified gene: GLRA2 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4688 GLRA2 Zornitza Stark Gene: glra2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4687 GLRA2 Zornitza Stark gene: GLRA2 was added
gene: GLRA2 was added to Intellectual disability syndromic and non-syndromic. Sources: Expert list
Mode of inheritance for gene: GLRA2 was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Publications for gene: GLRA2 were set to 26370147; 20479760; 35294868
Phenotypes for gene: GLRA2 were set to Intellectual developmental disorder, X-linked, syndromic, Pilorge type, MIM# 301076
Review for gene: GLRA2 was set to GREEN
Added comment: More than 10 unrelated families reported. Both males and females affected, though some mothers are asymptomatic or mild. Zebrafish model.
Sources: Expert list
Intellectual disability syndromic and non-syndromic v0.4686 FASTKD2 Bryony Thompson Publications for gene: FASTKD2 were set to 18771761; 28499982
Intellectual disability syndromic and non-syndromic v0.4685 FASTKD2 Bryony Thompson Classified gene: FASTKD2 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4685 FASTKD2 Bryony Thompson Gene: fastkd2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4684 FASTKD2 Bryony Thompson reviewed gene: FASTKD2: Rating: GREEN; Mode of pathogenicity: None; Publications: 18771761, 28499982, 31944455, 34234304; Phenotypes: FASTKD2-related infantile mitochondrial encephalomyopathy MONDO:0015632; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4684 PDE4D Krithika Murali reviewed gene: PDE4D: Rating: GREEN; Mode of pathogenicity: None; Publications: 24203977, 22464250; Phenotypes: Acrodysostosis 2, with or without hormone resistance - MIM#614613; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.4684 PPP1R15B Zornitza Stark Marked gene: PPP1R15B as ready
Intellectual disability syndromic and non-syndromic v0.4684 PPP1R15B Zornitza Stark Gene: ppp1r15b has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.4684 PPP1R15B Zornitza Stark Phenotypes for gene: PPP1R15B were changed from to Microcephaly, short stature, and impaired glucose metabolism 2, MIM# 616817
Intellectual disability syndromic and non-syndromic v0.4683 PPP1R15B Zornitza Stark Publications for gene: PPP1R15B were set to
Intellectual disability syndromic and non-syndromic v0.4682 PPP1R15B Zornitza Stark Mode of inheritance for gene: PPP1R15B was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4682 PPP1R15B Zornitza Stark Mode of inheritance for gene: PPP1R15B was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4681 PPP1R15B Zornitza Stark Classified gene: PPP1R15B as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.4681 PPP1R15B Zornitza Stark Gene: ppp1r15b has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.4680 PPP1R15B Zornitza Stark reviewed gene: PPP1R15B: Rating: AMBER; Mode of pathogenicity: None; Publications: 26159176, 26307080, 27640355; Phenotypes: Microcephaly, short stature, and impaired glucose metabolism 2, MIM# 616817; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4680 PRMT7 Zornitza Stark Marked gene: PRMT7 as ready
Intellectual disability syndromic and non-syndromic v0.4680 PRMT7 Zornitza Stark Gene: prmt7 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4680 PRMT7 Zornitza Stark Phenotypes for gene: PRMT7 were changed from to Short stature, brachydactyly, intellectual developmental disability, and seizures, MIM# 617157
Intellectual disability syndromic and non-syndromic v0.4679 PRMT7 Zornitza Stark Publications for gene: PRMT7 were set to
Intellectual disability syndromic and non-syndromic v0.4678 PRMT7 Zornitza Stark Mode of inheritance for gene: PRMT7 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4677 PRMT7 Zornitza Stark reviewed gene: PRMT7: Rating: GREEN; Mode of pathogenicity: None; Publications: 26437029, 27718516, 30513135; Phenotypes: Short stature, brachydactyly, intellectual developmental disability, and seizures, MIM# 617157; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4677 PRSS12 Zornitza Stark Marked gene: PRSS12 as ready
Intellectual disability syndromic and non-syndromic v0.4677 PRSS12 Zornitza Stark Gene: prss12 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.4677 PRSS12 Zornitza Stark Phenotypes for gene: PRSS12 were changed from to Intellectual disability, PRSS12 related MIM#249500
Intellectual disability syndromic and non-syndromic v0.4676 PRSS12 Zornitza Stark Publications for gene: PRSS12 were set to
Intellectual disability syndromic and non-syndromic v0.4675 PRSS12 Zornitza Stark Mode of inheritance for gene: PRSS12 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4674 PRSS12 Zornitza Stark Classified gene: PRSS12 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.4674 PRSS12 Zornitza Stark Gene: prss12 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.4673 PRSS12 Zornitza Stark reviewed gene: PRSS12: Rating: AMBER; Mode of pathogenicity: None; Publications: 12459588; Phenotypes: Intellectual disability, PRSS12 related MIM#249500; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4673 PSMD12 Zornitza Stark Marked gene: PSMD12 as ready
Intellectual disability syndromic and non-syndromic v0.4673 PSMD12 Zornitza Stark Gene: psmd12 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4673 PSMD12 Zornitza Stark Phenotypes for gene: PSMD12 were changed from to Stankiewicz-Isidor syndrome, MIM# 617516
Intellectual disability syndromic and non-syndromic v0.4672 PSMD12 Zornitza Stark Publications for gene: PSMD12 were set to
Intellectual disability syndromic and non-syndromic v0.4671 PSMD12 Zornitza Stark Mode of inheritance for gene: PSMD12 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.4670 PSMD12 Zornitza Stark reviewed gene: PSMD12: Rating: GREEN; Mode of pathogenicity: None; Publications: 28132691, 34906456; Phenotypes: Stankiewicz-Isidor syndrome, MIM# 617516; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.4670 PYCR2 Zornitza Stark Marked gene: PYCR2 as ready
Intellectual disability syndromic and non-syndromic v0.4670 PYCR2 Zornitza Stark Gene: pycr2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4670 PYCR2 Zornitza Stark Phenotypes for gene: PYCR2 were changed from to Leukodystrophy, hypomyelinating, 10, MIM# 616420
Intellectual disability syndromic and non-syndromic v0.4669 PYCR2 Zornitza Stark Publications for gene: PYCR2 were set to
Intellectual disability syndromic and non-syndromic v0.4668 PYCR2 Zornitza Stark Mode of inheritance for gene: PYCR2 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4667 PYCR2 Zornitza Stark reviewed gene: PYCR2: Rating: GREEN; Mode of pathogenicity: None; Publications: 25865492, 27130255; Phenotypes: Leukodystrophy, hypomyelinating, 10, MIM# 616420; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4667 SET Zornitza Stark Marked gene: SET as ready
Intellectual disability syndromic and non-syndromic v0.4667 SET Zornitza Stark Gene: set has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4667 SET Zornitza Stark Phenotypes for gene: SET were changed from to Intellectual developmental disorder, autosomal dominant 58, MIM#618106; intellectual disability, autosomal dominant 58, MONDO:0020847
Intellectual disability syndromic and non-syndromic v0.4666 SET Zornitza Stark Publications for gene: SET were set to
Intellectual disability syndromic and non-syndromic v0.4665 SET Zornitza Stark Mode of inheritance for gene: SET was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.4664 SET Zornitza Stark reviewed gene: SET: Rating: GREEN; Mode of pathogenicity: None; Publications: 29688601, 29907757, 25356899; Phenotypes: Intellectual developmental disorder, autosomal dominant 58, MIM#618106, intellectual disability, autosomal dominant 58, MONDO:0020847; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.4664 PIGA Zornitza Stark Phenotypes for gene: PIGA were changed from Multiple congenital anomalies-hypotonia-seizures syndrome 2, MIM#300868 to Multiple congenital anomalies-hypotonia-seizures syndrome 2, MIM# 300868, MONDO:0010466; Neurodevelopmental disorder with epilepsy and haemochromatosis, MIM# 301072
Intellectual disability syndromic and non-syndromic v0.4663 PIGA Zornitza Stark Publications for gene: PIGA were set to 24706016; 24259184; 29159939
Intellectual disability syndromic and non-syndromic v0.4662 PIGA Zornitza Stark edited their review of gene: PIGA: Added comment: PMID 34875027: variants in PIGA causing a neurodevelopment disorder and a juvenile form of hereditary hemochromatosis reported in > three unrelated patients. All patients had increased serum iron, ferritin and transferrin saturation levels, high ALP and low hepcidin. All patients had generalised seizures and intellectual disability. A subpopulation of patient blood cells showed a slight reduction of GPI-anchored proteins, suggesting that the mutations were hypomorphic and retained some residual activity. CRISPR/Cas12a-mediated knockdown of PIGA in Hep3B liver cells eliminated the cell surface expression of GPI-anchored proteins CD59 and hemojuvelin (HJV; 608374), as well as caused decreased expression of hepcidin (606464) compared to controls. These hypomorphic alleles could explain the milder neurologic phenotype, which allowed for sufficiently long survival for the iron overload phenotype to manifest.; Changed publications: 22305531, 24357517, 24706016, 26545172, 33333793, 32694024, 34875027; Changed phenotypes: Multiple congenital anomalies-hypotonia-seizures syndrome 2, MIM# 300868, MONDO:0010466, Neurodevelopmental disorder with epilepsy and haemochromatosis, MIM# 301072
Intellectual disability syndromic and non-syndromic v0.4662 ATP2B1 Zornitza Stark Marked gene: ATP2B1 as ready
Intellectual disability syndromic and non-syndromic v0.4662 ATP2B1 Zornitza Stark Gene: atp2b1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4662 ATP2B1 Zornitza Stark Classified gene: ATP2B1 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4662 ATP2B1 Zornitza Stark Gene: atp2b1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4661 CACNA2D1 Alison Yeung Marked gene: CACNA2D1 as ready
Intellectual disability syndromic and non-syndromic v0.4661 CACNA2D1 Alison Yeung Gene: cacna2d1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4661 CACNA2D1 Alison Yeung Phenotypes for gene: CACNA2D1 were changed from developmental and epileptic encephalopathy disorder MONDO:0100062 CACNA2D1-related to Developmental and epileptic encephalopathy disorder MONDO:0100062 CACNA2D1-related
Intellectual disability syndromic and non-syndromic v0.4660 CACNA2D1 Alison Yeung Classified gene: CACNA2D1 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4660 CACNA2D1 Alison Yeung Gene: cacna2d1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4659 TRAPPC10 Zornitza Stark Marked gene: TRAPPC10 as ready
Intellectual disability syndromic and non-syndromic v0.4659 TRAPPC10 Zornitza Stark Gene: trappc10 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4659 TRAPPC10 Zornitza Stark Classified gene: TRAPPC10 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4659 TRAPPC10 Zornitza Stark Gene: trappc10 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4658 CACNA2D1 Michelle Torres gene: CACNA2D1 was added
gene: CACNA2D1 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: CACNA2D1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CACNA2D1 were set to 35293990
Phenotypes for gene: CACNA2D1 were set to developmental and epileptic encephalopathy disorder MONDO:0100062 CACNA2D1-related
Review for gene: CACNA2D1 was set to GREEN
Added comment: PMID 35293990: WES of 2x unrelated individuals with early-onset developmental epileptic encephalopathy, microcephaly, severe hypotonia, absent speech, spasticity, choreiform movements, orofacial dyskinesia, and 2 cortical visual impairment, corpus callosum hypoplasia and progressive volume loss. Patient 2 also had a tiny patent foramen ovale.

Patient 1 is homozygous for p.(Ser275Asnfs*13). mRNA and protein expression were reduced to ~10% of WT in fibroblasts

Patient 2 is cHet for p.(Leu9Alafs*5) and p.(Gly209Asp). mRNA expression in patients fibroblasts was similar to controls, and protein expression reduced to 31-38%. Functional of the p.(Gly209Asp) showed impaired localization and mutagenesis showed complete loss of channel function.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4658 ATP2B1 Daniel Flanagan changed review comment from: 12 unrelated individuals with variants in ATP2B1 and an overlapping phenotype of mild to moderate global development delay. Additional common symptoms include autism (5), seizures (6), and distal limb abnormalities (4). 9 variants proven to be de novo, other 3 variants had unknown inheritance. 9 missense and 3 nonsense. Supporting functional analysis for missense.
Sources: Expert list; to: 12 unrelated individuals with variants in ATP2B1 and an overlapping phenotype of mild to moderate global development delay. Additional common symptoms include autism (5), dissimilar forms of seizures (6), and distal limb abnormalities (4). 9 variants proven to be de novo, other 3 variants had unknown inheritance. 9 missense and 3 nonsense. Supporting functional analysis for missense.
Sources: Expert list
Intellectual disability syndromic and non-syndromic v0.4658 TRAPPC10 Naomi Baker gene: TRAPPC10 was added
gene: TRAPPC10 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: TRAPPC10 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TRAPPC10 were set to PMID: 35298461; 30167849
Phenotypes for gene: TRAPPC10 were set to neurodevelopmental disorder (MONDO:0700092), TRAPPC10-related
Review for gene: TRAPPC10 was set to GREEN
Added comment: PMID: 35298461 – two Pakistani families reported with homozygous variants. Family 1 has frameshift variant in 8 affected individual and family 2 has missense variant in 2 affected individuals. Patients present with microcephaly, short stature, hypotonia, severe ID and behavioural abnormalities. Seizures also reported in 4/10 individuals. Paper also reported brain abnormalities in null mouse model and other functional in transfected cell lines.

PMID: 30167849 – initial report of family 2 above.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4658 ATP2B1 Daniel Flanagan gene: ATP2B1 was added
gene: ATP2B1 was added to Intellectual disability syndromic and non-syndromic. Sources: Expert list
Mode of inheritance for gene: ATP2B1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ATP2B1 were set to PMID: 35358416
Phenotypes for gene: ATP2B1 were set to Neurodevelopmental disorder, MONDO:0700092, ATP2B1-related
Review for gene: ATP2B1 was set to GREEN
Added comment: 12 unrelated individuals with variants in ATP2B1 and an overlapping phenotype of mild to moderate global development delay. Additional common symptoms include autism (5), seizures (6), and distal limb abnormalities (4). 9 variants proven to be de novo, other 3 variants had unknown inheritance. 9 missense and 3 nonsense. Supporting functional analysis for missense.
Sources: Expert list
Intellectual disability syndromic and non-syndromic v0.4658 ADAM22 Alison Yeung Phenotypes for gene: ADAM22 were changed from Epileptic encephalopathy, early infantile, 61, MIM# 617933 to Developmental and epileptic encephalopathy 61 (MIM#617933)
Intellectual disability syndromic and non-syndromic v0.4657 ADAM22 Alison Yeung Classified gene: ADAM22 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4657 ADAM22 Alison Yeung Gene: adam22 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4656 ADAM22 Lucy Spencer reviewed gene: ADAM22: Rating: GREEN; Mode of pathogenicity: None; Publications: 35373813; Phenotypes: Developmental and epileptic encephalopathy 61 (MIM#617933); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4656 AHSG Elena Savva gene: AHSG was added
gene: AHSG was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: AHSG was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AHSG were set to PMID: 28054173; 9395485; 31288248; 17389622
Phenotypes for gene: AHSG were set to ?Alopecia-intellectual disability syndrome 1 MIM#203650; infantile cortical hyperostosis
Review for gene: AHSG was set to RED
Added comment: PMID: 28054173 - 7 relatives within a large consanguinous fam w/ alopecia and ID, and a hom missense (p.Arg317His). Modelling predicts this variant to be a phosphorylation site, functional studies show a difference in protein size. Unclear biological significance.
Alt change with stronger GS (p.(Arg317Cys)) is a common poly with 19 homozygotes in gnomAD.

No hom PTCs in gnomAD

PMID: 9395485 - K/O mouse model shows no gross anatomical abnormalities, were fertile and "healthy". No mentioned of ID, alopecia
PMID: 17389622 - K/O mouse model on the calcification resistant genetic background C57BL/6, shows uraemia and phosphate challenge. No mentioned of ID, alopecia

PMID: 31288248 - 1 hom infant (p.K2*, within 5' NMD escape region) with infantile cortical hyperostosis, loss of enzyme in patient serum shown by ELISA. No mentioned of ID, alopecia
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4655 VPS16 Ain Roesley Classified gene: VPS16 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4655 VPS16 Ain Roesley Gene: vps16 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4655 VPS16 Ain Roesley Classified gene: VPS16 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4655 VPS16 Ain Roesley Gene: vps16 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4654 VPS16 Ain Roesley Marked gene: VPS16 as ready
Intellectual disability syndromic and non-syndromic v0.4654 VPS16 Ain Roesley Gene: vps16 has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v0.4654 VPS16 Ain Roesley gene: VPS16 was added
gene: VPS16 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: VPS16 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: VPS16 were set to 33938619; 34013567; 34901436
Phenotypes for gene: VPS16 were set to mucopolysaccharidosis-like disorder, VPS16-related MONDO#0100365
Review for gene: VPS16 was set to GREEN
gene: VPS16 was marked as current diagnostic
Added comment: for AR MPS - developmental delay reported
3 unrelated families - 2x hom c.2272‐18C>A and 1x hom p.Trp180Cys

RNA and functional studies done on the splice variant

also associated with AD dystonia
PMID:34901436 suggests dystonia is transcript specific
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4653 SOX5 Zornitza Stark Tag SV/CNV tag was added to gene: SOX5.
Intellectual disability syndromic and non-syndromic v0.4653 SPATA5 Zornitza Stark Phenotypes for gene: SPATA5 were changed from Epilepsy, hearing loss, and mental retardation syndrome MIM#616577 to Neurodevelopmental disorder with hearing loss, seizures, and brain abnormalities MIM#616577
Intellectual disability syndromic and non-syndromic v0.4652 SPATA5 Zornitza Stark edited their review of gene: SPATA5: Changed phenotypes: Neurodevelopmental disorder with hearing loss, seizures, and brain abnormalities 616577
Intellectual disability syndromic and non-syndromic v0.4652 TSPAN7 Zornitza Stark Marked gene: TSPAN7 as ready
Intellectual disability syndromic and non-syndromic v0.4652 TSPAN7 Zornitza Stark Gene: tspan7 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.4652 TSPAN7 Zornitza Stark Phenotypes for gene: TSPAN7 were changed from to Intellectual developmental disorder, X-linked 58, MIM #300210, MONDO:0010266
Intellectual disability syndromic and non-syndromic v0.4651 TSPAN7 Zornitza Stark Publications for gene: TSPAN7 were set to
Intellectual disability syndromic and non-syndromic v0.4650 TSPAN7 Zornitza Stark Mode of inheritance for gene: TSPAN7 was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability syndromic and non-syndromic v0.4649 TSPAN7 Zornitza Stark Mode of inheritance for gene: TSPAN7 was changed from Unknown to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability syndromic and non-syndromic v0.4648 TSPAN7 Zornitza Stark Classified gene: TSPAN7 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.4648 TSPAN7 Zornitza Stark Gene: tspan7 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.4647 TSPAN7 Zornitza Stark reviewed gene: TSPAN7: Rating: AMBER; Mode of pathogenicity: None; Publications: 10449641, 12070254, 10655063, 25081361; Phenotypes: Intellectual developmental disorder, X-linked 58, MIM #300210, MONDO:0010266; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability syndromic and non-syndromic v0.4647 SLC6A17 Zornitza Stark Marked gene: SLC6A17 as ready
Intellectual disability syndromic and non-syndromic v0.4647 SLC6A17 Zornitza Stark Gene: slc6a17 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.4647 SLC6A17 Zornitza Stark Phenotypes for gene: SLC6A17 were changed from to Mental retardation, autosomal recessive 48, MIM# 616269
Intellectual disability syndromic and non-syndromic v0.4646 SLC6A17 Zornitza Stark Publications for gene: SLC6A17 were set to
Intellectual disability syndromic and non-syndromic v0.4645 SLC6A17 Zornitza Stark Mode of inheritance for gene: SLC6A17 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4644 SLC6A17 Zornitza Stark Classified gene: SLC6A17 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.4644 SLC6A17 Zornitza Stark Gene: slc6a17 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.4643 SLC6A17 Zornitza Stark reviewed gene: SLC6A17: Rating: AMBER; Mode of pathogenicity: None; Publications: 25704603, 23672601; Phenotypes: Mental retardation, autosomal recessive 48, MIM# 616269; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4643 RBMX Zornitza Stark Marked gene: RBMX as ready
Intellectual disability syndromic and non-syndromic v0.4643 RBMX Zornitza Stark Gene: rbmx has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.4643 RBMX Zornitza Stark Classified gene: RBMX as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.4643 RBMX Zornitza Stark Gene: rbmx has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.4642 RBMX Zornitza Stark gene: RBMX was added
gene: RBMX was added to Intellectual disability syndromic and non-syndromic. Sources: Expert Review
Mode of inheritance for gene: RBMX was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: RBMX were set to 25256757; 34260915
Phenotypes for gene: RBMX were set to Intellectual developmental disorder, syndromic 11, Shashi type, MIM#300238
Review for gene: RBMX was set to AMBER
Added comment: Hemizygous truncating variant reported segregating in multiple affected individuals in a single family. Some supportive functional data.
Sources: Expert Review
Intellectual disability syndromic and non-syndromic v0.4641 WDR11 Elena Savva Phenotypes for gene: WDR11 were changed from Neurodevelopmental disorder, MONDO:0700092, WDR11-related to Neurodevelopmental disorder, MONDO:0700092, WDR11-related
Intellectual disability syndromic and non-syndromic v0.4640 WDR11 Elena Savva Phenotypes for gene: WDR11 were changed from Intellectual disability; Microcephaly; Short stature to Neurodevelopmental disorder, MONDO:0700092, WDR11-related
Intellectual disability syndromic and non-syndromic v0.4640 WDR11 Elena Savva Publications for gene: WDR11 were set to 34413497
Intellectual disability syndromic and non-syndromic v0.4639 WDR11 Elena Savva Mode of inheritance for gene: WDR11 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4638 WDR11 Elena Savva reviewed gene: WDR11: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder, MONDO:0700092, WDR11-related; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4638 RAB3GAP2 Zornitza Stark Marked gene: RAB3GAP2 as ready
Intellectual disability syndromic and non-syndromic v0.4638 RAB3GAP2 Zornitza Stark Gene: rab3gap2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4638 RAB3GAP2 Zornitza Stark Phenotypes for gene: RAB3GAP2 were changed from to Martsolf syndrome (MIM212720); Warburg micro syndrome 2 (MIM#614225)
Intellectual disability syndromic and non-syndromic v0.4637 RAB3GAP2 Zornitza Stark Publications for gene: RAB3GAP2 were set to
Intellectual disability syndromic and non-syndromic v0.4636 RAB3GAP2 Zornitza Stark Mode of inheritance for gene: RAB3GAP2 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4635 RAB3GAP2 Teresa Zhao reviewed gene: RAB3GAP2: Rating: GREEN; Mode of pathogenicity: None; Publications: 23420520, 32376645; Phenotypes: Martsolf syndrome (MIM212720), Warburg micro syndrome 2 (MIM#614225); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4635 KCND3 Elena Savva Publications for gene: KCND3 were set to 32823520
Intellectual disability syndromic and non-syndromic v0.4634 NUBPL Zornitza Stark Marked gene: NUBPL as ready
Intellectual disability syndromic and non-syndromic v0.4634 NUBPL Zornitza Stark Gene: nubpl has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4634 NUBPL Zornitza Stark Phenotypes for gene: NUBPL were changed from to Mitochondrial complex I deficiency, nuclear type 21 - MIM#618242
Intellectual disability syndromic and non-syndromic v0.4633 NUBPL Zornitza Stark Publications for gene: NUBPL were set to
Intellectual disability syndromic and non-syndromic v0.4632 NUBPL Zornitza Stark Mode of inheritance for gene: NUBPL was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4631 NTRK1 Zornitza Stark Marked gene: NTRK1 as ready
Intellectual disability syndromic and non-syndromic v0.4631 NTRK1 Zornitza Stark Gene: ntrk1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4631 NTRK1 Zornitza Stark Phenotypes for gene: NTRK1 were changed from to Insensitivity to pain, congenital, with anhidrosis - MIM#256800
Intellectual disability syndromic and non-syndromic v0.4630 NTRK1 Zornitza Stark Publications for gene: NTRK1 were set to
Intellectual disability syndromic and non-syndromic v0.4629 NTRK1 Zornitza Stark Mode of inheritance for gene: NTRK1 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4628 NTRK1 Zornitza Stark Mode of inheritance for gene: NTRK1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4627 NSUN2 Zornitza Stark Marked gene: NSUN2 as ready
Intellectual disability syndromic and non-syndromic v0.4627 NSUN2 Zornitza Stark Gene: nsun2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4627 NSUN2 Zornitza Stark Phenotypes for gene: NSUN2 were changed from to Mental retardation, autosomal recessive 5 - MIM#611091
Intellectual disability syndromic and non-syndromic v0.4626 NSUN2 Zornitza Stark Publications for gene: NSUN2 were set to
Intellectual disability syndromic and non-syndromic v0.4625 NSUN2 Zornitza Stark Mode of inheritance for gene: NSUN2 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4624 NSUN2 Zornitza Stark reviewed gene: NSUN2: Rating: GREEN; Mode of pathogenicity: None; Publications: 35126837; Phenotypes: Mental retardation, autosomal recessive 5 - MIM#611091; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4624 NRXN1 Zornitza Stark Marked gene: NRXN1 as ready
Intellectual disability syndromic and non-syndromic v0.4624 NRXN1 Zornitza Stark Gene: nrxn1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4624 NRXN1 Zornitza Stark Phenotypes for gene: NRXN1 were changed from to Pitt-Hopkins-like syndrome 2 - MIM#614325
Intellectual disability syndromic and non-syndromic v0.4623 NRXN1 Zornitza Stark Publications for gene: NRXN1 were set to
Intellectual disability syndromic and non-syndromic v0.4622 NRXN1 Zornitza Stark Mode of inheritance for gene: NRXN1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4621 NUBPL Krithika Murali reviewed gene: NUBPL: Rating: GREEN; Mode of pathogenicity: None; Publications: 20818383, 32518176, 23553477, 31917109, 32518176, 31787496, 30897263, 22826544; Phenotypes: Mitochondrial complex I deficiency, nuclear type 21 - MIM#618242; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4621 NTRK1 Krithika Murali reviewed gene: NTRK1: Rating: GREEN; Mode of pathogenicity: None; Publications: 10233776, 19250380, 10861667, 10982191, 20301726, 20089052; Phenotypes: Insensitivity to pain, congenital, with anhidrosis - MIM#256800; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4621 NSUN2 Krithika Murali reviewed gene: NSUN2: Rating: GREEN; Mode of pathogenicity: None; Publications: 22541559, 22541562, 21063731, 22577224; Phenotypes: Mental retardation, autosomal recessive 5 - MIM#611091; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4621 NRXN1 Krithika Murali reviewed gene: NRXN1: Rating: GREEN; Mode of pathogenicity: None; Publications: 25486015, 19896112, 21964664, 30873608, 35101781, 22337556, 22670139; Phenotypes: Pitt-Hopkins-like syndrome 2 - MIM#614325; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4621 SMARCE1 Zornitza Stark Marked gene: SMARCE1 as ready
Intellectual disability syndromic and non-syndromic v0.4621 SMARCE1 Zornitza Stark Gene: smarce1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4621 SMARCE1 Zornitza Stark Phenotypes for gene: SMARCE1 were changed from to Coffin-Siris syndrome 5, MIM# 616938
Intellectual disability syndromic and non-syndromic v0.4620 SMARCE1 Zornitza Stark Publications for gene: SMARCE1 were set to
Intellectual disability syndromic and non-syndromic v0.4619 SMARCE1 Zornitza Stark Mode of inheritance for gene: SMARCE1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.4618 SMARCE1 Zornitza Stark reviewed gene: SMARCE1: Rating: GREEN; Mode of pathogenicity: None; Publications: 22426308, 23906836, 23929686, 32732226, 32436246, 32410215, 34205270; Phenotypes: Coffin-Siris syndrome 5, MIM# 616938; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.4618 SNX14 Zornitza Stark Marked gene: SNX14 as ready
Intellectual disability syndromic and non-syndromic v0.4618 SNX14 Zornitza Stark Gene: snx14 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4618 SNX14 Zornitza Stark Phenotypes for gene: SNX14 were changed from to Spinocerebellar ataxia, autosomal recessive 20 (MIM#616354)
Intellectual disability syndromic and non-syndromic v0.4617 SNX14 Zornitza Stark Publications for gene: SNX14 were set to
Intellectual disability syndromic and non-syndromic v0.4616 SNX14 Zornitza Stark Mode of inheritance for gene: SNX14 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4615 SNX14 Zornitza Stark reviewed gene: SNX14: Rating: GREEN; Mode of pathogenicity: None; Publications: 25439728, 25848753, 27913285; Phenotypes: Spinocerebellar ataxia, autosomal recessive 20 (MIM#616354); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4615 SMS Zornitza Stark Marked gene: SMS as ready
Intellectual disability syndromic and non-syndromic v0.4615 SMS Zornitza Stark Gene: sms has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4615 SMS Zornitza Stark Phenotypes for gene: SMS were changed from to Intellectual developmental disorder, X-linked syndromic, Snyder-Robinson type, MIM# 309583; Syndromic X-linked intellectual disability Snyder type, MONDO:0010664
Intellectual disability syndromic and non-syndromic v0.4614 SMS Zornitza Stark Publications for gene: SMS were set to
Intellectual disability syndromic and non-syndromic v0.4613 SMS Zornitza Stark Mode of inheritance for gene: SMS was changed from Unknown to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability syndromic and non-syndromic v0.4612 SMS Zornitza Stark reviewed gene: SMS: Rating: GREEN; Mode of pathogenicity: None; Publications: 30237987, 34177437, 32838743, 23805436; Phenotypes: Intellectual developmental disorder, X-linked syndromic, Snyder-Robinson type, MIM# 309583, Syndromic X-linked intellectual disability Snyder type, MONDO:0010664; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability syndromic and non-syndromic v0.4612 GRIN1 Zornitza Stark Phenotypes for gene: GRIN1 were changed from Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal dominant, MIM# 614254; Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal recessive, MIM# 617820 to Developmental and epileptic encephalopathy 101 , MIM#619814; Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal dominant, MIM# 614254; Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal recessive, MIM# 617820
Intellectual disability syndromic and non-syndromic v0.4611 GRIN1 Zornitza Stark Publications for gene: GRIN1 were set to 29365063; 27164704; 27164704; 28051072
Intellectual disability syndromic and non-syndromic v0.4610 GRIN1 Zornitza Stark edited their review of gene: GRIN1: Changed publications: 29365063, 27164704, 27164704, 28051072, 34611970; Changed phenotypes: Developmental and epileptic encephalopathy 101 , MIM#619814, Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal dominant, MIM# 614254, Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal recessive, MIM# 617820
Intellectual disability syndromic and non-syndromic v0.4610 TBL1XR1 Zornitza Stark Marked gene: TBL1XR1 as ready
Intellectual disability syndromic and non-syndromic v0.4610 TBL1XR1 Zornitza Stark Gene: tbl1xr1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4610 TBL1XR1 Zornitza Stark Phenotypes for gene: TBL1XR1 were changed from to Mental retardation, autosomal dominant 41, MIM# 616944; Pierpont syndrome, MIM# 602342
Intellectual disability syndromic and non-syndromic v0.4609 TBL1XR1 Zornitza Stark Publications for gene: TBL1XR1 were set to
Intellectual disability syndromic and non-syndromic v0.4608 TBL1XR1 Zornitza Stark Mode of inheritance for gene: TBL1XR1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.4607 TBL1XR1 Zornitza Stark reviewed gene: TBL1XR1: Rating: GREEN; Mode of pathogenicity: None; Publications: 26769062, 30365874, 25425123, 9450851, 23160955, 28687524, 23176139, 16007632; Phenotypes: Mental retardation, autosomal dominant 41, MIM# 616944, Pierpont syndrome, MIM# 602342; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.4607 TBCK Zornitza Stark Marked gene: TBCK as ready
Intellectual disability syndromic and non-syndromic v0.4607 TBCK Zornitza Stark Gene: tbck has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4607 TBCK Zornitza Stark Phenotypes for gene: TBCK were changed from to Hypotonia, infantile, with psychomotor retardation and characteristic facies 3, MIM# 616900
Intellectual disability syndromic and non-syndromic v0.4606 TBCK Zornitza Stark Publications for gene: TBCK were set to
Intellectual disability syndromic and non-syndromic v0.4605 TBCK Zornitza Stark Mode of inheritance for gene: TBCK was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4604 TBCK Zornitza Stark reviewed gene: TBCK: Rating: GREEN; Mode of pathogenicity: None; Publications: 27040692, 30103036, 27040691; Phenotypes: Hypotonia, infantile, with psychomotor retardation and characteristic facies 3, MIM# 616900; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4604 TBC1D23 Zornitza Stark Marked gene: TBC1D23 as ready
Intellectual disability syndromic and non-syndromic v0.4604 TBC1D23 Zornitza Stark Gene: tbc1d23 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4604 TBC1D23 Zornitza Stark Phenotypes for gene: TBC1D23 were changed from to Pontocerebellar hypoplasia, type 11, MIM# 617695
Intellectual disability syndromic and non-syndromic v0.4603 TBC1D23 Zornitza Stark Publications for gene: TBC1D23 were set to
Intellectual disability syndromic and non-syndromic v0.4602 TBC1D23 Zornitza Stark Mode of inheritance for gene: TBC1D23 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4601 TBC1D23 Zornitza Stark reviewed gene: TBC1D23: Rating: GREEN; Mode of pathogenicity: None; Publications: 28823707, 28823706; Phenotypes: Pontocerebellar hypoplasia, type 11, MIM# 617695; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4601 NONO Zornitza Stark Marked gene: NONO as ready
Intellectual disability syndromic and non-syndromic v0.4601 NONO Zornitza Stark Gene: nono has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4601 NONO Zornitza Stark Phenotypes for gene: NONO were changed from to Intellectual developmental disorder, X-linked syndromic 34 - MIM#300967
Intellectual disability syndromic and non-syndromic v0.4600 NONO Zornitza Stark Publications for gene: NONO were set to
Intellectual disability syndromic and non-syndromic v0.4599 NONO Zornitza Stark Mode of inheritance for gene: NONO was changed from Unknown to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability syndromic and non-syndromic v0.4598 LAS1L Alison Yeung Classified gene: LAS1L as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4598 LAS1L Alison Yeung Gene: las1l has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4597 LAS1L Alison Yeung Publications for gene: LAS1L were set to 25644381; 26358559
Intellectual disability syndromic and non-syndromic v0.4596 LAS1L Alison Yeung Classified gene: LAS1L as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4596 LAS1L Alison Yeung Added comment: Comment on list classification: Additional patient reported in literature
Intellectual disability syndromic and non-syndromic v0.4596 LAS1L Alison Yeung Gene: las1l has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4595 NONO Krithika Murali reviewed gene: NONO: Rating: GREEN; Mode of pathogenicity: None; Publications: 26571461, 27329731, 27550220; Phenotypes: Intellectual developmental disorder, X-linked syndromic 34 - MIM#300967; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability syndromic and non-syndromic v0.4595 STAG1 Zornitza Stark Marked gene: STAG1 as ready
Intellectual disability syndromic and non-syndromic v0.4595 STAG1 Zornitza Stark Gene: stag1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4595 STAG1 Zornitza Stark Phenotypes for gene: STAG1 were changed from to Mental retardation, autosomal dominant 47, MIM# 617635
Intellectual disability syndromic and non-syndromic v0.4594 STAG1 Zornitza Stark Publications for gene: STAG1 were set to
Intellectual disability syndromic and non-syndromic v0.4593 STAG1 Zornitza Stark Mode of inheritance for gene: STAG1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.4592 STAG1 Zornitza Stark reviewed gene: STAG1: Rating: GREEN; Mode of pathogenicity: None; Publications: 28119487, 34440290; Phenotypes: Mental retardation, autosomal dominant 47, MIM# 617635; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.4592 NLGN3 Zornitza Stark Marked gene: NLGN3 as ready
Intellectual disability syndromic and non-syndromic v0.4592 NLGN3 Zornitza Stark Gene: nlgn3 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4592 NLGN3 Zornitza Stark Mode of inheritance for gene: NLGN3 was changed from Unknown to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability syndromic and non-syndromic v0.4591 NLGN3 Zornitza Stark Publications for gene: NLGN3 were set to
Intellectual disability syndromic and non-syndromic v0.4590 NLGN3 Zornitza Stark Phenotypes for gene: NLGN3 were changed from to X-linked complex neurodevelopmental disorder MONDO:0100148; {Asperger syndrome susceptibility, X-linked 1} - MIM#300494; {Autism susceptibility, X-linked 1} - MIM#300425
Intellectual disability syndromic and non-syndromic v0.4589 NHS Zornitza Stark Marked gene: NHS as ready
Intellectual disability syndromic and non-syndromic v0.4589 NHS Zornitza Stark Gene: nhs has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4589 NHS Zornitza Stark Phenotypes for gene: NHS were changed from to Nance-Horan syndrome - MIM#302350; Cataract 40, X-linked - MIM#302200
Intellectual disability syndromic and non-syndromic v0.4588 NHS Zornitza Stark Publications for gene: NHS were set to
Intellectual disability syndromic and non-syndromic v0.4587 NHS Zornitza Stark Mode of inheritance for gene: NHS was changed from Unknown to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Intellectual disability syndromic and non-syndromic v0.4586 NFIA Zornitza Stark Phenotypes for gene: NFIA were changed from to Brain malformations with or without urinary tract defects - MIM#613735
Intellectual disability syndromic and non-syndromic v0.4585 NFIA Zornitza Stark Publications for gene: NFIA were set to
Intellectual disability syndromic and non-syndromic v0.4584 NFIA Zornitza Stark Mode of inheritance for gene: NFIA was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.4584 NFIA Zornitza Stark Mode of inheritance for gene: NFIA was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.4583 STX1B Zornitza Stark Marked gene: STX1B as ready
Intellectual disability syndromic and non-syndromic v0.4583 STX1B Zornitza Stark Gene: stx1b has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4583 STX1B Zornitza Stark Phenotypes for gene: STX1B were changed from to Generalized epilepsy with febrile seizures plus, type 9, MIM# 616172
Intellectual disability syndromic and non-syndromic v0.4582 STX1B Zornitza Stark Publications for gene: STX1B were set to
Intellectual disability syndromic and non-syndromic v0.4581 STX1B Zornitza Stark Mode of inheritance for gene: STX1B was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.4580 STX1B Zornitza Stark reviewed gene: STX1B: Rating: GREEN; Mode of pathogenicity: None; Publications: 25362483, 33677401; Phenotypes: Generalized epilepsy with febrile seizures plus, type 9, MIM# 616172; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.4580 NLGN3 Krithika Murali reviewed gene: NLGN3: Rating: GREEN; Mode of pathogenicity: None; Publications: 28584888, 12669065, 25167861; Phenotypes: {Asperger syndrome susceptibility, X-linked 1} - MIM#300494, {Autism susceptibility, X-linked 1} - MIM#300425; 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 syndromic and non-syndromic v0.4580 KCND3 Elena Savva reviewed gene: KCND3: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 35021282, 32823520, 34067185, 34361012; Phenotypes: Spinocerebellar ataxia 19 MIM#607346; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability syndromic and non-syndromic v0.4580 NHS Krithika Murali reviewed gene: NHS: Rating: GREEN; Mode of pathogenicity: None; Publications: 31755796, 25266737; Phenotypes: Nance-Horan syndrome - MIM#302350, Cataract 40, X-linked - MIM#302200; 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 syndromic and non-syndromic v0.4580 NFIA Krithika Murali reviewed gene: NFIA: Rating: GREEN; Mode of pathogenicity: None; Publications: 35018717, 33973697, 32926563; Phenotypes: Brain malformations with or without urinary tract defects - MIM#613735; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.4580 NDUFV2 Zornitza Stark changed review comment from: Multiple unrelated families. Common presenting features include HOCM and encephalopathy, unclear in what proportion ID is likely to be the presenting or main feature.; to: Multiple unrelated families. Common presenting features include HOCM and encephalopathy, or episodic regression with cavitating leukoencephalopathy, unclear in what proportion ID is likely to be the presenting or main feature.
Intellectual disability syndromic and non-syndromic v0.4580 NDUFV2 Zornitza Stark edited their review of gene: NDUFV2: Changed publications: 12754703, 26008862, 29554876, 33811136
Intellectual disability syndromic and non-syndromic v0.4580 SYNJ1 Zornitza Stark Marked gene: SYNJ1 as ready
Intellectual disability syndromic and non-syndromic v0.4580 SYNJ1 Zornitza Stark Gene: synj1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4580 SYNJ1 Zornitza Stark Phenotypes for gene: SYNJ1 were changed from to Developmental and epileptic encephalopathy 53, MIM# 617389
Intellectual disability syndromic and non-syndromic v0.4579 SYNJ1 Zornitza Stark Publications for gene: SYNJ1 were set to
Intellectual disability syndromic and non-syndromic v0.4578 SYNJ1 Zornitza Stark Mode of inheritance for gene: SYNJ1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4577 SYNJ1 Zornitza Stark reviewed gene: SYNJ1: Rating: GREEN; Mode of pathogenicity: None; Publications: 32435303, 27435091; Phenotypes: Developmental and epileptic encephalopathy 53, MIM# 617389; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4577 SZT2 Zornitza Stark Marked gene: SZT2 as ready
Intellectual disability syndromic and non-syndromic v0.4577 SZT2 Zornitza Stark Gene: szt2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4577 SZT2 Zornitza Stark Publications for gene: SZT2 were set to
Intellectual disability syndromic and non-syndromic v0.4576 SZT2 Zornitza Stark Mode of inheritance for gene: SZT2 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4575 SZT2 Zornitza Stark reviewed gene: SZT2: Rating: GREEN; Mode of pathogenicity: None; Publications: 23932106, 30560016, 30359774, 28556953, 32402703; Phenotypes: Developmental and epileptic encephalopathy 18, OMIM #615476; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4575 NDST1 Zornitza Stark Marked gene: NDST1 as ready
Intellectual disability syndromic and non-syndromic v0.4575 NDST1 Zornitza Stark Gene: ndst1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4575 NDST1 Zornitza Stark Phenotypes for gene: NDST1 were changed from to Mental retardation, autosomal recessive 46 - MIM#616116
Intellectual disability syndromic and non-syndromic v0.4574 NDST1 Zornitza Stark Publications for gene: NDST1 were set to
Intellectual disability syndromic and non-syndromic v0.4573 NDST1 Zornitza Stark Mode of inheritance for gene: NDST1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4572 NDST1 Krithika Murali reviewed gene: NDST1: Rating: GREEN; Mode of pathogenicity: None; Publications: 25125150, 21937992, 32878022, 28211985; Phenotypes: Mental retardation, autosomal recessive 46 - MIM#616116; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4572 ITCH Zornitza Stark Publications for gene: ITCH were set to 20170897
Intellectual disability syndromic and non-syndromic v0.4571 ITCH Zornitza Stark edited their review of gene: ITCH: Added comment: Unrelated individual reported in PMID 31091003 had normal intellect.; Changed publications: 20170897, 31091003
Intellectual disability syndromic and non-syndromic v0.4571 ITPA Zornitza Stark Marked gene: ITPA as ready
Intellectual disability syndromic and non-syndromic v0.4571 ITPA Zornitza Stark Gene: itpa has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4571 ITPA Zornitza Stark Phenotypes for gene: ITPA were changed from to Developmental and epileptic encephalopathy 35, MIM# 616647
Intellectual disability syndromic and non-syndromic v0.4570 ITPA Zornitza Stark Publications for gene: ITPA were set to
Intellectual disability syndromic and non-syndromic v0.4569 ITPA Zornitza Stark Mode of inheritance for gene: ITPA was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4568 ITPA Zornitza Stark reviewed gene: ITPA: Rating: GREEN; Mode of pathogenicity: None; Publications: 26224535, 19498443, 35234647, 35098521; Phenotypes: Developmental and epileptic encephalopathy 35, MIM# 616647; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4568 C12orf57 Ain Roesley Marked gene: C12orf57 as ready
Intellectual disability syndromic and non-syndromic v0.4568 C12orf57 Ain Roesley Gene: c12orf57 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4568 C12orf4 Ain Roesley Marked gene: C12orf4 as ready
Intellectual disability syndromic and non-syndromic v0.4568 C12orf4 Ain Roesley Gene: c12orf4 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4568 C12orf57 Ain Roesley Phenotypes for gene: C12orf57 were changed from to Temtamy syndrome MIM#218340
Intellectual disability syndromic and non-syndromic v0.4568 C12orf57 Ain Roesley Mode of inheritance for gene: C12orf57 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4568 C12orf57 Ain Roesley Publications for gene: C12orf57 were set to
Intellectual disability syndromic and non-syndromic v0.4567 C12orf57 Ain Roesley reviewed gene: C12orf57: Rating: GREEN; Mode of pathogenicity: None; Publications: 29383837, 31853307; Phenotypes: Temtamy syndrome MIM#218340; Mode of inheritance: None; Current diagnostic: yes
Intellectual disability syndromic and non-syndromic v0.4567 C12orf4 Ain Roesley Phenotypes for gene: C12orf4 were changed from to Intellectual developmental disorder, autosomal recessive 66 MIM#618221
Intellectual disability syndromic and non-syndromic v0.4566 C12orf4 Ain Roesley Publications for gene: C12orf4 were set to 34967075; 31334606; 27311568; 25558065; 28097321
Intellectual disability syndromic and non-syndromic v0.4566 C12orf4 Ain Roesley Publications for gene: C12orf4 were set to 34967075; 31334606; 27311568; 25558065; 28097321
Intellectual disability syndromic and non-syndromic v0.4565 C12orf4 Ain Roesley Publications for gene: C12orf4 were set to
Intellectual disability syndromic and non-syndromic v0.4565 C12orf4 Ain Roesley Mode of pathogenicity for gene: C12orf4 was changed from to None
Intellectual disability syndromic and non-syndromic v0.4564 C12orf4 Ain Roesley Mode of inheritance for gene: C12orf4 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4563 C12orf4 Ain Roesley reviewed gene: C12orf4: Rating: GREEN; Mode of pathogenicity: None; Publications: 34967075, 31334606, 27311568, 25558065, 28097321; Phenotypes: Intellectual developmental disorder, autosomal recessive 66 MIM#618221; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability syndromic and non-syndromic v0.4563 KCND3 Zornitza Stark Publications for gene: KCND3 were set to
Intellectual disability syndromic and non-syndromic v0.4562 KCND3 Zornitza Stark Classified gene: KCND3 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4562 KCND3 Zornitza Stark Gene: kcnd3 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4561 KCND3 Zornitza Stark changed review comment from: Progressive neurological condition; ID only reported in some, most however reported as having normal cognition.; to: Progressive neurological condition; ID only reported in some. Recent review of all published patients, PMID 32823520 defined a group with early onset of disease, where DD/ID are the predominant presenting symptoms, with ataxia developing later.
Intellectual disability syndromic and non-syndromic v0.4561 KCND3 Zornitza Stark edited their review of gene: KCND3: Changed rating: GREEN; Changed publications: 32823520
Intellectual disability syndromic and non-syndromic v0.4561 KCNJ10 Zornitza Stark Marked gene: KCNJ10 as ready
Intellectual disability syndromic and non-syndromic v0.4561 KCNJ10 Zornitza Stark Gene: kcnj10 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4561 KCNJ10 Zornitza Stark Phenotypes for gene: KCNJ10 were changed from to SESAME syndrome, MIM# 612780
Intellectual disability syndromic and non-syndromic v0.4560 KCNJ10 Zornitza Stark Publications for gene: KCNJ10 were set to
Intellectual disability syndromic and non-syndromic v0.4559 KCNJ10 Zornitza Stark Mode of inheritance for gene: KCNJ10 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4558 KCNJ10 Zornitza Stark reviewed gene: KCNJ10: Rating: GREEN; Mode of pathogenicity: None; Publications: 19289823, 19420365, 21849804, 11466414; Phenotypes: SESAME syndrome, MIM# 612780; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4558 KCNK3 Zornitza Stark Marked gene: KCNK3 as ready
Intellectual disability syndromic and non-syndromic v0.4558 KCNK3 Zornitza Stark Gene: kcnk3 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.4558 KCNK3 Zornitza Stark Classified gene: KCNK3 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.4558 KCNK3 Zornitza Stark Gene: kcnk3 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.4558 KCNK3 Zornitza Stark Classified gene: KCNK3 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.4558 KCNK3 Zornitza Stark Gene: kcnk3 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.4557 KCNK3 Zornitza Stark gene: KCNK3 was added
gene: KCNK3 was added to Intellectual disability syndromic and non-syndromic. Sources: Expert Review
Mode of inheritance for gene: KCNK3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KCNK3 were set to 33057194
Phenotypes for gene: KCNK3 were set to Neurodevelopmental disorder, MONDO:0700092, KCNK3-related
Review for gene: KCNK3 was set to AMBER
Added comment: Established pulmonary hypertension gene.

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 (7 missense, 1 synonymous) identified in ~10,000 cases with developmental disorders (no other phenotype info provided).
Sources: Expert Review
Intellectual disability syndromic and non-syndromic v0.4556 NAT8L Zornitza Stark Marked gene: NAT8L as ready
Intellectual disability syndromic and non-syndromic v0.4556 NAT8L Zornitza Stark Gene: nat8l has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v0.4556 NAT8L Zornitza Stark Phenotypes for gene: NAT8L were changed from ?N-acetylaspartate deficiency - MIM#614063 to N-acetylaspartate deficiency - MIM#614063
Intellectual disability syndromic and non-syndromic v0.4555 NAT8L Zornitza Stark Classified gene: NAT8L as Red List (low evidence)
Intellectual disability syndromic and non-syndromic v0.4555 NAT8L Zornitza Stark Gene: nat8l has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v0.4554 NAT8L Zornitza Stark reviewed gene: NAT8L: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: N-acetylaspartate deficiency - MIM#614063; Mode of inheritance: None
Intellectual disability syndromic and non-syndromic v0.4554 ARHGAP35 Ain Roesley Phenotypes for gene: ARHGAP35 were changed from neurodevelopmental disorder, ARHGAP35-related MONDO#0700092 to neurodevelopmental disorder, ARHGAP35-related MONDO#0700092
Intellectual disability syndromic and non-syndromic v0.4553 ARHGAP35 Ain Roesley Phenotypes for gene: ARHGAP35 were changed from neurodevelopmental disorder, ARHGAP35-related MONDO#0700092 to neurodevelopmental disorder, ARHGAP35-related MONDO#0700092
Intellectual disability syndromic and non-syndromic v0.4552 ARHGAP35 Ain Roesley Phenotypes for gene: ARHGAP35 were changed from neurodevelopmental disorder, ARHGAP35-related MONDO#0700092 to neurodevelopmental disorder, ARHGAP35-related MONDO#0700092
Intellectual disability syndromic and non-syndromic v0.4552 ARHGAP35 Ain Roesley Phenotypes for gene: ARHGAP35 were changed from Developmental disorder to neurodevelopmental disorder, ARHGAP35-related MONDO#0700092
Intellectual disability syndromic and non-syndromic v0.4551 ARHGAP35 Ain Roesley Classified gene: ARHGAP35 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4551 ARHGAP35 Ain Roesley Gene: arhgap35 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4551 ARHGAP35 Ain Roesley Classified gene: ARHGAP35 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4551 ARHGAP35 Ain Roesley Gene: arhgap35 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4550 ARHGAP35 Ain Roesley reviewed gene: ARHGAP35: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: neurodevelopmental disorder, ARHGAP35-related MONDO#0700092; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Intellectual disability syndromic and non-syndromic v0.4550 KIAA1109 Zornitza Stark Phenotypes for gene: KIAA1109 were changed from Alkuraya-Kucinskas syndrome, MIM# 617822 to Alkuraya-Kucinskas syndrome, MIM# 617822
Intellectual disability syndromic and non-syndromic v0.4550 KIAA1109 Zornitza Stark Marked gene: KIAA1109 as ready
Intellectual disability syndromic and non-syndromic v0.4550 KIAA1109 Zornitza Stark Gene: kiaa1109 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4550 KIAA1109 Zornitza Stark Phenotypes for gene: KIAA1109 were changed from Alkuraya-Kucinskas syndrome, MIM# 617822 to Alkuraya-Kucinskas syndrome, MIM# 617822
Intellectual disability syndromic and non-syndromic v0.4550 KIAA1109 Zornitza Stark Phenotypes for gene: KIAA1109 were changed from to Alkuraya-Kucinskas syndrome, MIM# 617822
Intellectual disability syndromic and non-syndromic v0.4549 KIAA1109 Zornitza Stark Publications for gene: KIAA1109 were set to
Intellectual disability syndromic and non-syndromic v0.4548 KIAA1109 Zornitza Stark Mode of inheritance for gene: KIAA1109 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4547 KIAA1109 Zornitza Stark reviewed gene: KIAA1109: Rating: GREEN; Mode of pathogenicity: None; Publications: 29290337, 30906834; Phenotypes: Alkuraya-Kucinskas syndrome, MIM# 617822; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4547 FBXO28 Zornitza Stark Phenotypes for gene: FBXO28 were changed from Developmental and epileptic encephalopathy to Developmental and epileptic encephalopathy 100, MIM# 619777
Intellectual disability syndromic and non-syndromic v0.4546 FBXO28 Zornitza Stark edited their review of gene: FBXO28: Changed phenotypes: Developmental and epileptic encephalopathy 100, MIM# 619777
Intellectual disability syndromic and non-syndromic v0.4546 NAT8L Krithika Murali gene: NAT8L was added
gene: NAT8L was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: NAT8L was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NAT8L were set to 11310630; 19807691; 32275776
Phenotypes for gene: NAT8L were set to ?N-acetylaspartate deficiency - MIM#614063
Review for gene: NAT8L was set to AMBER
Added comment: Absence of brain N-acetylaspartate, has been described in only one patient, with truncal ataxia, marked developmental delay, seizures and secondary microcephaly (first described by - PMID: 11310630 Martin et al 2001). PMID: 19807691 - Wiame et al 2009 identified in this patient a homozygous 19 bp NAT8L gene deletion, resulting in a change in reading frame and the absence of production of a functional protein. The affected individual is adopted and testing of the biological parents was not possible. The authors provide supportive functional studies.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4546 NANS Zornitza Stark Marked gene: NANS as ready
Intellectual disability syndromic and non-syndromic v0.4546 NANS Zornitza Stark Gene: nans has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4546 NANS Zornitza Stark Phenotypes for gene: NANS were changed from to Spondyloepimetaphyseal dysplasia, Camera-Genevieve type - MIM#610442
Intellectual disability syndromic and non-syndromic v0.4545 NANS Zornitza Stark Publications for gene: NANS were set to
Intellectual disability syndromic and non-syndromic v0.4544 NANS Zornitza Stark Mode of inheritance for gene: NANS was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4543 NACC1 Zornitza Stark Phenotypes for gene: NACC1 were changed from to Neurodevelopmental disorder with epilepsy, cataracts, feeding difficulties, and delayed brain myelination - MIM#617393
Intellectual disability syndromic and non-syndromic v0.4542 NACC1 Zornitza Stark Publications for gene: NACC1 were set to
Intellectual disability syndromic and non-syndromic v0.4541 NACC1 Zornitza Stark Mode of inheritance for gene: NACC1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.4540 NACC1 Zornitza Stark reviewed gene: NACC1: Rating: GREEN; Mode of pathogenicity: None; Publications: 28132692; Phenotypes: Neurodevelopmental disorder with epilepsy, cataracts, feeding difficulties, and delayed brain myelination - MIM#617393; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.4540 NAA15 Zornitza Stark Marked gene: NAA15 as ready
Intellectual disability syndromic and non-syndromic v0.4540 NAA15 Zornitza Stark Gene: naa15 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4540 NAA15 Zornitza Stark Phenotypes for gene: NAA15 were changed from to Intellectual developmental disorder, autosomal dominant 50, with behavioral abnormalities - MIM#617787
Intellectual disability syndromic and non-syndromic v0.4539 NAA15 Zornitza Stark Publications for gene: NAA15 were set to
Intellectual disability syndromic and non-syndromic v0.4538 NAA15 Zornitza Stark Mode of inheritance for gene: NAA15 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.4537 NAA15 Zornitza Stark reviewed gene: NAA15: Rating: GREEN; Mode of pathogenicity: None; Publications: 33103328, 29656860, 31127942, 28191889, 33557580, 28990276; Phenotypes: Intellectual developmental disorder, autosomal dominant 50, with behavioral abnormalities - MIM#617787; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.4537 NANS Krithika Murali reviewed gene: NANS: Rating: GREEN; Mode of pathogenicity: None; Publications: 8152878, 15726110, 8723082, 27213289, 7551156; Phenotypes: Spondyloepimetaphyseal dysplasia, Camera-Genevieve type - MIM#610442; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4537 IRX5 Zornitza Stark Publications for gene: IRX5 were set to 22581230; 27453922
Intellectual disability syndromic and non-syndromic v0.4536 IRX5 Zornitza Stark Classified gene: IRX5 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4536 IRX5 Zornitza Stark Gene: irx5 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4535 IRX5 Zornitza Stark edited their review of gene: IRX5: Added comment: Third family with Hamamy syndrome and homozygous missense variant reported, p.Arg168His. Two cousins, >4 meioses, good segregation data. Intellectual disability.; Changed rating: GREEN; Changed publications: 22581230, 27453922, 34899143
Intellectual disability syndromic and non-syndromic v0.4535 MAN2C1 Zornitza Stark Marked gene: MAN2C1 as ready
Intellectual disability syndromic and non-syndromic v0.4535 MAN2C1 Zornitza Stark Gene: man2c1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4535 MAN2C1 Zornitza Stark Phenotypes for gene: MAN2C1 were changed from neurodevelopmental disorder MONDO:0700092 MAN2C1-related to Congenital disorder of deglycosylation 2, MIM# 619775
Intellectual disability syndromic and non-syndromic v0.4534 MAN2C1 Zornitza Stark Classified gene: MAN2C1 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4534 MAN2C1 Zornitza Stark Gene: man2c1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4533 MAN2C1 Zornitza Stark reviewed gene: MAN2C1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Congenital disorder of deglycosylation 2, MIM# 619775; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4533 NFE2L1 Zornitza Stark Marked gene: NFE2L1 as ready
Intellectual disability syndromic and non-syndromic v0.4533 NFE2L1 Zornitza Stark Gene: nfe2l1 has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v0.4533 NFE2L1 Zornitza Stark gene: NFE2L1 was added
gene: NFE2L1 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: NFE2L1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: NFE2L1 were set to 35112409
Phenotypes for gene: NFE2L1 were set to Syndromic disease, MONDO:0002254
Review for gene: NFE2L1 was set to RED
Added comment: A single patient with developmental delay, hypotonia, hypospadias, bifid scrotum, and failure to thrive, with a heterozygous nonsense variant in the last exon. In vitro functional assays suggest a dominant-negative effect.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4532 QDPR Zornitza Stark Marked gene: QDPR as ready
Intellectual disability syndromic and non-syndromic v0.4532 QDPR Zornitza Stark Gene: qdpr has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4532 QDPR Zornitza Stark Phenotypes for gene: QDPR were changed from to Hyperphenylalaninemia, BH4-deficient, C, MIM# 261630
Intellectual disability syndromic and non-syndromic v0.4531 QDPR Zornitza Stark Publications for gene: QDPR were set to
Intellectual disability syndromic and non-syndromic v0.4530 QDPR Zornitza Stark Mode of inheritance for gene: QDPR was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4529 QDPR Zornitza Stark reviewed gene: QDPR: Rating: GREEN; Mode of pathogenicity: None; Publications: 11153907; Phenotypes: Hyperphenylalaninemia, BH4-deficient, C, MIM# 261630; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4529 CRLS1 Zornitza Stark Marked gene: CRLS1 as ready
Intellectual disability syndromic and non-syndromic v0.4529 CRLS1 Zornitza Stark Gene: crls1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4529 CRLS1 Zornitza Stark Classified gene: CRLS1 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4529 CRLS1 Zornitza Stark Gene: crls1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4528 ZBTB7A Zornitza Stark Classified gene: ZBTB7A as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4528 ZBTB7A Zornitza Stark Gene: zbtb7a has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4528 CRLS1 Zornitza Stark reviewed gene: CRLS1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability syndromic and non-syndromic v0.4528 HIST1H4E Alison Yeung Classified gene: HIST1H4E as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4528 HIST1H4E Alison Yeung Gene: hist1h4e has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4528 ZBTB7A Zornitza Stark Marked gene: ZBTB7A as ready
Intellectual disability syndromic and non-syndromic v0.4528 ZBTB7A Zornitza Stark Gene: zbtb7a has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4528 ZBTB7A Zornitza Stark Classified gene: ZBTB7A as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4528 ZBTB7A Zornitza Stark Gene: zbtb7a has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4528 HIST1H4E Alison Yeung Classified gene: HIST1H4E as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4528 HIST1H4E Alison Yeung Gene: hist1h4e has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4527 HIST1H4E Alison Yeung Classified gene: HIST1H4E as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4527 HIST1H4E Alison Yeung Gene: hist1h4e has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4527 HIST1H4E Alison Yeung Classified gene: HIST1H4E as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4527 HIST1H4E Alison Yeung Gene: hist1h4e has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4526 HIST1H4E Alison Yeung Marked gene: HIST1H4E as ready
Intellectual disability syndromic and non-syndromic v0.4526 HIST1H4E Alison Yeung Gene: hist1h4e has been removed from the panel.
Intellectual disability syndromic and non-syndromic v0.4526 HIST1H4D Zornitza Stark Marked gene: HIST1H4D as ready
Intellectual disability syndromic and non-syndromic v0.4526 HIST1H4D Zornitza Stark Gene: hist1h4d has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.4526 HIST1H4D Zornitza Stark Classified gene: HIST1H4D as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.4526 HIST1H4D Zornitza Stark Gene: hist1h4d has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.4525 ZBTB11 Zornitza Stark Classified gene: ZBTB11 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4525 ZBTB11 Zornitza Stark Gene: zbtb11 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4525 CPSF3 Alison Yeung Phenotypes for gene: CPSF3 were changed from Neurodevelopmental disorder, CPSF3-related, MONDO:0700092 to Neurodevelopmental disorder, CPSF3-related, MONDO:0700092
Intellectual disability syndromic and non-syndromic v0.4524 ZBTB11 Zornitza Stark Classified gene: ZBTB11 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4524 ZBTB11 Zornitza Stark Gene: zbtb11 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4524 CPSF3 Alison Yeung Marked gene: CPSF3 as ready
Intellectual disability syndromic and non-syndromic v0.4524 CPSF3 Alison Yeung Gene: cpsf3 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4524 HIST1H4D Paul De Fazio changed review comment from: Single individual described with a de novo missense variant Arg41His (Arg40 in H4 nomenclature). Apart from langauge delay and moderate ID, phenotypes included facial dysmorphisms and cochlear abnormalities and arhinencephaly on MRI. Hearing was normal. Birth length, OFC, weight were all reduced (-2 to -2.5SD).
A zebrafish model has developmental defects.
Sources: Literature; to: HGNC recognised gene name: H4C4
Single individual described with a de novo missense variant Arg41His (Arg40 in H4 nomenclature). Apart from langauge delay and moderate ID, phenotypes included facial dysmorphisms and cochlear abnormalities and arhinencephaly on MRI. Hearing was normal. Birth length, OFC, weight were all reduced (-2 to -2.5SD).
A zebrafish model has developmental defects.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4524 CPSF3 Alison Yeung Phenotypes for gene: CPSF3 were changed from Intellectual disability syndrome to Neurodevelopmental disorder, CPSF3-related, MONDO:0700092
Intellectual disability syndromic and non-syndromic v0.4523 CPSF3 Alison Yeung Classified gene: CPSF3 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4523 CPSF3 Alison Yeung Gene: cpsf3 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4522 HIST1H4C Zornitza Stark Publications for gene: HIST1H4C were set to 28920961
Intellectual disability syndromic and non-syndromic v0.4521 HIST1H4C Zornitza Stark Phenotypes for gene: HIST1H4C were changed from Growth delay, microcephaly and intellectual disability to Tessadori-van Haaften neurodevelopmental syndrome 1 MIM#619758
Intellectual disability syndromic and non-syndromic v0.4520 NRCAM Alison Yeung Marked gene: NRCAM as ready
Intellectual disability syndromic and non-syndromic v0.4520 NRCAM Alison Yeung Gene: nrcam has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4520 CPSF3 Belinda Chong gene: CPSF3 was added
gene: CPSF3 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: CPSF3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CPSF3 were set to 35121750
Phenotypes for gene: CPSF3 were set to Intellectual disability syndrome
Review for gene: CPSF3 was set to GREEN
gene: CPSF3 was marked as current diagnostic
Added comment: Study of a deficit of observed homozygous carriers of missense variants, versus an expected number in a set of 153,054 chip-genotyped Icelanders, to identify potentially pathogenic genotypes

Six homozygous carriers of missense variants in CPSF3 show severe intellectual disability, seizures, microcephaly, and abnormal muscle tone.

- Four identified through Icelandic geneology (p.Gly468Glu), three carrier couples total of four children who had died prematurely. Tested archival samples for two of these children, and confirm a homozygous genotype.
- Two of Mexican descent (p.Ile354Thr), first-degree cousins
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4520 NRCAM Alison Yeung Classified gene: NRCAM as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4520 NRCAM Alison Yeung Gene: nrcam has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4520 NRCAM Alison Yeung Classified gene: NRCAM as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4520 NRCAM Alison Yeung Gene: nrcam has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4519 HIST1H4E Paul De Fazio changed review comment from: 17 patients identified with de novo missense variants affecting Lys31, Pro32, Arg35, Leu37, Arg40 (recurrent), Arg45 (recurrent), Tyr98 (recurrent). All individuals had ID/dev delay. Additional phenotypes in some but not all individuals included epilepsy, hypotonia, facial dysmorphism. Most had reduced birth length, OFC, weight (-1 to -3SD).
A zebrafish model has developmental defects.
Sources: Literature; to: HGNC recognised gene: H4C5
17 patients identified with de novo missense variants affecting Lys31, Pro32, Arg35, Leu37, Arg40 (recurrent), Arg45 (recurrent), Tyr98 (recurrent). All individuals had ID/dev delay. Additional phenotypes in some but not all individuals included epilepsy, hypotonia, facial dysmorphism. Most had reduced birth length, OFC, weight (-1 to -3SD).
A zebrafish model has developmental defects.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4519 HIST1H4C Paul De Fazio changed review comment from: 6 additional individuals with ID and dev delay. All variants were de novo. Lys92 (Lys91 in H4 nomenclature) and Pro33 (Pro32) were the only variants identified. Additional phenotypes in some but not all patients included hypotonia, facial dysmorphisms, conductive hearing loss. Most had reduced birth length, OFC, weight (-1 to -2.5SD).
A zebrafish model has developmental defects.; to: HGNC recognised gene name: H4C3
6 additional individuals with ID and dev delay. All variants were de novo. Lys92 (Lys91 in H4 nomenclature) and Pro33 (Pro32) were the only variants identified. Additional phenotypes in some but not all patients included hypotonia, facial dysmorphisms, conductive hearing loss. Most had reduced birth length, OFC, weight (-1 to -2.5SD).
A zebrafish model has developmental defects.
Intellectual disability syndromic and non-syndromic v0.4519 HIST1H4E Paul De Fazio gene: HIST1H4E was added
gene: HIST1H4E was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: HIST1H4E was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: HIST1H4E were set to 35202563
Phenotypes for gene: HIST1H4E were set to Neurodevelopmental disorder, HIST1H4E-related MONDO:0700092
Review for gene: HIST1H4E was set to GREEN
gene: HIST1H4E was marked as current diagnostic
Added comment: 17 patients identified with de novo missense variants affecting Lys31, Pro32, Arg35, Leu37, Arg40 (recurrent), Arg45 (recurrent), Tyr98 (recurrent). All individuals had ID/dev delay. Additional phenotypes in some but not all individuals included epilepsy, hypotonia, facial dysmorphism. Most had reduced birth length, OFC, weight (-1 to -3SD).
A zebrafish model has developmental defects.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4519 NRCAM Ee Ming Wong gene: NRCAM was added
gene: NRCAM was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: NRCAM was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NRCAM were set to PMID: 35108495
Phenotypes for gene: NRCAM were set to neurodevelopmental disorder, MONDO:0700092
Penetrance for gene: NRCAM were set to unknown
Review for gene: NRCAM was set to GREEN
gene: NRCAM was marked as current diagnostic
Added comment: -Ten individuals from 8 families with developmental delay/intellectual disability, hypotonia, peripheral neuropathy, and/or spasticity
- Affected individuals are biallelic for missense and/or LoF variants which are mainly in the fibronectin type III (Fn-III) domain
- Zebrafish mutants lacking the third Fn-III domain displayed significantly altered swimming behavior compared to wild-type larvae (p < 0.03) and a trend toward increased amounts of alpha-tubulin fibers in the dorsal telencephalon, demonstrating an alteration in white matter tracts and projections
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4519 HIST1H4D Paul De Fazio gene: HIST1H4D was added
gene: HIST1H4D was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: HIST1H4D was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: HIST1H4D were set to 35202563
Phenotypes for gene: HIST1H4D were set to Neurodevelopmental disorder, HIST1H4D-related MONDO:0700092
Review for gene: HIST1H4D was set to AMBER
gene: HIST1H4D was marked as current diagnostic
Added comment: Single individual described with a de novo missense variant Arg41His (Arg40 in H4 nomenclature). Apart from langauge delay and moderate ID, phenotypes included facial dysmorphisms and cochlear abnormalities and arhinencephaly on MRI. Hearing was normal. Birth length, OFC, weight were all reduced (-2 to -2.5SD).
A zebrafish model has developmental defects.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4519 CRLS1 Michelle Torres gene: CRLS1 was added
gene: CRLS1 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: CRLS1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CRLS1 were set to 35147173
Phenotypes for gene: CRLS1 were set to Mitochondrial disease MONDO:0044970 CRLS1-related
Added comment: - Three families (4 individuals) with cardiolipin deficiency.
- Two families (one consanguineous with 2 affected siblings) with homozygous the p.(Ile109Asn) had infantile progressive encephalopathy, bull’s eye maculopathy, auditory neuropathy, diabetes insipidus, autonomic instability, cardiac defects and early death.
- The fourth individual cHet p.(Ala172Asp) and p.(Leu217Phe) presented with chronic encephalopathy with neurodevelopmental regression, congenital nystagmus with decreased vision, sensorineural hearing loss, failure to thrive and acquired microcephaly.
- Functional studies on patient cells showed increased levels of the substrate of CRLS1 and impaired mitochondrial morphology and biogenesis
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4519 ZBTB7A Daniel Flanagan gene: ZBTB7A was added
gene: ZBTB7A was added to Intellectual disability syndromic and non-syndromic. Sources: Expert list
Mode of inheritance for gene: ZBTB7A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ZBTB7A were set to 34515416; 31645653
Phenotypes for gene: ZBTB7A were set to Macrocephaly, neurodevelopmental delay, lymphoid hyperplasia, and persistent fetal hemoglobin (MIM#619769)
Review for gene: ZBTB7A was set to GREEN
Added comment: PMID: 34515416. Monoallelic ZBTB7A variants identified in 12 individuals from 11 families, with macrocephaly (11/12), some degree of ID (12/12), autistic features (7/12) and hypertrophy of pharyngeal lymphoid tissue (12/12). Variants included LoF variants and missense, 8 variants were de novo.

PMID: 31645653. De novo ZBTB7A missense identified in a boy with macrocephaly, intellectual disability, and sleep apnea.
Sources: Expert list
Intellectual disability syndromic and non-syndromic v0.4519 HIST1H4C Paul De Fazio reviewed gene: HIST1H4C: Rating: GREEN; Mode of pathogenicity: None; Publications: 35202563; Phenotypes: Tessadori-van Haaften neurodevelopmental syndrome 1 MIM#619758, Neurodevelopmental disorder, HIST1H4C-related MONDO:0700092; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Intellectual disability syndromic and non-syndromic v0.4519 HIST1H4F Zornitza Stark Marked gene: HIST1H4F as ready
Intellectual disability syndromic and non-syndromic v0.4519 HIST1H4F Zornitza Stark Gene: hist1h4f has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.4519 HIST1H4F Zornitza Stark Phenotypes for gene: HIST1H4F were changed from Neurodevelopmental disorders to Neurodevelopmental disorder, MONDO:0700092, HIST1H4F-related
Intellectual disability syndromic and non-syndromic v0.4518 HIST1H4F Zornitza Stark Classified gene: HIST1H4F as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.4518 HIST1H4F Zornitza Stark Gene: hist1h4f has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.4517 HIST1H4F Elena Savva edited their review of gene: HIST1H4F: Added comment: PMID: 35202563 - single de novo missense in a patient with neurodevelopmental features of intellectual disability and motor and/or gross developmental delay.
- zebrafish studies show a significant increase in all of mild dev delay, necrosis, defective organogenesis and pre-gastrulation failure
Sources: Literature; Changed rating: AMBER
Intellectual disability syndromic and non-syndromic v0.4517 ZBTB11 Chern Lim reviewed gene: ZBTB11: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID:35104841; Phenotypes: Intellectual developmental disorder, autosomal recessive 69 (MIM#618383), AR; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability syndromic and non-syndromic v0.4517 HIST1H4F Elena Savva gene: HIST1H4F was added
gene: HIST1H4F was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: HIST1H4F was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: HIST1H4F were set to PMID: 35202563
Phenotypes for gene: HIST1H4F were set to Neurodevelopmental disorders
Review for gene: HIST1H4F was set to GREEN
Added comment: PMID: 35202563 - single de novo missense in a patient with neurodevelopmental features of intellectual disability and motor and/or gross developmental delay.
- zebrafish studies show a significant increase in all of mild dev delay, necrosis, defective organogenesis and pre-gastrulation failure
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4517 HIST1H4I Zornitza Stark Marked gene: HIST1H4I as ready
Intellectual disability syndromic and non-syndromic v0.4517 HIST1H4I Zornitza Stark Gene: hist1h4i has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4517 HIST1H4I Zornitza Stark Phenotypes for gene: HIST1H4I were changed from Neurodevelopmental syndrome to Neurodevelopmental syndrome, MONDO:0700092, HIST1H4I-related
Intellectual disability syndromic and non-syndromic v0.4516 HIST1H4I Zornitza Stark Classified gene: HIST1H4I as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4516 HIST1H4I Zornitza Stark Gene: hist1h4i has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4515 HIST1H4I Elena Savva gene: HIST1H4I was added
gene: HIST1H4I was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: HIST1H4I was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: HIST1H4I were set to PMID: 35202563
Phenotypes for gene: HIST1H4I were set to Neurodevelopmental syndrome
Review for gene: HIST1H4I was set to GREEN
Added comment: PMID: 35202563
- 3 unrelated de novo patients, p.His75Arg was recurring and observed in 2/3 probands.
- Zebrafish study shows both variants resulted in a significant increases in developmental issues such as in mild dev delay, necrosis and defective organogenesis.
- All patients had intellectual disability and motor and/or gross developmental delay and dysmorphisms.
- 2/3 patients showed bilateral conductive hearing loss
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4515 TIAM1 Alison Yeung Marked gene: TIAM1 as ready
Intellectual disability syndromic and non-syndromic v0.4515 TIAM1 Alison Yeung Gene: tiam1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4515 TIAM1 Alison Yeung Classified gene: TIAM1 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4515 TIAM1 Alison Yeung Gene: tiam1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4514 ATP6V0A1 Zornitza Stark Marked gene: ATP6V0A1 as ready
Intellectual disability syndromic and non-syndromic v0.4514 ATP6V0A1 Zornitza Stark Gene: atp6v0a1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4514 ATP6V0A1 Zornitza Stark Phenotypes for gene: ATP6V0A1 were changed from Developmental disorder; Rett syndrome-like to Neurodevelopmental disorder, MONDO:0700092, ATP6V0A1-related
Intellectual disability syndromic and non-syndromic v0.4513 ATP6V0A1 Zornitza Stark Publications for gene: ATP6V0A1 were set to 30842224; 33057194
Intellectual disability syndromic and non-syndromic v0.4512 ATP6V0A1 Zornitza Stark Mode of inheritance for gene: ATP6V0A1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4511 TIAM1 Alison Yeung gene: TIAM1 was added
gene: TIAM1 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: TIAM1 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: TIAM1 were set to Neurodevelopmental disorder, TIAM1-related, MONDO:0700092
Review for gene: TIAM1 was set to GREEN
Added comment: Reported in 4 unrelated individuals. Phenotype of developmental delay/intellectual disability and seizures. Loss of ortholog in Drosophila reduces the survival rate, and the surviving adults exhibit climbing defects, are prone to severe seizures, and have a short lifespan. Functional studies in 3 variants from two probands showed loss of function.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4511 ATP6V0A1 Zornitza Stark Classified gene: ATP6V0A1 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4511 ATP6V0A1 Zornitza Stark Gene: atp6v0a1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4510 ATP6V0A1 Chern Lim reviewed gene: ATP6V0A1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID:34909687; Phenotypes: Early-onset progressive myoclonus epilepsy with ataxia, AR, severe developmental and epileptic encephalopathy, AD.; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability syndromic and non-syndromic v0.4510 HIST1H4J Elena Savva reviewed gene: HIST1H4J: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 35202563, 31804630; Phenotypes: Neurodevelopmental syndrome, microcephaly, intellectual disability, dysmorphic features; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability syndromic and non-syndromic v0.4510 BAP1 Zornitza Stark Phenotypes for gene: BAP1 were changed from syndromic intellectual disability MONDO:0000508 to Kury-Isidor syndrome , MIM#619762
Intellectual disability syndromic and non-syndromic v0.4509 CHKA Zornitza Stark Marked gene: CHKA as ready
Intellectual disability syndromic and non-syndromic v0.4509 CHKA Zornitza Stark Gene: chka has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4509 CHKA Zornitza Stark Phenotypes for gene: CHKA were changed from Abnormal muscle tone; Global developmental delay; Intellectual disability; Seizures; Microcephaly; Abnormality of movement; Abnormality of nervous system morphology; Short stature to Neurodevelopmental disorder, MONDO:0700092; Abnormal muscle tone; Global developmental delay; Intellectual disability; Seizures; Microcephaly; Abnormality of movement; Abnormality of nervous system morphology; Short stature
Intellectual disability syndromic and non-syndromic v0.4508 CHKA Zornitza Stark Classified gene: CHKA as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4508 CHKA Zornitza Stark Gene: chka has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4507 CHKA Konstantinos Varvagiannis gene: CHKA was added
gene: CHKA was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: CHKA was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CHKA were set to 35202461
Phenotypes for gene: CHKA were set to Abnormal muscle tone; Global developmental delay; Intellectual disability; Seizures; Microcephaly; Abnormality of movement; Abnormality of nervous system morphology; Short stature
Penetrance for gene: CHKA were set to Complete
Review for gene: CHKA was set to GREEN
Added comment: Klöckner (2022 - PMID: 35202461) describe the phenotype of 6 individuals (from 5 unrelated families) harboring biallelic CHKA variants.

Shared features incl. abnormal muscle tone(6/6 - hypertonia or hypotonia, 3/6 each), DD/ID (6/6,severe in 4, severe/profound in 2), epilepsy (6/6 - onset: infancy - 3y2m | epileptic spasms or GS at onset), microcephaly (6/6), movement disorders (3/6 - incl. dyskinesia, rigidity, choreoatetotic movements). 2/5 individuals exhibited MRI abnormalities, notably hypomyelination. Short stature was observed in 4/6.

Eventual previous genetic testing was not discussed.

Exome sequencing (quattro ES for 2 sibs, trio ES for 1 individual, singleton for 3 probands) revealed biallelic CHKA variants in all affected individuals. Sanger sequencing was performed for confirmation and segregation studies.

Other variants (in suppl.) were not deemed to be causative for the neurodevelopmental phenotype.

3 different missense, 1 start-loss and 1 truncating variant were identified, namely (NM_0012772.2):
- c.421C>T/p.(Arg141Trp) [3 hmz subjects from 2 consanguineous families],
- c.580C>T/p.Pro194Ser [1 hmz individual born to consanguineous parents],
- c.2T>C/p.(Met1?) [1 hmz individual born to related parents],
- c.14dup/p.(Cys6Leufs*19) in trans with c.1021T>C/p.(Phe341Leu) in 1 individual.

CHKA encodes choline kinase alpha, an enzyme catalyzing the first step of phospholipid synthesis in the Kennedy pathway. The pathway is involved in de novo synthesis of glycerophospholipids, phosphatidylcholine and phosphatidylethanolamine being the most abundant in eukaryotic membranes.

CHKA with its paralog (CHKB) phosphorylates either choline or ethanolamine to phosphocholine or phosphoethanolamine respectively with conversion of ATP to ADP.

As the authors comment, biallelic pathogenic variants in CHKB cause a NDD with muscular dystrophy, hypotonia, ID, microcephaly and structural mitochondrial anomalies (MIM 602541). [Prominent mitochondrial patterning was observed in a single muscle biopsy available from an individual with biallelic CHKA variants].

Other disorders of the Kennedy pathway (due to biallelic PCYT2, SELENOI, PCYT1A variants) present with overlapping features incl. variable DD/ID (no-severe), microcephaly, seizures, visual impairment etc.

CHKA variants were either absent or observed once in gnomAD, affected highly conserved AAs with multiple in silico predictions in favor of a deleterious effect.

In silico modeling suggests structural effects for several of the missense variants (Arg141Trp, Pro194Ser presumably affect ADP binding, Phe341 lying close to the binding site of phosphocholine).

Each of the missense variants was expressed in yeast cells and W. Blot suggested expression at the expected molecular weight at comparative levels. The 3 aforementioned variants exhibited reduced catalytic activity (20%, 15%, 50% respectively).

NMD is thought to underly the deleterious effect of the frameshift one (not studied).

The start-loss variant is expected to result in significantly impaired expression and protein function as eventual utilization of the next possible start codon - occurring at position 123 - would remove 26% of the protein.

Chka(-/-) is embryonically lethal in mice, suggesting that complete loss is not compatible with life. Reduction of choline kinase activity by 30% in heterozygous mice did not appear to result in behavioral abnormalities although this was not studied in detail (PMID cited: 18029352). Finally, screening of 1566 mouse lines identified 198 genes whose disruption yields neuroanatomical phenotypes, Chka(+/-) mice being among these (PMID cited: 31371714).

There is no associated phenotype in OMIM, Gene2Phenotype or SysID.

Overall this gene can be considered for inclusion in the ID and epilepsy panes with green or amber rating (>3 individuals, >3 variants, variant studies, overlapping phenotype of disorders belonging to the same pathway, etc). Consider also inclusion in the microcephaly panel (where available this seemed to be of postnatal onset).
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4507 KIAA0391 Zornitza Stark Phenotypes for gene: KIAA0391 were changed from Combined oxidative phosphorylation deficiency 54, MIM# 619737 to Combined oxidative phosphorylation deficiency 54, MIM# 619737
Intellectual disability syndromic and non-syndromic v0.4507 KIAA0391 Zornitza Stark Phenotypes for gene: KIAA0391 were changed from Hearing loss, intellectual disability; Mitochondrial disorder to Combined oxidative phosphorylation deficiency 54, MIM# 619737
Intellectual disability syndromic and non-syndromic v0.4506 KIAA0391 Zornitza Stark Tag new gene name tag was added to gene: KIAA0391.
Intellectual disability syndromic and non-syndromic v0.4506 KIAA0391 Zornitza Stark edited their review of gene: KIAA0391: Changed phenotypes: Combined oxidative phosphorylation deficiency 54, MIM# 619737
Intellectual disability syndromic and non-syndromic v0.4506 THOC6 Zornitza Stark Marked gene: THOC6 as ready
Intellectual disability syndromic and non-syndromic v0.4506 THOC6 Zornitza Stark Gene: thoc6 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4506 THOC6 Zornitza Stark Phenotypes for gene: THOC6 were changed from to Beaulieu-Boycott-Innes syndrome, MIM# 613680
Intellectual disability syndromic and non-syndromic v0.4505 THOC6 Zornitza Stark Publications for gene: THOC6 were set to
Intellectual disability syndromic and non-syndromic v0.4504 THOC6 Zornitza Stark Mode of inheritance for gene: THOC6 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4503 THOC6 Zornitza Stark reviewed gene: THOC6: Rating: GREEN; Mode of pathogenicity: None; Publications: 23621916, 26739162, 27102954, 30238602, 30476144; Phenotypes: Beaulieu-Boycott-Innes syndrome, MIM# 613680; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4503 SYP Zornitza Stark Marked gene: SYP as ready
Intellectual disability syndromic and non-syndromic v0.4503 SYP Zornitza Stark Gene: syp has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4503 SYP Zornitza Stark Phenotypes for gene: SYP were changed from to Mental retardation, X-linked 96 MIM#300802
Intellectual disability syndromic and non-syndromic v0.4502 SYP Zornitza Stark Publications for gene: SYP were set to
Intellectual disability syndromic and non-syndromic v0.4501 SYP Zornitza Stark Mode of inheritance for gene: SYP was changed from Unknown to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability syndromic and non-syndromic v0.4500 SYP Zornitza Stark reviewed gene: SYP: Rating: GREEN; Mode of pathogenicity: None; Publications: 23966691, 19377476; Phenotypes: Mental retardation, X-linked 96 MIM#300802; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability syndromic and non-syndromic v0.4500 SPRED2 Zornitza Stark Phenotypes for gene: SPRED2 were changed from Rasopathy; developmental delay; intellectual disability; cardiac defects; short stature; skeletal anomalies; a typical facial gestalt to Noonan syndrome 14, MIM# 619745
Intellectual disability syndromic and non-syndromic v0.4499 SPRED2 Zornitza Stark reviewed gene: SPRED2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Noonan syndrome 14, MIM# 619745; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4499 POLRMT Zornitza Stark Phenotypes for gene: POLRMT were changed from Mitochondrial disorder; intellectual disability; hypotonia to Combined oxidative phosphorylation deficiency 55, MIM# 619743; intellectual disability; hypotonia
Intellectual disability syndromic and non-syndromic v0.4498 POLRMT Zornitza Stark edited their review of gene: POLRMT: Changed phenotypes: Combined oxidative phosphorylation deficiency 55, MIM# 619743, intellectual disability, hypotonia
Intellectual disability syndromic and non-syndromic v0.4498 ABHD16A Zornitza Stark Phenotypes for gene: ABHD16A were changed from Spastic paraplegia; Intellectual Disability; Callosome to Spastic paraplegia 86, autosomal recessive, MIM# 619735; Intellectual Disability; Corpus callosum abnormalities
Intellectual disability syndromic and non-syndromic v0.4497 ABHD16A Zornitza Stark edited their review of gene: ABHD16A: Changed phenotypes: Spastic paraplegia 86, autosomal recessive, MIM# 619735, Intellectual Disability, Corpus callosum abnormalities; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4497 THUMPD1 Zornitza Stark reviewed gene: THUMPD1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability syndromic and non-syndromic v0.4497 THUMPD1 Zornitza Stark Marked gene: THUMPD1 as ready
Intellectual disability syndromic and non-syndromic v0.4497 THUMPD1 Zornitza Stark Gene: thumpd1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4497 THUMPD1 Zornitza Stark Phenotypes for gene: THUMPD1 were changed from Syndromic form of intellectual disability associated with developmental delay, behavioral abnormalities, hearing loss and facial dysmorphism, AR to Syndromic disease, MONDO:0002254, THUMPD1-related
Intellectual disability syndromic and non-syndromic v0.4496 THUMPD1 Zornitza Stark Classified gene: THUMPD1 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4496 THUMPD1 Zornitza Stark Gene: thumpd1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4495 THUMPD1 Chern Lim changed review comment from: Broly, M. et al. (2022), AJHG:
- 13 individuals from 8 families, loss of function variants (PTVs, one missense, one single AA del).
- Common phenotypic findings included global developmental delay, speech delay, moderate to severe intellectual deficiency, behavioral abnormalities such as angry outbursts, facial dysmorphism and ophthalmological abnormalities.
Sources: Other; to: Broly, M. et al. (2022), AJHG:
- 13 individuals from 8 families, biallelic loss of function variants (PTVs, one missense, one single AA del).
- Common phenotypic findings included global developmental delay, speech delay, moderate to severe intellectual deficiency, behavioral abnormalities such as angry outbursts, facial dysmorphism and ophthalmological abnormalities.
Sources: Other
Intellectual disability syndromic and non-syndromic v0.4495 THUMPD1 Chern Lim changed review comment from: Broly, M. et al. (2022) manuscript accepted in AJHG:
- 13 individuals from 8 families, loss of function variants (PTVs, one missense, one single AA del).
- Common phenotypic findings included global developmental delay, speech delay, moderate to severe intellectual deficiency, behavioral abnormalities such as angry outbursts, facial dysmorphism and ophthalmological abnormalities.
Sources: Other; to: Broly, M. et al. (2022), AJHG:
- 13 individuals from 8 families, loss of function variants (PTVs, one missense, one single AA del).
- Common phenotypic findings included global developmental delay, speech delay, moderate to severe intellectual deficiency, behavioral abnormalities such as angry outbursts, facial dysmorphism and ophthalmological abnormalities.
Sources: Other
Intellectual disability syndromic and non-syndromic v0.4495 THUMPD1 Chern Lim gene: THUMPD1 was added
gene: THUMPD1 was added to Intellectual disability syndromic and non-syndromic. Sources: Other
Mode of inheritance for gene: THUMPD1 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: THUMPD1 were set to Syndromic form of intellectual disability associated with developmental delay, behavioral abnormalities, hearing loss and facial dysmorphism, AR
gene: THUMPD1 was marked as current diagnostic
Added comment: Broly, M. et al. (2022) manuscript accepted in AJHG:
- 13 individuals from 8 families, loss of function variants (PTVs, one missense, one single AA del).
- Common phenotypic findings included global developmental delay, speech delay, moderate to severe intellectual deficiency, behavioral abnormalities such as angry outbursts, facial dysmorphism and ophthalmological abnormalities.
Sources: Other
Intellectual disability syndromic and non-syndromic v0.4495 PRSS12 Ain Roesley reviewed gene: PRSS12: Rating: RED; Mode of pathogenicity: None; Publications: 12459588, 22090715, 23344636; Phenotypes: Intellectual disability, PRSS12 related MIM#249500; Mode of inheritance: None; Current diagnostic: yes
Intellectual disability syndromic and non-syndromic v0.4495 PAX5 Bryony Thompson Marked gene: PAX5 as ready
Intellectual disability syndromic and non-syndromic v0.4495 PAX5 Bryony Thompson Gene: pax5 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4495 PAX5 Bryony Thompson Classified gene: PAX5 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4495 PAX5 Bryony Thompson Gene: pax5 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4494 PAX5 Bryony Thompson gene: PAX5 was added
gene: PAX5 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: PAX5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PAX5 were set to 35094443; 31452935; 28263302; 25418537; 8001127; 27626380
Phenotypes for gene: PAX5 were set to neurodevelopmental disorder MONDO:0700092
Review for gene: PAX5 was set to GREEN
Added comment: 5 individuals from 4 families with large deletions involving PAX5 and 11 individuals from 9 families with frameshift/stopgain/missense variants and neurodevelopmental phenotypes that included delayed developmental milestones (DD), intellectual disability (ID), and/or ASD. 6 of the variants are de novo. Null mouse have retarded growth and altered patterning of the posterior midbrain. Pax5+/− mice of both sexes are hyperactive and have abnormal auditory brainstem responses.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4493 EEF1B2 Bryony Thompson Phenotypes for gene: EEF1B2 were changed from Intellectual disability to neurodevelopmental disorder MONDO:0700092; non-syndromic ID and seizures; Intellectual disability
Intellectual disability syndromic and non-syndromic v0.4492 EEF1B2 Bryony Thompson Publications for gene: EEF1B2 were set to 31845318; 21937992
Intellectual disability syndromic and non-syndromic v0.4491 EEF1B2 Bryony Thompson Classified gene: EEF1B2 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4491 EEF1B2 Bryony Thompson Gene: eef1b2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4490 EEF1B2 Bryony Thompson reviewed gene: EEF1B2: Rating: GREEN; Mode of pathogenicity: None; Publications: 31845318, 21937992, 35015920; Phenotypes: neurodevelopmental disorder MONDO:0700092, non-syndromic ID and seizures; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4490 BAP1 Zornitza Stark Marked gene: BAP1 as ready
Intellectual disability syndromic and non-syndromic v0.4490 BAP1 Zornitza Stark Gene: bap1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4490 BAP1 Zornitza Stark Classified gene: BAP1 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4490 BAP1 Zornitza Stark Gene: bap1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4489 CENPJ Zornitza Stark Publications for gene: CENPJ were set to 20522431; 23166506; 15793586; 20978018; 22775483; 32677750; 32549991
Intellectual disability syndromic and non-syndromic v0.4488 CENPJ Zornitza Stark commented on gene: CENPJ: PMID 34068194: two further families reported with Seckel syndrome, same homozygous missense, founder?
Intellectual disability syndromic and non-syndromic v0.4488 SOD1 Zornitza Stark Marked gene: SOD1 as ready
Intellectual disability syndromic and non-syndromic v0.4488 SOD1 Zornitza Stark Gene: sod1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4488 SOD1 Zornitza Stark Classified gene: SOD1 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4488 SOD1 Zornitza Stark Gene: sod1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4487 ITSN1 Zornitza Stark Marked gene: ITSN1 as ready
Intellectual disability syndromic and non-syndromic v0.4487 ITSN1 Zornitza Stark Gene: itsn1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4487 ITSN1 Zornitza Stark Classified gene: ITSN1 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4487 ITSN1 Zornitza Stark Gene: itsn1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4486 ATP5E Ain Roesley gene: ATP5E was added
gene: ATP5E was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: ATP5E was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ATP5E were set to 34954817; 20566710; 27626380; 20026007
Phenotypes for gene: ATP5E were set to Mitochondrial complex V (ATP synthase) deficiency, nuclear type 3 MIM#614053
Penetrance for gene: ATP5E were set to Complete
Review for gene: ATP5E was set to AMBER
gene: ATP5E was marked as current diagnostic
Added comment: 3 unrelated with the same Tyr12Cys avriant

3/3 with dev delay. 2/3 with ID (the other NA)
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4486 SLC38A3 Zornitza Stark Marked gene: SLC38A3 as ready
Intellectual disability syndromic and non-syndromic v0.4486 SLC38A3 Zornitza Stark Gene: slc38a3 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4486 RBL2 Alison Yeung Phenotypes for gene: RBL2 were changed from Intellectual disability; Brunet-Wagner neurodevelopmental syndrome MIM#619690 to Intellectual disability; Brunet-Wagner neurodevelopmental syndrome MIM#619690
Intellectual disability syndromic and non-syndromic v0.4486 RBL2 Alison Yeung Phenotypes for gene: RBL2 were changed from Intellectual disability to Intellectual disability; Brunet-Wagner neurodevelopmental syndrome MIM#619690
Intellectual disability syndromic and non-syndromic v0.4485 BAP1 Anna Ritchie gene: BAP1 was added
gene: BAP1 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: BAP1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: BAP1 were set to PMID: 35051358
Phenotypes for gene: BAP1 were set to syndromic intellectual disability MONDO:0000508
Penetrance for gene: BAP1 were set to unknown
Review for gene: BAP1 was set to GREEN
Added comment: 11 de novo germline heterozygous missense BAP1 variants associated with a rare syndromic neurodevelopmental disorder. Functional analysis showed that most of the variants cannot rescue the consequences of BAP1 inactivation, suggesting a loss-of-function mechanism. All affected individuals harboring a de novo BAP1 variant had DD or ID (11/11) characterized notably by speech (11/ 11) and motor delay (6/11). Most of them had hypotonia (7/11), seizures (6/11), and abnormal behavior (8/10), including autism spectrum disorder, attention deficit hyperactivity disorder, and hypersensitivity. Almost all individuals showed dysmorphic facial features (10/11), and more than half (6/11) had skeletal malformations (involving the hands [4/11], feet [3/11], or spine [2/11]). Most of the individuals had growth failure (9/11), including four individuals with a very short stature.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4485 RBL2 Alison Yeung Classified gene: RBL2 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4485 RBL2 Alison Yeung Gene: rbl2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4484 SOD1 Naomi Baker gene: SOD1 was added
gene: SOD1 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: SOD1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SOD1 were set to PMID: 31314961; 31332433; 34788402
Phenotypes for gene: SOD1 were set to Spastic tetraplegia and axial hypotonia, progressive, MIM#618598
Review for gene: SOD1 was set to GREEN
Added comment: Phenotypes include one individual with axial hypotonia and loss of gross and fine motor function beginning at 6 months of age, after which severe, progressive spastic tetraparesis developed and Babinski’s sign was present in both feet. MRI of brain detected mild frontoparietal atrophy.

The second individual had severe and marked by progressive loss of motor abilities from 9 months of age, tetraspasticity with predominance in the lower extremities, mild cerebellar atrophy, and hyperekplexia-like symptoms. Dysmorphic features such as low set, posteriorly rotated ears, and overlapping toes

The third individual is an infant with severe global developmental delay, axial hypotonia and limb spasticity. No dysmorphic facial features were noted, but she had a high arched palate, bilateral 5th finger clinodactyly, partial toe syndactyly of the second and third toes, and a single hyperpigmented macule tongue fasciculations, axial hypotonia with limb spasticity (more pronounced in the lower limbs), ankle clonus, and brisk patellar deep tendon reflexes.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4484 ITSN1 Ee Ming Wong changed review comment from: -10 individuals from eight unrelated with neurodevelopmental disorder spectrum including ASD, ID, major behavioral difficulties and/or verbal impairment.
-variants included heterozygous premature truncating and missense variants
-Majority of variants were de novo; in two patients the reported variant was inherited from paucisymptomatic father
Sources: Literature; to: -10 individuals from eight unrelated families with neurodevelopmental disorder spectrum including ASD, ID, major behavioral difficulties and/or verbal impairment.
-variants included heterozygous premature truncating and missense variants
-Majority of variants were de novo; in two patients the reported variant was inherited from paucisymptomatic father
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4484 ITSN1 Ee Ming Wong gene: ITSN1 was added
gene: ITSN1 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: ITSN1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ITSN1 were set to PMID: 34707297
Phenotypes for gene: ITSN1 were set to neurodevelopmental disorder MONDO:0700092 ITSN1-related
Penetrance for gene: ITSN1 were set to unknown
gene: ITSN1 was marked as current diagnostic
Added comment: -10 individuals from eight unrelated with neurodevelopmental disorder spectrum including ASD, ID, major behavioral difficulties and/or verbal impairment.
-variants included heterozygous premature truncating and missense variants
-Majority of variants were de novo; in two patients the reported variant was inherited from paucisymptomatic father
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4484 SLC38A3 Zornitza Stark Classified gene: SLC38A3 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4484 SLC38A3 Zornitza Stark Gene: slc38a3 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4483 SLC38A3 Zornitza Stark Classified gene: SLC38A3 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4483 SLC38A3 Zornitza Stark Gene: slc38a3 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4482 MAN2C1 Michelle Torres gene: MAN2C1 was added
gene: MAN2C1 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: MAN2C1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MAN2C1 were set to 35045343
Phenotypes for gene: MAN2C1 were set to neurodevelopmental disorder MONDO:0700092 MAN2C1-related
Review for gene: MAN2C1 was set to GREEN
Added comment: Six individuals from four different families, including two fetuses, exhibiting dysmorphic facial features, congenital anomalies such as tongue hamartoma, variable degrees of intellectual disability, and brain anomalies including polymicrogyria, interhemispheric cysts, hypothalamic hamartoma, callosal anomalies, and hypoplasia of brainstem and cerebellar vermis. Variants include PTC and missense.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4482 RBL2 Elena Savva reviewed gene: RBL2: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 33980986, 32105419, 9806916; Phenotypes: Severe motor and cognitive impairment, Intellectual disability, Brunet-Wagner neurodevelopmental syndrome MIM#619690; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4482 SLC38A3 Ain Roesley gene: SLC38A3 was added
gene: SLC38A3 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: SLC38A3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC38A3 were set to 34605855
Phenotypes for gene: SLC38A3 were set to developmental epileptic encephalopathy, SLC38A3-related MONDO:0100062
Penetrance for gene: SLC38A3 were set to Complete
Review for gene: SLC38A3 was set to GREEN
gene: SLC38A3 was marked as current diagnostic
Added comment: 7 families 6 of whom are consanguineous but unique variants in all of them

10/10 with GDD/ID
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4482 FRA10AC1 Zornitza Stark Marked gene: FRA10AC1 as ready
Intellectual disability syndromic and non-syndromic v0.4482 FRA10AC1 Zornitza Stark Gene: fra10ac1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4482 FRA10AC1 Zornitza Stark Classified gene: FRA10AC1 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4482 FRA10AC1 Zornitza Stark Gene: fra10ac1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4481 FRA10AC1 Zornitza Stark gene: FRA10AC1 was added
gene: FRA10AC1 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: FRA10AC1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FRA10AC1 were set to 34694367
Phenotypes for gene: FRA10AC1 were set to Neurodevelopmental disorder, MONDO:0700092, FRA10AC1-related
Review for gene: FRA10AC1 was set to GREEN
Added comment: PMID 34694367: 5 individuals from 3 unrelated families reported.

Variable ID, possibly related to variant type with LoF variants associated with more severe ID. All individuals had microcephaly, hypoplasia or agenesis of the corpus callosum, growth retardation, and craniofacial dysmorphism.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4480 PLAA Zornitza Stark Marked gene: PLAA as ready
Intellectual disability syndromic and non-syndromic v0.4480 PLAA Zornitza Stark Gene: plaa has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4480 PLAA Zornitza Stark Phenotypes for gene: PLAA were changed from to Neurodevelopmental disorder with progressive microcephaly, spasticity, and brain anomalies, MIM# 617527
Intellectual disability syndromic and non-syndromic v0.4479 PLAA Zornitza Stark Publications for gene: PLAA were set to
Intellectual disability syndromic and non-syndromic v0.4478 PLAA Zornitza Stark Mode of inheritance for gene: PLAA was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4477 PLAA Zornitza Stark reviewed gene: PLAA: Rating: GREEN; Mode of pathogenicity: None; Publications: 28007986, 28413018, 31322726; Phenotypes: Neurodevelopmental disorder with progressive microcephaly, spasticity, and brain anomalies, MIM# 617527; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4477 PGAP1 Zornitza Stark Marked gene: PGAP1 as ready
Intellectual disability syndromic and non-syndromic v0.4477 PGAP1 Zornitza Stark Gene: pgap1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4477 PGAP1 Zornitza Stark Phenotypes for gene: PGAP1 were changed from to Neurodevelopmental disorder with dysmorphic features, spasticity, and brain abnormalities, MIM# 615802
Intellectual disability syndromic and non-syndromic v0.4476 PGAP1 Zornitza Stark Publications for gene: PGAP1 were set to
Intellectual disability syndromic and non-syndromic v0.4475 PGAP1 Zornitza Stark Mode of inheritance for gene: PGAP1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4474 PGAP1 Zornitza Stark reviewed gene: PGAP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 24482476, 24784135, 25823418, 25804403, 26050939; Phenotypes: Neurodevelopmental disorder with dysmorphic features, spasticity, and brain abnormalities, MIM# 615802; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4474 KCNN2 Zornitza Stark Phenotypes for gene: KCNN2 were changed from Neurodevelopmental movement disorders; Developmental Delay; Seizures to Neurodevelopmental disorder with or without variable movement or behavioural abnormalities, MIM#619725
Intellectual disability syndromic and non-syndromic v0.4473 KCNN2 Zornitza Stark Mode of inheritance for gene: KCNN2 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.4472 KCNN2 Zornitza Stark reviewed gene: KCNN2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with or without variable movement or behavioural abnormalities, MIM#619725; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.4472 NAA20 Zornitza Stark Phenotypes for gene: NAA20 were changed from Autosomal recessive developmental delay, intellectual disability, and microcephaly to Intellectual developmental disorder, autosomal recessive 73, MIM# 619717
Intellectual disability syndromic and non-syndromic v0.4471 NAA20 Zornitza Stark edited their review of gene: NAA20: Changed phenotypes: Intellectual developmental disorder, autosomal recessive 73, MIM# 619717
Intellectual disability syndromic and non-syndromic v0.4471 SHANK1 Zornitza Stark Phenotypes for gene: SHANK1 were changed from Neurodevelopmental disorder, no OMIM# to Neurodevelopmental disorder, MONDO:0700092, SHANK1-related
Intellectual disability syndromic and non-syndromic v0.4470 SHANK1 Zornitza Stark reviewed gene: SHANK1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder, MONDO:0700092, SHANK1-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.4470 ABCC9 Zornitza Stark Marked gene: ABCC9 as ready
Intellectual disability syndromic and non-syndromic v0.4470 ABCC9 Zornitza Stark Gene: abcc9 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4470 ABCC9 Zornitza Stark Phenotypes for gene: ABCC9 were changed from to Intellectual disability and myopathy syndrome, MIM# 619719; Hypertrichotic osteochondrodysplasia, MIM# 239850 Cantu syndrome
Intellectual disability syndromic and non-syndromic v0.4469 ABCC9 Zornitza Stark Mode of inheritance for gene: ABCC9 was changed from Unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4468 ABCC9 Zornitza Stark reviewed gene: ABCC9: Rating: GREEN; Mode of pathogenicity: None; Publications: 31575858, 22610116, 22608503; Phenotypes: Intellectual disability and myopathy syndrome, MIM# 619719, Hypertrichotic osteochondrodysplasia, MIM# 239850 Cantu syndrome; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4468 CAMK2G Zornitza Stark Publications for gene: CAMK2G were set to 30184290
Intellectual disability syndromic and non-syndromic v0.4467 CAMK2G Zornitza Stark Phenotypes for gene: CAMK2G were changed from Intellectual disability to Mental retardation, autosomal dominant 59, MIM# 618522
Intellectual disability syndromic and non-syndromic v0.4466 CAMK2G Zornitza Stark Marked gene: CAMK2G as ready
Intellectual disability syndromic and non-syndromic v0.4466 CAMK2G Zornitza Stark Gene: camk2g has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.4466 CAMK2G Zornitza Stark Classified gene: CAMK2G as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.4466 CAMK2G Zornitza Stark Gene: camk2g has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.4465 CAMK2G Zornitza Stark edited their review of gene: CAMK2G: Changed publications: 30184290, 29100089
Intellectual disability syndromic and non-syndromic v0.4465 CAMK2G Zornitza Stark gene: CAMK2G was added
gene: CAMK2G was added to Intellectual disability syndromic and non-syndromic. Sources: Expert Review
Mode of inheritance for gene: CAMK2G was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CAMK2G were set to 30184290
Phenotypes for gene: CAMK2G were set to Intellectual disability
Mode of pathogenicity for gene: CAMK2G 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: CAMK2G was set to AMBER
Added comment: Two unrelated individuals reported with de novo (p.Arg292Pro) variant. Functional data suggests GoF.
Sources: Expert Review
Intellectual disability syndromic and non-syndromic v0.4464 CSNK2B Zornitza Stark Marked gene: CSNK2B as ready
Intellectual disability syndromic and non-syndromic v0.4464 CSNK2B Zornitza Stark Gene: csnk2b has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4464 CSNK2B Zornitza Stark Phenotypes for gene: CSNK2B were changed from to Poirier-Bienvenu neurodevelopmental syndrome , MIM#618732
Intellectual disability syndromic and non-syndromic v0.4463 CSNK2B Zornitza Stark Publications for gene: CSNK2B were set to
Intellectual disability syndromic and non-syndromic v0.4462 CSNK2B Zornitza Stark Mode of inheritance for gene: CSNK2B was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.4461 CSNK2B Zornitza Stark reviewed gene: CSNK2B: Rating: GREEN; Mode of pathogenicity: None; Publications: 28585349, 28762608; Phenotypes: Poirier-Bienvenu neurodevelopmental syndrome , MIM#618732; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.4461 GDI1 Zornitza Stark Marked gene: GDI1 as ready
Intellectual disability syndromic and non-syndromic v0.4461 GDI1 Zornitza Stark Gene: gdi1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4461 GDI1 Zornitza Stark Phenotypes for gene: GDI1 were changed from to Intellectual developmental disorder, X-linked 41 MIM#300849
Intellectual disability syndromic and non-syndromic v0.4460 GDI1 Zornitza Stark Publications for gene: GDI1 were set to
Intellectual disability syndromic and non-syndromic v0.4459 GDI1 Zornitza Stark Mode of inheritance for gene: GDI1 was changed from Unknown to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Intellectual disability syndromic and non-syndromic v0.4458 GDI1 Zornitza Stark reviewed gene: GDI1: Rating: GREEN; Mode of pathogenicity: None; Publications: 28863211, 22002931, 9620768, 9668174; Phenotypes: Intellectual developmental disorder, X-linked 41 MIM#300849; 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 syndromic and non-syndromic v0.4458 STT3A Zornitza Stark Phenotypes for gene: STT3A were changed from Congenital disorder of glycosylation, type Iw; OMIM #615596 to Congenital disorder of glycosylation, type Iw, AR, OMIM #615596; Congenital disorder of glycosylation, type Iw, autosomal dominant, MIM# 619714
Intellectual disability syndromic and non-syndromic v0.4457 FMN2 Zornitza Stark Marked gene: FMN2 as ready
Intellectual disability syndromic and non-syndromic v0.4457 FMN2 Zornitza Stark Gene: fmn2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4457 FMN2 Zornitza Stark Phenotypes for gene: FMN2 were changed from to Intellectual developmental disorder, autosomal recessive 47, MIM#616193
Intellectual disability syndromic and non-syndromic v0.4456 FMN2 Zornitza Stark Publications for gene: FMN2 were set to
Intellectual disability syndromic and non-syndromic v0.4455 FMN2 Zornitza Stark Mode of inheritance for gene: FMN2 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4454 FMN2 Zornitza Stark reviewed gene: FMN2: Rating: GREEN; Mode of pathogenicity: None; Publications: 25480035, 32162566, 24161494; Phenotypes: Intellectual developmental disorder, autosomal recessive 47, MIM#616193; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4454 MDH2 Zornitza Stark Marked gene: MDH2 as ready
Intellectual disability syndromic and non-syndromic v0.4454 MDH2 Zornitza Stark Gene: mdh2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4454 MDH2 Zornitza Stark Phenotypes for gene: MDH2 were changed from to Developmental and epileptic encephalopathy 51 MIM#617339
Intellectual disability syndromic and non-syndromic v0.4453 MDH2 Zornitza Stark Publications for gene: MDH2 were set to
Intellectual disability syndromic and non-syndromic v0.4452 MDH2 Zornitza Stark Mode of inheritance for gene: MDH2 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4451 MDH2 Zornitza Stark reviewed gene: MDH2: Rating: GREEN; Mode of pathogenicity: None; Publications: 27989324, 34766628; Phenotypes: Developmental and epileptic encephalopathy 51 MIM#617339; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4451 SIN3A Zornitza Stark Marked gene: SIN3A as ready
Intellectual disability syndromic and non-syndromic v0.4451 SIN3A Zornitza Stark Gene: sin3a has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4451 SIN3A Zornitza Stark Phenotypes for gene: SIN3A were changed from to Witteveen-Kolk syndrome, OMIM # 613406
Intellectual disability syndromic and non-syndromic v0.4450 SIN3A Zornitza Stark Publications for gene: SIN3A were set to
Intellectual disability syndromic and non-syndromic v0.4449 SIN3A Zornitza Stark Mode of inheritance for gene: SIN3A was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.4448 SIN3A Zornitza Stark Mode of inheritance for gene: SIN3A was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.4447 SOX11 Zornitza Stark Marked gene: SOX11 as ready
Intellectual disability syndromic and non-syndromic v0.4447 SOX11 Zornitza Stark Gene: sox11 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4447 SOX11 Zornitza Stark Phenotypes for gene: SOX11 were changed from to Coffin-Siris syndrome 9, OMIM # 615866
Intellectual disability syndromic and non-syndromic v0.4446 SOX11 Zornitza Stark Publications for gene: SOX11 were set to 24886874; 33785884; 33430815; 33086258; 31530938
Intellectual disability syndromic and non-syndromic v0.4446 SOX11 Zornitza Stark Publications for gene: SOX11 were set to
Intellectual disability syndromic and non-syndromic v0.4445 SOX11 Zornitza Stark Mode of inheritance for gene: SOX11 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.4444 OTUD6B Zornitza Stark Marked gene: OTUD6B as ready
Intellectual disability syndromic and non-syndromic v0.4444 OTUD6B Zornitza Stark Gene: otud6b has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4444 OTUD6B Zornitza Stark Phenotypes for gene: OTUD6B were changed from to Intellectual developmental disorder with dysmorphic facies, seizures, and distal limb anomalies, OMIM #617452
Intellectual disability syndromic and non-syndromic v0.4443 OTUD6B Zornitza Stark Publications for gene: OTUD6B were set to
Intellectual disability syndromic and non-syndromic v0.4442 OTUD6B Zornitza Stark Mode of inheritance for gene: OTUD6B was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4441 LMBRD2 Zornitza Stark Phenotypes for gene: LMBRD2 were changed from Global developmental delay; Intellectual disability; Microcephaly; Seizures; Abnormality of nervous system morphology; Abnormality of the eye to Developmental delay with variable neurologic and brain abnormalities, MIM# 619694; Global developmental delay; Intellectual disability; Microcephaly; Seizures; Abnormality of nervous system morphology; Abnormality of the eye
Intellectual disability syndromic and non-syndromic v0.4440 LMBRD2 Zornitza Stark edited their review of gene: LMBRD2: Changed phenotypes: Developmental delay with variable neurologic and brain abnormalities, MIM# 619694, Intellectual disability
Intellectual disability syndromic and non-syndromic v0.4440 OGDHL Zornitza Stark Phenotypes for gene: OGDHL were changed from Neurodevelopmental disorder featuring epilepsy, hearing loss and visual impairment to Yoon-Bellen neurodevelopmental syndrome, MIM# 619701; Neurodevelopmental disorder featuring epilepsy, hearing loss and visual impairment
Intellectual disability syndromic and non-syndromic v0.4439 OGDHL Zornitza Stark reviewed gene: OGDHL: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Yoon-Bellen neurodevelopmental syndrome, MIM# 619701; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4439 ANAPC7 Zornitza Stark Tag SV/CNV tag was added to gene: ANAPC7.
Tag founder tag was added to gene: ANAPC7.
Intellectual disability syndromic and non-syndromic v0.4439 ANAPC7 Zornitza Stark Marked gene: ANAPC7 as ready
Intellectual disability syndromic and non-syndromic v0.4439 ANAPC7 Zornitza Stark Gene: anapc7 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.4439 ANAPC7 Zornitza Stark Classified gene: ANAPC7 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.4439 ANAPC7 Zornitza Stark Gene: anapc7 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.4438 ANAPC7 Zornitza Stark gene: ANAPC7 was added
gene: ANAPC7 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: ANAPC7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ANAPC7 were set to 34942119
Phenotypes for gene: ANAPC7 were set to Ferguson-Bonni neurodevelopmental syndrome, MIM# 619699
Review for gene: ANAPC7 was set to AMBER
Added comment: 11 individuals of Amish heritage reported homozygous for an intragenic deletion. Clinical features included ID, hypotonia, deafness in 5, relatively small head size (but microcephaly only in 1), and occasional congenital anomalies.

Supportive mouse model.

Amber rating in light of this being a founder variant.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4437 DISP1 Zornitza Stark Phenotypes for gene: DISP1 were changed from Holoprosencephaly to Holoprosencephaly, MONDO:0016296
Intellectual disability syndromic and non-syndromic v0.4436 DISP1 Zornitza Stark Mode of inheritance for gene: DISP1 was changed from Unknown to Other
Intellectual disability syndromic and non-syndromic v0.4435 SIN3A Chirag Patel changed review comment from: 9 patients from 5 unrelated families reported with heterozygous truncating mutations in the SIN3A gene. Features include intellectual disability, ASD, seizures, dysmorphism, short stature, microcephaly, joint hypermotility, and small hands and feet. Brain imaging showed dilated ventricles, thin corpus callosum and, in some cases, dysgyria or polymicrogyria. Suitable for fetal anomalies panel.; to: 9 patients from 5 unrelated families reported with heterozygous truncating mutations in the SIN3A gene. Features include intellectual disability, ASD, seizures, dysmorphism, short stature, microcephaly, joint hypermotility, and small hands and feet. Brain imaging showed dilated ventricles, thin corpus callosum and, in some cases, dysgyria or polymicrogyria.
Intellectual disability syndromic and non-syndromic v0.4435 SIN3A Chirag Patel reviewed gene: SIN3A: Rating: GREEN; Mode of pathogenicity: None; Publications: PubMed: 27399968; Phenotypes: Witteveen-Kolk syndrome, OMIM # 613406; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.4435 SOX11 Chirag Patel reviewed gene: SOX11: Rating: GREEN; Mode of pathogenicity: None; Publications: PubMed: 24886874, 33785884, 33430815, 33086258, 31530938; Phenotypes: Coffin-Siris syndrome 9, OMIM # 615866; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.4435 OTUD6B Chirag Patel reviewed gene: OTUD6B: Rating: GREEN; Mode of pathogenicity: None; Publications: PubMed: 28343629, 32924626, 31147255; Phenotypes: Intellectual developmental disorder with dysmorphic facies, seizures, and distal limb anomalies, OMIM #617452; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4435 RNF220 Zornitza Stark Phenotypes for gene: RNF220 were changed from Leukodystrophy; CNS hypomyelination; Ataxia; Intellectual disability; Sensorineural hearing impairment; Elevated hepatic transaminases; Hepatic fibrosis; Dilated cardiomyopathy; Spastic paraplegia; Dysarthria; Abnormality of the corpus callosum to Leukodystrophy, hypomyelinating, 23, with ataxia, deafness, liver dysfunction, and dilated cardiomyopathy, MIM# 619688; Leukodystrophy; CNS hypomyelination; Ataxia; Intellectual disability; Sensorineural hearing impairment; Elevated hepatic transaminases; Hepatic fibrosis; Dilated cardiomyopathy; Spastic paraplegia; Dysarthria; Abnormality of the corpus callosum
Intellectual disability syndromic and non-syndromic v0.4434 RNF220 Zornitza Stark reviewed gene: RNF220: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Leukodystrophy, hypomyelinating, 23, with ataxia, deafness, liver dysfunction, and dilated cardiomyopathy, MIM# 619688, Leukodystrophy, CNS hypomyelination, Ataxia, Intellectual disability, Sensorineural hearing impairment, Elevated hepatic transaminases, Hepatic fibrosis, Dilated cardiomyopathy, Spastic paraplegia, Dysarthria, Abnormality of the corpus callosum; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4434 TCTN1 Zornitza Stark Marked gene: TCTN1 as ready
Intellectual disability syndromic and non-syndromic v0.4434 TCTN1 Zornitza Stark Gene: tctn1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4434 TCTN1 Zornitza Stark Classified gene: TCTN1 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4434 TCTN1 Zornitza Stark Gene: tctn1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4433 NSD2 Zornitza Stark Phenotypes for gene: NSD2 were changed from Microcephaly; intellectual disability to Rauch-Steindl syndrome, MIM# 619695; Microcephaly; intellectual disability
Intellectual disability syndromic and non-syndromic v0.4432 NSD2 Zornitza Stark edited their review of gene: NSD2: Changed phenotypes: Rauch-Steindl syndrome, MIM# 619695, Microcephaly, intellectual disability
Intellectual disability syndromic and non-syndromic v0.4432 HNRNPH2 Zornitza Stark Marked gene: HNRNPH2 as ready
Intellectual disability syndromic and non-syndromic v0.4432 HNRNPH2 Zornitza Stark Gene: hnrnph2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4432 HNRNPH2 Zornitza Stark Phenotypes for gene: HNRNPH2 were changed from to Intellectual developmental disorder, X-linked, syndromic, Bain type MIM#300986
Intellectual disability syndromic and non-syndromic v0.4431 HNRNPH2 Zornitza Stark Publications for gene: HNRNPH2 were set to
Intellectual disability syndromic and non-syndromic v0.4430 HNRNPH2 Zornitza Stark Mode of inheritance for gene: HNRNPH2 was changed from Unknown to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Intellectual disability syndromic and non-syndromic v0.4429 HNRNPH2 Zornitza Stark reviewed gene: HNRNPH2: Rating: GREEN; Mode of pathogenicity: None; Publications: 34907471, 33728377, 31670473, 31236915, 30887513; Phenotypes: Intellectual developmental disorder, X-linked, syndromic, Bain type MIM#300986; 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 syndromic and non-syndromic v0.4429 TCTN1 Ain Roesley gene: TCTN1 was added
gene: TCTN1 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: TCTN1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TCTN1 were set to 31302911; 28631893; 21725307; 26477546; 34980503
Phenotypes for gene: TCTN1 were set to Joubert syndrome 13, MIM# 614173; MONDO:0013608
Penetrance for gene: TCTN1 were set to Complete
Review for gene: TCTN1 was set to GREEN
gene: TCTN1 was marked as current diagnostic
Added comment: Rare cause of JBS, at least 6 families reported, mouse model.

ID/developmental delay described in at least 3 of them
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4429 PRKAR1B Zornitza Stark Phenotypes for gene: PRKAR1B were changed from Global developmental delay; Intellectual disability; Autism; Attention deficit hyperactivity disorder; Aggressive behavior; Abnormality of movement; Upslanted palpebral fissure to Marbach-Schaaf neurodevelopmental syndrome MIM#619680; Global developmental delay; Intellectual disability; Autism; Attention deficit hyperactivity disorder; Aggressive behavior; Abnormality of movement; Upslanted palpebral fissure
Intellectual disability syndromic and non-syndromic v0.4428 PRKAR1B Zornitza Stark Publications for gene: PRKAR1B were set to https://doi.org/10.1101/2020.09.10.20190314; 33057194
Intellectual disability syndromic and non-syndromic v0.4427 PRKAR1B Zornitza Stark Mode of inheritance for gene: PRKAR1B was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.4426 NAA10 Zornitza Stark Tag 5'UTR tag was added to gene: NAA10.
Intellectual disability syndromic and non-syndromic v0.4426 NAA10 Zornitza Stark Phenotypes for gene: NAA10 were changed from to Microphthalmia, syndromic 1, MIM# 309800; Ogden syndrome MIM#300855
Intellectual disability syndromic and non-syndromic v0.4425 NAA10 Zornitza Stark Publications for gene: NAA10 were set to
Intellectual disability syndromic and non-syndromic v0.4424 NAA10 Zornitza Stark Mode of inheritance for gene: NAA10 was changed from Unknown to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Intellectual disability syndromic and non-syndromic v0.4423 NAA10 Zornitza Stark reviewed gene: NAA10: Rating: GREEN; Mode of pathogenicity: None; Publications: 30842225, 34075687, 21700266; Phenotypes: Microphthalmia, syndromic 1, MIM# 309800, Ogden syndrome MIM#300855; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability syndromic and non-syndromic v0.4423 SLC35F1 Zornitza Stark Marked gene: SLC35F1 as ready
Intellectual disability syndromic and non-syndromic v0.4423 SLC35F1 Zornitza Stark Gene: slc35f1 has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v0.4423 SLC35F1 Zornitza Stark gene: SLC35F1 was added
gene: SLC35F1 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: SLC35F1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SLC35F1 were set to 33821533
Phenotypes for gene: SLC35F1 were set to Neruodevelopmental disorder, MONDO:0700092, SLC35F1-associated; Rett-like syndrome
Review for gene: SLC35F1 was set to RED
Added comment: WES found a de novo heterozygous c.1037T>C; p.(I346T) (absent in gnomad v2 and v3) in a female described to have Rett-like syndrome.

Global developmental delay, generalized tonic andtonic–clonic seizure, never acquired independent walking and developed spastictetraplegia in adulthood and limited speech

No functional data
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4422 VPS50 Zornitza Stark Phenotypes for gene: VPS50 were changed from Neonatal cholestatic liver disease; Failure to thrive; Profound global developmental delay; Postnatal microcephaly; Seizures; Abnormality of the corpus callosum to Neurodevelopmental disorder with microcephaly, seizures, and neonatal cholestasis , MIM#619685; Neonatal cholestatic liver disease; Failure to thrive; Profound global developmental delay; Postnatal microcephaly; Seizures; Abnormality of the corpus callosum
Intellectual disability syndromic and non-syndromic v0.4421 VPS50 Zornitza Stark reviewed gene: VPS50: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with microcephaly, seizures, and neonatal cholestasis , MIM#619685; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4421 PRDM13 Zornitza Stark Phenotypes for gene: PRDM13 were changed from intellectual disability, MONDO:0001071, PRDM13-associated; ataxia with cerebellar hypoplasia, MONDO:MONDO:0016054. PRDM13-associated; congenital hypogonadotropic hypogonadism, MONDO:0015770 to intellectual disability, MONDO:0001071, PRDM13-associated; ataxia with cerebellar hypoplasia, MONDO:0016054, PRDM13-associated; congenital hypogonadotropic hypogonadism, MONDO:0015770
Intellectual disability syndromic and non-syndromic v0.4420 PRDM13 Zornitza Stark Tag founder tag was added to gene: PRDM13.
Intellectual disability syndromic and non-syndromic v0.4420 CCND2 Alison Yeung Marked gene: CCND2 as ready
Intellectual disability syndromic and non-syndromic v0.4420 CCND2 Alison Yeung Gene: ccnd2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4420 CCND2 Alison Yeung Added comment: Comment on phenotypes: Distal variants associated with Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 3

Proximal variants associated with reciprocal phenotype of mild neurodevelopment disorder with microcephaly and short stature
Intellectual disability syndromic and non-syndromic v0.4420 CCND2 Alison Yeung Phenotypes for gene: CCND2 were changed from to Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 3, MIM# 615938; Neurodevelopmental disorder, CCND2-related MONDO: 0700092; Microcephaly, MONDO: 0001149
Intellectual disability syndromic and non-syndromic v0.4419 CCND2 Alison Yeung Mode of inheritance for gene: CCND2 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.4418 NAA10 Alison Yeung Marked gene: NAA10 as ready
Intellectual disability syndromic and non-syndromic v0.4418 NAA10 Alison Yeung Gene: naa10 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4418 PRKAR1B Paul De Fazio reviewed gene: PRKAR1B: Rating: GREEN; Mode of pathogenicity: None; Publications: 33833410; Phenotypes: Marbach-Schaaf neurodevelopmental syndrome MIM#619680; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Intellectual disability syndromic and non-syndromic v0.4418 NAA10 Ain Roesley reviewed gene: NAA10: Rating: GREEN; Mode of pathogenicity: None; Publications: 34075687; Phenotypes: syndromic intellectual disability MONDO:0000508; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males); Current diagnostic: yes
Intellectual disability syndromic and non-syndromic v0.4418 PRKAR1B Paul De Fazio Deleted their review
Intellectual disability syndromic and non-syndromic v0.4418 PRDM13 Alison Yeung Marked gene: PRDM13 as ready
Intellectual disability syndromic and non-syndromic v0.4418 PRDM13 Alison Yeung Gene: prdm13 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.4418 PRKAR1B Paul De Fazio reviewed gene: PRKAR1B: Rating: GREEN; Mode of pathogenicity: None; Publications: 33833410; Phenotypes: Marbach-Schaaf neurodevelopmental syndrome MIM#619680; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Intellectual disability syndromic and non-syndromic v0.4418 PRDM13 Seb Lunke Phenotypes for gene: PRDM13 were changed from intellectual disability, MONDO:0001071, PRDM13-associated; ataxia with cerebellar hypoplasia to intellectual disability, MONDO:0001071, PRDM13-associated; ataxia with cerebellar hypoplasia, MONDO:MONDO:0016054. PRDM13-associated; congenital hypogonadotropic hypogonadism, MONDO:0015770
Intellectual disability syndromic and non-syndromic v0.4417 PRDM13 Seb Lunke Classified gene: PRDM13 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.4417 PRDM13 Seb Lunke Added comment: Comment on list classification: Potential founder variant?
Intellectual disability syndromic and non-syndromic v0.4417 PRDM13 Seb Lunke Gene: prdm13 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.4416 PRDM13 Seb Lunke Tag founder was removed from gene: PRDM13.
Intellectual disability syndromic and non-syndromic v0.4416 PRDM13 Seb Lunke gene: PRDM13 was added
gene: PRDM13 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
founder tags were added to gene: PRDM13.
Mode of inheritance for gene: PRDM13 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PRDM13 were set to 34730112
Phenotypes for gene: PRDM13 were set to intellectual disability, MONDO:0001071, PRDM13-associated; ataxia with cerebellar hypoplasia
Review for gene: PRDM13 was set to AMBER
Added comment: Recessive disease causing ID and DSD described in three supposedly unrelated families (2 consanguine), but all are from Malta, and all share the same 13bp deletion spanning an exon-intron boundary. Mouse KO is embryonically lethal, and tissue specific KO failed to replicate many of the patients phenotypes, other than hypoplasia of the cerebellar vermis and hemispheres at P21.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4415 NAA20 Zornitza Stark Marked gene: NAA20 as ready
Intellectual disability syndromic and non-syndromic v0.4415 NAA20 Zornitza Stark Gene: naa20 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4415 NAA20 Zornitza Stark reviewed gene: NAA20: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Autosomal recessive developmental delay, intellectual disability, and microcephaly; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4415 RAB23 Zornitza Stark Marked gene: RAB23 as ready
Intellectual disability syndromic and non-syndromic v0.4415 RAB23 Zornitza Stark Gene: rab23 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4415 RAB23 Zornitza Stark Phenotypes for gene: RAB23 were changed from to Carpenter syndrome (MIM#201000)
Intellectual disability syndromic and non-syndromic v0.4414 RAB23 Zornitza Stark Publications for gene: RAB23 were set to
Intellectual disability syndromic and non-syndromic v0.4413 RAB23 Zornitza Stark Mode of inheritance for gene: RAB23 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4412 RAB23 Zornitza Stark reviewed gene: RAB23: Rating: GREEN; Mode of pathogenicity: None; Publications: 17503333, 21412941, 23599695, 25168863; Phenotypes: Carpenter syndrome (MIM#201000); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4412 DPF2 Zornitza Stark Marked gene: DPF2 as ready
Intellectual disability syndromic and non-syndromic v0.4412 DPF2 Zornitza Stark Gene: dpf2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4412 DPF2 Zornitza Stark Phenotypes for gene: DPF2 were changed from to Coffin-Siris syndrome 7, MIM#618027
Intellectual disability syndromic and non-syndromic v0.4411 DPF2 Zornitza Stark Publications for gene: DPF2 were set to
Intellectual disability syndromic and non-syndromic v0.4410 DPF2 Zornitza Stark Mode of inheritance for gene: DPF2 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.4409 NAA20 Chirag Patel Classified gene: NAA20 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4409 NAA20 Chirag Patel Gene: naa20 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4408 NAA20 Chirag Patel gene: NAA20 was added
gene: NAA20 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: NAA20 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NAA20 were set to PMID: 34230638
Phenotypes for gene: NAA20 were set to Autosomal recessive developmental delay, intellectual disability, and microcephaly
Added comment: 2 consanguineous families with 5 affected individuals with developmental delay, intellectual disability, and microcephaly (-2-4SD). Exome and genome sequencing identified 2 different homozygous variants in NAA20 gene (p.Met54Val and p.Ala80Val), and segregated with affected individuals. N-terminal acetyltransferases modify proteins by adding an acetyl moiety to the first amino acid and are vital for protein and cell function. The NatB complex acetylates 20% of the human proteome and is composed of the catalytic subunit NAA20 and the auxiliary subunit NAA25. Both NAA20-M54V and NAA20-A80V were impaired in their capacity to form a NatB complex with NAA25, and in vitro acetylation assays revealed reduced catalytic activities toward different NatB substrates.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4407 KCNC1 Zornitza Stark Marked gene: KCNC1 as ready
Intellectual disability syndromic and non-syndromic v0.4407 KCNC1 Zornitza Stark Gene: kcnc1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4407 KCNC1 Zornitza Stark Phenotypes for gene: KCNC1 were changed from to Intellectual disability; Movement disorders; Epilepsy, progressive myoclonic 7 (MIM#616187)
Intellectual disability syndromic and non-syndromic v0.4406 KCNC1 Zornitza Stark Publications for gene: KCNC1 were set to
Intellectual disability syndromic and non-syndromic v0.4405 KCNC1 Zornitza Stark Mode of inheritance for gene: KCNC1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.4404 KCNC1 Zornitza Stark reviewed gene: KCNC1: Rating: GREEN; Mode of pathogenicity: None; Publications: 28145425, 31353862, 25401298; Phenotypes: Intellectual disability, Movement disorders, Epilepsy, progressive myoclonic 7 (MIM#616187); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.4404 DPF2 Belinda Chong reviewed gene: DPF2: Rating: GREEN; Mode of pathogenicity: None; Publications: 29429572, 31706665; Phenotypes: Coffin-Siris syndrome 7 MIM#618027; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Intellectual disability syndromic and non-syndromic v0.4404 SGPL1 Seb Lunke Publications for gene: SGPL1 were set to
Intellectual disability syndromic and non-syndromic v0.4403 SGPL1 Seb Lunke Marked gene: SGPL1 as ready
Intellectual disability syndromic and non-syndromic v0.4403 SGPL1 Seb Lunke Gene: sgpl1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4403 SGPL1 Seb Lunke Phenotypes for gene: SGPL1 were changed from to Sphingosine Phosphate Lyase Insufficiency Syndrome; Nephrotic syndrome, type 14, MIM#617575
Intellectual disability syndromic and non-syndromic v0.4402 SGPL1 Seb Lunke Mode of inheritance for gene: SGPL1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4401 SGPL1 Seb Lunke reviewed gene: SGPL1: Rating: GREEN; Mode of pathogenicity: None; Publications: 33074640; Phenotypes: Sphingosine Phosphate Lyase Insufficiency Syndrome; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability syndromic and non-syndromic v0.4401 COX15 Zornitza Stark Publications for gene: COX15 were set to
Intellectual disability syndromic and non-syndromic v0.4401 COX15 Zornitza Stark Mode of inheritance for gene: COX15 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4400 COX15 Zornitza Stark Mode of inheritance for gene: COX15 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4399 COX15 Zornitza Stark reviewed gene: COX15: Rating: GREEN; Mode of pathogenicity: None; Publications: 33746038, 32232962, 26959537, 21412973, 12474143, 15235026; Phenotypes: Mitochondrial complex IV deficiency, nuclear type 6, MIM# 615119; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4399 BRWD3 Zornitza Stark Marked gene: BRWD3 as ready
Intellectual disability syndromic and non-syndromic v0.4399 BRWD3 Zornitza Stark Gene: brwd3 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4399 BRWD3 Zornitza Stark Phenotypes for gene: BRWD3 were changed from to Intellectual developmental disorder, X-linked 93, MIM # 300659
Intellectual disability syndromic and non-syndromic v0.4398 BRWD3 Zornitza Stark Publications for gene: BRWD3 were set to
Intellectual disability syndromic and non-syndromic v0.4397 BRWD3 Zornitza Stark Mode of inheritance for gene: BRWD3 was changed from Unknown to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Intellectual disability syndromic and non-syndromic v0.4396 BRWD3 Zornitza Stark reviewed gene: BRWD3: Rating: GREEN; Mode of pathogenicity: None; Publications: 17668385, 30628072, 24462886; Phenotypes: Intellectual developmental disorder, X-linked 93, MIM # 300659; 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 syndromic and non-syndromic v0.4396 AUTS2 Zornitza Stark Phenotypes for gene: AUTS2 were changed from Mental retardation, autosomal dominant 26, MIM#615834 to Intellectual developmental disorder, autosomal dominant 26, MIM# 615834
Intellectual disability syndromic and non-syndromic v0.4395 AUTS2 Zornitza Stark edited their review of gene: AUTS2: Changed phenotypes: Intellectual developmental disorder, autosomal dominant 26, MIM# 615834
Intellectual disability syndromic and non-syndromic v0.4395 ALDH4A1 Zornitza Stark Marked gene: ALDH4A1 as ready
Intellectual disability syndromic and non-syndromic v0.4395 ALDH4A1 Zornitza Stark Gene: aldh4a1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4395 ALDH4A1 Zornitza Stark Phenotypes for gene: ALDH4A1 were changed from to Hyperprolinemia, type II MIM#239510; disorders of ornithine or proline metabolism
Intellectual disability syndromic and non-syndromic v0.4394 ALDH4A1 Zornitza Stark Publications for gene: ALDH4A1 were set to
Intellectual disability syndromic and non-syndromic v0.4393 ALDH4A1 Zornitza Stark Mode of inheritance for gene: ALDH4A1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4392 ALDH4A1 Zornitza Stark reviewed gene: ALDH4A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 9700195, 34037900, 31884946; Phenotypes: Hyperprolinemia, type II MIM#239510, disorders of ornithine or proline metabolism; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4392 CSTF2 Zornitza Stark Marked gene: CSTF2 as ready
Intellectual disability syndromic and non-syndromic v0.4392 CSTF2 Zornitza Stark Gene: cstf2 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.4392 CSTF2 Zornitza Stark Classified gene: CSTF2 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.4392 CSTF2 Zornitza Stark Gene: cstf2 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.4391 CSTF2 Zornitza Stark gene: CSTF2 was added
gene: CSTF2 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: CSTF2 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: CSTF2 were set to 32816001
Phenotypes for gene: CSTF2 were set to Intellectual disability
Review for gene: CSTF2 was set to AMBER
Added comment: Four individuals from a single family, spanning two generations, segregating a missense variant. Functional data, including a mouse model and a gene reporter assay.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4390 FLVCR2 Zornitza Stark Marked gene: FLVCR2 as ready
Intellectual disability syndromic and non-syndromic v0.4390 FLVCR2 Zornitza Stark Gene: flvcr2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4390 FLVCR2 Zornitza Stark Phenotypes for gene: FLVCR2 were changed from to Proliferative vasculopathy and hydranencephaly-hydrocephaly syndrome, MIM# 225790
Intellectual disability syndromic and non-syndromic v0.4389 FLVCR2 Zornitza Stark Publications for gene: FLVCR2 were set to
Intellectual disability syndromic and non-syndromic v0.4388 FLVCR2 Zornitza Stark Mode of inheritance for gene: FLVCR2 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4387 FLVCR2 Zornitza Stark reviewed gene: FLVCR2: Rating: GREEN; Mode of pathogenicity: None; Publications: 30712878, 20206334, 20518025, 20690116, 25677735; Phenotypes: Proliferative vasculopathy and hydranencephaly-hydrocephaly syndrome, MIM# 225790; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4387 VPS53 Zornitza Stark Tag founder tag was added to gene: VPS53.
Intellectual disability syndromic and non-syndromic v0.4387 VPS53 Zornitza Stark Marked gene: VPS53 as ready
Intellectual disability syndromic and non-syndromic v0.4387 VPS53 Zornitza Stark Gene: vps53 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4387 VPS53 Zornitza Stark Phenotypes for gene: VPS53 were changed from to Pontocerebellar hypoplasia, type 2E, OMIM #615851
Intellectual disability syndromic and non-syndromic v0.4386 VPS53 Zornitza Stark Publications for gene: VPS53 were set to
Intellectual disability syndromic and non-syndromic v0.4385 VPS53 Zornitza Stark Mode of inheritance for gene: VPS53 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4384 VPS53 Zornitza Stark changed review comment from: Multiple Moroccan Jewish families reported, segregating two founder variants.; to: Multiple Moroccan Jewish families reported, segregating two founder variants. ID is part of the phenotype.
Intellectual disability syndromic and non-syndromic v0.4384 VPS53 Zornitza Stark reviewed gene: VPS53: Rating: GREEN; Mode of pathogenicity: None; Publications: 24577744, 12920088; Phenotypes: Pontocerebellar hypoplasia, type 2E, OMIM #615851; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4384 YY1 Zornitza Stark edited their review of gene: YY1: Changed publications: 28575647
Intellectual disability syndromic and non-syndromic v0.4384 YY1 Zornitza Stark Marked gene: YY1 as ready
Intellectual disability syndromic and non-syndromic v0.4384 YY1 Zornitza Stark Gene: yy1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4384 YY1 Zornitza Stark Phenotypes for gene: YY1 were changed from to Gabriele-de Vries syndrome, OMIM #617557
Intellectual disability syndromic and non-syndromic v0.4383 YY1 Zornitza Stark Publications for gene: YY1 were set to
Intellectual disability syndromic and non-syndromic v0.4382 YY1 Zornitza Stark Mode of inheritance for gene: YY1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.4381 YY1 Zornitza Stark reviewed gene: YY1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Gabriele-de Vries syndrome, OMIM #617557; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.4381 TNR Zornitza Stark Phenotypes for gene: TNR were changed from Spastic para- or tetraparesis; Axial muscular hypotonia; Intellectual disability; Transient opisthotonus to Neurodevelopmental disorder, nonprogressive, with spasticity and transient opisthotonus, MIM# 619653; Spastic para- or tetraparesis; Axial muscular hypotonia; Intellectual disability; Transient opisthotonus
Intellectual disability syndromic and non-syndromic v0.4380 TNR Zornitza Stark edited their review of gene: TNR: Changed phenotypes: Neurodevelopmental disorder, nonprogressive, with spasticity and transient opisthotonus, MIM# 619653, Spastic para- or tetraparesis, Axial muscular hypotonia, Intellectual disability, Transient opisthotonus
Intellectual disability syndromic and non-syndromic v0.4380 COL4A3BP Zornitza Stark Marked gene: COL4A3BP as ready
Intellectual disability syndromic and non-syndromic v0.4380 COL4A3BP Zornitza Stark Gene: col4a3bp has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4380 COL4A3BP Zornitza Stark Phenotypes for gene: COL4A3BP were changed from to Mental retardation, autosomal dominant 34, MIM# 616351
Intellectual disability syndromic and non-syndromic v0.4379 COL4A3BP Zornitza Stark Publications for gene: COL4A3BP were set to
Intellectual disability syndromic and non-syndromic v0.4378 COL4A3BP Zornitza Stark Mode of inheritance for gene: COL4A3BP was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.4377 COL4A3BP Zornitza Stark reviewed gene: COL4A3BP: Rating: GREEN; Mode of pathogenicity: None; Publications: 25533962; Phenotypes: Mental retardation, autosomal dominant 34, MIM# 616351; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.4377 ZBTB18 Zornitza Stark Marked gene: ZBTB18 as ready
Intellectual disability syndromic and non-syndromic v0.4377 ZBTB18 Zornitza Stark Gene: zbtb18 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4377 ZBTB18 Zornitza Stark Phenotypes for gene: ZBTB18 were changed from to Mental retardation, autosomal dominant 22, MIM# 612337; Intellectual disability; microcephaly; corpus callosum abnormalities
Intellectual disability syndromic and non-syndromic v0.4376 ZBTB18 Zornitza Stark Publications for gene: ZBTB18 were set to
Intellectual disability syndromic and non-syndromic v0.4375 ZBTB18 Zornitza Stark Mode of inheritance for gene: ZBTB18 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.4374 ZBTB18 Zornitza Stark reviewed gene: ZBTB18: Rating: GREEN; Mode of pathogenicity: None; Publications: 29573576; Phenotypes: Mental retardation, autosomal dominant 22, MIM# 612337, Intellectual disability, microcephaly, corpus callosum abnormalities; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.4374 ZBTB20 Zornitza Stark Marked gene: ZBTB20 as ready
Intellectual disability syndromic and non-syndromic v0.4374 ZBTB20 Zornitza Stark Gene: zbtb20 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4374 ZBTB20 Zornitza Stark Phenotypes for gene: ZBTB20 were changed from to Primrose syndrome, MIM# 259050
Intellectual disability syndromic and non-syndromic v0.4373 ZBTB20 Zornitza Stark Publications for gene: ZBTB20 were set to
Intellectual disability syndromic and non-syndromic v0.4372 ZBTB20 Zornitza Stark Mode of inheritance for gene: ZBTB20 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.4371 ZBTB20 Zornitza Stark reviewed gene: ZBTB20: Rating: GREEN; Mode of pathogenicity: None; Publications: 25017102, 27061120, 30256248; Phenotypes: Primrose syndrome, MIM# 259050; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.4371 KCND2 Zornitza Stark Marked gene: KCND2 as ready
Intellectual disability syndromic and non-syndromic v0.4371 KCND2 Zornitza Stark Gene: kcnd2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4371 KCND2 Zornitza Stark Classified gene: KCND2 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4371 KCND2 Zornitza Stark Gene: kcnd2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4370 KCND2 Zornitza Stark gene: KCND2 was added
gene: KCND2 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: KCND2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KCND2 were set to 24501278; 16934482; 29581270; 34245260
Phenotypes for gene: KCND2 were set to Neurodevelopmental disorder MONDO:0700092; global developmental delay, HP:0001263; seizure, HP:0001250
Review for gene: KCND2 was set to GREEN
Added comment: 6 new unrelated cases with developmental delay reported in PMID: 34245260 (Zhang et al 2021), 3 of whom had seizures. All had heterozygous missense variants of KCND2 in sites known to be critical for channel gating (E323K, P403A, two individuals, V404L, two individuals and V404M). Functional studies suggest that these missense changes cause both a partial loss-of-function (LOF) and gain-of-function (GOF). The V404 change appears to increase epileptic seizure susceptibility with the 3 patients with a V404 change showing this phenotype.

PMID:24501278 - Lee et al, 2014 - reports pair of monozygotic twin boys with infantile onset severe refractory epilepsy and autism. A de novo heterozygous missense variant was identified by WES - V404M.

PMID: 29581270 - Lin et al, 2018 - performed functional work that shows V404M enhances inactivation of channels that have not yet opened and dramatically impairs the inactivation of channels that have opened.

PMID:16934482 - Singh et al, 2006 - reports a patient with cognative impairment who also went on to have seizures starting from age 13 with a 5 bp deletion in KCND2 leading to premature stop codon. The proband's asymptomatic father also shared this variant.
Sources: Literature
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4369 EIF4A3 Zornitza Stark Tag STR tag was added to gene: EIF4A3.
Intellectual disability syndromic and non-syndromic v0.4369 UBE4A Zornitza Stark Marked gene: UBE4A as ready
Intellectual disability syndromic and non-syndromic v0.4369 UBE4A Zornitza Stark Gene: ube4a has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4369 UBE4A Zornitza Stark Phenotypes for gene: UBE4A were changed from Intellectual disability and global developmental delay to Neurodevelopmental disorder with hypotonia and gross motor and seech delay, MIM# 619639
Intellectual disability syndromic and non-syndromic v0.4368 UBE4A Zornitza Stark reviewed gene: UBE4A: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with hypotonia and gross motor and seech delay, MIM# 619639; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4368 CHD8 Zornitza Stark Marked gene: CHD8 as ready
Intellectual disability syndromic and non-syndromic v0.4368 CHD8 Zornitza Stark Gene: chd8 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4368 CHD8 Zornitza Stark Phenotypes for gene: CHD8 were changed from to {Autism, susceptibility to, 18} 615032; CHD8-related neurodevelopmental syndrome
Intellectual disability syndromic and non-syndromic v0.4367 CHD8 Zornitza Stark Publications for gene: CHD8 were set to
Intellectual disability syndromic and non-syndromic v0.4366 CHD8 Zornitza Stark Mode of inheritance for gene: CHD8 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.4365 CHD8 Zornitza Stark reviewed gene: CHD8: Rating: GREEN; Mode of pathogenicity: None; Publications: 31980904; Phenotypes: {Autism, susceptibility to, 18} 615032, CHD8-related neurodevelopmental syndrome; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.4365 CCDC22 Zornitza Stark Marked gene: CCDC22 as ready
Intellectual disability syndromic and non-syndromic v0.4365 CCDC22 Zornitza Stark Gene: ccdc22 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4365 CCDC22 Zornitza Stark Phenotypes for gene: CCDC22 were changed from to Ritscher-Schinzel syndrome 2, MIM# 300963
Intellectual disability syndromic and non-syndromic v0.4364 CCDC22 Zornitza Stark Publications for gene: CCDC22 were set to
Intellectual disability syndromic and non-syndromic v0.4363 CCDC22 Zornitza Stark Mode of inheritance for gene: CCDC22 was changed from Unknown to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability syndromic and non-syndromic v0.4362 CCDC22 Zornitza Stark reviewed gene: CCDC22: Rating: GREEN; Mode of pathogenicity: None; Publications: 21826058, 24916641, 34020006, 33059814, 31971710; Phenotypes: Ritscher-Schinzel syndrome 2, MIM# 300963; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability syndromic and non-syndromic v0.4362 ADCY5 Zornitza Stark Phenotypes for gene: ADCY5 were changed from Dyskinesia, familial, with facial myokymia, MIM#606703 to Neurodevelopmental disorder with hyperkinetic movements and dyskinesia (NEDHYD), MIM#619651
Intellectual disability syndromic and non-syndromic v0.4361 ADCY5 Zornitza Stark Publications for gene: ADCY5 were set to 22782511; 24700542; 33051786; 32647899; 33704598
Intellectual disability syndromic and non-syndromic v0.4360 ADCY5 Zornitza Stark Mode of inheritance for gene: ADCY5 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4359 ADCY5 Zornitza Stark Classified gene: ADCY5 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.4359 ADCY5 Zornitza Stark Gene: adcy5 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.4358 ADCY5 Zornitza Stark changed review comment from: Mono-allelic variants in this gene also cause a movement disorder, intellectual disability is not typically a feature.

Note also reports of a milder AR condition causing a movement disorder, where ID is not a feature.; to: Mono-allelic variants in this gene also cause a movement disorder, intellectual disability is not typically a feature.

Note also reports of a milder AR condition causing a movement disorder, where ID is not a feature, Hyperkinetic movement disorder with dyskinesia, myoclonus, chorea, and dystonia-2 (HYDMCD2), MIM#619647.
Intellectual disability syndromic and non-syndromic v0.4358 ADCY5 Zornitza Stark changed review comment from: Variants in this gene cause a movement disorder, intellectual disability is not typically a feature.

Note one report of two siblings with bi-allelic variants and much more severe phenotype including ID (PMID 33704598); however parents were asymptomatic so evidence for causality is limited.; to: Mono-allelic variants in this gene also cause a movement disorder, intellectual disability is not typically a feature.

Note also reports of a milder AR condition causing a movement disorder, where ID is not a feature.
Intellectual disability syndromic and non-syndromic v0.4358 ADCY5 Zornitza Stark edited their review of gene: ADCY5: Added comment: Neurodevelopmental disorder with hyperkinetic movements and dyskinesia (NEDHYD) is an autosomal recessive complex neurologic disorder characterized by severe global developmental delay with axial hypotonia, impaired intellectual development, poor overall growth, and abnormal involuntary hyperkinetic movements, including dystonia, myoclonus, spasticity, and orofacial dyskinesia. It is the most severe manifestation of ADCY5-related dyskinetic disorders. Five individuals from 2 families reported.; Changed rating: AMBER; Changed publications: 22782511, 24700542, 33051786, 32647899, 33704598, 34631954, 28971144, 30975617; Changed phenotypes: Neurodevelopmental disorder with hyperkinetic movements and dyskinesia (NEDHYD), MIM#619651; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4358 CAMK2A Zornitza Stark Marked gene: CAMK2A as ready
Intellectual disability syndromic and non-syndromic v0.4358 CAMK2A Zornitza Stark Gene: camk2a has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4358 CAMK2A Zornitza Stark Phenotypes for gene: CAMK2A were changed from to Mental retardation, autosomal recessive 63 MIM#618095; Mental retardation, autosomal dominant 53 MIM#617798
Intellectual disability syndromic and non-syndromic v0.4357 CAMK2A Zornitza Stark Publications for gene: CAMK2A were set to
Intellectual disability syndromic and non-syndromic v0.4356 CAMK2A Zornitza Stark Mode of inheritance for gene: CAMK2A was changed from Unknown to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4355 CAMK2A Zornitza Stark reviewed gene: CAMK2A: Rating: GREEN; Mode of pathogenicity: None; Publications: 32600977, 29784083, 29560374; Phenotypes: Mental retardation, autosomal recessive 63 MIM#618095, Mental retardation, autosomal dominant 53 MIM#617798; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4355 BCAS3 Zornitza Stark Phenotypes for gene: BCAS3 were changed from Syndromic neurodevelopmental disorder to Hengel-Maroofian-Schols syndrome, MIM# 619641
Intellectual disability syndromic and non-syndromic v0.4354 BCAS3 Zornitza Stark reviewed gene: BCAS3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Hengel-Maroofian-Schols syndrome, MIM# 619641; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4354 ASXL2 Zornitza Stark Marked gene: ASXL2 as ready
Intellectual disability syndromic and non-syndromic v0.4354 ASXL2 Zornitza Stark Gene: asxl2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4354 ASXL2 Zornitza Stark Phenotypes for gene: ASXL2 were changed from to Shashi-Pena syndrome, MIM# 617190
Intellectual disability syndromic and non-syndromic v0.4353 ASXL2 Zornitza Stark Publications for gene: ASXL2 were set to
Intellectual disability syndromic and non-syndromic v0.4352 ASXL2 Zornitza Stark Mode of inheritance for gene: ASXL2 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.4351 ASXL2 Zornitza Stark Deleted their comment
Intellectual disability syndromic and non-syndromic v0.4351 ASXL2 Zornitza Stark commented on gene: ASXL2: Shashi-Pena syndrome is a neurodevelopmental syndrome characterized by delayed psychomotor development, variable intellectual disability, hypotonia, facial dysmorphism, and some unusual features, including enlarged head circumference, glabellar nevus flammeus, and deep palmar creases. Some patients may also have atrial septal defect, episodic hypoglycaemia, changes in bone mineral density, and/or seizures.

At least 7 unrelated individuals reported.
Intellectual disability syndromic and non-syndromic v0.4351 ASXL2 Zornitza Stark reviewed gene: ASXL2: Rating: GREEN; Mode of pathogenicity: None; Publications: 27693232, 33751773; Phenotypes: Shashi-Pena syndrome, MIM# 617190; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.4351 ARFGEF2 Zornitza Stark Marked gene: ARFGEF2 as ready
Intellectual disability syndromic and non-syndromic v0.4351 ARFGEF2 Zornitza Stark Gene: arfgef2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4351 ARFGEF2 Zornitza Stark Phenotypes for gene: ARFGEF2 were changed from to Periventricular heterotopia with microcephaly (MIM#608097)
Intellectual disability syndromic and non-syndromic v0.4350 ARFGEF2 Zornitza Stark Publications for gene: ARFGEF2 were set to
Intellectual disability syndromic and non-syndromic v0.4349 ARFGEF2 Zornitza Stark Mode of inheritance for gene: ARFGEF2 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4348 ARFGEF2 Zornitza Stark reviewed gene: ARFGEF2: Rating: GREEN; Mode of pathogenicity: None; Publications: 25160555, 26126837, 23812912; Phenotypes: Periventricular heterotopia with microcephaly (MIM#608097); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4348 BLOC1S1 Zornitza Stark Marked gene: BLOC1S1 as ready
Intellectual disability syndromic and non-syndromic v0.4348 BLOC1S1 Zornitza Stark Gene: bloc1s1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4348 BLOC1S1 Zornitza Stark Classified gene: BLOC1S1 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4348 BLOC1S1 Zornitza Stark Gene: bloc1s1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4347 BLOC1S1 Zornitza Stark gene: BLOC1S1 was added
gene: BLOC1S1 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: BLOC1S1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BLOC1S1 were set to 33875846
Phenotypes for gene: BLOC1S1 were set to severe intellectual disability; severe global developmental delay; epilepsy
Review for gene: BLOC1S1 was set to GREEN
Added comment: 4 individuals reported.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4346 CLCN7 Zornitza Stark Classified gene: CLCN7 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.4346 CLCN7 Zornitza Stark Gene: clcn7 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.4346 CLCN7 Zornitza Stark Classified gene: CLCN7 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.4346 CLCN7 Zornitza Stark Gene: clcn7 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.4345 CLCN7 Zornitza Stark Marked gene: CLCN7 as ready
Intellectual disability syndromic and non-syndromic v0.4345 CLCN7 Zornitza Stark Gene: clcn7 has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v0.4345 CLCN7 Zornitza Stark gene: CLCN7 was added
gene: CLCN7 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: CLCN7 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CLCN7 were set to 31155284
Phenotypes for gene: CLCN7 were set to Hypopigmentation, organomegaly, and delayed myelination and development, MIM# 618541
Mode of pathogenicity for gene: CLCN7 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: CLCN7 was set to AMBER
Added comment: Two individuals reported with same missense variant and hypopigmentation, organomegaly, and delayed myelination and development. Variant is GoF. No osteopetrosis, biopsy findings from skin and other organs are consistent with a lysosomal storage disorder. IUGR, prematurity and polyhydramnios are features. Bi-allelic variants in this gene are associated with osteopetrosis.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4344 SNIP1 Zornitza Stark Classified gene: SNIP1 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.4344 SNIP1 Zornitza Stark Gene: snip1 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.4343 SNIP1 Zornitza Stark edited their review of gene: SNIP1: Added comment: A single (founder) variant NM_024700.4:c.1097A>G, p.(Glu366Gly) has been reported in over 30 cases of Psychomotor retardation, epilepsy, and craniofacial dysmorphism OMIM:614501 in the Amish community (PMIDs: 22279524; 34570759). Cases are homozygous for this variant and unaffected members of the families are heterozygous or wt. Overexpression of the equivalent mouse variant in mouse inner medullary collecting duct cells, resulted in a more aggregated appearance in the nucleus compared to wildtype. The variant protein maybe unstable as Western blots showed reduced levels of the variant protein (PMID: 22279524). Whole transcriptomic analysis of patient blood was performed in PMID: 34570759. This revealed 11 upregulated and 32 downregulated genes, of which 24 had previously been associated with neurological disease.; Changed rating: AMBER
Intellectual disability syndromic and non-syndromic v0.4343 TAF4 Zornitza Stark Marked gene: TAF4 as ready
Intellectual disability syndromic and non-syndromic v0.4343 TAF4 Zornitza Stark Gene: taf4 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.4343 TAF4 Zornitza Stark Classified gene: TAF4 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.4343 TAF4 Zornitza Stark Gene: taf4 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.4342 TAF4 Zornitza Stark gene: TAF4 was added
gene: TAF4 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: TAF4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TAF4 were set to 33875846; 28191890
Phenotypes for gene: TAF4 were set to Neurodevelopmental disorder
Review for gene: TAF4 was set to AMBER
Added comment: Three individuals reported with de novo LoF variants as part of large cohorts, limited phenotypic information available.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4341 RAB11A Zornitza Stark Classified gene: RAB11A as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4341 RAB11A Zornitza Stark Gene: rab11a has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4340 RAB11A Zornitza Stark edited their review of gene: RAB11A: Added comment: Two additional cases reported in PMID 33875846.; Changed rating: GREEN; Changed publications: 29100083, 33875846
Intellectual disability syndromic and non-syndromic v0.4340 PLK1 Zornitza Stark Classified gene: PLK1 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4340 PLK1 Zornitza Stark Gene: plk1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4339 PLK1 Zornitza Stark Marked gene: PLK1 as ready
Intellectual disability syndromic and non-syndromic v0.4339 PLK1 Zornitza Stark Gene: plk1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4339 PLK1 Zornitza Stark Classified gene: PLK1 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4339 PLK1 Zornitza Stark Gene: plk1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4338 PLK1 Zornitza Stark gene: PLK1 was added
gene: PLK1 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: PLK1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PLK1 were set to 33875846
Phenotypes for gene: PLK1 were set to Epilepsy; microcephaly; intellectual disability
Review for gene: PLK1 was set to GREEN
Added comment: More than 5 individuals reported.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4337 RAP1GDS1 Zornitza Stark Publications for gene: RAP1GDS1 were set to 32431071
Intellectual disability syndromic and non-syndromic v0.4336 RAP1GDS1 Zornitza Stark Classified gene: RAP1GDS1 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4336 RAP1GDS1 Zornitza Stark Gene: rap1gds1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4335 RAP1GDS1 Zornitza Stark edited their review of gene: RAP1GDS1: Added comment: Two additional families reported.; Changed rating: GREEN; Changed publications: 32431071, 33875846
Intellectual disability syndromic and non-syndromic v0.4335 TMEM218 Zornitza Stark Marked gene: TMEM218 as ready
Intellectual disability syndromic and non-syndromic v0.4335 TMEM218 Zornitza Stark Gene: tmem218 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4335 TMEM218 Zornitza Stark Classified gene: TMEM218 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4335 TMEM218 Zornitza Stark Gene: tmem218 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4334 TMEM218 Zornitza Stark gene: TMEM218 was added
gene: TMEM218 was added to Intellectual disability syndromic and non-syndromic. Sources: Expert Review
Mode of inheritance for gene: TMEM218 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TMEM218 were set to 33791682; 25161209
Phenotypes for gene: TMEM218 were set to Joubert syndrome 39, MIM#619562
Review for gene: TMEM218 was set to GREEN
Added comment: 11 cases in 6 families with homozygous or compound heterozygous missense and nonsense (1) variants, with a Joubert/Meckel syndrome phenotype. Clinical features included the molar tooth sign (N=2), occipital encephalocele (N=5, all fetuses), retinal dystrophy (N=4, all living individuals), polycystic kidneys (N=2), and polydactyly (N=2), without liver involvement. A null mouse model had nephronophthisis and retinal degeneration. No OMIM entry.
Sources: Expert Review
Intellectual disability syndromic and non-syndromic v0.4333 ATP9A Zornitza Stark Publications for gene: ATP9A were set to http://dx.doi.org/10.1136/jmedgenet-2021-107843
Intellectual disability syndromic and non-syndromic v0.4332 ATP9A Zornitza Stark Classified gene: ATP9A as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4332 ATP9A Zornitza Stark Gene: atp9a has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4331 ATP9A Zornitza Stark edited their review of gene: ATP9A: Changed rating: GREEN
Intellectual disability syndromic and non-syndromic v0.4331 ATP9A Zornitza Stark edited their review of gene: ATP9A: Added comment: Four unrelated families and mouse model.; Changed publications: 34379057, 34764295
Intellectual disability syndromic and non-syndromic v0.4331 CNKSR2 Zornitza Stark Marked gene: CNKSR2 as ready
Intellectual disability syndromic and non-syndromic v0.4331 CNKSR2 Zornitza Stark Gene: cnksr2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4331 CNKSR2 Zornitza Stark Phenotypes for gene: CNKSR2 were changed from to Intellectual developmental disorder, X-linked, syndromic, Houge type, MIM# 301008
Intellectual disability syndromic and non-syndromic v0.4330 CNKSR2 Zornitza Stark Publications for gene: CNKSR2 were set to
Intellectual disability syndromic and non-syndromic v0.4329 CNKSR2 Zornitza Stark Mode of inheritance for gene: CNKSR2 was changed from Unknown to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Intellectual disability syndromic and non-syndromic v0.4328 CNKSR2 Zornitza Stark edited their review of gene: CNKSR2: Changed mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Intellectual disability syndromic and non-syndromic v0.4328 CNKSR2 Zornitza Stark reviewed gene: CNKSR2: Rating: GREEN; Mode of pathogenicity: None; Publications: 34266427; Phenotypes: Intellectual developmental disorder, X-linked, syndromic, Houge type, MIM# 301008; Mode of inheritance: None
Intellectual disability syndromic and non-syndromic v0.4328 ANK3 Zornitza Stark Phenotypes for gene: ANK3 were changed from Mental retardation, autosomal recessive, 37 615493 to Mental retardation, autosomal recessive, 37 615493; Intellectual disability, autosomal dominant
Intellectual disability syndromic and non-syndromic v0.4327 ANK3 Zornitza Stark Classified gene: ANK3 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4327 ANK3 Zornitza Stark Gene: ank3 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4326 ANK3 Zornitza Stark edited their review of gene: ANK3: Added comment: PMID 34218362: four unrelated novel, and two previously published patients with heterozygos ANK3 LoF variants are reported/summarized.; Changed rating: GREEN; Changed publications: 23390136, 28687526, 34218362
Intellectual disability syndromic and non-syndromic v0.4326 OGDHL Zornitza Stark Marked gene: OGDHL as ready
Intellectual disability syndromic and non-syndromic v0.4326 OGDHL Zornitza Stark Gene: ogdhl has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4326 OGDHL Zornitza Stark Classified gene: OGDHL as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4326 OGDHL Zornitza Stark Gene: ogdhl has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4325 FOXR1 Zornitza Stark Mode of pathogenicity for gene: FOXR1 was changed from Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments to None
Intellectual disability syndromic and non-syndromic v0.4324 FOXR1 Zornitza Stark Marked gene: FOXR1 as ready
Intellectual disability syndromic and non-syndromic v0.4324 FOXR1 Zornitza Stark Gene: foxr1 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.4324 FOXR1 Zornitza Stark Classified gene: FOXR1 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.4324 FOXR1 Zornitza Stark Gene: foxr1 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.4323 Zornitza Stark removed gene:FOXR2 from the panel
Intellectual disability syndromic and non-syndromic v0.4322 OGDHL Melanie Marty Deleted their comment
Intellectual disability syndromic and non-syndromic v0.4322 OGDHL Melanie Marty edited their review of gene: OGDHL: Added comment: Nine individuals from eight unrelated families carrying bi-allelic variants in OGDHL with a range of neurological and neurodevelopmental phenotypes including epilepsy, hearing
loss, visual impairment, gait ataxia, microcephaly, and hypoplastic corpus callosum.

Homozygous and compound heterozygous variants reported. Variant types reported include missense, PTCs and a synonymous variant that was shown to affect splicing.

Functional studies with a CRISPR-Cas9-mediated tissue knockout with cDNA rescue system showed that the missense variants result in loss-of-function.; Changed rating: GREEN
Intellectual disability syndromic and non-syndromic v0.4322 OGDHL Melanie Marty commented on gene: OGDHL: Nine individuals from eight unrelated families carrying bi-allelic variants in OGDHL with a range of neurological and neurodevelopmental phenotypes including epilepsy, hearing
loss, visual impairment, gait ataxia, microcephaly, and hypoplastic corpus callosum.

Homozygous and compound heterozygous variants reported. Variant types reported include missense, PTCs and a synonymous variant that was shown to affect splicing.

Functional studies with a CRISPR-Cas9-mediated tissue knockout with cDNA rescue system showed that the missense variants result in loss-of-function.
Intellectual disability syndromic and non-syndromic v0.4322 OGDHL Melanie Marty Deleted their comment
Intellectual disability syndromic and non-syndromic v0.4322 OGDHL Melanie Marty changed review comment from: Nine individuals from eight unrelated families carrying bi-allelic variants in OGDHL with a range of neurological and neurodevelopmental phenotypes including epilepsy, hearing
loss, visual impairment, gait ataxia, microcephaly, and hypoplastic corpus callosum.

Homozygous and compound heterozygous variants reported. Variant types reported include missense, PTCs and a synonymous variant that was shown to affect splicing.

Functional studies with a CRISPR-Cas9-mediated tissue knockout with cDNA rescue system showed that the missense variants result in loss-of-function.
Sources: Literature; to: Nine individuals from eight unrelated families carrying bi-allelic variants in OGDHL with a range of neurological and neurodevelopmental phenotypes including epilepsy, hearing
loss, visual impairment, gait ataxia, microcephaly, and hypoplastic corpus callosum.

Homozygous and compound heterozygous variants reported. Variant types reported include missense, PTCs and a synonymous variant that was shown to affect splicing.

Functional studies with a CRISPR-Cas9-mediated tissue knockout with cDNA rescue system showed that the missense variants result in loss-of-function.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4322 OGDHL Melanie Marty gene: OGDHL was added
gene: OGDHL was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: OGDHL was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: OGDHL were set to PMID: 34800363
Phenotypes for gene: OGDHL were set to Neurodevelopmental disorder featuring epilepsy, hearing loss and visual impairment
Added comment: Nine individuals from eight unrelated families carrying bi-allelic variants in OGDHL with a range of neurological and neurodevelopmental phenotypes including epilepsy, hearing
loss, visual impairment, gait ataxia, microcephaly, and hypoplastic corpus callosum.

Homozygous and compound heterozygous variants reported. Variant types reported include missense, PTCs and a synonymous variant that was shown to affect splicing.

Functional studies with a CRISPR-Cas9-mediated tissue knockout with cDNA rescue system showed that the missense variants result in loss-of-function.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4322 FOXR2 Paul De Fazio reviewed gene: FOXR2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: Other; Current diagnostic: yes
Intellectual disability syndromic and non-syndromic v0.4322 FOXR2 Paul De Fazio Deleted their review
Intellectual disability syndromic and non-syndromic v0.4322 FOXR2 Paul De Fazio edited their review of gene: FOXR2: Changed publications: -; Changed phenotypes: -
Intellectual disability syndromic and non-syndromic v0.4322 FOXR2 Paul De Fazio edited their review of gene: FOXR2: Changed rating: RED; Changed mode of inheritance: Other
Intellectual disability syndromic and non-syndromic v0.4322 FOXR2 Paul De Fazio changed review comment from: Geme added incorrectly.; to: Gene added incorrectly.
Intellectual disability syndromic and non-syndromic v0.4322 FOXR2 Paul De Fazio changed review comment from: 1 patient described with a de novo missense variant. Phenotypes include: postnatal microcephaly, progressive brain atrophy, skeletal abnormalities, brain abnormalities, ophthalmic abnormalities, neuromuscular abnormalities, and dysmorphic features. A variant in ATP1A3 was considered to have contributed to the final phenotype.

In vitro functional evidence is supportive of pathogenicity (variant causes protein instability and abnormal nuclear aggregation).

A mouse knockout has comparable phenotypes, and a severe survival deficit.

Rated amber (1 patient, functional evidence, mouse model).
Sources: Literature; to: Geme added incorrectly.
Intellectual disability syndromic and non-syndromic v0.4322 FOXR1 Paul De Fazio gene: FOXR1 was added
gene: FOXR1 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: FOXR1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: FOXR1 were set to 34723967
Phenotypes for gene: FOXR1 were set to Postnatal microcephaly, progressive brain atrophy and global developmental delay
Mode of pathogenicity for gene: FOXR1 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: FOXR1 was set to AMBER
gene: FOXR1 was marked as current diagnostic
Added comment: 1 patient described with a de novo missense variant. Phenotypes include: postnatal microcephaly, progressive brain atrophy, skeletal abnormalities, brain abnormalities, ophthalmic abnormalities, neuromuscular abnormalities, and dysmorphic features. A variant in ATP1A3 was considered to have contributed to the final phenotype.

In vitro functional evidence is supportive of pathogenicity (variant causes protein instability and abnormal nuclear aggregation).

A mouse knockout has comparable phenotypes, and a severe survival deficit.

Rated amber (1 patient, functional evidence, mouse model).
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4322 FOXR2 Paul De Fazio gene: FOXR2 was added
gene: FOXR2 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: FOXR2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: FOXR2 were set to 34723967
Phenotypes for gene: FOXR2 were set to Postnatal microcephaly, progressive brain atrophy and global developmental delay
Review for gene: FOXR2 was set to AMBER
gene: FOXR2 was marked as current diagnostic
Added comment: 1 patient described with a de novo missense variant. Phenotypes include: postnatal microcephaly, progressive brain atrophy, skeletal abnormalities, brain abnormalities, ophthalmic abnormalities, neuromuscular abnormalities, and dysmorphic features. A variant in ATP1A3 was considered to have contributed to the final phenotype.

In vitro functional evidence is supportive of pathogenicity (variant causes protein instability and abnormal nuclear aggregation).

A mouse knockout has comparable phenotypes, and a severe survival deficit.

Rated amber (1 patient, functional evidence, mouse model).
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4322 RNF125 Zornitza Stark Marked gene: RNF125 as ready
Intellectual disability syndromic and non-syndromic v0.4322 RNF125 Zornitza Stark Gene: rnf125 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4322 RNF125 Zornitza Stark Phenotypes for gene: RNF125 were changed from to Tenorio syndrome - MIM# 616260
Intellectual disability syndromic and non-syndromic v0.4321 RNF125 Zornitza Stark Publications for gene: RNF125 were set to
Intellectual disability syndromic and non-syndromic v0.4320 RNF125 Zornitza Stark Mode of inheritance for gene: RNF125 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.4319 RNF125 Zornitza Stark reviewed gene: RNF125: Rating: GREEN; Mode of pathogenicity: None; Publications: 25196541; Phenotypes: Tenorio syndrome - MIM# 616260; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.4319 GTPBP3 Zornitza Stark Marked gene: GTPBP3 as ready
Intellectual disability syndromic and non-syndromic v0.4319 GTPBP3 Zornitza Stark Gene: gtpbp3 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4319 GTPBP3 Zornitza Stark Phenotypes for gene: GTPBP3 were changed from to Combined oxidative phosphorylation deficiency 23, MIM#616198
Intellectual disability syndromic and non-syndromic v0.4318 GTPBP3 Zornitza Stark Publications for gene: GTPBP3 were set to
Intellectual disability syndromic and non-syndromic v0.4317 GTPBP3 Zornitza Stark Mode of inheritance for gene: GTPBP3 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4316 GTPBP3 Zornitza Stark reviewed gene: GTPBP3: Rating: GREEN; Mode of pathogenicity: None; Publications: 34276756, 25434004; Phenotypes: Combined oxidative phosphorylation deficiency 23 MIM#616198; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4316 CWC27 Zornitza Stark Marked gene: CWC27 as ready
Intellectual disability syndromic and non-syndromic v0.4316 CWC27 Zornitza Stark Gene: cwc27 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4316 CWC27 Zornitza Stark Phenotypes for gene: CWC27 were changed from to Retinitis pigmentosa with or without skeletal anomalies, MIM# 250410
Intellectual disability syndromic and non-syndromic v0.4315 CWC27 Zornitza Stark Publications for gene: CWC27 were set to
Intellectual disability syndromic and non-syndromic v0.4314 CWC27 Zornitza Stark Mode of inheritance for gene: CWC27 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4313 CWC27 Zornitza Stark reviewed gene: CWC27: Rating: GREEN; Mode of pathogenicity: None; Publications: 28285769, 31481716; Phenotypes: Retinitis pigmentosa with or without skeletal anomalies, MIM# 250410; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4313 ELAC2 Zornitza Stark Marked gene: ELAC2 as ready
Intellectual disability syndromic and non-syndromic v0.4313 ELAC2 Zornitza Stark Gene: elac2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4313 ELAC2 Zornitza Stark Phenotypes for gene: ELAC2 were changed from to Combined oxidative phosphorylation deficiency 17, MIM#615440
Intellectual disability syndromic and non-syndromic v0.4312 ELAC2 Zornitza Stark Publications for gene: ELAC2 were set to
Intellectual disability syndromic and non-syndromic v0.4311 ELAC2 Zornitza Stark Mode of inheritance for gene: ELAC2 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4310 ELAC2 Zornitza Stark reviewed gene: ELAC2: Rating: GREEN; Mode of pathogenicity: None; Publications: 23849775, 31045291; Phenotypes: Combined oxidative phosphorylation deficiency 17, MIM#615440; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4310 CUL4B Zornitza Stark Marked gene: CUL4B as ready
Intellectual disability syndromic and non-syndromic v0.4310 CUL4B Zornitza Stark Gene: cul4b has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4310 CUL4B Zornitza Stark Phenotypes for gene: CUL4B were changed from to Mental retardation, X-linked, syndromic 15 (Cabezas type), MIM# 300354
Intellectual disability syndromic and non-syndromic v0.4309 CUL4B Zornitza Stark Publications for gene: CUL4B were set to
Intellectual disability syndromic and non-syndromic v0.4308 CUL4B Zornitza Stark Mode of inheritance for gene: CUL4B was changed from Unknown to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability syndromic and non-syndromic v0.4307 CUL4B Zornitza Stark reviewed gene: CUL4B: Rating: GREEN; Mode of pathogenicity: None; Publications: 17236139, 19377476; Phenotypes: Mental retardation, X-linked, syndromic 15 (Cabezas type), MIM# 300354; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability syndromic and non-syndromic v0.4307 CTNNB1 Zornitza Stark Marked gene: CTNNB1 as ready
Intellectual disability syndromic and non-syndromic v0.4307 CTNNB1 Zornitza Stark Gene: ctnnb1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4307 CTNNB1 Zornitza Stark Phenotypes for gene: CTNNB1 were changed from to Neurodevelopmental disorder with spastic diplegia and visual defects , MIM#615075
Intellectual disability syndromic and non-syndromic v0.4306 CTNNB1 Zornitza Stark Publications for gene: CTNNB1 were set to
Intellectual disability syndromic and non-syndromic v0.4305 CTNNB1 Zornitza Stark Mode of inheritance for gene: CTNNB1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.4304 CTNNB1 Zornitza Stark reviewed gene: CTNNB1: Rating: GREEN; Mode of pathogenicity: None; Publications: 23033978, 24614104, 25326669, 27915094; Phenotypes: Neurodevelopmental disorder with spastic diplegia and visual defects , MIM#615075; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.4304 CSNK2A1 Zornitza Stark Marked gene: CSNK2A1 as ready
Intellectual disability syndromic and non-syndromic v0.4304 CSNK2A1 Zornitza Stark Gene: csnk2a1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4304 CSNK2A1 Zornitza Stark Phenotypes for gene: CSNK2A1 were changed from to Okur-Chung neurodevelopmental syndrome, MIM# 617062
Intellectual disability syndromic and non-syndromic v0.4303 CSNK2A1 Zornitza Stark Publications for gene: CSNK2A1 were set to
Intellectual disability syndromic and non-syndromic v0.4302 CSNK2A1 Zornitza Stark Mode of inheritance for gene: CSNK2A1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.4301 CSNK2A1 Zornitza Stark reviewed gene: CSNK2A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 27048600, 29240241, 29383814; Phenotypes: Okur-Chung neurodevelopmental syndrome, MIM# 617062; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.4301 MAF Zornitza Stark Marked gene: MAF as ready
Intellectual disability syndromic and non-syndromic v0.4301 MAF Zornitza Stark Gene: maf has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4301 MAF Zornitza Stark Phenotypes for gene: MAF were changed from to Ayme-Gripp syndrome (MIM#601088)
Intellectual disability syndromic and non-syndromic v0.4300 MAF Zornitza Stark Publications for gene: MAF were set to
Intellectual disability syndromic and non-syndromic v0.4299 MAF Zornitza Stark Mode of inheritance for gene: MAF was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.4298 MAF Zornitza Stark reviewed gene: MAF: Rating: GREEN; Mode of pathogenicity: None; Publications: 30160832, 34643041; Phenotypes: Ayme-Gripp syndrome (MIM#601088); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.4298 CRB2 Zornitza Stark Marked gene: CRB2 as ready
Intellectual disability syndromic and non-syndromic v0.4298 CRB2 Zornitza Stark Gene: crb2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4298 CRB2 Zornitza Stark Phenotypes for gene: CRB2 were changed from to Ventriculomegaly with cystic kidney disease, MIM# 219730
Intellectual disability syndromic and non-syndromic v0.4297 CRB2 Zornitza Stark Publications for gene: CRB2 were set to
Intellectual disability syndromic and non-syndromic v0.4296 CRB2 Zornitza Stark Mode of inheritance for gene: CRB2 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4295 CRB2 Zornitza Stark reviewed gene: CRB2: Rating: GREEN; Mode of pathogenicity: None; Publications: 25557780, 33687977, 32051522, 30212996, 33575434, 31438467, 30593785; Phenotypes: Ventriculomegaly with cystic kidney disease, MIM# 219730; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4295 COLEC11 Zornitza Stark Marked gene: COLEC11 as ready
Intellectual disability syndromic and non-syndromic v0.4295 COLEC11 Zornitza Stark Gene: colec11 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4295 COLEC11 Zornitza Stark Phenotypes for gene: COLEC11 were changed from to 3MC syndrome 2, MIM# 265050
Intellectual disability syndromic and non-syndromic v0.4294 COLEC11 Zornitza Stark Publications for gene: COLEC11 were set to
Intellectual disability syndromic and non-syndromic v0.4293 COLEC11 Zornitza Stark Mode of inheritance for gene: COLEC11 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4292 COLEC11 Zornitza Stark reviewed gene: COLEC11: Rating: GREEN; Mode of pathogenicity: None; Publications: 21258343, 26789649, 28301481; Phenotypes: 3MC syndrome 2, MIM# 265050; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4292 SPATA5L1 Zornitza Stark Phenotypes for gene: SPATA5L1 were changed from Intellectual disability; spastic-dystonic cerebral palsy; epilepsy; hearing loss to Neurodevelopmental disorder with hearing loss and spasticity, MIM# 619616
Intellectual disability syndromic and non-syndromic v0.4291 SPATA5L1 Zornitza Stark reviewed gene: SPATA5L1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with hearing loss and spasticity, MIM# 619616; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4291 MEIS2 Zornitza Stark Marked gene: MEIS2 as ready
Intellectual disability syndromic and non-syndromic v0.4291 MEIS2 Zornitza Stark Gene: meis2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4291 MEIS2 Zornitza Stark Phenotypes for gene: MEIS2 were changed from to Cleft palate, cardiac defects, and mental retardation (MIM#600987)
Intellectual disability syndromic and non-syndromic v0.4290 MEIS2 Zornitza Stark Publications for gene: MEIS2 were set to
Intellectual disability syndromic and non-syndromic v0.4289 MEIS2 Zornitza Stark Mode of inheritance for gene: MEIS2 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.4288 MEIS2 Zornitza Stark reviewed gene: MEIS2: Rating: GREEN; Mode of pathogenicity: None; Publications: 33427397, 25712757; Phenotypes: Cleft palate, cardiac defects, and mental retardation (MIM#600987); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.4288 ATP1A2 Zornitza Stark Phenotypes for gene: ATP1A2 were changed from Alternating hemiplegia of childhood 1, MIM# 104290; Developmental and epileptic encephalopathy, polymicrogyria to Alternating hemiplegia of childhood 1, MIM# 104290; Developmental and epileptic encephalopathy 98, MIM# 619605
Intellectual disability syndromic and non-syndromic v0.4287 ATP1A2 Zornitza Stark edited their review of gene: ATP1A2: Changed phenotypes: Alternating hemiplegia of childhood 1, MIM# 104290, Developmental and epileptic encephalopathy 98, MIM# 619605
Intellectual disability syndromic and non-syndromic v0.4287 CNTNAP2 Zornitza Stark Marked gene: CNTNAP2 as ready
Intellectual disability syndromic and non-syndromic v0.4287 CNTNAP2 Zornitza Stark Gene: cntnap2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4287 CNTNAP2 Zornitza Stark Phenotypes for gene: CNTNAP2 were changed from to Cortical dysplasia-focal epilepsy syndrome, MIM# 610042
Intellectual disability syndromic and non-syndromic v0.4286 CNTNAP2 Zornitza Stark Publications for gene: CNTNAP2 were set to
Intellectual disability syndromic and non-syndromic v0.4285 CNTNAP2 Zornitza Stark Mode of inheritance for gene: CNTNAP2 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4285 CNTNAP2 Zornitza Stark Mode of inheritance for gene: CNTNAP2 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4284 CNTNAP2 Zornitza Stark reviewed gene: CNTNAP2: Rating: GREEN; Mode of pathogenicity: None; Publications: 16571880, 19896112, 27439707; Phenotypes: Cortical dysplasia-focal epilepsy syndrome, MIM# 610042; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4284 CKAP2L Zornitza Stark Marked gene: CKAP2L as ready
Intellectual disability syndromic and non-syndromic v0.4284 CKAP2L Zornitza Stark Gene: ckap2l has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4284 CKAP2L Zornitza Stark Phenotypes for gene: CKAP2L were changed from to Filippi syndrome, MIM# 272440
Intellectual disability syndromic and non-syndromic v0.4283 CKAP2L Zornitza Stark Publications for gene: CKAP2L were set to
Intellectual disability syndromic and non-syndromic v0.4282 CKAP2L Zornitza Stark Mode of inheritance for gene: CKAP2L was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4281 CKAP2L Zornitza Stark reviewed gene: CKAP2L: Rating: GREEN; Mode of pathogenicity: None; Publications: 25439729, 33913579, 29473684; Phenotypes: Filippi syndrome, MIM# 272440; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4281 IL1RAPL1 Zornitza Stark Marked gene: IL1RAPL1 as ready
Intellectual disability syndromic and non-syndromic v0.4281 IL1RAPL1 Zornitza Stark Gene: il1rapl1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4281 IL1RAPL1 Zornitza Stark Phenotypes for gene: IL1RAPL1 were changed from to Intellectual developmental disorder, X-linked 21 MIM#300143
Intellectual disability syndromic and non-syndromic v0.4280 IL1RAPL1 Zornitza Stark Publications for gene: IL1RAPL1 were set to
Intellectual disability syndromic and non-syndromic v0.4279 IL1RAPL1 Zornitza Stark Mode of inheritance for gene: IL1RAPL1 was changed from Unknown to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability syndromic and non-syndromic v0.4278 IL1RAPL1 Ain Roesley reviewed gene: IL1RAPL1: Rating: GREEN; Mode of pathogenicity: None; Publications: 34452636, 27470653, 21484992, 18801879, 18801879; Phenotypes: Intellectual developmental disorder, X-linked 21 MIM#300143; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females; Current diagnostic: yes
Intellectual disability syndromic and non-syndromic v0.4278 CHKB Zornitza Stark Marked gene: CHKB as ready
Intellectual disability syndromic and non-syndromic v0.4278 CHKB Zornitza Stark Gene: chkb has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4278 CHKB Zornitza Stark Phenotypes for gene: CHKB were changed from to Muscular dystrophy, congenital, megaconial type, MIM# 602541
Intellectual disability syndromic and non-syndromic v0.4277 CHKB Zornitza Stark Publications for gene: CHKB were set to
Intellectual disability syndromic and non-syndromic v0.4276 CHKB Zornitza Stark Mode of inheritance for gene: CHKB was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4275 CHKB Zornitza Stark reviewed gene: CHKB: Rating: GREEN; Mode of pathogenicity: None; Publications: 21665002, 23692895, 24997086; Phenotypes: Muscular dystrophy, congenital, megaconial type, MIM# 602541; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4275 CHAMP1 Zornitza Stark Marked gene: CHAMP1 as ready
Intellectual disability syndromic and non-syndromic v0.4275 CHAMP1 Zornitza Stark Gene: champ1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4275 CHAMP1 Zornitza Stark Phenotypes for gene: CHAMP1 were changed from to Mental retardation, autosomal dominant 40 (MIM#616579)
Intellectual disability syndromic and non-syndromic v0.4274 CHAMP1 Zornitza Stark Publications for gene: CHAMP1 were set to
Intellectual disability syndromic and non-syndromic v0.4273 CHAMP1 Zornitza Stark Mode of inheritance for gene: CHAMP1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.4272 CHAMP1 Zornitza Stark reviewed gene: CHAMP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 27148580, 26340335; Phenotypes: Mental retardation, autosomal dominant 40 (MIM#616579); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.4272 CEP290 Zornitza Stark Marked gene: CEP290 as ready
Intellectual disability syndromic and non-syndromic v0.4272 CEP290 Zornitza Stark Gene: cep290 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4272 CEP290 Zornitza Stark Phenotypes for gene: CEP290 were changed from to Joubert syndrome 5, MIM# 610188; Meckel syndrome 4, MIM# 611134; Bardet-Biedl syndrome 14, MIM# 615991
Intellectual disability syndromic and non-syndromic v0.4271 CEP290 Zornitza Stark Publications for gene: CEP290 were set to
Intellectual disability syndromic and non-syndromic v0.4270 CEP290 Zornitza Stark Mode of inheritance for gene: CEP290 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4269 CEP290 Zornitza Stark reviewed gene: CEP290: Rating: GREEN; Mode of pathogenicity: None; Publications: 16682973, 16682970, 17705300, 33370260, 32600475; Phenotypes: Joubert syndrome 5, MIM# 610188, Meckel syndrome 4, MIM# 611134, Bardet-Biedl syndrome 14, MIM# 615991; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4269 CENPJ Zornitza Stark Marked gene: CENPJ as ready
Intellectual disability syndromic and non-syndromic v0.4269 CENPJ Zornitza Stark Gene: cenpj has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4269 CENPJ Zornitza Stark Phenotypes for gene: CENPJ were changed from to Microcephaly 6, primary, autosomal recessive, MIM# 608393, MONDO:0012029; Seckel syndrome 4, MIM# 613676, MONDO:0013358
Intellectual disability syndromic and non-syndromic v0.4268 CENPJ Zornitza Stark Publications for gene: CENPJ were set to
Intellectual disability syndromic and non-syndromic v0.4267 CENPJ Zornitza Stark Mode of inheritance for gene: CENPJ was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4266 CENPJ Zornitza Stark reviewed gene: CENPJ: Rating: GREEN; Mode of pathogenicity: None; Publications: 20522431, 23166506, 15793586, 20978018, 22775483, 32677750, 32549991; Phenotypes: Microcephaly 6, primary, autosomal recessive, MIM# 608393, MONDO:0012029, Seckel syndrome 4, MIM# 613676, MONDO:0013358; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4266 CDKL5 Zornitza Stark Marked gene: CDKL5 as ready
Intellectual disability syndromic and non-syndromic v0.4266 CDKL5 Zornitza Stark Gene: cdkl5 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4266 CDKL5 Zornitza Stark Phenotypes for gene: CDKL5 were changed from to Developmental and epileptic encephalopathy 2, MIM# 300672
Intellectual disability syndromic and non-syndromic v0.4265 CDKL5 Zornitza Stark Publications for gene: CDKL5 were set to
Intellectual disability syndromic and non-syndromic v0.4264 CDKL5 Zornitza Stark Mode of inheritance for gene: CDKL5 was changed from Unknown to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Intellectual disability syndromic and non-syndromic v0.4263 CDKL5 Zornitza Stark reviewed gene: CDKL5: Rating: GREEN; Mode of pathogenicity: None; Publications: 19793311; Phenotypes: Developmental and epileptic encephalopathy 2, MIM# 300672; 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 syndromic and non-syndromic v0.4263 SRCAP Zornitza Stark Phenotypes for gene: SRCAP were changed from Floating-Harbor syndrome MIM#136140; Neurodevelopmental disorder, non-Floating Harbor to Floating-Harbor syndrome MIM#136140; Developmental delay, hypotonia, musculoskeletal defects, and behavioral abnormalities, MIM# 619595
Intellectual disability syndromic and non-syndromic v0.4262 SRCAP Zornitza Stark edited their review of gene: SRCAP: Changed phenotypes: Developmental delay, hypotonia, musculoskeletal defects, and behavioral abnormalities, MIM# 619595
Intellectual disability syndromic and non-syndromic v0.4262 DDX3X Zornitza Stark Marked gene: DDX3X as ready
Intellectual disability syndromic and non-syndromic v0.4262 DDX3X Zornitza Stark Gene: ddx3x has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4262 DDX3X Zornitza Stark Phenotypes for gene: DDX3X were changed from to Intellectual developmental disorder, X-linked, syndrome, Snijders Blok type MIM# 300958
Intellectual disability syndromic and non-syndromic v0.4261 DDX3X Zornitza Stark Publications for gene: DDX3X were set to
Intellectual disability syndromic and non-syndromic v0.4260 DDX3X Zornitza Stark Mode of inheritance for gene: DDX3X was changed from X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Intellectual disability syndromic and non-syndromic v0.4260 DDX3X Zornitza Stark Mode of inheritance for gene: DDX3X was changed from Unknown to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Intellectual disability syndromic and non-syndromic v0.4259 DDX3X Zornitza Stark reviewed gene: DDX3X: Rating: GREEN; Mode of pathogenicity: None; Publications: 30266093, 26235985, 25533962, 33528536, 30936465, 31274575, 30817323; Phenotypes: Intellectual developmental disorder, X-linked, syndrome, Snijders Blok type MIM# 300958; 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 syndromic and non-syndromic v0.4259 MYH10 Zornitza Stark Marked gene: MYH10 as ready
Intellectual disability syndromic and non-syndromic v0.4259 MYH10 Zornitza Stark Gene: myh10 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4259 MYH10 Zornitza Stark Classified gene: MYH10 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4259 MYH10 Zornitza Stark Gene: myh10 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4258 ASXL1 Zornitza Stark Marked gene: ASXL1 as ready
Intellectual disability syndromic and non-syndromic v0.4258 ASXL1 Zornitza Stark Gene: asxl1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4258 ASXL1 Zornitza Stark Phenotypes for gene: ASXL1 were changed from to Bohring-Opitz syndrome , MIM#605039
Intellectual disability syndromic and non-syndromic v0.4257 ASXL1 Zornitza Stark Publications for gene: ASXL1 were set to
Intellectual disability syndromic and non-syndromic v0.4256 ASXL1 Zornitza Stark Mode of inheritance for gene: ASXL1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.4255 ASXL1 Zornitza Stark reviewed gene: ASXL1: Rating: GREEN; Mode of pathogenicity: None; Publications: 29446906, 21706002; Phenotypes: Bohring-Opitz syndrome , MIM#605039; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.4255 MYH10 Krithika Murali gene: MYH10 was added
gene: MYH10 was added to Intellectual disability syndromic and non-syndromic. Sources: Expert list,Literature
Mode of inheritance for gene: MYH10 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MYH10 were set to 24825879; 24901346; 25356899; 22495309; 25003005
Phenotypes for gene: MYH10 were set to Microcephaly; Intellectual Disability
Review for gene: MYH10 was set to GREEN
Added comment: De novo variants were identified in 5 unrelated individuals with moderate-severe ID and developmental delay.

Other reported phenotypic features include microcephaly (4/5), IUGR/failure to thrive (4/5), cerebral atrophy (3/5), hydrocephalus (2/5), congenital bilateral hip dysplasia (2/5), cerebellar atrophy (1/5), congenital diaphragmatic hernia (1/5), cranial nerve palsy (1/5), nystagmus (1/5), dysplastic kidney (1/5).

Defects in heart development, body wall closure and other birth defects noted in mouse models.
Sources: Expert list, Literature
Intellectual disability syndromic and non-syndromic v0.4255 CSF1R Zornitza Stark Marked gene: CSF1R as ready
Intellectual disability syndromic and non-syndromic v0.4255 CSF1R Zornitza Stark Gene: csf1r has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.4255 CSF1R Zornitza Stark Classified gene: CSF1R as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.4255 CSF1R Zornitza Stark Gene: csf1r has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.4254 CSF1R Zornitza Stark gene: CSF1R was added
gene: CSF1R was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: CSF1R was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CSF1R were set to 30982609; 33749994; 34135456
Phenotypes for gene: CSF1R were set to Brain abnormalities, neurodegeneration, and dysosteosclerosis, MIM# 618476; BANDDOS
Review for gene: CSF1R was set to AMBER
Added comment: Brain abnormalities, neurodegeneration, and dysosteosclerosis (BANDDOS) is an autosomal recessive disorder characterized by brain abnormalities, progressive neurologic deterioration, and sclerotic bone dysplasia similar to dysosteosclerosis (DOS). The age at onset is highly variable: some patients may present in infancy with hydrocephalus, global developmental delay, and hypotonia, whereas others may have onset of symptoms in the late teens or early twenties after normal development. Neurologic features include loss of previous motor and language skills, cognitive impairment, spasticity, and focal seizures. Brain imaging shows periventricular white matter abnormalities and calcifications, large cisterna magna or Dandy-Walker malformation, and sometimes agenesis of the corpus callosum.

Four unrelated families reported.

Note mono-allelic variants cause an adult-onset disorder.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4253 RNPC3 Zornitza Stark Marked gene: RNPC3 as ready
Intellectual disability syndromic and non-syndromic v0.4253 RNPC3 Zornitza Stark Gene: rnpc3 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.4253 RNPC3 Zornitza Stark Classified gene: RNPC3 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.4253 RNPC3 Zornitza Stark Gene: rnpc3 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.4252 RNPC3 Zornitza Stark gene: RNPC3 was added
gene: RNPC3 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: RNPC3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RNPC3 were set to 29866761; 32462814; 33650182
Phenotypes for gene: RNPC3 were set to Growth hormone deficiency; Intellectual disability
Review for gene: RNPC3 was set to AMBER
Added comment: Three families reported, ID in two.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4251 KCNQ2 Zornitza Stark Marked gene: KCNQ2 as ready
Intellectual disability syndromic and non-syndromic v0.4251 KCNQ2 Zornitza Stark Gene: kcnq2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4251 KCNQ2 Zornitza Stark Phenotypes for gene: KCNQ2 were changed from to Developmental and epileptic encephalopathy 7, MIM# 613720; Intellectual disability
Intellectual disability syndromic and non-syndromic v0.4250 KCNQ2 Zornitza Stark Publications for gene: KCNQ2 were set to
Intellectual disability syndromic and non-syndromic v0.4249 KCNQ2 Zornitza Stark Mode of inheritance for gene: KCNQ2 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.4248 KCNQ2 Zornitza Stark reviewed gene: KCNQ2: Rating: GREEN; Mode of pathogenicity: None; Publications: 33659638, 33754465; Phenotypes: Developmental and epileptic encephalopathy 7, MIM# 613720, Intellectual disability; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.4248 OTUD7A Zornitza Stark Phenotypes for gene: OTUD7A were changed from Epileptic encephalopathy, intellectual disability, no OMIM# yet to Intellectual disability; Epilepsy
Intellectual disability syndromic and non-syndromic v0.4247 OTUD7A Zornitza Stark Publications for gene: OTUD7A were set to PMID: 31997314; 29395075; 29395074
Intellectual disability syndromic and non-syndromic v0.4246 OTUD7A Zornitza Stark Classified gene: OTUD7A as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.4246 OTUD7A Zornitza Stark Gene: otud7a has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.4245 OTUD7A Zornitza Stark edited their review of gene: OTUD7A: Added comment: Additional patient reported in PMID 33381903, with hypotonia, ID and seizures. Bi-allelic LoF variants. Some supportive functional data.; Changed rating: AMBER; Changed publications: 31997314, 29395075, 29395074, 33381903; Changed phenotypes: Intellectual disability, Epilepsy
Intellectual disability syndromic and non-syndromic v0.4245 NUP85 Zornitza Stark Classified gene: NUP85 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.4245 NUP85 Zornitza Stark Gene: nup85 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.4244 NUP85 Zornitza Stark gene: NUP85 was added
gene: NUP85 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: NUP85 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NUP85 were set to 34170319; 30179222
Phenotypes for gene: NUP85 were set to Intellectual disability
Review for gene: NUP85 was set to AMBER
Added comment: Bi-allelic variants in this gene are associated with nephrotic syndrome in 3 families.

Phenotype expansion:

PMID: 34170319 - Ravindran et al 2021 report two pedigrees with an MCPH-SCKS phenotype spectrum without SRNS. In the first family, a 9 yo female, with consanguineous parents, is reported to have a missense variant in NUP85 (c.932G > A; p.R311Q). Intrauterine growth restriction was noticed. At birth microcephaly was observed (OFC < 3rd centile, < −3.6 SD) as well as hypotrophy [weight −2.8 SD), length 45 cm (−2.7 SD), both <3rd centile], facial dysmorphism, syndactyly, long and thin fingers, and bilateral pes adductus. She has severe developmental delay with strongly delayed motor milestones and absent speech. Drug-resistant, genetic epilepsy with focal-onset seizures started in the first year of life. She had no clinical, laboratory or radiological findings indicative of kidney dysfunction. In the second family, compound heterozygous missense variants in NUP85 were detected (c.1109A > G, c.1589 T > C;p.N370S, p.M530T ) in a fetus. MRI of the fetal brain at 24 + 2 GW indicated complete agenesis of the corpus callosum, abnormal sulcation in the left frontal lobe, nodularity of the frontal horn and trigone with focal puckering of the left lateral ventricle.

PMID: 30179222 - Braun et al 2018 - 2 individuals from 1 of the families reported with steroid-resistant nephrotic syndrome were also reported to have intellectual disability but showed no structural brain defects. The degree of intellectual disability is not stated. They were found to have 2 compound heterozygous alleles (c.405+1G>A and c.1741G>C, p.Ala581Pro) in NUP85.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4243 ALG1 Zornitza Stark Marked gene: ALG1 as ready
Intellectual disability syndromic and non-syndromic v0.4243 ALG1 Zornitza Stark Gene: alg1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4243 ALG1 Zornitza Stark Phenotypes for gene: ALG1 were changed from to Congenital disorder of glycosylation, type Ik, MIM# 608540
Intellectual disability syndromic and non-syndromic v0.4242 ALG1 Zornitza Stark Publications for gene: ALG1 were set to
Intellectual disability syndromic and non-syndromic v0.4241 ALG1 Zornitza Stark Mode of inheritance for gene: ALG1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4240 ALG1 Zornitza Stark reviewed gene: ALG1: Rating: GREEN; Mode of pathogenicity: None; Publications: 26931382; Phenotypes: Congenital disorder of glycosylation, type Ik, MIM# 608540; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4240 STT3A Zornitza Stark Publications for gene: STT3A were set to PMID: 23842455; 30701557; 28424003
Intellectual disability syndromic and non-syndromic v0.4239 STT3A Zornitza Stark Mode of inheritance for gene: STT3A was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4238 KIAA0391 Zornitza Stark reviewed gene: KIAA0391: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Mitochondrial disorder; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4238 KIAA0391 Zornitza Stark Marked gene: KIAA0391 as ready
Intellectual disability syndromic and non-syndromic v0.4238 KIAA0391 Zornitza Stark Gene: kiaa0391 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.4238 KIAA0391 Zornitza Stark Phenotypes for gene: KIAA0391 were changed from Hearing loss, intellectual disability to Hearing loss, intellectual disability; Mitochondrial disorder
Intellectual disability syndromic and non-syndromic v0.4237 KIAA0391 Zornitza Stark Classified gene: KIAA0391 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.4237 KIAA0391 Zornitza Stark Gene: kiaa0391 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.4236 SPRED2 Zornitza Stark Marked gene: SPRED2 as ready
Intellectual disability syndromic and non-syndromic v0.4236 SPRED2 Zornitza Stark Gene: spred2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4236 SPRED2 Zornitza Stark Phenotypes for gene: SPRED2 were changed from developmental delay; intellectual disability; cardiac defects; short stature; skeletal anomalies; a typical facial gestalt to Rasopathy; developmental delay; intellectual disability; cardiac defects; short stature; skeletal anomalies; a typical facial gestalt
Intellectual disability syndromic and non-syndromic v0.4235 SPRED2 Zornitza Stark Classified gene: SPRED2 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4235 SPRED2 Zornitza Stark Gene: spred2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4234 KIAA0391 Lucy Spencer gene: KIAA0391 was added
gene: KIAA0391 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: KIAA0391 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KIAA0391 were set to PMID: 34715011
Phenotypes for gene: KIAA0391 were set to Hearing loss, intellectual disability
Review for gene: KIAA0391 was set to RED
Added comment: Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4234 SPATA5L1 Zornitza Stark Marked gene: SPATA5L1 as ready
Intellectual disability syndromic and non-syndromic v0.4234 SPATA5L1 Zornitza Stark Gene: spata5l1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4234 SPATA5L1 Zornitza Stark Classified gene: SPATA5L1 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4234 SPATA5L1 Zornitza Stark Gene: spata5l1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4233 STT3A Elena Savva reviewed gene: STT3A: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID: 34653363, 23842455, 30701557, 28424003; Phenotypes: Congenital disorder of glycosylation, type Iw MIM#615596; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4233 SPRED2 Dean Phelan gene: SPRED2 was added
gene: SPRED2 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: SPRED2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SPRED2 were set to PMID: 34626534
Phenotypes for gene: SPRED2 were set to developmental delay; intellectual disability; cardiac defects; short stature; skeletal anomalies; a typical facial gestalt
Review for gene: SPRED2 was set to GREEN
Added comment: PMID: 34626534
Homozygosity for three different variants c.187C>T (p.Arg63∗), c.299T>C (p.Leu100Pro), and c.1142_1143delTT (p.Leu381Hisfs∗95) were identified in four subjects from three families. All variants severely affected protein stability, causing accelerated degradation, and variably perturbed SPRED2 functional behaviour. The clinical phenotype of the four affected individuals included developmental delay, intellectual disability, cardiac defects, short stature, skeletal anomalies, and a typical facial gestalt as major features, without the occurrence of the distinctive skin signs characterizing Legius syndrome.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4233 SPATA5L1 Paul De Fazio changed review comment from: 47 individuals from 26 unrelated families from various ethnicities with biallelic variants reported. Phenotypes include ID, hearing impairment, movement disorder, abnormal MRI, hypotonia, visual impairment, epilepsy, and microcephaly.

In 25 patients for whom full phenotype datasets were available, all 25 had ID.
Sources: Literature; to: 47 individuals from 26 unrelated families from various ethnicities with biallelic variants reported. Phenotypes include ID, hearing impairment, movement disorder, abnormal MRI, hypotonia, visual impairment, epilepsy, and microcephaly.

~53% of patients had ID.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4233 SPATA5L1 Paul De Fazio gene: SPATA5L1 was added
gene: SPATA5L1 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: SPATA5L1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SPATA5L1 were set to 34626583
Phenotypes for gene: SPATA5L1 were set to Intellectual disability; spastic-dystonic cerebral palsy; epilepsy; hearing loss
Review for gene: SPATA5L1 was set to GREEN
gene: SPATA5L1 was marked as current diagnostic
Added comment: 47 individuals from 26 unrelated families from various ethnicities with biallelic variants reported. Phenotypes include ID, hearing impairment, movement disorder, abnormal MRI, hypotonia, visual impairment, epilepsy, and microcephaly.

In 25 patients for whom full phenotype datasets were available, all 25 had ID.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4233 PHF6 Zornitza Stark Marked gene: PHF6 as ready
Intellectual disability syndromic and non-syndromic v0.4233 PHF6 Zornitza Stark Gene: phf6 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4233 PHF6 Zornitza Stark Phenotypes for gene: PHF6 were changed from to Borjeson-Forssman-Lehmann syndrome, MIM# 301900
Intellectual disability syndromic and non-syndromic v0.4232 PHF6 Zornitza Stark Publications for gene: PHF6 were set to
Intellectual disability syndromic and non-syndromic v0.4231 PHF6 Zornitza Stark Mode of inheritance for gene: PHF6 was changed from Unknown to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability syndromic and non-syndromic v0.4230 PHF6 Zornitza Stark reviewed gene: PHF6: Rating: GREEN; Mode of pathogenicity: None; Publications: 16912705; Phenotypes: Borjeson-Forssman-Lehmann syndrome, MIM# 301900; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability syndromic and non-syndromic v0.4230 GRIK2 Zornitza Stark Phenotypes for gene: GRIK2 were changed from Mental retardation, autosomal recessive, 6 MIM# 611092; nonsyndromic neurodevelopmental disorder (NDD), autosomal dominant to Mental retardation, autosomal recessive, 6 MIM# 611092; Neurodevelopmental disorder with impaired language and ataxia and with or without seizures, MIM# 619580
Intellectual disability syndromic and non-syndromic v0.4229 AHDC1 Zornitza Stark Marked gene: AHDC1 as ready
Intellectual disability syndromic and non-syndromic v0.4229 AHDC1 Zornitza Stark Gene: ahdc1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4229 AHDC1 Zornitza Stark Phenotypes for gene: AHDC1 were changed from to Xia-Gibbs syndrome, MIM# 615829; AHDC1-related intellectual disability, obstructive sleep apnoea, mild dysmorphism syndrome MONDO:0014358
Intellectual disability syndromic and non-syndromic v0.4228 AHDC1 Zornitza Stark Publications for gene: AHDC1 were set to
Intellectual disability syndromic and non-syndromic v0.4227 AHDC1 Zornitza Stark Mode of inheritance for gene: AHDC1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.4226 AHDC1 Zornitza Stark reviewed gene: AHDC1: Rating: GREEN; Mode of pathogenicity: None; Publications: 24791903, 27148574, 30152016; Phenotypes: Xia-Gibbs syndrome, MIM# 615829, AHDC1-related intellectual disability, obstructive sleep apnoea, mild dysmorphism syndrome MONDO:0014358; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.4226 ACY1 Zornitza Stark Marked gene: ACY1 as ready
Intellectual disability syndromic and non-syndromic v0.4226 ACY1 Zornitza Stark Gene: acy1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4226 ACY1 Zornitza Stark Phenotypes for gene: ACY1 were changed from to Aminoacylase 1 deficiency, MIM# 609924
Intellectual disability syndromic and non-syndromic v0.4225 ACY1 Zornitza Stark Publications for gene: ACY1 were set to
Intellectual disability syndromic and non-syndromic v0.4224 ACY1 Zornitza Stark Mode of inheritance for gene: ACY1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4223 ACY1 Zornitza Stark reviewed gene: ACY1: Rating: GREEN; Mode of pathogenicity: None; Publications: 16274666, 16465618, 17562838, 24117009; Phenotypes: Aminoacylase 1 deficiency, MIM# 609924; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4223 TFE3 Zornitza Stark Phenotypes for gene: TFE3 were changed from TFE3-associated neurodevelopmental disorder; Intellectual disability; Epilepsy; Coarse facial features to Intellectual developmental disorder, X-linked, syndromic, with pigmentary mosaicism and coarse facies, MIM# 301066; Intellectual disability; Epilepsy; Coarse facial features
Intellectual disability syndromic and non-syndromic v0.4222 TFE3 Zornitza Stark edited their review of gene: TFE3: Changed phenotypes: Intellectual developmental disorder, X-linked, syndromic, with pigmentary mosaicism and coarse facies, MIM# 301066, Intellectual disability, Epilepsy, Coarse facial features
Intellectual disability syndromic and non-syndromic v0.4222 ETHE1 Zornitza Stark Marked gene: ETHE1 as ready
Intellectual disability syndromic and non-syndromic v0.4222 ETHE1 Zornitza Stark Gene: ethe1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4222 ETHE1 Zornitza Stark Phenotypes for gene: ETHE1 were changed from to Ethylmalonic encephalopathy , MIM#602473
Intellectual disability syndromic and non-syndromic v0.4221 ETHE1 Zornitza Stark Publications for gene: ETHE1 were set to
Intellectual disability syndromic and non-syndromic v0.4220 ETHE1 Zornitza Stark Mode of inheritance for gene: ETHE1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4219 ETHE1 Zornitza Stark reviewed gene: ETHE1: Rating: GREEN; Mode of pathogenicity: None; Publications: 14732903, 28933811; Phenotypes: Ethylmalonic encephalopathy , MIM#602473; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4219 IFT74 Zornitza Stark Marked gene: IFT74 as ready
Intellectual disability syndromic and non-syndromic v0.4219 IFT74 Zornitza Stark Gene: ift74 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4219 IFT74 Zornitza Stark Phenotypes for gene: IFT74 were changed from Bardet-Biedl syndrome 20, MIM# 617119; Joubert syndrome to Bardet-Biedl syndrome 20, MIM# 617119; Joubert syndrome 40, MIM# 619582; Spermatogenic failure 58, MIM# 619585
Intellectual disability syndromic and non-syndromic v0.4218 IFT74 Zornitza Stark edited their review of gene: IFT74: Changed phenotypes: Bardet-Biedl syndrome 20, MIM# 617119, Joubert syndrome 40, MIM# 619582, Spermatogenic failure 58, MIM# 619585
Intellectual disability syndromic and non-syndromic v0.4218 ZFHX4 Zornitza Stark Marked gene: ZFHX4 as ready
Intellectual disability syndromic and non-syndromic v0.4218 ZFHX4 Zornitza Stark Gene: zfhx4 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4218 TAOK1 Zornitza Stark Phenotypes for gene: TAOK1 were changed from Intellectual disability; hypotonia; macrocephaly to Developmental delay with or without intellectual impairment or behavioural abnormalities, MIM#619575; Intellectual disability; hypotonia; macrocephaly
Intellectual disability syndromic and non-syndromic v0.4217 TAOK1 Zornitza Stark reviewed gene: TAOK1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Developmental delay with or without intellectual impairment or behavioural abnormalities, MIM#619575; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.4217 KIAA0556 Zornitza Stark Marked gene: KIAA0556 as ready
Intellectual disability syndromic and non-syndromic v0.4217 KIAA0556 Zornitza Stark Gene: kiaa0556 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4217 KIAA0556 Zornitza Stark Classified gene: KIAA0556 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4217 KIAA0556 Zornitza Stark Gene: kiaa0556 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4216 ZNHIT3 Zornitza Stark Tag founder tag was added to gene: ZNHIT3.
Intellectual disability syndromic and non-syndromic v0.4216 ZNHIT3 Zornitza Stark Classified gene: ZNHIT3 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4216 ZNHIT3 Zornitza Stark Gene: znhit3 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4215 ZNHIT3 Zornitza Stark Classified gene: ZNHIT3 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4215 ZNHIT3 Zornitza Stark Gene: znhit3 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4214 ZNHIT3 Zornitza Stark Marked gene: ZNHIT3 as ready
Intellectual disability syndromic and non-syndromic v0.4214 ZNHIT3 Zornitza Stark Gene: znhit3 has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v0.4214 ZNHIT3 Zornitza Stark gene: ZNHIT3 was added
gene: ZNHIT3 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: ZNHIT3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZNHIT3 were set to 28335020; 28335020; 31048081
Phenotypes for gene: ZNHIT3 were set to PEHO syndrome, MIM# 260565
Review for gene: ZNHIT3 was set to GREEN
Added comment: PEHO is a severe autosomal recessive neurodevelopmental disorder characterized by extreme cerebellar atrophy due to almost total loss of granule neurons. Affected individuals present in early infancy with hypotonia, profoundly delayed psychomotor development, optic atrophy, progressive atrophy of the cerebellum and brainstem, and dysmyelination. Most patients also develop infantile seizures that are often associated with hypsarrhythmia on EEG, and many have peripheral oedema. More than 20 affected individuals reported of Finnish origin, p.Ser31Leu is a founder variant. One compound het reported and supportive animal model.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4213 KIAA0556 Paul De Fazio gene: KIAA0556 was added
gene: KIAA0556 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: KIAA0556 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KIAA0556 were set to 26714646; 27245168
Phenotypes for gene: KIAA0556 were set to Joubert syndrome 26, MIM# 616784
Review for gene: KIAA0556 was set to GREEN
gene: KIAA0556 was marked as current diagnostic
Added comment: 5 individuals from two families reported, supportive mouse model. Individuals were reported to have (global) developmental delay.

New HGNC approved name is KATNIP.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4213 FGF12 Zornitza Stark Marked gene: FGF12 as ready
Intellectual disability syndromic and non-syndromic v0.4213 FGF12 Zornitza Stark Gene: fgf12 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4213 FGF12 Zornitza Stark Phenotypes for gene: FGF12 were changed from to Developmental and epileptic encephalopathy 47, MIM# 617166
Intellectual disability syndromic and non-syndromic v0.4212 FGF12 Zornitza Stark Publications for gene: FGF12 were set to
Intellectual disability syndromic and non-syndromic v0.4211 FGF12 Zornitza Stark Mode of inheritance for gene: FGF12 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.4210 FGF12 Zornitza Stark reviewed gene: FGF12: Rating: GREEN; Mode of pathogenicity: None; Publications: 32645220, 27164707, 27830185, 27872899; Phenotypes: Developmental and epileptic encephalopathy 47, MIM# 617166; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.4210 KCTD13 Zornitza Stark Mode of inheritance for gene: KCTD13 was changed from Unknown to Unknown
Intellectual disability syndromic and non-syndromic v0.4209 KCTD13 Zornitza Stark Mode of inheritance for gene: KCTD13 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to Unknown
Intellectual disability syndromic and non-syndromic v0.4208 KCTD13 Zornitza Stark edited their review of gene: KCTD13: Changed mode of inheritance: Unknown
Intellectual disability syndromic and non-syndromic v0.4208 NDUFA8 Zornitza Stark Marked gene: NDUFA8 as ready
Intellectual disability syndromic and non-syndromic v0.4208 NDUFA8 Zornitza Stark Gene: ndufa8 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.4208 NDUFA8 Zornitza Stark Classified gene: NDUFA8 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.4208 NDUFA8 Zornitza Stark Gene: ndufa8 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.4207 NDUFA8 Krithika Murali gene: NDUFA8 was added
gene: NDUFA8 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: NDUFA8 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NDUFA8 were set to 32385911; 33153867
Phenotypes for gene: NDUFA8 were set to Mitochondrial complex I deficiency, nuclear type 37- 619272; Epilepsy; Microcephaly; Developmental Delay
Review for gene: NDUFA8 was set to AMBER
Added comment: 3 individuals from 2 unrelated families reported with phenotypic features including microcephaly (1/3), seizures (2/3), developmental delay (3/3) and MRI-B changes (3/3).
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4207 MAGEL2 Zornitza Stark Marked gene: MAGEL2 as ready
Intellectual disability syndromic and non-syndromic v0.4207 MAGEL2 Zornitza Stark Gene: magel2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4207 MAGEL2 Zornitza Stark Phenotypes for gene: MAGEL2 were changed from to Schaaf-Yang syndrome, MIM# 615547
Intellectual disability syndromic and non-syndromic v0.4206 MAGEL2 Zornitza Stark Publications for gene: MAGEL2 were set to
Intellectual disability syndromic and non-syndromic v0.4205 MAGEL2 Zornitza Stark Mode of inheritance for gene: MAGEL2 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, maternally imprinted (paternal allele expressed)
Intellectual disability syndromic and non-syndromic v0.4204 MAGEL2 Zornitza Stark reviewed gene: MAGEL2: Rating: GREEN; Mode of pathogenicity: None; Publications: 24076603, 31397880, 29599419, 30302899; Phenotypes: Schaaf-Yang syndrome, MIM# 615547; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, maternally imprinted (paternal allele expressed)
Intellectual disability syndromic and non-syndromic v0.4204 NSRP1 Zornitza Stark Marked gene: NSRP1 as ready
Intellectual disability syndromic and non-syndromic v0.4204 NSRP1 Zornitza Stark Gene: nsrp1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4204 NSRP1 Zornitza Stark Classified gene: NSRP1 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4204 NSRP1 Zornitza Stark Gene: nsrp1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4203 NSRP1 Zornitza Stark reviewed gene: NSRP1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4203 NSRP1 Krithika Murali gene: NSRP1 was added
gene: NSRP1 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: NSRP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NSRP1 were set to 34385670
Phenotypes for gene: NSRP1 were set to Epilepsy; Cerebral palsy; microcephaly; Intellectual disability
Review for gene: NSRP1 was set to AMBER
Added comment: Novel gene regulating splicing. Biallelic LoF pathogenic variants reported in 6 individuals from 3 unrelated families associated with a phenotype characterized by developmental delay, epilepsy, microcephaly, and spastic cerebral palsy.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4203 GABRD Zornitza Stark Marked gene: GABRD as ready
Intellectual disability syndromic and non-syndromic v0.4203 GABRD Zornitza Stark Gene: gabrd has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4203 GABRD Zornitza Stark Classified gene: GABRD as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4203 GABRD Zornitza Stark Gene: gabrd has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4202 GABRD Zornitza Stark gene: GABRD was added
gene: GABRD was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: GABRD was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: GABRD were set to 15115768; 34633442
Phenotypes for gene: GABRD were set to Intellectual disability; Epilepsy; Susceptibility to epilepsy, MIM#613060
Review for gene: GABRD was set to GREEN
Added comment: Susceptibility to epilepsy, MIM#613060: Limited reports. The variant originally reported in PMID 15115768 in association with epilepsy is present in >4,000 hets in gnomad and 55 homs which is not consistent with a Mendelian disorder.

PMID 34633442: 10 individuals with 7 unique variants reported in individuals with neurodevelopmental disorders and epilepsy. Six of the variants were demonstrated to be GoF, and those individuals with neurodevelopmental disorders with behavioural issues, various degrees of intellectual disability, generalized epilepsy with atypical absences and generalized myoclonic and/or bilateral tonic-clonic seizures. In contrast, the one individual carrying a loss-of-function variant had normal intelligence, no seizure history but has a diagnosis of autism spectrum disorder and suffering from elevated internalizing psychiatric symptoms.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4201 TNPO2 Zornitza Stark Phenotypes for gene: TNPO2 were changed from Intellectual disability, neurologic deficits and dysmorphic features to Intellectual developmental disorder with hypotonia, impaired speech, and dysmorphic facies, MIM# 619556
Intellectual disability syndromic and non-syndromic v0.4200 TNPO2 Zornitza Stark reviewed gene: TNPO2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Intellectual developmental disorder with hypotonia, impaired speech, and dysmorphic facies, MIM# 619556; Mode of inheritance: None
Intellectual disability syndromic and non-syndromic v0.4200 KCTD3 Zornitza Stark Marked gene: KCTD3 as ready
Intellectual disability syndromic and non-syndromic v0.4200 KCTD3 Zornitza Stark Gene: kctd3 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4200 KCTD3 Zornitza Stark Phenotypes for gene: KCTD3 were changed from to Epilepsy; Intellectual disability; Posterior fossa abnormalities
Intellectual disability syndromic and non-syndromic v0.4199 KCTD3 Zornitza Stark Publications for gene: KCTD3 were set to
Intellectual disability syndromic and non-syndromic v0.4198 KCTD3 Zornitza Stark Mode of inheritance for gene: KCTD3 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4197 KCTD3 Zornitza Stark reviewed gene: KCTD3: Rating: GREEN; Mode of pathogenicity: None; Publications: 29406573; Phenotypes: Epilepsy, Intellectual disability, Posterior fossa abnormalities; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4197 TARS2 Zornitza Stark Marked gene: TARS2 as ready
Intellectual disability syndromic and non-syndromic v0.4197 TARS2 Zornitza Stark Gene: tars2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4197 TARS2 Zornitza Stark Phenotypes for gene: TARS2 were changed from Combined oxidative phosphorylation deficiency 21 - 615918; Epilepsy; Developmental Delay to Combined oxidative phosphorylation deficiency 21, MIM# 615918; Epilepsy; Developmental Delay
Intellectual disability syndromic and non-syndromic v0.4196 TARS2 Zornitza Stark Classified gene: TARS2 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4196 TARS2 Zornitza Stark Gene: tars2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4195 ABHD16A Zornitza Stark reviewed gene: ABHD16A: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability syndromic and non-syndromic v0.4195 TARS2 Krithika Murali gene: TARS2 was added
gene: TARS2 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: TARS2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TARS2 were set to 33153448; 24827421; 34508595
Phenotypes for gene: TARS2 were set to Combined oxidative phosphorylation deficiency 21 - 615918; Epilepsy; Developmental Delay
Review for gene: TARS2 was set to GREEN
Added comment: 8 cases from 7 unrelated families are reported in the literature with a heterogenous phenotype characterised by either early-onset illness within the first months, of severe hypotonia, failure to thrive, epilepsy and early death, or onset after six months with a milder course and longer survival. Other phenotypic features include developmental delay (at least 3 out of 8 cases), MRI-B abnormalities and more rarely dystonia, regression, hyperhidrosis and hearing impairment.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4195 THG1L Zornitza Stark Marked gene: THG1L as ready
Intellectual disability syndromic and non-syndromic v0.4195 THG1L Zornitza Stark Gene: thg1l has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.4195 THG1L Zornitza Stark Classified gene: THG1L as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.4195 THG1L Zornitza Stark Gene: thg1l has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.4194 THG1L Krithika Murali gene: THG1L was added
gene: THG1L was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: THG1L was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: THG1L were set to 33682303
Phenotypes for gene: THG1L were set to Spinocerebellar ataxia, autosomal recessive 28 - 618800; Epilepsy; Intellectual Disability
Review for gene: THG1L was set to AMBER
Added comment: 3 individuals from 2 unrelated families of Ashkenazi Jewish descent with compound heterozygous variants ( p.Cys51Trp and p.Val55Ala) presented with profound developmental delays, microcephaly, intractable epilepsy, and cerebellar hypoplasia.

Homozygous variants associated with ataxia phenotype.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4194 CELF2 Zornitza Stark Phenotypes for gene: CELF2 were changed from Developmental and epileptic encephalopathy to Developmental and epileptic encephalopathy 97, MIM#619561
Intellectual disability syndromic and non-syndromic v0.4193 CELF2 Zornitza Stark edited their review of gene: CELF2: Changed phenotypes: Developmental and epileptic encephalopathy 97, MIM#619561
Intellectual disability syndromic and non-syndromic v0.4193 AP1G1 Zornitza Stark Phenotypes for gene: AP1G1 were changed from Neurodevelopmental disorder (NDD); Intellectual Disability; Epilepsy to Usmani-Riazuddin syndrome, autosomal dominant, MIM# 619467; Usmani-Riazuddin syndrome, autosomal recessive, MIM# 619548; Neurodevelopmental disorder (NDD); Intellectual Disability; Epilepsy
Intellectual disability syndromic and non-syndromic v0.4192 AP1G1 Zornitza Stark edited their review of gene: AP1G1: Changed phenotypes: Usmani-Riazuddin syndrome, autosomal dominant, MIM# 619467, Usmani-Riazuddin syndrome, autosomal recessive, MIM# 619548, Neurodevelopmental disorder (NDD), Intellectual Disability, Epilepsy
Intellectual disability syndromic and non-syndromic v0.4192 CACNA1C Zornitza Stark Publications for gene: CACNA1C were set to
Intellectual disability syndromic and non-syndromic v0.4191 CACNA1C Zornitza Stark Mode of inheritance for gene: CACNA1C was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.4190 SHANK1 Zornitza Stark Phenotypes for gene: SHANK1 were changed from Autism to Neurodevelopmental disorder, no OMIM#
Intellectual disability syndromic and non-syndromic v0.4189 SHANK1 Zornitza Stark Publications for gene: SHANK1 were set to 22503632; 25188300
Intellectual disability syndromic and non-syndromic v0.4188 SHANK1 Zornitza Stark Mode of inheritance for gene: SHANK1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.4187 PLXNA1 Zornitza Stark Marked gene: PLXNA1 as ready
Intellectual disability syndromic and non-syndromic v0.4187 PLXNA1 Zornitza Stark Gene: plxna1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4187 CACNA1C Chirag Patel reviewed gene: CACNA1C: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 34163037; Phenotypes: Neurodevelopmental abnormalities and epilepsy, no OMIM#; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.4187 SHANK1 Chirag Patel Classified gene: SHANK1 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4187 SHANK1 Chirag Patel Gene: shank1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4186 SHANK1 Chirag Patel Classified gene: SHANK1 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4186 SHANK1 Chirag Patel Gene: shank1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4185 SHANK1 Chirag Patel reviewed gene: SHANK1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 34113010; Phenotypes: Neurodevelopmental disorder, no OMIM#; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.4185 PLXNA1 Chirag Patel Classified gene: PLXNA1 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4185 PLXNA1 Chirag Patel Gene: plxna1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4184 PLXNA1 Chirag Patel gene: PLXNA1 was added
gene: PLXNA1 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: PLXNA1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: PLXNA1 were set to PMID: 34054129
Phenotypes for gene: PLXNA1 were set to Neurodevelopmental disorder with cerebral and eye anomalies
Review for gene: PLXNA1 was set to GREEN
Added comment: Dworschak et al. (2021) via WES reported 10 patients from 7 families with biallelic (n=7) or de novo (n=3) PLXNA1 variants. Shared phenotypic features include global developmental delay (9/10), brain anomalies (6/10), and eye anomalies (7/10). Seizures were predominantly reported in patients with monoallelic variants. Zebrafish studies showed an embryonic role of plxna1a in the development of the central nervous system and the eye. Biallelic variants in the extracellular Plexin-A1 domains lead to impaired dimerization or lack of receptor molecules, whereas monoallelic variants in the intracellular Plexin-A1 domains might impair downstream signaling through a dominant-negative effect.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4183 HNRNPD Zornitza Stark Publications for gene: HNRNPD were set to 33057194
Intellectual disability syndromic and non-syndromic v0.4182 HNRNPD Zornitza Stark Phenotypes for gene: HNRNPD were changed from Developmental disorders to Neurodevelopmental disorder
Intellectual disability syndromic and non-syndromic v0.4181 HNRNPD Zornitza Stark Classified gene: HNRNPD as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4181 HNRNPD Zornitza Stark Gene: hnrnpd has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4180 HNRNPD Ee Ming Wong reviewed gene: HNRNPD: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 33874999; Phenotypes: Neurodevelopmental disorder; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Intellectual disability syndromic and non-syndromic v0.4180 BPTF Zornitza Stark Publications for gene: BPTF were set to 28942966; 33522091
Intellectual disability syndromic and non-syndromic v0.4180 BPTF Zornitza Stark Publications for gene: BPTF were set to 28942966
Intellectual disability syndromic and non-syndromic v0.4179 BPTF Zornitza Stark commented on gene: BPTF: Over 30 unrelated individuals reported, mostly de novo, some inherited variants. Clinical features include intellectual disability, seizures, poor growth with small head size, dysmorphic facial features, and mild abnormalities of the hands and feet.
Intellectual disability syndromic and non-syndromic v0.4179 BPTF Zornitza Stark edited their review of gene: BPTF: Changed publications: 28942966, 33522091
Intellectual disability syndromic and non-syndromic v0.4179 BCL11A Zornitza Stark Marked gene: BCL11A as ready
Intellectual disability syndromic and non-syndromic v0.4179 BCL11A Zornitza Stark Gene: bcl11a has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4179 BCL11A Zornitza Stark Phenotypes for gene: BCL11A were changed from to Dias-Logan syndrome, MIM# 617101
Intellectual disability syndromic and non-syndromic v0.4178 BCL11A Zornitza Stark Publications for gene: BCL11A were set to
Intellectual disability syndromic and non-syndromic v0.4177 BCL11A Zornitza Stark Mode of inheritance for gene: BCL11A was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.4176 BCL11A Zornitza Stark reviewed gene: BCL11A: Rating: GREEN; Mode of pathogenicity: None; Publications: 27453576, 32903878; Phenotypes: Dias-Logan syndrome, MIM# 617101; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.4176 SNIP1 Zornitza Stark Publications for gene: SNIP1 were set to 22279524
Intellectual disability syndromic and non-syndromic v0.4175 SNIP1 Zornitza Stark changed review comment from: Three Amish individuals with same homozygous variant, founder effect.; to: Four Amish individuals with same homozygous variant, founder effect.
Intellectual disability syndromic and non-syndromic v0.4175 SNIP1 Zornitza Stark edited their review of gene: SNIP1: Changed publications: 22279524, 34570759
Intellectual disability syndromic and non-syndromic v0.4175 LONP1 Zornitza Stark Marked gene: LONP1 as ready
Intellectual disability syndromic and non-syndromic v0.4175 LONP1 Zornitza Stark Gene: lonp1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4175 ERBB4 Zornitza Stark Phenotypes for gene: ERBB4 were changed from to Intellectual disability
Intellectual disability syndromic and non-syndromic v0.4174 ERBB4 Zornitza Stark Tag SV/CNV tag was added to gene: ERBB4.
Intellectual disability syndromic and non-syndromic v0.4174 LONP1 Zornitza Stark Phenotypes for gene: LONP1 were changed from CODAS syndrome, MIM#600373; Mitochondrial cytopathy to CODAS syndrome, MIM#600373; Mitochondrial cytopathy
Intellectual disability syndromic and non-syndromic v0.4174 LONP1 Zornitza Stark Phenotypes for gene: LONP1 were changed from to CODAS syndrome, MIM#600373; Mitochondrial cytopathy
Intellectual disability syndromic and non-syndromic v0.4173 LONP1 Zornitza Stark Publications for gene: LONP1 were set to
Intellectual disability syndromic and non-syndromic v0.4172 LONP1 Zornitza Stark Mode of inheritance for gene: LONP1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4171 LONP1 Zornitza Stark reviewed gene: LONP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 31636596; Phenotypes: CODAS syndrome, MIM#600373, Mitochondrial cytopathy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4171 WIPI2 Zornitza Stark Phenotypes for gene: WIPI2 were changed from Intellectual developmental disorder with short stature and variable skeletal anomalies 618453 to Intellectual developmental disorder with short stature and variable skeletal anomalies 618453; global developmental delay; intellectual disability; refractory infantile/childhood-onset epilepsy; progressive tetraplegia with joint contractures; dyskinesia; speech and visual impairment; autistic features; ataxic gait
Intellectual disability syndromic and non-syndromic v0.4171 WIPI2 Zornitza Stark Publications for gene: WIPI2 were set to 30968111
Intellectual disability syndromic and non-syndromic v0.4170 WIPI2 Zornitza Stark Classified gene: WIPI2 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4170 WIPI2 Zornitza Stark Gene: wipi2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4169 ZDHHC15 Zornitza Stark Phenotypes for gene: ZDHHC15 were changed from to Mental retardation, X-linked 91, 300577
Intellectual disability syndromic and non-syndromic v0.4168 ZDHHC15 Zornitza Stark Publications for gene: ZDHHC15 were set to
Intellectual disability syndromic and non-syndromic v0.4167 ZDHHC15 Zornitza Stark Mode of inheritance for gene: ZDHHC15 was changed from Unknown to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability syndromic and non-syndromic v0.4166 ZDHHC15 Zornitza Stark reviewed gene: ZDHHC15: Rating: RED; Mode of pathogenicity: None; Publications: 34345675, 32989326; Phenotypes: Mental retardation, X-linked 91, 300577; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability syndromic and non-syndromic v0.4166 ERBB4 Seb Lunke Marked gene: ERBB4 as ready
Intellectual disability syndromic and non-syndromic v0.4166 ERBB4 Seb Lunke Gene: erbb4 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.4166 ERBB4 Seb Lunke Classified gene: ERBB4 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.4166 ERBB4 Seb Lunke Added comment: Comment on list classification: CNVs only, not clear on the differentiation between ID and ALS.
Intellectual disability syndromic and non-syndromic v0.4166 ERBB4 Seb Lunke Gene: erbb4 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.4165 ABHD16A Seb Lunke Marked gene: ABHD16A as ready
Intellectual disability syndromic and non-syndromic v0.4165 ABHD16A Seb Lunke Gene: abhd16a has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4165 ABHD16A Seb Lunke Phenotypes for gene: ABHD16A were changed from Spastic paraplegia to Spastic paraplegia; Intellectual Disability; Callosome
Intellectual disability syndromic and non-syndromic v0.4164 WIPI2 Dean Phelan reviewed gene: WIPI2: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 30968111, 34557665; Phenotypes: global developmental delay, intellectual disability, refractory infantile/childhood-onset epilepsy, progressive tetraplegia with joint contractures, dyskinesia, speech and visual impairment, autistic features, ataxic gait; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability syndromic and non-syndromic v0.4164 ABHD16A Seb Lunke Classified gene: ABHD16A as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4164 ABHD16A Seb Lunke Gene: abhd16a has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4163 ABHD16A Lucy Spencer gene: ABHD16A was added
gene: ABHD16A was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: ABHD16A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ABHD16A were set to PMID: 34587489
Phenotypes for gene: ABHD16A were set to Spastic paraplegia
Added comment: 11 individuals from 6 families with a complicated form of hereditary spastic paraplegia who carry bi-allelic deleterious variants in ABHD16A. Affected individuals present with a similar phenotype consisting of global developmental delay/intellectual disability, progressive spasticity affecting the upper and lower limbs, and corpus callosum and white matter anomalies. Immunoblot analysis on extracts from fibroblasts from four affected individuals demonstrated little to no ABHD16A protein levels compared to controls.
In 5 of the families the affected members were homozygous, 3 of these families were consanguineous. 2 families have the same variant- both families are French-Canadian.
4 missense variants, 1 frameshift, 1 nonsense.
From PMID: 34587489
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4163 ATP11A Zornitza Stark Marked gene: ATP11A as ready
Intellectual disability syndromic and non-syndromic v0.4163 ATP11A Zornitza Stark Gene: atp11a has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.4163 ATP11A Zornitza Stark Classified gene: ATP11A as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.4163 ATP11A Zornitza Stark Gene: atp11a has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.4162 ATP11A Elena Savva gene: ATP11A was added
gene: ATP11A was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: ATP11A was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ATP11A were set to PMID: 34403372
Phenotypes for gene: ATP11A were set to Neurological disorder
Mode of pathogenicity for gene: ATP11A was set to Other
Review for gene: ATP11A was set to AMBER
Added comment: PMID: 34403372:
- Single de novo missense variant reported in a patient with developmental delay and neurological deterioration.
- Patient MRI showed severe cerebral atrophy, ventriculomegaly, hypomyelination leukodystrophy, thinned corpus callosum. Axonal neuropathy suggested.
- K/I heterozygous mice died perinatally.
- Functional studies on missense variant show plasma membrane lipid content impairment, reduced ATPase activity etc.

gnomAD: some NMD PTCs present, good quality variants found with 4-5 hets.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4162 ERBB4 Ain Roesley edited their review of gene: ERBB4: Changed phenotypes: intellectual disability
Intellectual disability syndromic and non-syndromic v0.4162 ERBB4 Ain Roesley gene: ERBB4 was added
gene: ERBB4 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: ERBB4 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ERBB4 were set to 33603162
Penetrance for gene: ERBB4 were set to unknown
Review for gene: ERBB4 was set to GREEN
Added comment: CNVs reported only
exonic deletions:
3x families with ID, speech delays, aggressive outbursts (including 1x de novo)
1x family with global dev delay inherited from unaffected parent

exonic del with limited clinical info:
1x severe expressive language delay
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4162 SARS Bryony Thompson Marked gene: SARS as ready
Intellectual disability syndromic and non-syndromic v0.4162 SARS Bryony Thompson Gene: sars has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.4162 SARS Bryony Thompson Classified gene: SARS as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.4162 SARS Bryony Thompson Gene: sars has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.4161 SARS Bryony Thompson gene: SARS was added
gene: SARS was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: SARS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SARS were set to 28236339; 34570399
Phenotypes for gene: SARS were set to Intellectual disability
Review for gene: SARS was set to AMBER
Added comment: Summary - 2 unrelated families with overlapping ID phenotype, and supporting in vitro and patient cell assays.
PMID: 28236339 - an Iranian family (distantly related) segregating a homozygous missense (c.514G>A, p.Asp172Asn) with moderate ID, microcephaly, ataxia, speech impairment, and aggressive behaviour. Also, supporting in vitro functional assays demonstrating altered protein function.
PMID: 34570399 - a consanguineous Turkish family segregating a homozygous missense (c.638G>T, p.(Arg213Leu)) with developmental delay, central deafness, cardiomyopathy, and metabolic decompensation during fever leading to death. Also, reduced protein level and enzymatic activity in patient cells.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4160 NDN Zornitza Stark Phenotypes for gene: NDN were changed from to Prader-Willi syndrome, MIM# 176270
Intellectual disability syndromic and non-syndromic v0.4159 ZNF407 Zornitza Stark Phenotypes for gene: ZNF407 were changed from Global developmental delay; Intellectual disability to SIMHA syndrome, MIM# 619557; Global developmental delay; Intellectual disability
Intellectual disability syndromic and non-syndromic v0.4158 ZNF407 Zornitza Stark edited their review of gene: ZNF407: Changed rating: AMBER; Changed phenotypes: SIMHA syndrome, MIM# 619557; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4158 RNF113A Zornitza Stark Publications for gene: RNF113A were set to PMID: 25612912; 31793730
Intellectual disability syndromic and non-syndromic v0.4157 RNF113A Zornitza Stark Classified gene: RNF113A as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4157 RNF113A Zornitza Stark Gene: rnf113a has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4156 RNF113A Zornitza Stark reviewed gene: RNF113A: Rating: GREEN; Mode of pathogenicity: None; Publications: 31880405; Phenotypes: Trichothiodystrophy 5, nonphotosensitive, OMIM #300953; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability syndromic and non-syndromic v0.4156 RNF113A Zornitza Stark Mode of inheritance for gene: RNF113A was changed from X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability syndromic and non-syndromic v0.4155 EIF3F Zornitza Stark Publications for gene: EIF3F were set to 30409806
Intellectual disability syndromic and non-syndromic v0.4154 EIF3F Chirag Patel reviewed gene: EIF3F: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 33736665; Phenotypes: EIF3F-related neurodevelopmental disorder; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4154 CDH15 Zornitza Stark reviewed gene: CDH15: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability syndromic and non-syndromic v0.4154 CDH15 Zornitza Stark Marked gene: CDH15 as ready
Intellectual disability syndromic and non-syndromic v0.4154 CDH15 Zornitza Stark Gene: cdh15 has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v0.4154 CDH15 Zornitza Stark Phenotypes for gene: CDH15 were changed from to Mental retardation, autosomal dominant 3 MIM#612580
Intellectual disability syndromic and non-syndromic v0.4153 CDH15 Zornitza Stark Publications for gene: CDH15 were set to
Intellectual disability syndromic and non-syndromic v0.4152 CDH15 Zornitza Stark Mode of inheritance for gene: CDH15 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.4151 CDH15 Zornitza Stark Tag disputed tag was added to gene: CDH15.
Intellectual disability syndromic and non-syndromic v0.4151 CDH15 Zornitza Stark Classified gene: CDH15 as Red List (low evidence)
Intellectual disability syndromic and non-syndromic v0.4151 CDH15 Zornitza Stark Gene: cdh15 has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v0.4150 CDH15 Elena Savva reviewed gene: CDH15: Rating: RED; Mode of pathogenicity: Other; Publications: PMID: 19012874, 12052883, 28422132, 26506440; Phenotypes: Mental retardation, autosomal dominant 3 MIM#612580; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability syndromic and non-syndromic v0.4150 CPE Zornitza Stark Publications for gene: CPE were set to 26120850; 32936766
Intellectual disability syndromic and non-syndromic v0.4149 CPE Zornitza Stark Classified gene: CPE as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4149 CPE Zornitza Stark Gene: cpe has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4148 CPE Zornitza Stark edited their review of gene: CPE: Added comment: Bosch et al. 2021 (PMID: 34383079) reported on 4 individuals from 3 additional families harbouring 2 different homozygous truncating variants in this gene. Clinical presentation was prominent for obesity and intellectual disability. Hypogonadotropic hypogonadism was confirmed in one individual and was suspected but not tested for in another two subjects.; Changed rating: GREEN; Changed publications: 26120850, 32936766, 34383079; Changed phenotypes: Intellectual developmental disorder and hypogonadotropic hypogonadism, MIM# 619326
Intellectual disability syndromic and non-syndromic v0.4148 HCFC1 Zornitza Stark Marked gene: HCFC1 as ready
Intellectual disability syndromic and non-syndromic v0.4148 HCFC1 Zornitza Stark Gene: hcfc1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4148 HCFC1 Zornitza Stark Phenotypes for gene: HCFC1 were changed from to Mental retardation, X-linked 3 (methylmalonic acidaemia and homocysteinaemia, cblX type) MIM# 309541
Intellectual disability syndromic and non-syndromic v0.4147 HCFC1 Zornitza Stark Publications for gene: HCFC1 were set to
Intellectual disability syndromic and non-syndromic v0.4146 HCFC1 Zornitza Stark Mode of inheritance for gene: HCFC1 was changed from Unknown to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability syndromic and non-syndromic v0.4145 HCFC1 Zornitza Stark reviewed gene: HCFC1: Rating: GREEN; Mode of pathogenicity: None; Publications: 34164576, 24011988; Phenotypes: Mental retardation, X-linked 3 (methylmalonic acidaemia and homocysteinaemia, cblX type) MIM# 309541; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability syndromic and non-syndromic v0.4145 CSTB Zornitza Stark Marked gene: CSTB as ready
Intellectual disability syndromic and non-syndromic v0.4145 CSTB Zornitza Stark Gene: cstb has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v0.4145 CSTB Zornitza Stark Phenotypes for gene: CSTB were changed from to Epilepsy, progressive myoclonic 1A (Unverricht and Lundborg), MIM# 254800
Intellectual disability syndromic and non-syndromic v0.4144 CSTB Zornitza Stark Publications for gene: CSTB were set to
Intellectual disability syndromic and non-syndromic v0.4143 CSTB Zornitza Stark Mode of inheritance for gene: CSTB was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4142 CSTB Zornitza Stark Classified gene: CSTB as Red List (low evidence)
Intellectual disability syndromic and non-syndromic v0.4142 CSTB Zornitza Stark Gene: cstb has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v0.4141 CSTB Zornitza Stark reviewed gene: CSTB: Rating: RED; Mode of pathogenicity: None; Publications: 9012407, 9054946; Phenotypes: Epilepsy, progressive myoclonic 1A (Unverricht and Lundborg), MIM# 254800; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4141 ATP6V0C Zornitza Stark Marked gene: ATP6V0C as ready
Intellectual disability syndromic and non-syndromic v0.4141 ATP6V0C Zornitza Stark Gene: atp6v0c has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.4141 ATP6V0C Zornitza Stark Classified gene: ATP6V0C as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.4141 ATP6V0C Zornitza Stark Gene: atp6v0c has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.4140 ATP6V0C Zornitza Stark gene: ATP6V0C was added
gene: ATP6V0C was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
SV/CNV tags were added to gene: ATP6V0C.
Mode of inheritance for gene: ATP6V0C was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ATP6V0C were set to 33190975; 33090716
Phenotypes for gene: ATP6V0C were set to Epilepsy; Intellectual Disability; microcephaly
Review for gene: ATP6V0C was set to AMBER
Added comment: 9 individuals reported with deletions and ID/seizures/microcephaly, minimum overlapping region implicates ATP6V0C as the causative gene. Single case report of de novo SNV and ID/seizures.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4139 ARFGEF1 Zornitza Stark Marked gene: ARFGEF1 as ready
Intellectual disability syndromic and non-syndromic v0.4139 ARFGEF1 Zornitza Stark Gene: arfgef1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4139 ARFGEF1 Zornitza Stark Classified gene: ARFGEF1 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4139 ARFGEF1 Zornitza Stark Gene: arfgef1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4138 ARFGEF1 Zornitza Stark gene: ARFGEF1 was added
gene: ARFGEF1 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: ARFGEF1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ARFGEF1 were set to 34113008
Phenotypes for gene: ARFGEF1 were set to Intellectual disability; Epilepsy
Review for gene: ARFGEF1 was set to GREEN
Added comment: 13 individuals reported with variants in this gene and a neurodevelopmental disorder characterised by variable ID, seizures present in around half. Variants were inherited from mildly affected parents in 40% of families.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4137 PRR12 Zornitza Stark Phenotypes for gene: PRR12 were changed from intellectual disability; iris abnormalities to Neuroocular syndrome, MIM#619539; Intellectual disability; Iris abnormalities; Complex microphthalmia
Intellectual disability syndromic and non-syndromic v0.4136 PRR12 Zornitza Stark edited their review of gene: PRR12: Changed phenotypes: Neuroocular syndrome, MIM#619539, Intellectual disability, Iris abnormalities, Complex microphthalmia
Intellectual disability syndromic and non-syndromic v0.4136 ZC4H2 Zornitza Stark Marked gene: ZC4H2 as ready
Intellectual disability syndromic and non-syndromic v0.4136 ZC4H2 Zornitza Stark Gene: zc4h2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4136 ZC4H2 Zornitza Stark Phenotypes for gene: ZC4H2 were changed from to Wieacker-Wolff syndrome, MIM# 314580
Intellectual disability syndromic and non-syndromic v0.4135 ZC4H2 Zornitza Stark Publications for gene: ZC4H2 were set to
Intellectual disability syndromic and non-syndromic v0.4134 ZC4H2 Zornitza Stark Mode of inheritance for gene: ZC4H2 was changed from Unknown to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Intellectual disability syndromic and non-syndromic v0.4133 ZC4H2 Zornitza Stark reviewed gene: ZC4H2: Rating: GREEN; Mode of pathogenicity: None; Publications: 23623388, 34322088, 33949289, 31885220, 31206972; Phenotypes: Wieacker-Wolff syndrome, MIM# 314580; 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 syndromic and non-syndromic v0.4133 KIF4A Zornitza Stark Publications for gene: KIF4A were set to 24812067; 34346154
Intellectual disability syndromic and non-syndromic v0.4133 KIF4A Zornitza Stark Publications for gene: KIF4A were set to 24812067
Intellectual disability syndromic and non-syndromic v0.4132 KIF4A Zornitza Stark Classified gene: KIF4A as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4132 KIF4A Zornitza Stark Gene: kif4a has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4131 KIF4A Zornitza Stark edited their review of gene: KIF4A: Added comment: Further 11 families reported. Major structural brain abnormalities present in at least 3 (hydrocephalus), variable ID in several.; Changed rating: GREEN; Changed publications: 24812067, 34346154
Intellectual disability syndromic and non-syndromic v0.4131 FAM149B1 Zornitza Stark Marked gene: FAM149B1 as ready
Intellectual disability syndromic and non-syndromic v0.4131 FAM149B1 Zornitza Stark Gene: fam149b1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4131 FAM149B1 Zornitza Stark Classified gene: FAM149B1 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4131 FAM149B1 Zornitza Stark Gene: fam149b1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4130 FAM149B1 Michelle Torres gene: FAM149B1 was added
gene: FAM149B1 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: FAM149B1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FAM149B1 were set to 30905400
Phenotypes for gene: FAM149B1 were set to Joubert; Ciliopathy
Review for gene: FAM149B1 was set to GREEN
gene: FAM149B1 was marked as current diagnostic
Added comment: Four unrelated, but consanguineous, families reported with 2 truncating variants. Developmental delay with hypotonia and intellectual disability are typical features, and many children have characteristic facies.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4130 ZMYM2 Zornitza Stark Phenotypes for gene: ZMYM2 were changed from Abnormality of the urinary system; Global developmental delay; Intellectual disability; Microcephaly; Abnormality of the cardiovascular system; Autism; Seizures; Abnormality of the head or neck; Abnormality of the nail; Small hand; Short foot; Clinodactyly to Neurodevelopmental-craniofacial syndrome with variable renal and cardiac abnormalities, MIM# 619522
Intellectual disability syndromic and non-syndromic v0.4129 ZMYM2 Zornitza Stark edited their review of gene: ZMYM2: Changed phenotypes: Neurodevelopmental-craniofacial syndrome with variable renal and cardiac abnormalities, MIM# 619522
Intellectual disability syndromic and non-syndromic v0.4129 BCAP31 Zornitza Stark Marked gene: BCAP31 as ready
Intellectual disability syndromic and non-syndromic v0.4129 BCAP31 Zornitza Stark Gene: bcap31 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4129 BCAP31 Zornitza Stark Phenotypes for gene: BCAP31 were changed from to Deafness, dystonia, and cerebral hypomyelination, MIM# 300475
Intellectual disability syndromic and non-syndromic v0.4128 BCAP31 Zornitza Stark Publications for gene: BCAP31 were set to
Intellectual disability syndromic and non-syndromic v0.4127 BCAP31 Zornitza Stark Mode of inheritance for gene: BCAP31 was changed from Unknown to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability syndromic and non-syndromic v0.4126 BCAP31 Zornitza Stark reviewed gene: BCAP31: Rating: GREEN; Mode of pathogenicity: None; Publications: 24011989, 31330203, 33603160; Phenotypes: Deafness, dystonia, and cerebral hypomyelination, MIM# 300475; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability syndromic and non-syndromic v0.4126 AMPD2 Zornitza Stark Marked gene: AMPD2 as ready
Intellectual disability syndromic and non-syndromic v0.4126 AMPD2 Zornitza Stark Gene: ampd2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4126 AMPD2 Zornitza Stark Phenotypes for gene: AMPD2 were changed from to Pontocerebellar hypoplasia, type 9, MIM#615809
Intellectual disability syndromic and non-syndromic v0.4125 AMPD2 Zornitza Stark Publications for gene: AMPD2 were set to
Intellectual disability syndromic and non-syndromic v0.4124 AMPD2 Zornitza Stark Mode of inheritance for gene: AMPD2 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4123 AMPD2 Zornitza Stark reviewed gene: AMPD2: Rating: GREEN; Mode of pathogenicity: None; Publications: 23911318, 27066553; Phenotypes: Pontocerebellar hypoplasia, type 9, MIM#615809; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4123 DDX23 Zornitza Stark Phenotypes for gene: DDX23 were changed from Developmental disorder to DDX23-associated neurodevelopmental disorder
Intellectual disability syndromic and non-syndromic v0.4122 DDX23 Zornitza Stark Publications for gene: DDX23 were set to 33057194
Intellectual disability syndromic and non-syndromic v0.4121 TAF2 Zornitza Stark Publications for gene: TAF2 were set to 21937992; 22633631; 26350204
Intellectual disability syndromic and non-syndromic v0.4120 HMGB1 Zornitza Stark Marked gene: HMGB1 as ready
Intellectual disability syndromic and non-syndromic v0.4120 HMGB1 Zornitza Stark Gene: hmgb1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4120 HMGB1 Chirag Patel Classified gene: HMGB1 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4120 HMGB1 Chirag Patel Gene: hmgb1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4119 HMGB1 Chirag Patel gene: HMGB1 was added
gene: HMGB1 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: HMGB1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: HMGB1 were set to PMID: 34164801
Phenotypes for gene: HMGB1 were set to Developmental delay and microcephaly, no OMIM #
Review for gene: HMGB1 was set to GREEN
Added comment: 13q12.3 microdeletion syndrome is a rare cause of syndromic ID. Previous studies identified four genes within the ~300 Kb minimal critical region including two candidate protein coding genes: KATNAL1 and HMGB1. Uguen et al. (2021) report 6 patients with LOF variants involving HMGB1 with features similar to 13q12.3 microdeletion syndrome (i.e. developmental delay, language delay, microcephaly, obesity and dysmorphic features). In silico analyses suggest that HMGB1 is likely to be intolerant to LOF, and previous in vitro data are in line with the role of HMGB1 in neurodevelopment. They suggest that haploinsufficiency of the HMGB1 gene may play a critical role in the pathogenesis of the 13q12.3 microdeletion syndrome.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4118 TAF2 Chirag Patel Classified gene: TAF2 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4118 TAF2 Chirag Patel Gene: taf2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4117 TAF2 Chirag Patel reviewed gene: TAF2: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 34474177; Phenotypes: Mental retardation, autosomal recessive 40, OMIM # 615599; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4117 DDX23 Chirag Patel Classified gene: DDX23 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4117 DDX23 Chirag Patel Gene: ddx23 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4117 DDX23 Chirag Patel Classified gene: DDX23 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4117 DDX23 Chirag Patel Gene: ddx23 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4116 DDX23 Chirag Patel reviewed gene: DDX23: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 34050707; Phenotypes: Neurodevelopmental disorder, no OMIM #; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.4116 COPB2 Zornitza Stark Classified gene: COPB2 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4116 COPB2 Zornitza Stark Gene: copb2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4115 COPB2 Zornitza Stark reviewed gene: COPB2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4115 MTRR Zornitza Stark Marked gene: MTRR as ready
Intellectual disability syndromic and non-syndromic v0.4115 MTRR Zornitza Stark Gene: mtrr has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4115 MTRR Zornitza Stark Phenotypes for gene: MTRR were changed from to Homocystinuria-megaloblastic anaemia, cbl E type, MIM# 236270
Intellectual disability syndromic and non-syndromic v0.4114 MTRR Zornitza Stark Publications for gene: MTRR were set to
Intellectual disability syndromic and non-syndromic v0.4113 MTRR Zornitza Stark Mode of inheritance for gene: MTRR was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4112 MTRR Zornitza Stark reviewed gene: MTRR: Rating: GREEN; Mode of pathogenicity: None; Publications: 12555939, 15714522; Phenotypes: Homocystinuria-megaloblastic anaemia, cbl E type, MIM# 236270; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4112 MTR Zornitza Stark Marked gene: MTR as ready
Intellectual disability syndromic and non-syndromic v0.4112 MTR Zornitza Stark Gene: mtr has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4112 MTR Zornitza Stark Phenotypes for gene: MTR were changed from to Homocystinuria-megaloblastic anaemia, cblG complementation type, MIM# 250940
Intellectual disability syndromic and non-syndromic v0.4111 MTR Zornitza Stark Publications for gene: MTR were set to
Intellectual disability syndromic and non-syndromic v0.4110 MTR Zornitza Stark Mode of inheritance for gene: MTR was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4109 MTR Zornitza Stark reviewed gene: MTR: Rating: GREEN; Mode of pathogenicity: None; Publications: 8968736, 8968737, 9683607, 12068375; Phenotypes: Homocystinuria-megaloblastic anaemia, cblG complementation type, MIM# 250940; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4109 UMPS Zornitza Stark Marked gene: UMPS as ready
Intellectual disability syndromic and non-syndromic v0.4109 UMPS Zornitza Stark Gene: umps has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4109 UMPS Zornitza Stark Phenotypes for gene: UMPS were changed from to Orotic aciduria MIM# 258900
Intellectual disability syndromic and non-syndromic v0.4108 UMPS Zornitza Stark Publications for gene: UMPS were set to
Intellectual disability syndromic and non-syndromic v0.4107 UMPS Zornitza Stark Mode of inheritance for gene: UMPS was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4106 UMPS Zornitza Stark reviewed gene: UMPS: Rating: GREEN; Mode of pathogenicity: None; Publications: 9042911, 33489760; Phenotypes: Orotic aciduria MIM# 258900; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4106 MAGEL2 Anna Le Fevre reviewed gene: MAGEL2: Rating: GREEN; Mode of pathogenicity: None; Publications: 24076603, 31397880, 29599419, 30302899; Phenotypes: Schaaf-Yang syndrome, Chitayat-Hall Syndrome; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, maternally imprinted (paternal allele expressed)
Intellectual disability syndromic and non-syndromic v0.4106 MAGEL2 Anna Le Fevre Deleted their review
Intellectual disability syndromic and non-syndromic v0.4106 MAGEL2 Anna Le Fevre reviewed gene: MAGEL2: Rating: ; Mode of pathogenicity: None; Publications: 24076603, 30302899, 31397880; Phenotypes: Schaaf-Yang syndrome, Chitayat-Hall Syndrome; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, maternally imprinted (paternal allele expressed)
Intellectual disability syndromic and non-syndromic v0.4106 UBE2U Zornitza Stark Marked gene: UBE2U as ready
Intellectual disability syndromic and non-syndromic v0.4106 UBE2U Zornitza Stark Gene: ube2u has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v0.4106 UBE2U Zornitza Stark Classified gene: UBE2U as Red List (low evidence)
Intellectual disability syndromic and non-syndromic v0.4106 UBE2U Zornitza Stark Gene: ube2u has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v0.4105 PRICKLE2 Zornitza Stark Marked gene: PRICKLE2 as ready
Intellectual disability syndromic and non-syndromic v0.4105 PRICKLE2 Zornitza Stark Gene: prickle2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4105 PRICKLE2 Zornitza Stark Marked gene: PRICKLE2 as ready
Intellectual disability syndromic and non-syndromic v0.4105 PRICKLE2 Zornitza Stark Gene: prickle2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4105 PRICKLE2 Zornitza Stark Classified gene: PRICKLE2 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4105 PRICKLE2 Zornitza Stark Gene: prickle2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4104 PRICKLE2 Hazel Phillimore gene: PRICKLE2 was added
gene: PRICKLE2 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: PRICKLE2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PRICKLE2 were set to PMID: 34092786
Phenotypes for gene: PRICKLE2 were set to Neurodevelopmental disorder; global developmental delay; behavioural difficulties ± epilepsy; autistic features; attention deficit hyperactive disorder; psychiatric symptoms
Review for gene: PRICKLE2 was set to GREEN
Added comment: Six subjects from four unrelated families with neurodevelopmental delay, behavioural difficulties and epilepsy had heterozygous variants, either de novo or segregating with disease.

Two missense were de novo, c.122 C>T; p.(Pro41Leu) and c.680C>G; p.(Thr227Arg); one nonsense variant was de novo (c.214 C>T; p.(Arg72*); and one frameshift variant segregated with the disorder in three affected females (c.1286_1287delGT; p.(Ser429Thrfs*56)).

Loss-of-function (homozygous) variants have been shown to cause seizures in flies; and both heterozygous and homozygous mice have shown behavioral abnormalities including altered social interaction, learning abnormalities, and behavioral inflexibility (PMID: 21276947).
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4104 UBE2U Ee Ming Wong gene: UBE2U was added
gene: UBE2U was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: UBE2U was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: UBE2U were set to PMID: 33776059
Phenotypes for gene: UBE2U were set to Retinoschisis; cataracts; learning disabilities; developmental delay
Penetrance for gene: UBE2U were set to Complete
Review for gene: UBE2U was set to RED
gene: UBE2U was marked as current diagnostic
Added comment: - one missense UBE2U variant identified in one family with five affected individuals (includes proband)
- in silico analyses predicts the UBE2U variant to be damaging
- no functional
- another STUM missense variant identified in the same family predicted to be benign
- additional clinical assessment indicated that the family shared some systemic dysmorphisms and learning disabilities similar to RIDDLE syndrome
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4104 COPB2 Zornitza Stark Marked gene: COPB2 as ready
Intellectual disability syndromic and non-syndromic v0.4104 COPB2 Zornitza Stark Gene: copb2 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.4104 COPB2 Zornitza Stark Classified gene: COPB2 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.4104 COPB2 Zornitza Stark Gene: copb2 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.4103 CACNA1I Seb Lunke Marked gene: CACNA1I as ready
Intellectual disability syndromic and non-syndromic v0.4103 CACNA1I Seb Lunke Gene: cacna1i has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4103 CACNA1I Seb Lunke Classified gene: CACNA1I as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4103 CACNA1I Seb Lunke Gene: cacna1i has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4102 COPB2 Belinda Chong gene: COPB2 was added
gene: COPB2 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: COPB2 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: COPB2 were set to PMID: 34450031
Phenotypes for gene: COPB2 were set to Osteoporosis and developmental delay
Review for gene: COPB2 was set to AMBER
Added comment: Loss-of-function variants in COPB2 (MIM: 606990), a component of the COPI coatomer complex, in six individuals from five unrelated families presenting with a clinical spectrum of osteoporosis or os- teopenia, with or without fractures, and developmental delay of variable severity. A hypomorphic, homozygous missense variant in COPB2 was previously reported in two siblings with microcephaly, spasticity, and develop- mental delay (MIM: 617800) in whom we also here identified low bone mass. Data demonstrate that pathogenic variants in COPB2 lead to early onset osteoporosis and variable developmental delay and that COPB2 and the COPI complex are essential regulators of skeletal homeostasis

3 frameshift (2 de novo, 1 not maternal), 1 x splice (de novo), 2 missense (homozygous).
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4102 CACNA1I Kristin Rigbye gene: CACNA1I was added
gene: CACNA1I was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: CACNA1I was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CACNA1I were set to 33704440
Phenotypes for gene: CACNA1I were set to Neurodevelopmental disorder
Mode of pathogenicity for gene: CACNA1I was set to Other
Review for gene: CACNA1I was set to GREEN
Added comment: 4 different missense variants identified and shown to result in a gain of function.

2 individuals with de novo variants (a 3rd also suspected de novo but their father was unavailable for testing) - these patients all had severe neurodevelopmental disorders, involving severe global developmental delay, absence of speech, gross motor delay, muscular hypotonia, early-onset seizures, cortical visual impairment, and feeding difficulties. Variable clinical features include various brain malformations, startle response or seizures, postnatal growth retardation, gastroesophageal reflux, and gastrostomy.

1 family had three affected individuals - variable cognitive impairment in all, involving borderline intellectual functioning or mild or moderate intellectual disability as main clinical feature, with late-onset seizures in the mother and speech retardation in one of the children. This variant had a milder functional effect than the variants in sporadic cases.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4102 GRIK2 Zornitza Stark Marked gene: GRIK2 as ready
Intellectual disability syndromic and non-syndromic v0.4102 GRIK2 Zornitza Stark Gene: grik2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4102 GRIK2 Zornitza Stark Phenotypes for gene: GRIK2 were changed from to Mental retardation, autosomal recessive, 6 MIM# 611092; nonsyndromic neurodevelopmental disorder (NDD), autosomal dominant
Intellectual disability syndromic and non-syndromic v0.4101 GRIK2 Zornitza Stark Publications for gene: GRIK2 were set to
Intellectual disability syndromic and non-syndromic v0.4100 GRIK2 Zornitza Stark Mode of inheritance for gene: GRIK2 was changed from Unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4099 GRIK2 Danielle Ariti reviewed gene: GRIK2: Rating: GREEN; Mode of pathogenicity: None; Publications: 34375587, 17847003, 25039795; Phenotypes: Mental retardation, autosomal recessive, 6 MIM# 611092, nonsyndromic neurodevelopmental disorder (NDD); Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4099 ZNF668 Zornitza Stark Marked gene: ZNF668 as ready
Intellectual disability syndromic and non-syndromic v0.4099 ZNF668 Zornitza Stark Gene: znf668 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.4099 ZNF668 Zornitza Stark Classified gene: ZNF668 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.4099 ZNF668 Zornitza Stark Gene: znf668 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.4098 ZNF668 Paul De Fazio changed review comment from: 5 individuals from 3 consanguineous families reported with different biallelic truncating (not NMD) variants in ZNF668. Phenotypes included microcephaly, growth deficiency, severe global developmental delay, brain malformation, and distinct facial dysmorphism.

Immunofluorescence indicated ZNF668 deficiency. An increased DNA damage phenotype was demonstrated in patient fibroblasts.
Sources: Literature; to: 2 consanguineous families reported with different biallelic truncating (not NMD) variants in ZNF668. Phenotypes included microcephaly, growth deficiency, severe global developmental delay, brain malformation, and distinct facial dysmorphism.

Immunofluorescence indicated ZNF668 deficiency. An increased DNA damage phenotype was demonstrated in patient fibroblasts.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4098 ZNF668 Paul De Fazio edited their review of gene: ZNF668: Changed rating: AMBER
Intellectual disability syndromic and non-syndromic v0.4098 ZNF668 Paul De Fazio gene: ZNF668 was added
gene: ZNF668 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: ZNF668 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZNF668 were set to 34313816; 26633546
Phenotypes for gene: ZNF668 were set to DNA damage repair defect; microcephaly; growth deficiency; severe global developmental delay; brain malformation; facial dysmorphism
Review for gene: ZNF668 was set to GREEN
gene: ZNF668 was marked as current diagnostic
Added comment: 5 individuals from 3 consanguineous families reported with different biallelic truncating (not NMD) variants in ZNF668. Phenotypes included microcephaly, growth deficiency, severe global developmental delay, brain malformation, and distinct facial dysmorphism.

Immunofluorescence indicated ZNF668 deficiency. An increased DNA damage phenotype was demonstrated in patient fibroblasts.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4098 ARF1 Zornitza Stark Marked gene: ARF1 as ready
Intellectual disability syndromic and non-syndromic v0.4098 ARF1 Zornitza Stark Gene: arf1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4098 ARF1 Zornitza Stark Classified gene: ARF1 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4098 ARF1 Zornitza Stark Gene: arf1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4097 ARF1 Zornitza Stark gene: ARF1 was added
gene: ARF1 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: ARF1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ARF1 were set to 28868155; 34353862
Phenotypes for gene: ARF1 were set to Periventricular nodular heterotopia 8, MIM# 618185
Review for gene: ARF1 was set to GREEN
Added comment: 5 individuals from 4 untreated families reported. 3/5 individuals presented with seizures and all had developmental delays, especially in speech (one patient had a diagnosis of moderate ID).
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4096 CLCN3 Zornitza Stark Phenotypes for gene: CLCN3 were changed from Neurodevelopmental disorder to Neurodevelopmental disorder with hypotonia and brain abnormalities, MIM# 619512; Neurodevelopmental disorder with seizures and brain abnormalities, MIM# 619517
Intellectual disability syndromic and non-syndromic v0.4095 CLCN3 Zornitza Stark edited their review of gene: CLCN3: Changed phenotypes: Neurodevelopmental disorder with hypotonia and brain abnormalities, MIM# 619512, Neurodevelopmental disorder with seizures and brain abnormalities, MIM# 619517
Intellectual disability syndromic and non-syndromic v0.4095 CLCN3 Zornitza Stark edited their review of gene: CLCN3: Changed phenotypes: Neurodevelopmental disorder with hypotonia and brain abnormalities, MIM# 619512
Intellectual disability syndromic and non-syndromic v0.4095 GNB2 Zornitza Stark Phenotypes for gene: GNB2 were changed from intellectual disability; dysmorphic features to Neurodevelopmental disorder with hypotonia and dysmorphic facies, MIM# 619503
Intellectual disability syndromic and non-syndromic v0.4094 GNB2 Zornitza Stark edited their review of gene: GNB2: Changed phenotypes: Neurodevelopmental disorder with hypotonia and dysmorphic facies 619503
Intellectual disability syndromic and non-syndromic v0.4094 CHRM1 Bryony Thompson Marked gene: CHRM1 as ready
Intellectual disability syndromic and non-syndromic v0.4094 CHRM1 Bryony Thompson Gene: chrm1 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.4094 CHRM1 Bryony Thompson Classified gene: CHRM1 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.4094 CHRM1 Bryony Thompson Gene: chrm1 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.4093 CHRM1 Bryony Thompson gene: CHRM1 was added
gene: CHRM1 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: CHRM1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CHRM1 were set to 34212451; 31981491; 12483218
Phenotypes for gene: CHRM1 were set to Neurodevelopmental delay; intellectual disability; autism
Review for gene: CHRM1 was set to AMBER
Added comment: PMID: 34212451 - 2 unrelated cases with de novo missense variants (p.Pro380Leu and p.Phe425Ser), one case with early-onset refractory epilepsy, severe disability, and progressive cerebral and cerebellar atrophy, and the second case with mild dysmorphism, global developmental delay, and moderate intellectual disability. In vitro biochemical analyses of p.Pro380Leu demonstrated a reduction in protein levels, impaired cellular trafficking, and defective activation of intracellular signaling pathways.
PMID: 31981491 - an autism spectrum disorder (no other information on phenotype, except ascertained to have severe neurodevelopmental delay) case with a de novo missense variant p.(Arg210Leu)
PMID: 12483218 - null mouse model assessing memory demonstrated selective cognitive dysfunction.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4092 ANKRD17 Zornitza Stark Phenotypes for gene: ANKRD17 were changed from Intellectual disability; dysmorphic features to Chopra-Amiel-Gordan syndrome, MIM# 619504; Intellectual disability; dysmorphic features
Intellectual disability syndromic and non-syndromic v0.4091 ANKRD17 Zornitza Stark edited their review of gene: ANKRD17: Changed phenotypes: Chopra-Amiel-Gordan syndrome, MIM# 619504, Intellectual disability, dysmorphic features
Intellectual disability syndromic and non-syndromic v0.4091 PI4KA Zornitza Stark Marked gene: PI4KA as ready
Intellectual disability syndromic and non-syndromic v0.4091 PI4KA Zornitza Stark Gene: pi4ka has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4091 PI4KA Chirag Patel Classified gene: PI4KA as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4091 PI4KA Chirag Patel Gene: pi4ka has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4090 PI4KA Chirag Patel gene: PI4KA was added
gene: PI4KA was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: PI4KA was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PI4KA were set to PMID: 34415322
Phenotypes for gene: PI4KA were set to Neurodevelopmental syndrome with hypomyelinating leukodystrophy
Review for gene: PI4KA was set to GREEN
Added comment: Used WES/WGS to identify 10 unrelated patients harbouring biallelic variants in PI4KA, and a spectrum of severe global neurodevelopmental delay, hypomyelination, and developmental brain abnormalities, and pure spastic paraplegia. Some patients presented immunological deficits or genito-urinary abnormalities. Western blotting and immunofluorescence showed decreased PI4KA levels in the patients' fibroblasts. Immunofluorescence and targeted lipidomics indicated that PI4KA activity was diminished in fibroblasts and peripheral blood mononuclear cells.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4089 EDEM3 Zornitza Stark Phenotypes for gene: EDEM3 were changed from Congenital disorder of glycosylation; Developmental delay to Congenital disorder of glycosylation, type 2V, MIM# 619493
Intellectual disability syndromic and non-syndromic v0.4088 EDEM3 Zornitza Stark reviewed gene: EDEM3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Congenital disorder of glycosylation, type 2V, MIM# 619493; Mode of inheritance: None
Intellectual disability syndromic and non-syndromic v0.4088 PDE6D Zornitza Stark Classified gene: PDE6D as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4088 PDE6D Zornitza Stark Gene: pde6d has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4087 PDE6D Zornitza Stark changed review comment from: Two families and functional data.; to: Two families and good functional data.
Intellectual disability syndromic and non-syndromic v0.4087 PDE6D Zornitza Stark edited their review of gene: PDE6D: Changed rating: GREEN
Intellectual disability syndromic and non-syndromic v0.4087 RNU7-1 Zornitza Stark Phenotypes for gene: RNU7-1 were changed from Aicardi–Goutières syndrome-like to Aicardi-Goutieres syndrome 9, MIM# 619487
Intellectual disability syndromic and non-syndromic v0.4086 RNU7-1 Zornitza Stark reviewed gene: RNU7-1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Aicardi-Goutieres syndrome 9, MIM# 619487; Mode of inheritance: None
Intellectual disability syndromic and non-syndromic v0.4086 LSM11 Zornitza Stark Phenotypes for gene: LSM11 were changed from type I interferonopathy Aicardi–Goutières syndrome to Aicardi-Goutieres syndrome 8, MIM# 619486
Intellectual disability syndromic and non-syndromic v0.4085 LSM11 Zornitza Stark reviewed gene: LSM11: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Aicardi-Goutieres syndrome 8, MIM# 619486; Mode of inheritance: None
Intellectual disability syndromic and non-syndromic v0.4085 WDR11 Zornitza Stark Phenotypes for gene: WDR11 were changed from to Intellectual disability; Microcephaly; Short stature
Intellectual disability syndromic and non-syndromic v0.4084 WDR11 Zornitza Stark Publications for gene: WDR11 were set to
Intellectual disability syndromic and non-syndromic v0.4083 WDR11 Zornitza Stark Mode of inheritance for gene: WDR11 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4082 WDR11 Zornitza Stark Classified gene: WDR11 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4082 WDR11 Zornitza Stark Gene: wdr11 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4081 WDR11 Konstantinos Varvagiannis reviewed gene: WDR11: Rating: AMBER; Mode of pathogenicity: None; Publications: 34413497; Phenotypes: Intellectual disability, Microcephaly, Short stature; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4081 FGD1 Zornitza Stark Marked gene: FGD1 as ready
Intellectual disability syndromic and non-syndromic v0.4081 FGD1 Zornitza Stark Gene: fgd1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4081 FGD1 Zornitza Stark Phenotypes for gene: FGD1 were changed from to Aarskog-Scott syndrome, MIM # 305400; Mental retardation, X-linked syndromic 16, MIM# 305400
Intellectual disability syndromic and non-syndromic v0.4080 FGD1 Zornitza Stark Publications for gene: FGD1 were set to
Intellectual disability syndromic and non-syndromic v0.4079 FGD1 Zornitza Stark Mode of inheritance for gene: FGD1 was changed from Unknown to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability syndromic and non-syndromic v0.4078 FGD1 Zornitza Stark reviewed gene: FGD1: Rating: GREEN; Mode of pathogenicity: None; Publications: 7954831, 20082460; Phenotypes: Aarskog-Scott syndrome, MIM # 305400, Mental retardation, X-linked syndromic 16, MIM# 305400; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability syndromic and non-syndromic v0.4078 RAD21 Zornitza Stark Phenotypes for gene: RAD21 were changed from Cornelia de Lange syndrome 4, MIM # 614701 to Cornelia de Lange syndrome 4, MIM # 614701
Intellectual disability syndromic and non-syndromic v0.4078 RAD21 Zornitza Stark Marked gene: RAD21 as ready
Intellectual disability syndromic and non-syndromic v0.4078 RAD21 Zornitza Stark Gene: rad21 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4078 RAD21 Zornitza Stark Phenotypes for gene: RAD21 were changed from to Cornelia de Lange syndrome 4, MIM # 614701
Intellectual disability syndromic and non-syndromic v0.4077 RAD21 Zornitza Stark Publications for gene: RAD21 were set to
Intellectual disability syndromic and non-syndromic v0.4076 RAD21 Zornitza Stark Mode of inheritance for gene: RAD21 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.4075 RAD21 Zornitza Stark reviewed gene: RAD21: Rating: GREEN; Mode of pathogenicity: None; Publications: 22633399, 32193685, 27882533, 30716475, 30125677, 24378232; Phenotypes: Cornelia de Lange syndrome 4, MIM # 614701; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.4075 BRD4 Zornitza Stark Marked gene: BRD4 as ready
Intellectual disability syndromic and non-syndromic v0.4075 BRD4 Zornitza Stark Gene: brd4 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4075 BRD4 Zornitza Stark Phenotypes for gene: BRD4 were changed from to Cornelia de Lange syndrome
Intellectual disability syndromic and non-syndromic v0.4074 BRD4 Zornitza Stark Publications for gene: BRD4 were set to
Intellectual disability syndromic and non-syndromic v0.4073 BRD4 Zornitza Stark Mode of inheritance for gene: BRD4 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.4072 BRD4 Zornitza Stark Classified gene: BRD4 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4072 BRD4 Zornitza Stark Gene: brd4 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4071 BRD4 Zornitza Stark reviewed gene: BRD4: Rating: GREEN; Mode of pathogenicity: None; Publications: 29379197, 30302754, 11997514, 34035299; Phenotypes: Cornelia de Lange syndrome; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.4071 ZNF699 Zornitza Stark Marked gene: ZNF699 as ready
Intellectual disability syndromic and non-syndromic v0.4071 ZNF699 Zornitza Stark Gene: znf699 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4071 ZNF699 Zornitza Stark Classified gene: ZNF699 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4071 ZNF699 Zornitza Stark Gene: znf699 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4070 ZNF699 Zornitza Stark gene: ZNF699 was added
gene: ZNF699 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: ZNF699 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZNF699 were set to 33875846
Phenotypes for gene: ZNF699 were set to DEGCAGS syndrome, MIM# 619488
Review for gene: ZNF699 was set to GREEN
Added comment: DEGCAGS syndrome is a neurodevelopmental disorder characterized by global developmental delay, coarse and dysmorphic facial features, and poor growth and feeding apparent from infancy. Affected individuals have variable systemic manifestations often with significant structural defects of the cardiovascular, genitourinary, gastrointestinal, and/or skeletal systems. Additional features may include sensorineural hearing loss, hypotonia, anaemia or pancytopaenia, and immunodeficiency with recurrent infections.

12 unrelated families reported, 5 different homozygous frameshift variants.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4069 NIPBL Zornitza Stark Marked gene: NIPBL as ready
Intellectual disability syndromic and non-syndromic v0.4069 NIPBL Zornitza Stark Gene: nipbl has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4069 NIPBL Zornitza Stark Phenotypes for gene: NIPBL were changed from to Cornelia de Lange syndrome 1, MIM # 122470
Intellectual disability syndromic and non-syndromic v0.4068 NIPBL Zornitza Stark Publications for gene: NIPBL were set to
Intellectual disability syndromic and non-syndromic v0.4067 NIPBL Zornitza Stark Mode of inheritance for gene: NIPBL was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.4066 NIPBL Zornitza Stark reviewed gene: NIPBL: Rating: GREEN; Mode of pathogenicity: None; Publications: 16604071, 20358602, 16236812, 17661813; Phenotypes: Cornelia de Lange syndrome 1, MIM # 122470; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.4066 IGF1 Zornitza Stark Marked gene: IGF1 as ready
Intellectual disability syndromic and non-syndromic v0.4066 IGF1 Zornitza Stark Gene: igf1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4066 IGF1 Zornitza Stark Phenotypes for gene: IGF1 were changed from to Growth retardation with deafness and mental retardation due to IGF1 deficiency, MIM # 608747
Intellectual disability syndromic and non-syndromic v0.4065 IGF1 Zornitza Stark Publications for gene: IGF1 were set to
Intellectual disability syndromic and non-syndromic v0.4064 IGF1 Zornitza Stark Mode of inheritance for gene: IGF1 was changed from Unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4063 IGF1 Zornitza Stark reviewed gene: IGF1: Rating: GREEN; Mode of pathogenicity: None; Publications: 8857020, 15769976, 14684690, 31539878, 28768959, 34125705, 22832530; Phenotypes: Growth retardation with deafness and mental retardation due to IGF1 deficiency, MIM # 608747; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4063 TCN2 Zornitza Stark Marked gene: TCN2 as ready
Intellectual disability syndromic and non-syndromic v0.4063 TCN2 Zornitza Stark Gene: tcn2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4063 TCN2 Zornitza Stark Phenotypes for gene: TCN2 were changed from to Transcobalamin II deficiency, 275350
Intellectual disability syndromic and non-syndromic v0.4062 TCN2 Zornitza Stark Publications for gene: TCN2 were set to
Intellectual disability syndromic and non-syndromic v0.4061 TCN2 Zornitza Stark Mode of inheritance for gene: TCN2 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4060 TCN2 Zornitza Stark reviewed gene: TCN2: Rating: GREEN; Mode of pathogenicity: None; Publications: 19373259, 32841161, 33023511, 30124850; Phenotypes: Transcobalamin II deficiency, 275350; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4060 RNF220 Zornitza Stark Marked gene: RNF220 as ready
Intellectual disability syndromic and non-syndromic v0.4060 RNF220 Zornitza Stark Gene: rnf220 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4060 RNF220 Zornitza Stark Classified gene: RNF220 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4060 RNF220 Zornitza Stark Gene: rnf220 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4059 RNF220 Konstantinos Varvagiannis changed review comment from: Sferra et al (2021 - PMID: 33964137) provide extensive evidence that biallelic RNF220 mutations cause a disorder characterized by hypomyelinating leukodystrophy, ataxia (9/9 - onset 1-5y), borderline intellectual functioning (3/9) / intellectual disability (5/9 - in most cases mild), sensorineural deafness (9/9) with complete hearing loss in the first decade of life, hepatopathy (9/9) with associated periportal fibrosis, and dilated cardiomyopathy (9/9) which was fatal.

Other neurologic manifestations apart from ataxia incl. hyperreflexia (8/8), spastic paraplegia (9/9), dysarthria (9/9), peripheral neuropathy (4/9), seizures in one case (1/9). Upon brain MRI there was thin corpus callosum (9/9) or cerebellar atrophy in some (2/9).

The authors identified homozygosity for 2 recurrent missense RNF220 variants in affected members belonging to these 5 broad consanguineous pedigrees (7 families), namely NM_018150.4:c.1094G>A / p.Arg365Gly in 4 Roma families in the context of a shared haplotype (/founder effect) as well as c.1088G>A / p.Arg363Gly in a large pedigree from southern Italy initially reported by Leuzzi et al (2000 - PMID: 10881263).

Extensive segregation analyses were carried out including several affected and unaffected members.

RNF220 encodes ring finger protein 220, which functions as an E3 ubiquitin ligase. Previous studies have shown among others a role in modulation of Sonic hedgehog/GLI signaling and cerebellar development

Evidence for the role of RNF220 included relevant expression, localization within the cell, interaction partners (lamin B1, 20S proteasome), similarities with other laminopathies in terms of phenotype, etc :
*RNF220 has a relevant expression pattern in CNS (based on qRT-PCR analyses in human brain, cerebellum, cerebral cortex / mRNA levels in human fetal CNS with higher expression in cerebellum, spinal cord and cortex / previous GTEx data / protein levels in mouse CNS)
*The protein displays nuclear localization based on iPSC cells differentiated to motor neurons (also supported by data from the Human Protein Atlas). Transfection of COS-1 cells demonstrated localization primarily to the nucleus (as also previously demonstrated in HEK293T cells) in vesicle like structures with ASF2/SF2 colocalization suggesting enrichment in nuclear speckles. There was also partial co-distribution with the 20S proteasome. R363Q and R365Q additionally coalesced in the cytoplasm forming protein aggregates/inclusions.
*Immunofluorescence studies in patient fibroblasts also confirmed abnormal increase of the protein in the cytoplasm and increased fluorescence with the 20S proteasome.
*Proteomic identification of RNF220-interacting proteins in transfected HEK293T cells demonstrated enrichment for all members of the lamin protein family (incl . lamin B1, AC, B2).
*RNAi-mediated downregulation of RNF222 in Drosophila suggested altered subcellular localization and accumulation of the fly orthologue for human lamin B1.
*Immunoprecipitation of lamin B1 from the nuclear matrix of cerebellar cells suggested significant interaction of endogenous lamin B1 with RNF220, while transfection studies in HEK293T cells for wt/mt suggested reduced binding to endogenous lamin B1 for RNF220 mt compared to wt (more prominent for R365Q). RNF220 mutants also reduced ubiquitination of nuclear lamin B1 compared to wt.
*Patient fibroblasts immunostained with different nuclear envelope markers displayed abnormal nuclear shapes with multiple invaginations and lobulations, findings also observed in laminopathies.

There is currently no associated phenotype in OMIM or G2P. SysID includes RNF220 among the current primary ID genes.
Sources: Literature, Other; to: Sferra et al (2021 - PMID: 33964137) provide extensive evidence that biallelic RNF220 mutations cause a disorder characterized by hypomyelinating leukodystrophy, ataxia (9/9 - onset 1-5y), borderline intellectual functioning (3/9) / intellectual disability (5/9 - in most cases mild), sensorineural deafness (9/9) with complete hearing loss in the first decade of life, hepatopathy (9/9) with associated periportal fibrosis, and dilated cardiomyopathy (9/9) which was fatal.

Other neurologic manifestations apart from ataxia incl. hyperreflexia (8/8), spastic paraplegia (9/9), dysarthria (9/9), peripheral neuropathy (4/9), seizures in one case (1/9). Upon brain MRI there was thin corpus callosum (9/9) or cerebellar atrophy in some (2/9).

The authors identified homozygosity for 2 recurrent missense RNF220 variants in affected members belonging to these 5 broad consanguineous pedigrees (7 families), namely NM_018150.4:c.1094G>A / p.Arg365Gly in 4 Roma families in the context of a shared haplotype (/founder effect) as well as c.1088G>A / p.Arg363Gly in a large pedigree from southern Italy initially reported by Leuzzi et al (2000 - PMID: 10881263).

Extensive segregation analyses were carried out including several affected and unaffected members.

RNF220 encodes ring finger protein 220, which functions as an E3 ubiquitin ligase. Previous studies have shown among others a role in modulation of Sonic hedgehog/GLI signaling and cerebellar development

Evidence for the role of RNF220 included relevant expression, localization within the cell, interaction partners (lamin B1, 20S proteasome), similarities with other laminopathies in terms of phenotype, etc :
*RNF220 has a relevant expression pattern in CNS (based on qRT-PCR analyses in human brain, cerebellum, cerebral cortex / mRNA levels in human fetal CNS with higher expression in cerebellum, spinal cord and cortex / previous GTEx data / protein levels in mouse CNS)
*The protein displays nuclear localization based on iPSC cells differentiated to motor neurons (also supported by data from the Human Protein Atlas). Transfection of COS-1 cells demonstrated localization primarily to the nucleus (as also previously demonstrated in HEK293T cells) in vesicle like structures with ASF2/SF2 colocalization suggesting enrichment in nuclear speckles. There was also partial co-distribution with the 20S proteasome. R363Q and R365Q additionally coalesced in the cytoplasm forming protein aggregates/inclusions.
*Immunofluorescence studies in patient fibroblasts also confirmed abnormal increase of the protein in the cytoplasm and increased fluorescence with the 20S proteasome.
*Proteomic identification of RNF220-interacting proteins in transfected HEK293T cells demonstrated enrichment for all members of the lamin protein family (incl . lamin B1, AC, B2).
*RNAi-mediated downregulation of RNF222 in Drosophila suggested altered subcellular localization and accumulation of the fly orthologue for human lamin B1.
*Immunoprecipitation of lamin B1 from the nuclear matrix of cerebellar cells suggested significant interaction of endogenous lamin B1 with RNF220, while transfection studies in HEK293T cells for wt/mt suggested reduced binding to endogenous lamin B1 for RNF220 mt compared to wt (more prominent for R365Q). RNF220 mutants also reduced ubiquitination of nuclear lamin B1 compared to wt.
*Patient fibroblasts immunostained with different nuclear envelope markers displayed abnormal nuclear shapes with multiple invaginations and lobulations, findings also observed in laminopathies.

There is currently no associated phenotype in OMIM or G2P. SysID includes RNF220 among the current primary ID genes.

Consider inclusion in panels for leukodystrophies, childhood onset ataxia, sensorineural hearing loss, corpus callosum anomalies, cardiomyopathies, hepatopathies, etc in all cases with green rating.

Sources: Literature, Other
Intellectual disability syndromic and non-syndromic v0.4059 RNF220 Konstantinos Varvagiannis gene: RNF220 was added
gene: RNF220 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature,Other
Mode of inheritance for gene: RNF220 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RNF220 were set to 33964137; 10881263
Phenotypes for gene: RNF220 were set to Leukodystrophy; CNS hypomyelination; Ataxia; Intellectual disability; Sensorineural hearing impairment; Elevated hepatic transaminases; Hepatic fibrosis; Dilated cardiomyopathy; Spastic paraplegia; Dysarthria; Abnormality of the corpus callosum
Penetrance for gene: RNF220 were set to Complete
Review for gene: RNF220 was set to GREEN
Added comment: Sferra et al (2021 - PMID: 33964137) provide extensive evidence that biallelic RNF220 mutations cause a disorder characterized by hypomyelinating leukodystrophy, ataxia (9/9 - onset 1-5y), borderline intellectual functioning (3/9) / intellectual disability (5/9 - in most cases mild), sensorineural deafness (9/9) with complete hearing loss in the first decade of life, hepatopathy (9/9) with associated periportal fibrosis, and dilated cardiomyopathy (9/9) which was fatal.

Other neurologic manifestations apart from ataxia incl. hyperreflexia (8/8), spastic paraplegia (9/9), dysarthria (9/9), peripheral neuropathy (4/9), seizures in one case (1/9). Upon brain MRI there was thin corpus callosum (9/9) or cerebellar atrophy in some (2/9).

The authors identified homozygosity for 2 recurrent missense RNF220 variants in affected members belonging to these 5 broad consanguineous pedigrees (7 families), namely NM_018150.4:c.1094G>A / p.Arg365Gly in 4 Roma families in the context of a shared haplotype (/founder effect) as well as c.1088G>A / p.Arg363Gly in a large pedigree from southern Italy initially reported by Leuzzi et al (2000 - PMID: 10881263).

Extensive segregation analyses were carried out including several affected and unaffected members.

RNF220 encodes ring finger protein 220, which functions as an E3 ubiquitin ligase. Previous studies have shown among others a role in modulation of Sonic hedgehog/GLI signaling and cerebellar development

Evidence for the role of RNF220 included relevant expression, localization within the cell, interaction partners (lamin B1, 20S proteasome), similarities with other laminopathies in terms of phenotype, etc :
*RNF220 has a relevant expression pattern in CNS (based on qRT-PCR analyses in human brain, cerebellum, cerebral cortex / mRNA levels in human fetal CNS with higher expression in cerebellum, spinal cord and cortex / previous GTEx data / protein levels in mouse CNS)
*The protein displays nuclear localization based on iPSC cells differentiated to motor neurons (also supported by data from the Human Protein Atlas). Transfection of COS-1 cells demonstrated localization primarily to the nucleus (as also previously demonstrated in HEK293T cells) in vesicle like structures with ASF2/SF2 colocalization suggesting enrichment in nuclear speckles. There was also partial co-distribution with the 20S proteasome. R363Q and R365Q additionally coalesced in the cytoplasm forming protein aggregates/inclusions.
*Immunofluorescence studies in patient fibroblasts also confirmed abnormal increase of the protein in the cytoplasm and increased fluorescence with the 20S proteasome.
*Proteomic identification of RNF220-interacting proteins in transfected HEK293T cells demonstrated enrichment for all members of the lamin protein family (incl . lamin B1, AC, B2).
*RNAi-mediated downregulation of RNF222 in Drosophila suggested altered subcellular localization and accumulation of the fly orthologue for human lamin B1.
*Immunoprecipitation of lamin B1 from the nuclear matrix of cerebellar cells suggested significant interaction of endogenous lamin B1 with RNF220, while transfection studies in HEK293T cells for wt/mt suggested reduced binding to endogenous lamin B1 for RNF220 mt compared to wt (more prominent for R365Q). RNF220 mutants also reduced ubiquitination of nuclear lamin B1 compared to wt.
*Patient fibroblasts immunostained with different nuclear envelope markers displayed abnormal nuclear shapes with multiple invaginations and lobulations, findings also observed in laminopathies.

There is currently no associated phenotype in OMIM or G2P. SysID includes RNF220 among the current primary ID genes.
Sources: Literature, Other
Intellectual disability syndromic and non-syndromic v0.4059 ARF3 Zornitza Stark Classified gene: ARF3 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.4059 ARF3 Zornitza Stark Gene: arf3 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.4058 ARF3 Zornitza Stark reviewed gene: ARF3: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability syndromic and non-syndromic v0.4058 ARF3 Konstantinos Varvagiannis gene: ARF3 was added
gene: ARF3 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: ARF3 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ARF3 were set to 34346499
Phenotypes for gene: ARF3 were set to Global developmental delay; Intellectual disability; Seizures; Morphological abnormality of the central nervous system
Penetrance for gene: ARF3 were set to unknown
Added comment: Sakamoto et al (2021 - PMID: 34346499) provide some evidence that monoallelic ARF3 pathogenic variants may be associated with a NDD with brain abnormality.

Using trio exome sequencing, the authors identified 2 individuals with NDD harboring de novo ARF3 variants, namely: NM_001659.2:c.200A>T / p.Asp67Val and c.296G>T / p.Arg99Leu.

Individual 1 (with Asp67Val / age : 4y10m), appeared to be more severelely affected with prenatal onset progressive microcephaly, severe global DD, epilepsy. Upon MRI there was cerebellar and brainstem atrophy. Individual 2 (Arg99Leu / 14y) had severe DD and ID (IQ of 23), epilepsy and upon MRI cerebellar hypoplasia. This subject did not exhibit microcephaly. Common facial features incl. broad nose, full cheeks, small philtrum, strabismus, thin upper lips and abnormal jaw. There was no evidence of systemic involvement in both.

ARF3 encodes ADP-ribosylation factor 3. Adenosine diphosphate ribosylation factors (ARFs) are key proteins for regulation of cargo sorting at the Golgi network, with ARF3 mainly working at the trans-Golgi network. ARFs belong to the small GTP-binding protein (G protein) superfamily. ARF3 switches between an active GTP-bound form and an inactive GDP-bound form, regulated by guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs) respectively.

Members of the ARF superfamily regulate various aspects of membrane traffic, among others in neurons.

There are 5 homologs of ARF families, divided in 3 classes. ARF3 and ARF1 belong to class I. Monoallelic ARF1 mutations are associated with Periventricular nodular heterotopia 8 (MIM 618185).

In vivo, in vitro and in silico studies for the 2 variants suggest that both impair the Golgi transport system although each variant most likely exerts a different effect (gain-of-function for Arg99Leu vs loss-of-function/dominant-negative for Asp67Val).

This was also reflected in somewhat different phenotype of the subjects with the respective variants. Common features included severe DD, epilepsy and brain abnormalities although Asp67Val was associated with diffuse brain atrophy as well as congenital microcephaly and Arg99Leu with cerebellar hypoplasia.

Evidence to support the effect of each variant include:

Arg99Leu:
Had identical Golgi localization to that of wt
Had increased binding activity with GGA1, a protein recruited by the GTP-bound active form of ARF3 to the TGN membrane (supporting GoF)
In silico structural analysis suggested it may fail to stabilize the conformation of Asp26, resulting in impaired GTP hydrolysis (GoF).
In transgenic fruit flies, evaluation of the ARF3 variant toxicity using the rough eye phenotype this variant was associated with increased severity of the r-e phenotype similar to a previously studied GoF variant (Gln71Leu)

Asp67Val:
Did not show a Golgi-like pattern of localization (similar to Thr31Asn a previously studied dominant-negative variant)
Displayed decreased protein stability
In silico structural analysis suggested that Asp67Val may lead to compromised binding of GTP or GDP (suggestive of LoF)
In transgenic Drosophila eye-specific expression of Asp67Val (similar to Thr31Asn, a known dominant-negative variant) was lethal possibly due to high toxicity in very small amounts in tissues outside the eye.

There is no associated phenotype in OMIM, G2P or SysID.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4058 CEP57 Zornitza Stark Marked gene: CEP57 as ready
Intellectual disability syndromic and non-syndromic v0.4058 CEP57 Zornitza Stark Gene: cep57 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4058 CEP57 Zornitza Stark Phenotypes for gene: CEP57 were changed from to Mosaic variegated aneuploidy syndrome 2, #MIM 614114
Intellectual disability syndromic and non-syndromic v0.4057 CEP57 Zornitza Stark Publications for gene: CEP57 were set to
Intellectual disability syndromic and non-syndromic v0.4056 CEP57 Zornitza Stark Mode of inheritance for gene: CEP57 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4055 CEP57 Zornitza Stark reviewed gene: CEP57: Rating: GREEN; Mode of pathogenicity: None; Publications: 24259107, 21552266, 32861809, 30147898; Phenotypes: Mosaic variegated aneuploidy syndrome 2, #MIM 614114; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4055 PLXNA2 Zornitza Stark Marked gene: PLXNA2 as ready
Intellectual disability syndromic and non-syndromic v0.4055 PLXNA2 Zornitza Stark Gene: plxna2 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.4055 PLXNA2 Zornitza Stark Classified gene: PLXNA2 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.4055 PLXNA2 Zornitza Stark Gene: plxna2 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.4054 SUPT16H Zornitza Stark Phenotypes for gene: SUPT16H were changed from Intellectual disability; Abnormality of the corpus callosum to Neurodevelopmental disorder with dysmorphic facies and thin corpus callosum, MIM# 619480; Intellectual disability; Abnormality of the corpus callosum
Intellectual disability syndromic and non-syndromic v0.4053 SUPT16H Zornitza Stark edited their review of gene: SUPT16H: Changed phenotypes: Neurodevelopmental disorder with dysmorphic facies and thin corpus callosum, MIM# 619480, Intellectual disability, Abnormality of the corpus callosum
Intellectual disability syndromic and non-syndromic v0.4053 PLXNA2 Konstantinos Varvagiannis gene: PLXNA2 was added
gene: PLXNA2 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature,Other
Mode of inheritance for gene: PLXNA2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PLXNA2 were set to 34327814
Phenotypes for gene: PLXNA2 were set to Intellectual disability; Abnormality of the face; Failure to thrive; Abnormal heart morphology
Penetrance for gene: PLXNA2 were set to Incomplete
Review for gene: PLXNA2 was set to AMBER
Added comment: Altuame et al (2021 - PMID: 34327814) describe 3 individuals from 2 consanguineous Arab families with biallelic PLXNA2 variants.

The index patient from the 1st family presented with CHD (hypoplastic right ventricle, ASD), DD and moderate ID (IQ of 40), failure to thrive as well as some dysmorphic features (obtuse mandibular angle, mild overbite, synophrys with downslanting p-f, strabismus, etc). There were additional features (eg. postaxial polydactyly) which were found in other affected and unaffected family members.

Exome sequencing with autozygome analysis revealed homozygosity for a PLXNA2 stopgain variant (NM_025179:c.3603C>A / p.(Cys1201*)).

Sanger confirmation was carried out and segregation analyses confirmed carrier status of the unaffected parents and a sib as well as a brother homozygous for the same variant. Clinical evaluation of the latter, following this finding revealed borderline intellectual functioning, ADHD, failure to thrive. There was no mandibular anomaly or overbite and no clinical evidence of CHD (no echo performed).

The index patient from the 2nd consanguineous family was evaluated for ID (IQ of 63), with previous borderline motor development, ADHD and some dysmorphic features (obtuse mandibular angle and overbite). There was no clinical evidence of CHD (no echo performed).

Exome sequencing with autozygosity mapping revealed a homozygous missense PLXNA2 variant (c.3073G>A / p.(Asp1025Asn), present only once in gnomAD (htz), with rather non-concordant in silico predictions SIFT 0.22, PolyPhen 0.682 and CADD 23.5. The aa was however highly conserved.

Segregation analysis confirmed carrier state of the parents and 2 unaffected sibs, with a 3rd sib homozygous for the wt allele.

As the authors discuss:
*PLXNA2 belongs to the plexin family of genes, encoding transmbembrane proteins functioning as semaphorin receptors. It has predominant expression in neural tissue. The protein is thought to bind semaphorin-3A, -3C or -5 followed by plexin A2 dimerization, activation of its GTPase-activating protein domain, negative regulation of Rap1B GTPase and initiation of a signal transduction cascade mediating axonal repulsion/guidance, dendritic guidance, neuronal migration.
*Murine Plxna2 knockout models display structural brain defects. In addition they display congenital heart defects incl. persistent truncus arteriosus and interrupted aortic arch.
*Rare CNVs in adult humans with tetralogy of Fallot have suggested a potential role of PLXNA2 in cardiac development and CHD.
*Expression and the role of PLXNA2 in human chondrocytes as well as a GWAS in 240 japanese patients with mandibular prognathism where PLXNA2 was suggested as a susceptibility locus.

Overall, the authors recognize some common features (as for cognitive functioning, some dysmorphic features incl. obtuse mandibular angle and overbite in 2 unrelated subjects, failure to thrive 3/3) and provide plausible explanations for the variability / discordance of others eg:
- Cyanotic heart disease explaining discordance in cognitive outcome among sibs
- Incomplete penetrance for CHD (and/or ID or mandibular anomaly) as for few AR disorders and/or
- Additional pathogenic variants possibly explaining the CHD in the first subject.

There is no associated phenotype in OMIM or G2P. SysID includes PLXNA2 among the candidate ID genes.
Sources: Literature, Other
Intellectual disability syndromic and non-syndromic v0.4053 HNMT Zornitza Stark Publications for gene: HNMT were set to 26206890; 30744146
Intellectual disability syndromic and non-syndromic v0.4052 HNMT Zornitza Stark edited their review of gene: HNMT: Added comment: Verhoeven et al. 2020 (PMID: 33310825) report an adult male patient with severe intellectual disability and autism, born to second cousins, with a homozygous nonsense variant (c.88C>T; p.Gln30*). Treatment with antihistaminergic medication and a histamine-restricted diet resulted in significant general improvement, supporting an etiological role for HNMT deficiency. Taskiran et al. 2021 (PMID: 33739554) report an adult male patient with severe intellectual disability, pervasive developmental disorder and ADHD, born to consanguineous parents, with a homozygous nonsense variant (c.100G>T; p.Glu34*).; Changed publications: 26206890, 30744146, 33310825, 33739554
Intellectual disability syndromic and non-syndromic v0.4052 VPS50 Zornitza Stark Marked gene: VPS50 as ready
Intellectual disability syndromic and non-syndromic v0.4052 VPS50 Zornitza Stark Gene: vps50 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.4052 VPS50 Zornitza Stark Classified gene: VPS50 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.4052 VPS50 Zornitza Stark Gene: vps50 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.4051 VPS50 Konstantinos Varvagiannis gene: VPS50 was added
gene: VPS50 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: VPS50 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: VPS50 were set to 34037727
Phenotypes for gene: VPS50 were set to Neonatal cholestatic liver disease; Failure to thrive; Profound global developmental delay; Postnatal microcephaly; Seizures; Abnormality of the corpus callosum
Penetrance for gene: VPS50 were set to Complete
Review for gene: VPS50 was set to AMBER
Added comment: Schneeberger et al (2021 - PMID: 34037727) describe the phenotype of 2 unrelated individuals with biallelic VPS50 variants.

Common features included transient neonatal cholestasis, failure to thrive, severe DD with failure to achieve milestones (last examination at 2y and 2y2m respectively), postnatal microcephaly, seizures (onset at 6m and 25m) and irritability. There was corpus callosum hypoplasia on brain imaging.

Both individuals were homozygous for variants private to each family (no/not known consanguinity applying to each case). The first individual was homozygous for a splicing variant (NM_017667.4:c.1978-1G>T) and had a similarly unaffected sister deceased with no available DNA for testing. The other individual was homozygous for an in-frame deletion (c.1823_1825delCAA / p.(Thr608del)).

VPS50 encodes a critical component of the endosome-associated recycling protein (EARP) complex, which functions in recycling endocytic vesicles back to the plasma membrane [OMIM based on Schindler et al]. The complex contains VPS50, VPS51, VPS52, VPS53, the three latter also being components of GARP (Golgi-associated-retrograde protein) complex. GARP contains VPS54 instead of VPS50 and is required for trafficking of proteins to the trans-golgi network. Thus VPS50 (also named syndetin) and VPS54 function in the EARP and GARP complexes, to define directional movement of their endocytic vesicles [OMIM based on Schindler et al]. The VPS50 subunit is required for recycling of the transferrin receptor.

As discussed by Schneeberger et al (refs provided in text):
- VPS50 has a high expression in mouse and human brain as well as throughout mouse brain development.
- Mice deficient for Vps50 have not been reported. vps50 knockdown in zebrafish results in severe developmental defects of the body axis. Knockout mice for other proteins of the EARP/GARP complex (e.g. Vps52, 53 and 54) display embryonic lethality.

Studies performed by Schneeberger et al included:
- Transcript analysis for the 1st variant demonstrated skipping of ex21 (in patient derived fabriblasts) leading to an in frame deletion of 81 bp (r.1978_2058del) with predicted loss of 27 residues (p.Leu660_Leu686del).
- Similar VPS50 mRNA levels but significant reduction of protein levels (~5% and ~8% of controls) were observed in fibroblasts from patients 1 and 2. Additionally, significant reductions in the amounts of VPS52 and VPS53 protein levels were observed despite mRNA levels similar to controls. Overall, this suggested drastic reduction of functional EARP complex levels.
- Lysosomes appeared to have similar morphology, cellular distribution and likely unaffected function in patient fibroblasts.
- Transferrin receptor recycling was shown to be delayed in patient fibroblasts suggestive of compromise of endocytic-recycling function.

As the authors comment, the phenotype of both individuals with biallelic VPS50 variants overlaps with the corresponding phenotype reported in 15 subjects with biallelic VPS53 or VPS51 mutations notably, severe DD/ID, microcephaly and early onset epilepsy, CC anomalies. Overall, for this group, they propose the term "GARP and/or EARP deficiency disorders".

There is no VPS50-associated phenotype in OMIM or G2P. SysID includes VPS50 among the ID candidate genes.

Consider inclusion in other relevant gene panels (e.g. for neonatal cholestasis, epilepsy, microcephaly, growth failure in early infancy, corpus callosum anomalies, etc) with amber rating pending further reports.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4051 ROGDI Zornitza Stark Marked gene: ROGDI as ready
Intellectual disability syndromic and non-syndromic v0.4051 ROGDI Zornitza Stark Gene: rogdi has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4051 ROGDI Zornitza Stark Phenotypes for gene: ROGDI were changed from to Kohlschutter-Tonz syndrome, MIM# 226750
Intellectual disability syndromic and non-syndromic v0.4050 ROGDI Zornitza Stark Publications for gene: ROGDI were set to
Intellectual disability syndromic and non-syndromic v0.4049 ROGDI Zornitza Stark Mode of inheritance for gene: ROGDI was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4048 ROGDI Zornitza Stark reviewed gene: ROGDI: Rating: GREEN; Mode of pathogenicity: None; Publications: 22424600, 23086778, 33866847; Phenotypes: Kohlschutter-Tonz syndrome, MIM# 226750; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4048 SPTBN1 Zornitza Stark Phenotypes for gene: SPTBN1 were changed from Neurodevelopmental Syndrome to Developmental delay, impaired speech, and behavioural abnormalities, MIM# 619475
Intellectual disability syndromic and non-syndromic v0.4047 TMEM222 Zornitza Stark Marked gene: TMEM222 as ready
Intellectual disability syndromic and non-syndromic v0.4047 TMEM222 Zornitza Stark Gene: tmem222 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4047 TMEM222 Zornitza Stark Phenotypes for gene: TMEM222 were changed from Motor delay; Delayed speech and language development; Intellectual disability; Generalized hypotonia; Broad-based gait; Abnormality of nervous system morphology; Seizures; Microcephaly; Behavioral abnormality to Neurodevelopmental disorder with motor and speech delay and behavioural abnormalities, MIM# 619470; Motor delay; Delayed speech and language development; Intellectual disability; Generalized hypotonia; Broad-based gait; Abnormality of nervous system morphology; Seizures; Microcephaly; Behavioral abnormality
Intellectual disability syndromic and non-syndromic v0.4046 TMEM222 Zornitza Stark reviewed gene: TMEM222: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with motor and speech delay and behavioural abnormalities, MIM# 619470; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4046 TCF7L2 Zornitza Stark Marked gene: TCF7L2 as ready
Intellectual disability syndromic and non-syndromic v0.4046 TCF7L2 Zornitza Stark Added comment: Comment when marking as ready: Sufficient cases/detail to upgrade to Green.
Intellectual disability syndromic and non-syndromic v0.4046 TCF7L2 Zornitza Stark Gene: tcf7l2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4046 TCF7L2 Zornitza Stark Phenotypes for gene: TCF7L2 were changed from Developmental disorders to Global developmental delay; Intellectual disability; Autism; Attention deficit hyperactivity disorder; Myopia; Abnormality of skeletal system
Intellectual disability syndromic and non-syndromic v0.4045 TCF7L2 Zornitza Stark Publications for gene: TCF7L2 were set to 33057194
Intellectual disability syndromic and non-syndromic v0.4044 TCF7L2 Zornitza Stark Classified gene: TCF7L2 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4044 TCF7L2 Zornitza Stark Gene: tcf7l2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4043 TCF7L2 Konstantinos Varvagiannis reviewed gene: TCF7L2: Rating: AMBER; Mode of pathogenicity: None; Publications: 34003604; Phenotypes: Global developmental delay, Intellectual disability, Autism, Attention deficit hyperactivity disorder, Myopia, Abnormality of skeletal system; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability syndromic and non-syndromic v0.4043 PIDD1 Zornitza Stark Marked gene: PIDD1 as ready
Intellectual disability syndromic and non-syndromic v0.4043 PIDD1 Zornitza Stark Gene: pidd1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4043 PIDD1 Zornitza Stark Classified gene: PIDD1 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4043 PIDD1 Zornitza Stark Gene: pidd1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4042 JAKMIP1 Seb Lunke Marked gene: JAKMIP1 as ready
Intellectual disability syndromic and non-syndromic v0.4042 JAKMIP1 Seb Lunke Gene: jakmip1 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.4042 JAKMIP1 Seb Lunke Classified gene: JAKMIP1 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.4042 JAKMIP1 Seb Lunke Gene: jakmip1 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.4041 JAKMIP1 Seb Lunke gene: JAKMIP1 was added
gene: JAKMIP1 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: JAKMIP1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: JAKMIP1 were set to 29158550; 26627310; 27799067
Phenotypes for gene: JAKMIP1 were set to Intellectual disability; Seizures
Review for gene: JAKMIP1 was set to AMBER
Added comment: Identified in two independent patients in the literature with a mouse model. Patient 1 (27799067) with developmental delay, speech delay, and cognitive impairment; self-injurious and aggressive behaviour, seizures, dysmorphic features. De-novo missense JAKMIP1 (p.D586H). Patient 2 (29158550) with feeding difficulties, hypotonia, epilepsy, severe ID, no active speech, kyphoscoliosis, constipation, autism, short stature. Splice variant c.1432-2A>G, no segregation or RNA data available. KO mouse model (27799067) displays social deficits, stereotyped activity, abnormal postnatal vocalizations, and other autistic-like behaviors.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4040 PIDD1 Konstantinos Varvagiannis gene: PIDD1 was added
gene: PIDD1 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: PIDD1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PIDD1 were set to 28397838; 29302074; 33414379; 34163010
Phenotypes for gene: PIDD1 were set to Global developmental delay; Intellectual disability; Seizures; Autism; Behavioral abnormality; Psychosis; Pachygyria; Lissencephaly; Abnormality of the corpus callosum
Penetrance for gene: PIDD1 were set to Complete
Review for gene: PIDD1 was set to GREEN
Added comment: There is enough evidence to include this gene in the current panel with green rating.

Biallelic PIDD1 pathogenic variants have been reported in 26 individuals (11 families) with DD (all), variable degrees of ID (mild to severe), behavioral (eg. aggression/self-mutilation in several, ADHD) and/or psychiatric abnormalities (ASD, psychosis in 5 belonging to 3 families), well-controlled epilepsy is some (9 subjects from 6 families) and MRI abnormalities notably abnormal gyration pattern (pachygyria with predominant anterior gradient) as well as corpus callosum anomalies (commonly thinning) in several. Dysmorphic features have been reported in almost all, although there has been no specific feature suggested.

The first reports on the phenotype associated with biallelic PIDD1 mutations were made by Harripaul et al (2018 - PMID: 28397838) and Hu et al (2019 - PMID: 29302074) [both studies investigating large cohorts of individuals with ID from consanguineous families].

Sheikh et al (2021 - PMID: 33414379) provided details on the phenotype of 15 individuals from 5 families including those from the previous 2 reports and studied provided evidence on the role of PIDD1 and the effect of variants.

Zaki et al (2021 - PMID: 34163010) reported 11 additional individuals from 6 consanguineous families, summarize the features of all subjects published in the literature and review the neuroradiological features of the disorder.

PIDD1 encodes p53-induced death domain protein 1. The protein is part of the PIDDosome, a multiprotein complex also composed of the bipartite linker protein CRADD (also known as RAIDD) and the proform of caspase-2 and induces apoptosis in response to DNA damage.

There are 5 potential PIDD1 mRNA transcript variants with NM_145886.4 corresponding to the longest. Similar to the protein encoded by CRADD, PIDD1 contains a death domain (DD - aa 774-893). Constitutive post-translational processing gives PIDD1-N, PIDD1-C the latter further processed into PIDD1-CC (by auto-cleavage). Serine residues at pos. 446 and 588 are involved in this autoprocessing generating PIDD1-C (aa 446-910) and PIDD1-CC (aa 774-893). The latter is needed for caspase-2 activation.

Most (if not all) individuals belonged to consanguineous families of different origins and harbored pLoF or missense variants.

Variants reported so far include : c.2587C>T; p.Gln863* / c.1909C>T ; p.Arg637* / c.2443C>T / p.Arg815Trp / c.2275-1G>A which upon trap assay was shown to lead to skipping of ex15 with direct splicing form exon14 to the terminal exon 16 (resulting to p.Arg759Glyfs*1 with exlcusion of the entire DD) / c.2584C>T; p.Arg862Trp / c.1340G>A; p.Trp447* / c.2116_2120del; p.Val706His*, c.1564_1565del; p.Gly602fs*26

Evidence so far provided includes:
- Biallelic CRADD variants cause a NDD disorder and a highly similar gyration pattern.
- Confirmation of splicing effect (eg. for c.2275-1G>A premature stop in position 760) or poor expression (NM_145886.3:c.2587C>T; p.Gln863*). Arg815Trp did not affect autoprocessing or protein stability.
- Abnormal localization pattern, loss of interaction with CRADD and failure to activate caspase-2 (MDM2 cleavage assay) [p.Gln863* and Arg815Trp]
- Available expression data from GTEx (PIDD1 having broad expression in multiple tissues, but higher in brain cerebellum) as well as BrainSpan and PsychEncode studies suggesting high coexpression of PIDD1, CRADD and CASP2 in many regions in the developing human brain.
- Variants in other genes encoding proteins interacting with PIDD1 (MADD, FADD, DNAJ, etc) are associated with NDD.

Pidd-1 ko mice (ex3-15 removal) lack however CNS-related phenotypes. These show decreased anxiety but no motor anomalies. This has also been the case with Cradd-/- mice displaying no significant CNS phenotypes without lamination defects.

There is currently no associated phenotype in OMIM, PanelApp Australia. PIDD1 is listed in the DD panel of G2P (PIDD1-related NDD / biallelic / loss of function / probable) . SysID includes PIDD1 among the current primary ID genes.

Overall the gene appears to be relevant for the epilepsy panel, panels for gyration and/or corpus callosum anomalies etc.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4040 SHOC2 Zornitza Stark Marked gene: SHOC2 as ready
Intellectual disability syndromic and non-syndromic v0.4040 SHOC2 Zornitza Stark Gene: shoc2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4040 SHOC2 Zornitza Stark Phenotypes for gene: SHOC2 were changed from to Noonan syndrome-like with loose anagen hair 1, MIM# 607721
Intellectual disability syndromic and non-syndromic v0.4039 SHOC2 Zornitza Stark Publications for gene: SHOC2 were set to
Intellectual disability syndromic and non-syndromic v0.4038 SHOC2 Zornitza Stark Mode of pathogenicity for gene: SHOC2 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 syndromic and non-syndromic v0.4037 SHOC2 Zornitza Stark Mode of inheritance for gene: SHOC2 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.4036 SHOC2 Zornitza Stark reviewed gene: SHOC2: 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: 19684605, 23918763, 20882035; Phenotypes: Noonan syndrome-like with loose anagen hair 1, MIM# 607721; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.4036 UBR1 Zornitza Stark Marked gene: UBR1 as ready
Intellectual disability syndromic and non-syndromic v0.4036 UBR1 Zornitza Stark Gene: ubr1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4036 UBR1 Zornitza Stark Phenotypes for gene: UBR1 were changed from to Johanson-Blizzard syndrome (MIM#243800)
Intellectual disability syndromic and non-syndromic v0.4035 UBR1 Zornitza Stark Publications for gene: UBR1 were set to
Intellectual disability syndromic and non-syndromic v0.4034 UBR1 Zornitza Stark Mode of inheritance for gene: UBR1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4033 UBR1 Zornitza Stark changed review comment from: >50 unrelated families reported, reviewed in PMID: 24599544. Common clinical features include poor growth, mental retardation, and variable dysmorphic features, including aplasia or hypoplasia of the nasal alae, abnormal hair patterns or scalp defects, and oligodontia. Other features include hypothyroidism, sensorineural hearing loss, imperforate anus, and pancreatic exocrine insufficiency.; to: >50 unrelated families reported, reviewed in PMID: 24599544. Common clinical features include poor growth, intellectual disability, and variable dysmorphic features, including aplasia or hypoplasia of the nasal alae, abnormal hair patterns or scalp defects, and oligodontia. Other features include hypothyroidism, sensorineural hearing loss, imperforate anus, and pancreatic exocrine insufficiency.
Intellectual disability syndromic and non-syndromic v0.4033 UBR1 Zornitza Stark reviewed gene: UBR1: Rating: GREEN; Mode of pathogenicity: None; Publications: 24599544; Phenotypes: Johanson-Blizzard syndrome (MIM#243800); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4033 ACTL6A Zornitza Stark changed review comment from: Two individuals from unrelated families reported with missense variants in this gene, and one with a splice-site variant. Part of the BAF complex. Only one missense confirmed de novo, pathogenicity of the other variant uncertain.; to: Two individuals from unrelated families reported with missense variants in this gene, and one with a splice-site variant. Part of the BAF complex. Only one missense confirmed de novo, pathogenicity of the other variant uncertain.
PMID 31994175: fourth individual reported, recurrent de novo p.Arg377Trp
Intellectual disability syndromic and non-syndromic v0.4033 ACTL6A Zornitza Stark edited their review of gene: ACTL6A: Changed publications: 28649782, 31994175
Intellectual disability syndromic and non-syndromic v0.4033 ACTL6A Zornitza Stark changed review comment from: Two individuals from unrelated families reported with missense variants in this gene. Part of the BAF complex. Only one confirmed de novo.; to: Two individuals from unrelated families reported with missense variants in this gene, and one with a splice-site variant. Part of the BAF complex. Only one missense confirmed de novo, pathogenicity of the other variant uncertain.
Intellectual disability syndromic and non-syndromic v0.4033 SNRPB Zornitza Stark Marked gene: SNRPB as ready
Intellectual disability syndromic and non-syndromic v0.4033 SNRPB Zornitza Stark Gene: snrpb has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4033 SNRPB Zornitza Stark Phenotypes for gene: SNRPB were changed from to Cerebrocostomandibular syndrome, MIM# 117650
Intellectual disability syndromic and non-syndromic v0.4032 SNRPB Zornitza Stark Publications for gene: SNRPB were set to
Intellectual disability syndromic and non-syndromic v0.4031 SNRPB Zornitza Stark Mode of inheritance for gene: SNRPB was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.4030 SNRPB Zornitza Stark reviewed gene: SNRPB: Rating: GREEN; Mode of pathogenicity: None; Publications: 25047197, 25504470, 26971886; Phenotypes: Cerebrocostomandibular syndrome, MIM# 117650; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.4030 TP73 Zornitza Stark Phenotypes for gene: TP73 were changed from Intellectual disability; lissencephaly to Ciliary dyskinesia, primary, 47, and lissencephaly, MIM#619466; Intellectual disability; lissencephaly
Intellectual disability syndromic and non-syndromic v0.4029 TP73 Zornitza Stark edited their review of gene: TP73: Added comment: Additional 5 families reported in PMID 34077761; Changed rating: GREEN; Changed publications: 31130284, 34077761; Changed phenotypes: Ciliary dyskinesia, primary, 47, and lissencephaly, MIM#619466, Intellectual disability, lissencephaly
Intellectual disability syndromic and non-syndromic v0.4029 MAST3 Zornitza Stark Marked gene: MAST3 as ready
Intellectual disability syndromic and non-syndromic v0.4029 MAST3 Zornitza Stark Gene: mast3 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4029 MAST3 Zornitza Stark Classified gene: MAST3 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4029 MAST3 Zornitza Stark Gene: mast3 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4028 MAST3 Zornitza Stark gene: MAST3 was added
gene: MAST3 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: MAST3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MAST3 were set to 34185323
Phenotypes for gene: MAST3 were set to Developmental and epileptic encephalopathy
Review for gene: MAST3 was set to GREEN
Added comment: Eleven individuals reported with de novo missense variants in the STK domain, including two recurrent variants p.G510S (n = 5) and p.G515S (n = 3). All 11 individuals had developmental and epileptic encephalopathy, with 8 having normal development prior to seizure onset at <2 years of age. All patients developed multiple seizure types, 9 of 11 patients had seizures triggered by fever and 9 of 11 patients had drug-resistant seizures. Limited functional data.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4027 TRIM8 Zornitza Stark Phenotypes for gene: TRIM8 were changed from Intellectual disability; Seizures; FSGS to Focal segmental glomerulosclerosis and neurodevelopmental syndrome, MIM# 619428; Intellectual disability; Seizures; FSGS
Intellectual disability syndromic and non-syndromic v0.4026 TRIM8 Zornitza Stark edited their review of gene: TRIM8: Changed phenotypes: Focal segmental glomerulosclerosis and neurodevelopmental syndrome, MIM# 619428, Intellectual disability, Seizures, FSGS
Intellectual disability syndromic and non-syndromic v0.4026 RNF2 Zornitza Stark Phenotypes for gene: RNF2 were changed from epilepsy; intellectual disability; intrauterine growth retardation to Lou-Schoch-Yamamoto syndrome , MIM#619460; epilepsy; intellectual disability; intrauterine growth retardation
Intellectual disability syndromic and non-syndromic v0.4025 RNF2 Zornitza Stark edited their review of gene: RNF2: Changed phenotypes: Lou-Schoch-Yamamoto syndrome , MIM#619460, epilepsy, intellectual disability, intrauterine growth retardation
Intellectual disability syndromic and non-syndromic v0.4025 USP7 Zornitza Stark Phenotypes for gene: USP7 were changed from Hao-Fountain syndrome, MIM# 616863; ID; Autism to Hao-Fountain syndrome, MIM# 616863; MONDO:0014805; Intellectual disability; Autism
Intellectual disability syndromic and non-syndromic v0.4024 USP7 Zornitza Stark edited their review of gene: USP7: Changed phenotypes: Hao-Fountain syndrome, MIM# 616863, MONDO:0014805, Intellectual disability, Autism
Intellectual disability syndromic and non-syndromic v0.4024 AP1G1 Zornitza Stark Marked gene: AP1G1 as ready
Intellectual disability syndromic and non-syndromic v0.4024 AP1G1 Zornitza Stark Gene: ap1g1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4024 AP1G1 Zornitza Stark Marked gene: AP1G1 as ready
Intellectual disability syndromic and non-syndromic v0.4024 AP1G1 Zornitza Stark Gene: ap1g1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4024 AP1G1 Zornitza Stark Classified gene: AP1G1 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4024 AP1G1 Zornitza Stark Gene: ap1g1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4023 AP1G1 Zornitza Stark changed review comment from: Two bi-allelic homozygous missense variants were found in two distinct families with Italian and Pakistani origins; homozygous missense variants.

Eight de novo heterozygous variants were identified in nine isolated affected individuals from nine families; including five missense, two frameshift, and one intronic variant that disrupts the canonical splice acceptor site.

Knocking out AP1G1 Zebrafish model resulted in severe developmental abnormalities and increased lethality.

All individuals had neurodevelopmental disorder (NDD) including global developmental delay and ID, which varied in severity from mild to severe.
Sources: Literature; to: Two bi-allelic homozygous missense variants were found in two distinct families with Italian and Pakistani origins; homozygous missense variants.

Eight de novo heterozygous variants were identified in nine isolated affected individuals from nine families; including five missense, two frameshift, and one intronic variant that disrupts the canonical splice acceptor site.

Knocking out AP1G1 Zebrafish model resulted in severe developmental abnormalities and increased lethality.

All individuals had neurodevelopmental disorder (NDD) including global developmental delay and ID, which varied in severity from mild to severe.

GREEN for mono-allelic, AMBER for bi-allelic.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4023 AP1G1 Zornitza Stark gene: AP1G1 was added
gene: AP1G1 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: AP1G1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: AP1G1 were set to 34102099
Phenotypes for gene: AP1G1 were set to Neurodevelopmental disorder (NDD); Intellectual Disability; Epilepsy
Review for gene: AP1G1 was set to GREEN
Added comment: Two bi-allelic homozygous missense variants were found in two distinct families with Italian and Pakistani origins; homozygous missense variants.

Eight de novo heterozygous variants were identified in nine isolated affected individuals from nine families; including five missense, two frameshift, and one intronic variant that disrupts the canonical splice acceptor site.

Knocking out AP1G1 Zebrafish model resulted in severe developmental abnormalities and increased lethality.

All individuals had neurodevelopmental disorder (NDD) including global developmental delay and ID, which varied in severity from mild to severe.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4022 SPTBN1 Zornitza Stark Marked gene: SPTBN1 as ready
Intellectual disability syndromic and non-syndromic v0.4022 SPTBN1 Zornitza Stark Gene: sptbn1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4022 SPTBN1 Zornitza Stark Classified gene: SPTBN1 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4022 SPTBN1 Zornitza Stark Gene: sptbn1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4021 CLCN3 Zornitza Stark Marked gene: CLCN3 as ready
Intellectual disability syndromic and non-syndromic v0.4021 CLCN3 Zornitza Stark Gene: clcn3 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4021 CLCN3 Zornitza Stark Classified gene: CLCN3 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4021 CLCN3 Zornitza Stark Gene: clcn3 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4020 CLCN3 Zornitza Stark gene: CLCN3 was added
gene: CLCN3 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: CLCN3 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Publications for gene: CLCN3 were set to 34186028
Phenotypes for gene: CLCN3 were set to Neurodevelopmental disorder
Mode of pathogenicity for gene: CLCN3 was set to Other
Review for gene: CLCN3 was set to GREEN
Added comment: 11 individuals reported, 9 that carried 8 different rare heterozygous missense variants in CLCN3, and 2 siblings that were homozygous for an NMD-predicted frameshift variant likely abolishing ClC-3 function. All missense variants were confirmed to be de novo in eight individuals for whom parental data was available.

The 11 individuals in the cohort share clinical features of variable severity. All 11 have GDD or ID and dysmorphic features, and a majority has mood or behavioural disorders and structural brain abnormalities:
- Structural brain abnormalities on MRI (9/11) included partial or full agenesis of the corpus callosum (6/9), disorganized cerebellar folia (4/9), delayed myelination (3/9), decreased white matter volume (3/9), pons hypoplasia (3/9), and dysmorphic dentate nuclei (3/9). Six of those with brain abnormalities also presented with seizures.
- Nine have abnormal vision, including strabismus in four and inability to fix or follow in the two with homozygous loss-of-function variants.
- Hypotonia ranging from mild to severe was reported in 7 of the 11 individuals.
- Six have mood or behavioural disorders, particularly anxiety (3/6).
- Consistent dysmorphic facial features included microcephaly, prominent forehead, hypertelorism, down-slanting palpebral fissures, full cheeks, and micrognathia.

The severity of disease in the two siblings with homozygous disruption of ClC-3 is consistent with the drastic phenotype seen in Clcn3 KO mice. The disease was more severe in two siblings carrying homozygous loss-of-function variants with the presence of GDD, absent speech, seizures, and salt and pepper fundal pigmentation in both individuals, with one deceased at 14 months of age. The siblings also had significant neuroanatomical findings including diffusely decreased white matter volume, thin corpora callosa, small hippocampi, and disorganized cerebellar folia. Supporting biallelic inheritance for LoF variants, disruption of mouse Clcn3 results in drastic neurodegeneration with loss of the hippocampus a few months after birth and early retinal degeneration. Clcn3−/− mice display severe neurodegeneration, whereas heterozygous Clcn3+/− mice appear normal.

Patch-clamp studies were used to investigate four of the missense variants. These suggested a gain of function in two variants with increased current in HEK cells, however they also showed reduced rectification of voltage and a loss of transient current, plus decreased current amplitude, glycosylation and surface expression when expressed in oocytes, and were suspected to interfere with channel gating and a negative feedback mechanism. These effects were also shown to vary depending on pH levels. The current of the remaining two variants did not differ from WT. For heterozygous missense variants, the disruption induced may be at least partially conferred to mutant/WT homodimers and mutant/ClC-4 heterodimers.

Both loss and gain of function in this gene resulted in the same phenotype.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4019 TNPO2 Zornitza Stark Marked gene: TNPO2 as ready
Intellectual disability syndromic and non-syndromic v0.4019 TNPO2 Zornitza Stark Gene: tnpo2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4019 TNPO2 Zornitza Stark Phenotypes for gene: TNPO2 were changed from Developmental delays, neurologic deficits and dysmorphic features to Intellectual disability, neurologic deficits and dysmorphic features
Intellectual disability syndromic and non-syndromic v0.4018 TNPO2 Zornitza Stark Classified gene: TNPO2 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4018 TNPO2 Zornitza Stark Gene: tnpo2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4017 TNPO2 Elena Savva gene: TNPO2 was added
gene: TNPO2 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: TNPO2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: TNPO2 were set to PMID: 34314705
Phenotypes for gene: TNPO2 were set to Developmental delays, neurologic deficits and dysmorphic features
Mode of pathogenicity for gene: TNPO2 was set to Other
Review for gene: TNPO2 was set to GREEN
Added comment: PMID: 34314705 - all de novo missense variants with intellectual disability (9/9), speech impairment (15/15), motor impairment (15/15), ophthalmologic abnormalities (10/15), muscle tone abnormalities (11/15, primarily hypotonia), seizures (6/15, febrile to non-febrile), microcephaly (5/15) and MRI anomalies (7/13, 3/13 had cerebellar hypoplasia/dysplasia).

Null fly model was homozygous lethal, no obvious phenotypes in heterozygotes. Upregulated gene expression also resulted in lethality. Overexpression of some human variants in fly models resulted in "toxicity" and phenotypic defects, authors speculate two variants are GOF, 1 variant is LOF.

gnomAD: minimal PTCs present
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4017 TP73 Seb Lunke Publications for gene: TP73 were set to 31130284
Intellectual disability syndromic and non-syndromic v0.4016 SPTBN1 Belinda Chong changed review comment from: PMID: 34211179
- Heterozygous SPTBN1 variants in 29 individuals with developmental, language and motor delays; mild to severe intellectual disability; autistic features; seizures; behavioral and movement abnormalities; hypotonia; and variable dysmorphic facial features.
- Show that these SPTBN1 variants lead to effects that affect βII-spectrin stability, disrupt binding to key molecular partners, and disturb cytoskeleton organization and dynamics.

PMID: 33847457
- Common features include global developmental delays, intellectual disability, and behavioral disturbances. Autistic features (4/6) and epilepsy (2/7) or abnormal electroencephalogram without overt seizures (1/7) were present in a subset.
- identified seven unrelated individuals with heterozygous SPTBN1 variants: two with de novo missense variants and five with predicted loss-of-function variants (found to be de novo in two, while one was inherited from a mother with a history of learning disabilities).
- Identification of loss-of-function variants suggests a haploinsufficiency mechanism, but additional functional studies are required to fully elucidate disease pathogenesis.
Sources: Literature
Sources: Literature; to: PMID: 34211179
- Heterozygous SPTBN1 variants in 29 individuals with developmental, language and motor delays; mild to severe intellectual disability; autistic features; seizures (9/29); behavioral and movement abnormalities; hypotonia; and variable dysmorphic facial features.
- Show that these SPTBN1 variants lead to effects that affect βII-spectrin stability, disrupt binding to key molecular partners, and disturb cytoskeleton organization and dynamics.

PMID: 33847457
- Common features include global developmental delays, intellectual disability, and behavioral disturbances. Autistic features (4/6) and epilepsy (2/7) or abnormal electroencephalogram without overt seizures (1/7) were present in a subset.
- identified seven unrelated individuals with heterozygous SPTBN1 variants: two with de novo missense variants and five with predicted loss-of-function variants (found to be de novo in two, while one was inherited from a mother with a history of learning disabilities).
- Identification of loss-of-function variants suggests a haploinsufficiency mechanism, but additional functional studies are required to fully elucidate disease pathogenesis.
Sources: Literature
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4016 TP73 Seb Lunke Classified gene: TP73 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4016 TP73 Seb Lunke Gene: tp73 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4015 SPTBN1 Belinda Chong gene: SPTBN1 was added
gene: SPTBN1 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: SPTBN1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SPTBN1 were set to PMID: 34211179 PMID: 33847457
Phenotypes for gene: SPTBN1 were set to Neurodevelopmental Syndrome
Review for gene: SPTBN1 was set to GREEN
Added comment: PMID: 34211179
- Heterozygous SPTBN1 variants in 29 individuals with developmental, language and motor delays; mild to severe intellectual disability; autistic features; seizures; behavioral and movement abnormalities; hypotonia; and variable dysmorphic facial features.
- Show that these SPTBN1 variants lead to effects that affect βII-spectrin stability, disrupt binding to key molecular partners, and disturb cytoskeleton organization and dynamics.

PMID: 33847457
- Common features include global developmental delays, intellectual disability, and behavioral disturbances. Autistic features (4/6) and epilepsy (2/7) or abnormal electroencephalogram without overt seizures (1/7) were present in a subset.
- identified seven unrelated individuals with heterozygous SPTBN1 variants: two with de novo missense variants and five with predicted loss-of-function variants (found to be de novo in two, while one was inherited from a mother with a history of learning disabilities).
- Identification of loss-of-function variants suggests a haploinsufficiency mechanism, but additional functional studies are required to fully elucidate disease pathogenesis.
Sources: Literature
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4015 EDEM3 Seb Lunke Marked gene: EDEM3 as ready
Intellectual disability syndromic and non-syndromic v0.4015 EDEM3 Seb Lunke Gene: edem3 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4015 EDEM3 Seb Lunke Phenotypes for gene: EDEM3 were changed from EDEM3-congenital disorder of glycosylation to Congenital disorder of glycosylation; Developmental delay
Intellectual disability syndromic and non-syndromic v0.4014 EDEM3 Seb Lunke Classified gene: EDEM3 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4014 EDEM3 Seb Lunke Gene: edem3 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4013 EDEM3 Michelle Torres gene: EDEM3 was added
gene: EDEM3 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: EDEM3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EDEM3 were set to 34143952
Phenotypes for gene: EDEM3 were set to EDEM3-congenital disorder of glycosylation
Review for gene: EDEM3 was set to GREEN
Added comment: PMID: 34143952: 7 families (11 individuals) with 6x PTV and 2x missense variants with neurodevelopmental delay and variable facial dysmorphisms. The unaffected parents were all heterozygous carriers. Functional show LoF of EDEM3 enzymatic activity.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4013 ANK2 Zornitza Stark Marked gene: ANK2 as ready
Intellectual disability syndromic and non-syndromic v0.4013 ANK2 Zornitza Stark Gene: ank2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4013 ANK2 Zornitza Stark Phenotypes for gene: ANK2 were changed from Complex neurodevelopmental disorder, MONDO:0100038 to Complex neurodevelopmental disorder, MONDO:0100038
Intellectual disability syndromic and non-syndromic v0.4012 ANK2 Zornitza Stark Publications for gene: ANK2 were set to 22542183; 25363768; 27479843; 28554332; 30564305; 30755392; 31981491; 33004838; 33057194
Intellectual disability syndromic and non-syndromic v0.4011 ANK2 Zornitza Stark Phenotypes for gene: ANK2 were changed from intellectual disability to Complex neurodevelopmental disorder, MONDO:0100038
Intellectual disability syndromic and non-syndromic v0.4010 ANK2 Zornitza Stark Publications for gene: ANK2 were set to 22542183, 25363768, 27479843, 28554332, 30564305, 30755392, 31981491
Intellectual disability syndromic and non-syndromic v0.4010 ANK2 Zornitza Stark Classified gene: ANK2 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4010 ANK2 Zornitza Stark Gene: ank2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4009 ANK2 Zornitza Stark reviewed gene: ANK2: Rating: GREEN; Mode of pathogenicity: None; Publications: 22542183, 25363768, 27479843, 28554332, 30564305, 30755392, 31981491, 33004838, 33057194; Phenotypes: Complex neurodevelopmental disorder, MONDO:0100038; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.4009 ANK2 Anna Le Fevre commented on gene: ANK2: Publications largely cover autism risk and discovery in large cohorts. ClinGen review mentions ID, seizures and microcephaly but phenotype and penetrance appear incompletely described.
Intellectual disability syndromic and non-syndromic v0.4009 ANK2 Anna Le Fevre edited their review of gene: ANK2: Changed phenotypes: intellectual disability, autism
Intellectual disability syndromic and non-syndromic v0.4009 ANK2 Anna Le Fevre gene: ANK2 was added
gene: ANK2 was added to Intellectual disability syndromic and non-syndromic. Sources: Other
Mode of inheritance for gene: ANK2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ANK2 were set to 22542183, 25363768, 27479843, 28554332, 30564305, 30755392, 31981491
Phenotypes for gene: ANK2 were set to intellectual disability
Penetrance for gene: ANK2 were set to unknown
Added comment: Curated by ClinGen 2020 as definitively associated
? consider taking gene off incidentalome gene list
Sources: Other
Intellectual disability syndromic and non-syndromic v0.4009 EIF4A3 Zornitza Stark Marked gene: EIF4A3 as ready
Intellectual disability syndromic and non-syndromic v0.4009 EIF4A3 Zornitza Stark Gene: eif4a3 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4009 EIF4A3 Zornitza Stark Phenotypes for gene: EIF4A3 were changed from to Robin sequence with cleft mandible and limb anomalies, MIM# 268305; Richieri-Costa-Pereira syndrome
Intellectual disability syndromic and non-syndromic v0.4008 EIF4A3 Zornitza Stark Publications for gene: EIF4A3 were set to
Intellectual disability syndromic and non-syndromic v0.4007 EIF4A3 Zornitza Stark Mode of inheritance for gene: EIF4A3 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4006 EIF4A3 Zornitza Stark reviewed gene: EIF4A3: Rating: GREEN; Mode of pathogenicity: None; Publications: 24360810; Phenotypes: Robin sequence with cleft mandible and limb anomalies, MIM# 268305, Richieri-Costa-Pereira syndrome; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4006 HSD17B4 Zornitza Stark Marked gene: HSD17B4 as ready
Intellectual disability syndromic and non-syndromic v0.4006 HSD17B4 Zornitza Stark Gene: hsd17b4 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4006 HSD17B4 Zornitza Stark Phenotypes for gene: HSD17B4 were changed from to D-bifunctional protein deficiency, AR (MIM#261515); Perrault syndrome 1, AR (MIM#233400)
Intellectual disability syndromic and non-syndromic v0.4005 HSD17B4 Zornitza Stark Publications for gene: HSD17B4 were set to
Intellectual disability syndromic and non-syndromic v0.4004 HSD17B4 Zornitza Stark Mode of inheritance for gene: HSD17B4 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4003 HSD17B4 Zornitza Stark reviewed gene: HSD17B4: Rating: GREEN; Mode of pathogenicity: None; Publications: 27790638; Phenotypes: D-bifunctional protein deficiency, AR (MIM#261515), Perrault syndrome 1, AR (MIM#233400); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4003 SYNCRIP Zornitza Stark Marked gene: SYNCRIP as ready
Intellectual disability syndromic and non-syndromic v0.4003 SYNCRIP Zornitza Stark Added comment: Comment when marking as ready: Sufficient cases for Green rating on ID panel.
Intellectual disability syndromic and non-syndromic v0.4003 SYNCRIP Zornitza Stark Gene: syncrip has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4003 SYNCRIP Zornitza Stark Classified gene: SYNCRIP as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4003 SYNCRIP Zornitza Stark Gene: syncrip has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4002 SYNCRIP Konstantinos Varvagiannis gene: SYNCRIP was added
gene: SYNCRIP was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: SYNCRIP was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SYNCRIP were set to 34157790; 30504930; 27479843; 23020937
Phenotypes for gene: SYNCRIP were set to Global developmental delay; Intellectual disability; Autism; Myoclonic atonic seizures; Abnormality of nervous system morphology
Review for gene: SYNCRIP was set to AMBER
Added comment: Semino et al (2021 - PMID: 34157790) provide clinical details on 3 unrelated individuals with de novo SYNCRIP variants and provide a review of 5 additional subjects previously identified within large cohorts in the literature and databases.

Features included DD, ID (7/7 for whom this information was available), ASD or autistic features (4/7). MRI abnormalities were observed in 3 (widening of CSF spaces, periventricular nodular heterotopia, prominent lat. ventricles). Epilepsy (myoclonic-astatic epilepsy / Doose syndrome) was reported for 2(/8) individuals.

The 3 patients here reported were identified following trio/singleton exome with Sanger confirmation of the variants and their de novo occurrence.

Variants are in almost all cases de novo (7/7 for whom this was known) and in 5/8 cases were pLoF, in 2/8 missense SNVs while a case from DECIPHER had a 77.92 kb whole gene deletion not involving other genes with unknown inheritance.

Overall the variants reported to date include [NM_006372.5]:
1 - c.858_859del p.(Gly287Leufs*5)
2 - c.854dupA p.(Asn285Lysfs*8)
3 - c.734T>C p.(Leu245Pro)
4 - chr6:85605276-85683190 deletion (GRCh38)
5 - c.629T>C p.(Phe210Ser)
6 - c.1573_1574delinsTT p.(Gln525Leu)
7 - c.1247_1250del p.(Arg416Lysfs*145)
8 - c.1518_1519insC p.(Ala507Argfs*14)

[P1-3: this report, P4: DECIPHER 254774, P5-6: Guo et al 2019 - PMID: 30504930, P7: Lelieveld et al 2016 - PMID: 27479843, P8: Rauch et al 2012 - PMID: 23020937 / all other Refs not here reviewed, clinical details summarized by Semino et al in table 1]

SYNCRIP (also known as HNRNPQ) encodes synaptotagmin‐binding cytoplasmic RNA‐interacting protein. As the authors note, this RNA-binding protein is involved in multiple pathways associated with neuronal/muscular developmental disorders. Several references are provided for its involvement in regulation of RNA metabolism, among others sequence recognition, pre-mRNA splicing, translation, transport and degradation.

Mutations in other RNA-interacting proteins and hnRNP members (e.g. HNRNPU, HNRNPD) are associated with NDD.

The missense variant (p.Leu245Pro) is within RRM2 one of the 3 RNA recognition motif (RRM) domains of the protein. These 3 domains, corresponding to the central part of the protein (aa 150-400), are relatively intolerant to variation (based on in silico predictions and/or variation in gnomAD). Leu245 localizes within an RNA binding pocket and in silico modeling suggests alteration of the tertiary structure and RNA-binding capacity of RRM2.

There are no additional studies performed.

Overall haploinsufficiency appears to be the underlying disease mechanism based on the truncating variants and the gene deletion. [pLI in gnomAD : 1, %HI : 2.48%]

Animal models are not discussed.

There is no associated phenotype in OMIM. This gene is included in the DD panel of G2P (monoallelic LoF variants / SYNCRIP-related developmental disorder). SysID also lists SYNCRIP within the current primary ID genes.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4002 CAMK4 Zornitza Stark Marked gene: CAMK4 as ready
Intellectual disability syndromic and non-syndromic v0.4002 CAMK4 Zornitza Stark Gene: camk4 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4002 CAMK4 Zornitza Stark Classified gene: CAMK4 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4002 CAMK4 Zornitza Stark Gene: camk4 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4001 CAMK4 Konstantinos Varvagiannis gene: CAMK4 was added
gene: CAMK4 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature,Other
Mode of inheritance for gene: CAMK4 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CAMK4 were set to 30262571; 33098801; 33211350
Phenotypes for gene: CAMK4 were set to Global developmental delay; Intellectual disability; Autism; Behavioral abnormality; Abnormality of movement; Dystonia; Ataxia; Chorea; Myoclonus
Penetrance for gene: CAMK4 were set to Complete
Review for gene: CAMK4 was set to GREEN
Added comment: 3 publications by Zech et al (2018, 2020 - PMIDs : 30262571, 33098801, 33211350) provide clinical details on 3 individuals, each harboring a private de novo CAMK4 variant.

Overlapping features included DD, ID, behavoral issues, autism and abnormal hyperkinetic movements. Dystonia and chorea in all 3 appeared 3-20 years after initial symptoms.

CAMK4 encodes Calcium/Calmodulin-dependent protein kinase IV, an important mediator of calcium-mediated activity and dynamics, particularly in the brain. It is involved in neuronal transmission, synaptic plasticity, and neuronal gene expression required for brain development and neuronal homeostasis (summary by OMIM based on Zech et al, 2018).

The 473 aa enzyme has a protein kinase domain (aa 46-300) and a C-terminal autoregulatory domain (aa 305-341) the latter comprising an autoinhibitory domain (AID / aa 305-321) and a calmodulin-binding domain (CBD / aa 322-341) [NP_001735.1 / NM_001744.4 - also used below].

Variants in all 3 subjects were identified following trio-WES and were in all cases protein-truncating, mapping to exon 10 or exon 10-intron 10 junction, expected to escape NMD and cause selective abrogation of the autoinhibitory domain (aa 305-321) leading overall to gain-of-function.

Variation databases include pLoF CAMK4 variants albeit in all cases usptream or downstream of this region (pLI of this gene in gnomAD: 0.51). Variants leading to selective abrogation of the autoregulatory domain have not been reported.

Extensive evidence for the GoF effect of the variant has been provided in the first publication. Several previous studies have demonstrated that abrogation of the AID domain leads to consitutive activation (details below).

Mouse models - though corresponding to homozygous loss of function - support a role for CAMKIV in cognitive and motor symptoms. Null mice display tremulous and ataxic movements, deficiencies in balance and sensorimotor performance associated with reduced number of Purkinje neurons (Ribar et al 2000, PMID: 11069976 - not reviewed). Wei et al (2002, PMID: 12006982 - not reviewed) provided evidence for alteration in hippocampal physiology and memory function.

Heterozygous mutations in other genes for calcium/calmodulin-dependent protein kinases (CAMKs) e.g. CAMK2A/CAMK2B (encoding subunits of CAMKII) have been reported in individuals with ID.

---

The proband in the first publication (PMID: 30262571) was a male with DD, ID, behavioral difficulties (ASD, autoaggression, stereotypies) and hyperkinetic movement disorder (myoclonus, chorea, ataxia) with severe generalized dystonia (onset at the age of 13y). Brain MRI demonstrated cerebellar atrophy.

Extensive work-up incl. karyotyping, CMA, DYT-TOR1A, THAP1, GCH1, SCA1/2/3/6/7/8/12/17, Friedreich's ataxia and FMR1 analysis was negative.F

Trio WES identified a dn splice site variant (c.981+1G>A) in the last exon-intron junction. RT-PCR followed by gel electrophoresis and Sanger in fibroblasts from an affected and control subject revealed that the proband had - as predicted by the type/location of the variant - in equal amount 2 cDNA products, a normal as well as a truncated one.

Sequencing of the shortest revealed utilization of a cryptic donor splice site upstream of the mutated donor leading to a 77bp out-of-frame deletion and introduction of a premature stop codon in the last codon (p.Lys303Serfs*28). Western blot in fibroblast cell lines revealed 2 bands corresponding to the normal protein product as well as to the p.Lys303Serfs*28 although expression of the latter was lower than that of the full length protein.

Several previous studies have shown that mutant CAMKIV species that lack the autoinhibitory domain are consitutively active (several Refs provided). Among others Chatila et al (1996, PMID: 8702940) studied an in vitro-engineered truncation mutant (Δ1-317 - truncation at position 317 of the protein) with functionally validated gain-of-function effect.

To prove enhanced activity of the splicing variant, Zech et al assessed phosphorylation of CREB (cyclic AMP-responsive element binding protein), a downstream substrate of CAMKIV. Immunobloting revealed significant increase of CREB phosphorylation in patient fibroblasts compared to controls. Overactivation of CAMKIV signaling was reversed when cells were treated with STO-609 an inhibitor of CAMKK, the ustream activator of CAMKIV.

Overall the authors demonstrated that loss of CAMKIV autoregulatory domain due to this splice variant had a gain-of-function effect.

----

Following trio-WES, Zech et al (2020 - PMID: 33098801) identified another relevant subject within cohort of 764 individuals with dystonia. This 12-y.o. male, harboring a different variant affecting the same donor site (c.981+1G>T), presented DD, ID, dystonia (onset at 3y) and additional movement disorders (myoclonus, ataxia) as well as similar behavior (ASD, autoaggression, stereotypies). [Details in suppl. p20].

----

Finally Zech et al (2020 - PMID: 33211350) reported on a 24-y.o. woman with adolescence onset choreodystonia. Other features included DD, moderate ID, absence seizures in infancy, OCD with anxiety and later diagnosis of ASD. Trio WES revealed a dn stopgain variant (c.940C>T; p.Gln314*).

----

There is no associated phenotype in OMIM, G2P.

In SysID CAMK4 is listed among the current primary ID genes.

----

Please consider inclusion in other relevant panels.
Sources: Literature, Other
Intellectual disability syndromic and non-syndromic v0.4001 DPYSL5 Zornitza Stark Phenotypes for gene: DPYSL5 were changed from Neurodevelopmental disorder with corpus callosum agenesis and cerebellar abnormalities to Ritscher-Schinzel syndrome 4, MIM# 619435; Neurodevelopmental disorder with corpus callosum agenesis and cerebellar abnormalities
Intellectual disability syndromic and non-syndromic v0.4000 DPYSL5 Zornitza Stark edited their review of gene: DPYSL5: Changed phenotypes: Ritscher-Schinzel syndrome 4, MIM# 619435, Neurodevelopmental disorder with corpus callosum agenesis and cerebellar abnormalities
Intellectual disability syndromic and non-syndromic v0.4000 LTBP1 Zornitza Stark Marked gene: LTBP1 as ready
Intellectual disability syndromic and non-syndromic v0.4000 LTBP1 Zornitza Stark Gene: ltbp1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4000 LTBP1 Zornitza Stark Phenotypes for gene: LTBP1 were changed from cutis laxa syndrome to Cutis laxa, autosomal recessive, type IIE MIM#619451
Intellectual disability syndromic and non-syndromic v0.3999 WDR26 Zornitza Stark Marked gene: WDR26 as ready
Intellectual disability syndromic and non-syndromic v0.3999 WDR26 Zornitza Stark Gene: wdr26 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3999 WDR26 Zornitza Stark Phenotypes for gene: WDR26 were changed from to Skraban-Deardorff syndrome, MIM#617616
Intellectual disability syndromic and non-syndromic v0.3998 WDR26 Zornitza Stark Publications for gene: WDR26 were set to
Intellectual disability syndromic and non-syndromic v0.3997 WDR26 Zornitza Stark Mode of inheritance for gene: WDR26 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3996 DDB1 Zornitza Stark Phenotypes for gene: DDB1 were changed from Syndromic intellectual disability to White-Kernohan syndrome, MIM# 619426; Syndromic intellectual disability
Intellectual disability syndromic and non-syndromic v0.3995 DDB1 Zornitza Stark edited their review of gene: DDB1: Changed phenotypes: White-Kernohan syndrome, MIM# 619426, Syndromic intellectual disability
Intellectual disability syndromic and non-syndromic v0.3995 WDR26 Paul De Fazio reviewed gene: WDR26: Rating: GREEN; Mode of pathogenicity: None; Publications: 28686853, 33506510, 33675273; Phenotypes: Skraban-Deardorff syndrome; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Intellectual disability syndromic and non-syndromic v0.3995 ABCD4 Zornitza Stark Marked gene: ABCD4 as ready
Intellectual disability syndromic and non-syndromic v0.3995 ABCD4 Zornitza Stark Gene: abcd4 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3995 ABCD4 Zornitza Stark Phenotypes for gene: ABCD4 were changed from to Methylmalonic aciduria and homocystinuria, cblJ type, MIM# 614857
Intellectual disability syndromic and non-syndromic v0.3994 ABCD4 Zornitza Stark Publications for gene: ABCD4 were set to
Intellectual disability syndromic and non-syndromic v0.3993 ABCD4 Zornitza Stark Mode of inheritance for gene: ABCD4 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3992 ABCD4 Zornitza Stark reviewed gene: ABCD4: Rating: GREEN; Mode of pathogenicity: None; Publications: 22922874, 31113616, 30651581, 28572511, 33729671; Phenotypes: Methylmalonic aciduria and homocystinuria, cblJ type, MIM# 614857; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3992 CCBE1 Zornitza Stark Marked gene: CCBE1 as ready
Intellectual disability syndromic and non-syndromic v0.3992 CCBE1 Zornitza Stark Gene: ccbe1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3992 CCBE1 Zornitza Stark Phenotypes for gene: CCBE1 were changed from to Hennekam lymphangiectasia- lymphoedema syndrome MIM# 235510; lymphangiectasia and lymphoedema; facial abnormalities; dysmorphic features; hypoalbuminaemia; intellectual disability; hypoglobulinaemia
Intellectual disability syndromic and non-syndromic v0.3991 CCBE1 Zornitza Stark Publications for gene: CCBE1 were set to
Intellectual disability syndromic and non-syndromic v0.3990 CCBE1 Zornitza Stark Mode of inheritance for gene: CCBE1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3989 CCBE1 Zornitza Stark reviewed gene: CCBE1: Rating: GREEN; Mode of pathogenicity: None; Publications: 19935664, 19911200, 19287381, 25925991, 27345729, 21778431; Phenotypes: Hennekam lymphangiectasia- lymphoedema syndrome MIM# 235510, lymphangiectasia and lymphoedema, facial abnormalities, dysmorphic features, hypoalbuminaemia, intellectual disability, hypoglobulinaemia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3989 SUFU Zornitza Stark Phenotypes for gene: SUFU were changed from Joubert syndrome 32, MIM#617757 to Joubert syndrome 32, MIM#617757; SUFU-related neurodevelopmental syndrome
Intellectual disability syndromic and non-syndromic v0.3988 SUFU Zornitza Stark Publications for gene: SUFU were set to 28965847
Intellectual disability syndromic and non-syndromic v0.3987 SUFU Zornitza Stark Mode of inheritance for gene: SUFU was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3986 SUFU Zornitza Stark Classified gene: SUFU as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.3986 SUFU Zornitza Stark Gene: sufu has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3985 SUFU Zornitza Stark edited their review of gene: SUFU: Added comment: Heterozygous truncating variants in SUFU in 15 subjects from 6 unrelated families of various ethnic backgrounds (familial and de novo cases). Clinical features of early-onset (congenital) ocular ataxia and developmental delay, with some phenotypic variability. Neuroimaging revealed subtle cerebellar changes, but no full-blown molar tooth sign of Joubert syndrome. Paper reports that condition reported here and SUFU-associated Basal cell nevus syndrome (Gorlin) are likely allelic disorders, as there is currently no convincing evidence for a clinical overlap.

Functional studies showed no differences in cilia occurrence, morphology, or localization of ciliary proteins, such as smoothened. However, analysis of expression of HH signaling target genes detected a significant increase in the general signaling activity in COMA patient–derived fibroblasts compared with control cells. We observed higher basal HH signaling activity resulting in increased basal expression levels of GLI1, GLI2, GLI3, and Patched1. Neuroimaging revealed subtle cerebellar changes, but no full-blown molar tooth sign. Knockout mice with SuFu deficiency demonstrated that SuFu is required for proper midhindbrain patterning and controls cerebellar patterning.; Changed rating: GREEN; Changed publications: 28965847, 33024317; Changed phenotypes: Joubert syndrome 32, MIM#617757, SUFU-related neurodevelopmental syndrome; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3985 PCDHGC4 Zornitza Stark Marked gene: PCDHGC4 as ready
Intellectual disability syndromic and non-syndromic v0.3985 PCDHGC4 Zornitza Stark Gene: pcdhgc4 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3985 PCDHGC4 Zornitza Stark Classified gene: PCDHGC4 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.3985 PCDHGC4 Zornitza Stark Gene: pcdhgc4 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3984 PCDHGC4 Zornitza Stark gene: PCDHGC4 was added
gene: PCDHGC4 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: PCDHGC4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PCDHGC4 were set to 34244665
Phenotypes for gene: PCDHGC4 were set to Intellectual disability; Seizures
Review for gene: PCDHGC4 was set to GREEN
Added comment: Eight variants reported in 19 members of nine unreleted families with a neurodevelopmental syndrome. Severe or moderate intellectual disabilty in eight families and seizures in four families. Four of the variants were LoF, in silico analysis of the remaining missense (n=3) and splice variants were predicted to be pathogenic.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.3983 CEP85L Zornitza Stark Marked gene: CEP85L as ready
Intellectual disability syndromic and non-syndromic v0.3983 CEP85L Zornitza Stark Gene: cep85l has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3983 CEP85L Zornitza Stark Classified gene: CEP85L as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.3983 CEP85L Zornitza Stark Gene: cep85l has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3982 CEP85L Zornitza Stark gene: CEP85L was added
gene: CEP85L was added to Intellectual disability syndromic and non-syndromic. Sources: Expert Review
Mode of inheritance for gene: CEP85L was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CEP85L were set to 32097630
Phenotypes for gene: CEP85L were set to Lissencephaly, posterior predominant
Review for gene: CEP85L was set to GREEN
Added comment: Thirteen individuals reported with mono allelic variants in this gene, inherited in two of the families. Mouse model had neuronal migration defects.
Sources: Expert Review
Intellectual disability syndromic and non-syndromic v0.3981 LINGO4 Zornitza Stark Marked gene: LINGO4 as ready
Intellectual disability syndromic and non-syndromic v0.3981 LINGO4 Zornitza Stark Gene: lingo4 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3981 LINGO4 Zornitza Stark Classified gene: LINGO4 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.3981 LINGO4 Zornitza Stark Gene: lingo4 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3980 LINGO1 Zornitza Stark edited their review of gene: LINGO1: Changed rating: AMBER
Intellectual disability syndromic and non-syndromic v0.3980 IMPDH2 Zornitza Stark reviewed gene: IMPDH2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with dystonia; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3980 IMPDH2 Zornitza Stark Marked gene: IMPDH2 as ready
Intellectual disability syndromic and non-syndromic v0.3980 IMPDH2 Zornitza Stark Gene: impdh2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3980 IMPDH2 Zornitza Stark Phenotypes for gene: IMPDH2 were changed from to Neurodevelopmental disorder with dystonia
Intellectual disability syndromic and non-syndromic v0.3979 IMPDH2 Zornitza Stark Classified gene: IMPDH2 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.3979 IMPDH2 Zornitza Stark Gene: impdh2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3978 LINGO4 Laura Raiti gene: LINGO4 was added
gene: LINGO4 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: LINGO4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LINGO4 were set to PMID: 33098801
Phenotypes for gene: LINGO4 were set to Developmental Delay, Intellectual disability, speech disorder
Review for gene: LINGO4 was set to GREEN
Added comment: 3 unrelated individuals
1 x individual compound heterozygous for 2x missense variants:
c.679C>A; c.1262G>A p.Leu227Met; p.Arg421Gln comp het. Phenotype: infancy-onset
generalized dystonia; DD/hypo, ID, speech disorder (isolated plus non-MD symptoms) NDD

1 x individual homozygous for missense variant: c.679C>A p.Leu227Met Phenotype: DD/hypo, ID, speech disorder

1 x individual homozygous for missense variant: c.1673G>A p.Ser558Asn Phenotype: DD/hypo, ID, speech disorder
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.3978 IMPDH2 Laura Raiti gene: IMPDH2 was added
gene: IMPDH2 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: IMPDH2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: IMPDH2 were set to PMID: 33098801
Added comment: 6 unrelated individuals
1x individual in a dystonia cohort index case with infancy-onset dystonia and other neurological manifestations with a de-novo missense variant, c.338G>A (p.Gly113Glu) in IMPDH2, predicted to disrupt an invariant residue within the cystathionine-β-synthase (CBS) domain pair of the encoded protein.
IMPDH2 encodes IMPDH2, a key enzyme in the purine biosynthetic pathway, expressed throughout the brain and not linked previously to any human Mendelian condition.
1x individual with a de-novo substitution, c.337G>A (p.Gly113Arg), was found in in-house whole-exome sequencing data from 500 individuals with neurodevelopmental disorders. Through GeneMatcher, de novo variants identified:
3 x missense: c.729G>C (p.Gln243His), c.619G>C (p.Gly207Arg), and c.619G>A (p.Gly207Arg)
1 x deletion: c.478_480delTCC (p.Ser160del)
The six variants were predicted to be deleterious and none of them seen in control databases. All affected conserved amino acids and resided in and around the cystathionine-β-synthase domain pair.
The described variants are situated in and around the CBS domain pair, a regulatory element in which clustering of pathogenic missense variants has already been shown for the homologue of IMPDH2, IMPDH1.

The variant carriers shared similar neurodevelopmental phenotypes. Apart from the dystonia cohort index case, one participant had evidence of dystonic posturing. Modelling of the variants on 3D protein structures revealed spatial clustering near specific functional sites, predicted to result in deregulation of IMPDH2 activity. Additionally, thermal-shift assays showed that the c.619G>A (p.Gly207Arg) variant, identified as within the CBS domain pair, and c.729G>C (p.Gln243His), which is in close vicinity, affected the stability or folding behaviour of IMPDH2.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.3978 ATG7 Zornitza Stark changed review comment from: 12 individuals from 5 unrelated families reported with a complex neurodevelopmental disorder and bi-allelic variants in this gene. Age range from 21 months to 71 years of age. Main clinical features included axial hypotonia, variably impaired intellectual development with poor or absent speech, and delayed walking (up to 7 years of age) or inability to walk. All had ataxia, often with tremor or dyskinesia, as well as dysarthria associated with cerebellar hypoplasia on brain imaging. Most had optic atrophy, and some had ptosis, chronic progressive external ophthalmoplegia, retinopathy, and strabismus; 1 had early-onset cataracts. The more severely affected individuals had spastic paraplegia and inability to walk.

Functional data including mouse model.
Sources: Literature; to: 12 individuals from 5 unrelated families reported with a complex neurodevelopmental disorder and bi-allelic variants in this gene. Age range from 21 months to 71 years of age. Main clinical features included axial hypotonia, variably impaired intellectual development with poor or absent speech, and delayed walking (up to 7 years of age) or inability to walk. All had ataxia, often with tremor or dyskinesia, as well as dysarthria associated with cerebellar hypoplasia on brain imaging. Most had optic atrophy, and some had ptosis, chronic progressive external ophthalmoplegia, retinopathy, and strabismus; 1 had early-onset cataracts. The more severely affected individuals had spastic paraplegia and inability to walk.

Functional data including mouse model.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.3978 ATG7 Zornitza Stark changed review comment from: 12 individuals from 5 unrelated families reported with a complex neurodevelopmental disorder and bi-allelic variants in this gene. Age range from 21 months to 71 years of age. Main clinical features included axial hypotonia, variably impaired intellectual development with poor or absent speech, and delayed walking (up to 7 years of age) or inability to walk. All had ataxia, often with tremor or dyskinesia, as well as dysarthria associated with cerebellar hypoplasia on brain imaging. Most had optic atrophy, and some had ptosis, chronic progressive external ophthalmoplegia, retinopathy, and strabismus; 1 had early-onset cataracts. The ore severely affected individuals had spastic paraplegia and inability to walk.

Functional data including mouse model.
Sources: Literature; to: 12 individuals from 5 unrelated families reported with a complex neurodevelopmental disorder and bi-allelic variants in this gene. Age range from 21 months to 71 years of age. Main clinical features included axial hypotonia, variably impaired intellectual development with poor or absent speech, and delayed walking (up to 7 years of age) or inability to walk. All had ataxia, often with tremor or dyskinesia, as well as dysarthria associated with cerebellar hypoplasia on brain imaging. Most had optic atrophy, and some had ptosis, chronic progressive external ophthalmoplegia, retinopathy, and strabismus; 1 had early-onset cataracts. The more severely affected individuals had spastic paraplegia and inability to walk.

Functional data including mouse model.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.3978 ATG7 Zornitza Stark Marked gene: ATG7 as ready
Intellectual disability syndromic and non-syndromic v0.3978 ATG7 Zornitza Stark Gene: atg7 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3978 ATG7 Zornitza Stark Classified gene: ATG7 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.3978 ATG7 Zornitza Stark Gene: atg7 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3977 ATG7 Zornitza Stark gene: ATG7 was added
gene: ATG7 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: ATG7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ATG7 were set to 34161705
Phenotypes for gene: ATG7 were set to Spinocerebellar ataxia, SCAR31, MIM#619422
Review for gene: ATG7 was set to GREEN
Added comment: 12 individuals from 5 unrelated families reported with a complex neurodevelopmental disorder and bi-allelic variants in this gene. Age range from 21 months to 71 years of age. Main clinical features included axial hypotonia, variably impaired intellectual development with poor or absent speech, and delayed walking (up to 7 years of age) or inability to walk. All had ataxia, often with tremor or dyskinesia, as well as dysarthria associated with cerebellar hypoplasia on brain imaging. Most had optic atrophy, and some had ptosis, chronic progressive external ophthalmoplegia, retinopathy, and strabismus; 1 had early-onset cataracts. The ore severely affected individuals had spastic paraplegia and inability to walk.

Functional data including mouse model.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.3976 C2orf69 Zornitza Stark Marked gene: C2orf69 as ready