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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
Intellectual disability syndromic and non-syndromic v0.3976 C2orf69 Zornitza Stark Gene: c2orf69 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3976 C2orf69 Zornitza Stark Classified gene: C2orf69 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.3976 C2orf69 Zornitza Stark Gene: c2orf69 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3975 C2orf69 Zornitza Stark gene: C2orf69 was added
gene: C2orf69 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: C2orf69 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: C2orf69 were set to 34038740; 33945503
Phenotypes for gene: C2orf69 were set to Combined oxidative phosphorylation deficiency-53 (COXPD53), MIM#619423
Review for gene: C2orf69 was set to GREEN
Added comment: PMID 34038740: 20 affected children from 8 unrelated families reported, presenting with fatal syndrome consisting of severe autoinflammation and progredient leukoencephalopathy with recurrent seizures; 12 of these subjects, whose DNA was available, segregated homozygous loss-of-function C2orf69 variants. Endogenous C2ORF69 was found to be (1) loosely bound to mitochondria, (2) affects mitochondrial membrane potential and oxidative respiration in cultured neurons, and (3) controls the levels of the glycogen branching enzyme 1 (GBE1) consistent with a glycogen-storage-associated mitochondriopathy. Zebrafish model.

PMID 33945503: 8 individuals from 5 families reported with muscle hypotonia, developmental delay, progressive microcephaly, and brain MRI abnormalities. Age at onset ranged from birth to 6 months of age. Six patients had vision impairment, liver abnormalities, inflammation/inflammatory arthritis, and 5 patients had seizures.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.3974 KDM3B Zornitza Stark Phenotypes for gene: KDM3B were changed from Intellectual disability; dysmorphic features; short stature; no OMIM number yet to Diets-Jongmans syndrome, MIM# 618846; Intellectual disability; dysmorphic features; short stature
Intellectual disability syndromic and non-syndromic v0.3973 KDM3B Zornitza Stark reviewed gene: KDM3B: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Diets-Jongmans syndrome, MIM# 618846, Intellectual disability, dysmorphic features, short stature, Intellectual disability, short stature, deafness; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3973 YARS Zornitza Stark Phenotypes for gene: YARS were changed from Intellectual disability; deafness; nystagmus; liver dysfunction to Infantile-onset multisystem neurologic, endocrine, and pancreatic disease 2, MIM# 619418
Intellectual disability syndromic and non-syndromic v0.3972 YARS Zornitza Stark edited their review of gene: YARS: Changed phenotypes: Infantile-onset multisystem neurologic, endocrine, and pancreatic disease 2, MIM# 619418
Intellectual disability syndromic and non-syndromic v0.3972 ERGIC3 Zornitza Stark Phenotypes for gene: ERGIC3 were changed from 33710394; 31585110 to Intellectual disability
Intellectual disability syndromic and non-syndromic v0.3971 ERGIC3 Zornitza Stark Publications for gene: ERGIC3 were set to ERGIC3
Intellectual disability syndromic and non-syndromic v0.3970 ERGIC3 Zornitza Stark reviewed gene: ERGIC3: Rating: AMBER; Mode of pathogenicity: None; Publications: 33710394, 31585110; Phenotypes: Intellectual disability; Mode of inheritance: None
Intellectual disability syndromic and non-syndromic v0.3970 ZC3H14 Zornitza Stark Publications for gene: ZC3H14 were set to 21734151; 33710394
Intellectual disability syndromic and non-syndromic v0.3969 ZC3H14 Zornitza Stark reviewed gene: ZC3H14: Rating: AMBER; Mode of pathogenicity: None; Publications: 28666327; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3969 RNF2 Zornitza Stark Marked gene: RNF2 as ready
Intellectual disability syndromic and non-syndromic v0.3969 RNF2 Zornitza Stark Gene: rnf2 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.3969 RNF2 Zornitza Stark Classified gene: RNF2 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.3969 RNF2 Zornitza Stark Gene: rnf2 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.3968 RNF2 Zornitza Stark gene: RNF2 was added
gene: RNF2 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: RNF2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RNF2 were set to 33864376
Phenotypes for gene: RNF2 were set to epilepsy; intellectual disability; intrauterine growth retardation
Review for gene: RNF2 was set to AMBER
Added comment: Not associated with any phenotype in OMIM. PMID:33864376 (Luo et al 2021) report 2 cases of children with de novo missense variants (p.R70H and p.S82R) in RNF2 and a phenotype of intrauterine growth retardation, severe intellectual disabilities, behavioral problems, seizures, feeding difficulties and dysmorphic features. Seizures started in infancy. Both variants are absent from gnomad. Functional studies in Drosophila showed that the disease-linked variants (p.R70H and p.S82R) behave as LoF alleles.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.3967 RING1 Zornitza Stark Marked gene: RING1 as ready
Intellectual disability syndromic and non-syndromic v0.3967 RING1 Zornitza Stark Gene: ring1 has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v0.3967 RING1 Zornitza Stark gene: RING1 was added
gene: RING1 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: RING1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RING1 were set to 29386386
Phenotypes for gene: RING1 were set to microcephaly; intellectual disability
Review for gene: RING1 was set to RED
Added comment: Not associated with any phenotype in OMIM. PMID: 29386386 - Pierce et al 2018 - report a 13 yo female with a de novo RING1 p.R95Q variant and syndromic neurodevelopmental disabilities. Early motor and language development were normal but were delayed after the first year of life. Cognitive testing showed a verbal IQ of 55 and a visual performance IQ of 63. Head circumference at birth was -4.9 SD, and -4.2 SD at age 13 which falls into the severe microcephaly category. C. elegans with either the missense mutation or complete knockout of spat-3 (the suggested RING1 ortholog) were defective in monoubiquitylation of histone H2A and had defects in neuronal migration and axon guidance.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.3966 IRX5 Zornitza Stark Marked gene: IRX5 as ready
Intellectual disability syndromic and non-syndromic v0.3966 IRX5 Zornitza Stark Gene: irx5 has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v0.3966 IRX5 Zornitza Stark Phenotypes for gene: IRX5 were changed from to Hamamy syndrome, MIM# 611174
Intellectual disability syndromic and non-syndromic v0.3965 IRX5 Zornitza Stark Publications for gene: IRX5 were set to
Intellectual disability syndromic and non-syndromic v0.3964 IRX5 Zornitza Stark Mode of inheritance for gene: IRX5 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3963 IRX5 Zornitza Stark Classified gene: IRX5 as Red List (low evidence)
Intellectual disability syndromic and non-syndromic v0.3963 IRX5 Zornitza Stark Gene: irx5 has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v0.3962 IRX5 Zornitza Stark reviewed gene: IRX5: Rating: RED; Mode of pathogenicity: None; Publications: 22581230, 27453922; Phenotypes: Hamamy syndrome, MIM# 611174; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3962 RAB3GAP1 Zornitza Stark Marked gene: RAB3GAP1 as ready
Intellectual disability syndromic and non-syndromic v0.3962 RAB3GAP1 Zornitza Stark Gene: rab3gap1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3962 RAB3GAP1 Zornitza Stark Phenotypes for gene: RAB3GAP1 were changed from to Warburg micro syndrome 1, MIM# 600118; Martsolf syndrome 2, MIM# 619420
Intellectual disability syndromic and non-syndromic v0.3961 RAB3GAP1 Zornitza Stark Publications for gene: RAB3GAP1 were set to
Intellectual disability syndromic and non-syndromic v0.3960 RAB3GAP1 Zornitza Stark Mode of inheritance for gene: RAB3GAP1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3959 RAB3GAP1 Zornitza Stark reviewed gene: RAB3GAP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 15696165, 20512159, 23420520, 23420520, 30730599; Phenotypes: Warburg micro syndrome 1, MIM# 600118, Martsolf syndrome 2, MIM# 619420; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3959 GNB2 Zornitza Stark Marked gene: GNB2 as ready
Intellectual disability syndromic and non-syndromic v0.3959 GNB2 Zornitza Stark Gene: gnb2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3959 GNB2 Zornitza Stark Publications for gene: GNB2 were set to 31698099
Intellectual disability syndromic and non-syndromic v0.3958 GNB2 Zornitza Stark Classified gene: GNB2 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.3958 GNB2 Zornitza Stark Gene: gnb2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3957 GNB2 Zornitza Stark reviewed gene: GNB2: Rating: GREEN; Mode of pathogenicity: None; Publications: 31698099, 33971351, 34183358, 33057194; Phenotypes: Intellectual disability; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3957 HID1 Zornitza Stark Marked gene: HID1 as ready
Intellectual disability syndromic and non-syndromic v0.3957 HID1 Zornitza Stark Gene: hid1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3957 HID1 Zornitza Stark Classified gene: HID1 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.3957 HID1 Zornitza Stark Gene: hid1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3956 HID1 Zornitza Stark Classified gene: HID1 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.3956 HID1 Zornitza Stark Gene: hid1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3955 HID1 Zornitza Stark gene: HID1 was added
gene: HID1 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: HID1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HID1 were set to 33999436
Phenotypes for gene: HID1 were set to Syndromic infantile encephalopathy; Hypopituitarism
Review for gene: HID1 was set to GREEN
Added comment: 7 individuals from 6 unrelated families reported. Clinical features included: hypopituitarism in combination with brain atrophy, thin corpus callosum, severe developmental delay, visual impairment, and epilepsy
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.3954 KIF1B Zornitza Stark Marked gene: KIF1B as ready
Intellectual disability syndromic and non-syndromic v0.3954 KIF1B Zornitza Stark Gene: kif1b has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v0.3954 KIF1B Zornitza Stark Classified gene: KIF1B as Red List (low evidence)
Intellectual disability syndromic and non-syndromic v0.3954 KIF1B Zornitza Stark Gene: kif1b has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v0.3953 ERGIC3 Seb Lunke Marked gene: ERGIC3 as ready
Intellectual disability syndromic and non-syndromic v0.3953 ERGIC3 Seb Lunke Gene: ergic3 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.3953 ERGIC3 Seb Lunke Classified gene: ERGIC3 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.3953 ERGIC3 Seb Lunke Gene: ergic3 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.3952 ERGIC3 Seb Lunke gene: ERGIC3 was added
gene: ERGIC3 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: ERGIC3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ERGIC3 were set to ERGIC3
Phenotypes for gene: ERGIC3 were set to 33710394; 31585110
Review for gene: ERGIC3 was set to AMBER
Added comment: PMID: 33710394 - two homozygous sibs with mild ID, a novel canonical splice (c.717+1G>A). Absent in gnomAD, no splice studies. Classed as a VUS.

PMID: 31585110 - 1 hom (p.Gln233Argfs*10) in a male 8yo with Growth retardation, Microcephaly, Learning disability, Facial dysmorphism, Abnormal pigmentation.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.3951 JPH3 Seb Lunke Marked gene: JPH3 as ready
Intellectual disability syndromic and non-syndromic v0.3951 JPH3 Seb Lunke Gene: jph3 has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v0.3951 JPH3 Seb Lunke gene: JPH3 was added
gene: JPH3 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: JPH3 was set to Unknown
Publications for gene: JPH3 were set to 33824468
Phenotypes for gene: JPH3 were set to Intellectual disability; dystonia
Review for gene: JPH3 was set to RED
Added comment: One homozygous truncating variant (NM_020655.4: c.1740dup; p.(Val581Argfs*137)) found in a female individual affected with genetically undetermined neurodevelopmental anomalies (including delayed motor milestones, abnormal social communication, language difficulties and borderline cognitive impairment) and paroxysmal attacks of dystonia since her early infancy. No functional work were performed.

Only STRs disease causing, see separate STR list. No evidence for SNVs etc.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.3950 HEATR5B Seb Lunke Marked gene: HEATR5B as ready
Intellectual disability syndromic and non-syndromic v0.3950 HEATR5B Seb Lunke Gene: heatr5b has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.3950 HEATR5B Seb Lunke Classified gene: HEATR5B as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.3950 HEATR5B Seb Lunke Gene: heatr5b has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.3949 MYT1 Zornitza Stark Marked gene: MYT1 as ready
Intellectual disability syndromic and non-syndromic v0.3949 MYT1 Zornitza Stark Gene: myt1 has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v0.3949 MYT1 Zornitza Stark Classified gene: MYT1 as Red List (low evidence)
Intellectual disability syndromic and non-syndromic v0.3949 MYT1 Zornitza Stark Gene: myt1 has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v0.3948 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, polymicrogyria
Intellectual disability syndromic and non-syndromic v0.3947 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, polymicrogyria
Intellectual disability syndromic and non-syndromic v0.3947 HEATR5B Seb Lunke gene: HEATR5B was added
gene: HEATR5B was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: HEATR5B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HEATR5B were set to 33824466
Phenotypes for gene: HEATR5B were set to pontocerebellar hypoplasia; intellectual disability; seizures
Review for gene: HEATR5B was set to AMBER
Added comment: Four affected children from two families presenting with pontocerebellar hypoplasiawith neonatal seizures, severe ID and motor delay. Two homozygous splice variants were reported (c.5051–1G>A and c.5050+4A>G) in intron 31 of HEATR5B gene. Aberrant splicing was found in patient fibroblasts, which correlated with reduced levels of HEATR5B protein. Homozygous knockout mice were not viable. *NOTE: gene (and alias) not found in OMIM
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.3947 ATP1A2 Zornitza Stark Phenotypes for gene: ATP1A2 were changed from Alternating hemiplegia of childhood 1, MIM# 104290 to Alternating hemiplegia of childhood 1, MIM# 104290; Developmental and epileptic encephalopathy, polymicrogyria
Intellectual disability syndromic and non-syndromic v0.3946 ATP1A2 Zornitza Stark Publications for gene: ATP1A2 were set to
Intellectual disability syndromic and non-syndromic v0.3945 ATP1A2 Zornitza Stark changed review comment from: Although some of the symptoms of this condition are episodic, intellectual disability is a recognised feature.; to: Alternating hemiplegia: Although some of the symptoms of this condition are episodic, intellectual disability is a recognised feature.
Intellectual disability syndromic and non-syndromic v0.3945 ATP1A2 Zornitza Stark edited their review of gene: ATP1A2: Added comment: PMID 33880529: six individuals with de novo missense variants reported and DD/EE/PMG.; Changed publications: 33880529; Changed phenotypes: Alternating hemiplegia of childhood 1, MIM# 104290, Developmental and epileptic encephalopathy, polymicrogyria
Intellectual disability syndromic and non-syndromic v0.3945 ATP1A3 Zornitza Stark Phenotypes for gene: ATP1A3 were changed from Alternating hemiplegia of childhood 2, MIM#614820 to Alternating hemiplegia of childhood 2, MIM#614820; Developmental and epileptic encephalopathy, polymicrogyria
Intellectual disability syndromic and non-syndromic v0.3944 ATP1A3 Zornitza Stark Publications for gene: ATP1A3 were set to
Intellectual disability syndromic and non-syndromic v0.3943 ATP1A3 Zornitza Stark edited their review of gene: ATP1A3: Added comment: PMID 33880529: 16 individuals reported with DD/EE and PMG.; Changed rating: GREEN; Changed publications: 33880529; Changed phenotypes: Alternating hemiplegia of childhood 2, MIM#614820, Developmental and epileptic encephalopathy, polymicrogyria
Intellectual disability syndromic and non-syndromic v0.3943 ZC3H14 Seb Lunke reviewed gene: ZC3H14: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability syndromic and non-syndromic v0.3943 ZC3H14 Seb Lunke Publications for gene: ZC3H14 were set to PubMed: 21734151
Intellectual disability syndromic and non-syndromic v0.3942 SAMD9L Zornitza Stark Publications for gene: SAMD9L were set to
Intellectual disability syndromic and non-syndromic v0.3941 SAMD9L Zornitza Stark Marked gene: SAMD9L as ready
Intellectual disability syndromic and non-syndromic v0.3941 SAMD9L Zornitza Stark Gene: samd9l has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v0.3941 SAMD9L Zornitza Stark Classified gene: SAMD9L as Red List (low evidence)
Intellectual disability syndromic and non-syndromic v0.3941 SAMD9L Zornitza Stark Gene: samd9l has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v0.3940 PITRM1 Zornitza Stark Phenotypes for gene: PITRM1 were changed from Ataxia; Intellectual disability to Spinocerebellar ataxia-30 (SCAR30), MIM#619405; intellectual disability; cognitive decline; psychosis
Intellectual disability syndromic and non-syndromic v0.3939 PITRM1 Zornitza Stark edited their review of gene: PITRM1: Changed phenotypes: Spinocerebellar ataxia-30 (SCAR30), MIM#619405, intellectual disability, cognitive decline, psychosis
Intellectual disability syndromic and non-syndromic v0.3939 VPS41 Zornitza Stark Phenotypes for gene: VPS41 were changed from Dystonia; intellectual disability to Spinocerebellar ataxia-29 (SCAR29), MIM#619389; Progressive neurodevelopmental disorder with ataxia, hypotonia, dystonia, intellectual disability and speech delay
Intellectual disability syndromic and non-syndromic v0.3938 VPS41 Zornitza Stark edited their review of gene: VPS41: Changed phenotypes: Spinocerebellar ataxia-29 (SCAR29), MIM#619389, Progressive neurodevelopmental disorder with ataxia, hypotonia, dystonia, intellectual disability and speech delay
Intellectual disability syndromic and non-syndromic v0.3938 GNB2 Arina Puzriakova reviewed gene: GNB2: Rating: GREEN; Mode of pathogenicity: None; Publications: 31698099, 33971351, 34183358; Phenotypes: Intellectual disability; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability syndromic and non-syndromic v0.3938 EPHA7 Zornitza Stark Marked gene: EPHA7 as ready
Intellectual disability syndromic and non-syndromic v0.3938 EPHA7 Zornitza Stark Gene: epha7 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.3938 EPHA7 Zornitza Stark Classified gene: EPHA7 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.3938 EPHA7 Zornitza Stark Gene: epha7 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.3937 EPHA7 Zornitza Stark gene: EPHA7 was added
gene: EPHA7 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
SV/CNV tags were added to gene: EPHA7.
Mode of inheritance for gene: EPHA7 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: EPHA7 were set to 34176129
Phenotypes for gene: EPHA7 were set to Intellectual disability
Review for gene: EPHA7 was set to AMBER
Added comment: Lévy et al (2021 - PMID: 34176129) provide evidence that haploinssuficiency of EPHA7 results in a neurodevelopmental disorder.

The authors report on 12 individuals belonging to 9 unrelated families, all harboring with 6q microdeletions spanning EPHA7.

Overlapping features included DD (13/13), ID (10/10 - mild in most cases, individuals with larger CNVs/additional variants had more severe phenotype), speech delay and behavioral disorders. Variable other features incl. hypotonia (70%), non specific facial features, eye abnormalities (40%) and cardiac defects (25%).

The CNVs ranged from 152 kb to few Mb in size but in 4 subjects (P5-8) were only minimal, involving only EPHA7.



9 out of 12 individuals had inherited the deletion (5 subjects paternal, 4 maternal), in 1 subject (P12) this occured de novo, while for 2 others inheritance was not specified. Most deletions were inherited from an unaffected parent (in 6/7 families), with unclear contribution in a further one.

The authors discuss on previous studies suggesting an important role for EphA7 in brain development (modulation of cell-cell adhesion and repulsion, regulation of dendrite morphogenesis in early corticogenesis, role in dendritic spine formation later in development. EphA7 has also been proposed to drive neuronal maturation and synaptic function).

Haploinsufficiency for other ephrins or ephrin receptors has been implicated in other NDDs.

Overall Lévy et al promote incomplete penetrance and variable expressivity with haploinsufficiency of this gene being a risk factor for NDD. [The gene has also an %HI of 2.76% and a pLI of 1].
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.3936 DNM1 Zornitza Stark Marked gene: DNM1 as ready
Intellectual disability syndromic and non-syndromic v0.3936 DNM1 Zornitza Stark Gene: dnm1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3936 DNM1 Zornitza Stark Phenotypes for gene: DNM1 were changed from to Developmental and epileptic encephalopathy 31, OMIM:616346
Intellectual disability syndromic and non-syndromic v0.3935 DNM1 Zornitza Stark Publications for gene: DNM1 were set to
Intellectual disability syndromic and non-syndromic v0.3934 DNM1 Zornitza Stark Mode of inheritance for gene: DNM1 was changed from Unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3933 DNM1 Zornitza Stark reviewed gene: DNM1: Rating: GREEN; Mode of pathogenicity: None; Publications: 25262651, 27066543, 33372033, 34172529; Phenotypes: Developmental and epileptic encephalopathy 31, OMIM:616346; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3933 TTC8 Zornitza Stark Marked gene: TTC8 as ready
Intellectual disability syndromic and non-syndromic v0.3933 TTC8 Zornitza Stark Gene: ttc8 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3933 TTC8 Zornitza Stark Phenotypes for gene: TTC8 were changed from to Bardet-Biedl syndrome 8, MIM# 615985
Intellectual disability syndromic and non-syndromic v0.3932 TTC8 Zornitza Stark Publications for gene: TTC8 were set to
Intellectual disability syndromic and non-syndromic v0.3931 TTC8 Zornitza Stark Mode of inheritance for gene: TTC8 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3930 TTC8 Zornitza Stark reviewed gene: TTC8: Rating: GREEN; Mode of pathogenicity: None; Publications: 14520415, 19797195; Phenotypes: Bardet-Biedl syndrome 8, MIM# 615985; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3930 FTCD Elena Savva reviewed gene: FTCD: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 29178637, 30740726; Phenotypes: Glutamate formiminotransferase deficiency MIM#229100; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3930 ATP9A Zornitza Stark Marked gene: ATP9A as ready
Intellectual disability syndromic and non-syndromic v0.3930 ATP9A Zornitza Stark Gene: atp9a has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.3930 ATP9A Zornitza Stark Classified gene: ATP9A as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.3930 ATP9A Zornitza Stark Gene: atp9a has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.3929 ATP9A Zornitza Stark gene: ATP9A was added
gene: ATP9A was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: ATP9A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ATP9A were set to http://dx.doi.org/10.1136/jmedgenet-2021-107843
Phenotypes for gene: ATP9A were set to Neurodevelopmental delay; Postnatal microcephaly; Failure to thrive; Gastrointestinal symptoms
Review for gene: ATP9A was set to AMBER
Added comment: Vogt et al. 2021 report on 3 individuals from 2 unrelated consanguineous families with different homozygous truncating variants in ATP9A, presenting with DD/ID of variable degree (2 mild, 1 severe), postnatal microcephaly (OFC range: −2.33 SD to −3.58 SD), failure to thrive, and gastrointestinal symptoms. Patient-derived fibroblasts showed reduced expression of ATP9A, and consistent with previous findings also overexpression of interacting partners, ARPC3 and SNX3.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.3928 ATP2C2 Zornitza Stark Marked gene: ATP2C2 as ready
Intellectual disability syndromic and non-syndromic v0.3928 ATP2C2 Zornitza Stark Gene: atp2c2 has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v0.3928 ATP2C2 Zornitza Stark gene: ATP2C2 was added
gene: ATP2C2 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: ATP2C2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ATP2C2 were set to 33864365; 28440294
Phenotypes for gene: ATP2C2 were set to language impairment, HP:0002463
Review for gene: ATP2C2 was set to RED
Added comment: PMID: 33864365 - Martinelli et al 2021 - report a family with a missense variant NM_001286527.2:c.304G>A, p.(Val102Met) in ATP2C2 in a father and two siblings with specific language impairment. However two other affected siblings did not have this variant. This variant was also reported by Chen et al. They found that the variant had a higher frequency in language cases (1.8%, N = 360) compared with cohorts selected for dyslexia (0.8%, N = 520) and ADHD (0.7%, N = 150), which presented frequencies comparable to reference databases (0.9%, N = 24 046 gnomAD controls). They postulate that variant is not sufficient on its own to cause a disorder but is a susceptibility factor which increases the risk for language impairment. PMID: 28440294 - Chen et al 2017 - report 2 probands with severe learning impairment, and missense variants in ATP2C2 (NM_001286527: c.G304A:p.V102M and NM_001291454:exon21: c.C1936T:p.R646W).
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.3927 TMEM67 Zornitza Stark Marked gene: TMEM67 as ready
Intellectual disability syndromic and non-syndromic v0.3927 TMEM67 Zornitza Stark Gene: tmem67 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3927 TMEM67 Zornitza Stark Phenotypes for gene: TMEM67 were changed from Joubert syndrome 6, MIM# 610688; Meckel syndrome 3, MIM# 607361; COACH syndrome 1, MIM# 216360 to Joubert syndrome 6, MIM# 610688; Meckel syndrome 3, MIM# 607361; COACH syndrome 1, MIM# 216360
Intellectual disability syndromic and non-syndromic v0.3927 TMEM67 Zornitza Stark Phenotypes for gene: TMEM67 were changed from to Joubert syndrome 6, MIM# 610688; Meckel syndrome 3, MIM# 607361; COACH syndrome 1, MIM# 216360
Intellectual disability syndromic and non-syndromic v0.3926 TMEM67 Zornitza Stark Publications for gene: TMEM67 were set to
Intellectual disability syndromic and non-syndromic v0.3925 TMEM67 Zornitza Stark Mode of inheritance for gene: TMEM67 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3924 TMEM67 Zornitza Stark reviewed gene: TMEM67: Rating: GREEN; Mode of pathogenicity: None; Publications: 16415887, 17377820, 17160906, 19508969; Phenotypes: Joubert syndrome 6, MIM# 610688, Meckel syndrome 3, MIM# 607361, COACH syndrome 1, MIM# 216360; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3924 SDCCAG8 Zornitza Stark Marked gene: SDCCAG8 as ready
Intellectual disability syndromic and non-syndromic v0.3924 SDCCAG8 Zornitza Stark Gene: sdccag8 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3924 SDCCAG8 Zornitza Stark Phenotypes for gene: SDCCAG8 were changed from to Bardet-Biedl syndrome 16, MIM# 615993; MONDO:0014444; Senior-Loken syndrome 7, MIM# 613615; MONDO:0013326; Nephronophthisis
Intellectual disability syndromic and non-syndromic v0.3923 SDCCAG8 Zornitza Stark Publications for gene: SDCCAG8 were set to
Intellectual disability syndromic and non-syndromic v0.3922 SDCCAG8 Zornitza Stark Mode of inheritance for gene: SDCCAG8 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3921 SDCCAG8 Zornitza Stark reviewed gene: SDCCAG8: Rating: GREEN; Mode of pathogenicity: None; Publications: 20835237, 22626039, 22626039, 32432520, 31534065, 26968886; Phenotypes: Bardet-Biedl syndrome 16, MIM# 615993, MONDO:0014444, Senior-Loken syndrome 7, MIM# 613615, MONDO:0013326, Nephronophthisis; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3921 KIF1B Paul De Fazio gene: KIF1B was added
gene: KIF1B was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: KIF1B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KIF1B were set to 33710394
Phenotypes for gene: KIF1B were set to Hypotonia; coloboma; hypoplasia of the corpus callosum; severe neurodevelopmental delay
Review for gene: KIF1B was set to RED
gene: KIF1B was marked as current diagnostic
Added comment: Compound heterozygous missense variants reported in a woman with severe hypotonia, hypsarrhythmia, coloboma, hypoplasia of corpus callosum, severe neurodevelopmental delay.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.3921 MYT1 Paul De Fazio changed review comment from: Missense variant reported de novo in a patient with mild ID. Patient also had a COL9A2 variant and skeletal features.
Sources: Literature; to: Missense variant reported de novo in a patient with mild ID reported in a cohort study, Patient also had a COL9A2 variant and skeletal features. Authors referred to it as an extended phenotype and dual diagnosis.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.3921 MYT1 Paul De Fazio gene: MYT1 was added
gene: MYT1 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: MYT1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: MYT1 were set to 33710394
Phenotypes for gene: MYT1 were set to Intellectual disability
Review for gene: MYT1 was set to RED
gene: MYT1 was marked as current diagnostic
Added comment: Missense variant reported de novo in a patient with mild ID. Patient also had a COL9A2 variant and skeletal features.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.3921 ZC3H14 Elena Savva reviewed gene: ZC3H14: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 21734151, 33710394; Phenotypes: Mental retardation, autosomal recessive 56 MIM#617125; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3921 SAMD9L Paul De Fazio edited their review of gene: SAMD9L: Changed publications: 33710394
Intellectual disability syndromic and non-syndromic v0.3921 SAMD9L Paul De Fazio gene: SAMD9L was added
gene: SAMD9L was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: SAMD9L was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: SAMD9L were set to Intellectual disability
Review for gene: SAMD9L was set to RED
gene: SAMD9L was marked as current diagnostic
Added comment: Missense variant reported de novo in a patient with moderate ID, in a large cohort study. Author described it as a phenotype expansion as ataxia-pancytopenia not found in that patient.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.3921 ARHGEF9 Zornitza Stark Marked gene: ARHGEF9 as ready
Intellectual disability syndromic and non-syndromic v0.3921 ARHGEF9 Zornitza Stark Gene: arhgef9 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3921 ARHGEF9 Zornitza Stark Phenotypes for gene: ARHGEF9 were changed from to Developmental and epileptic encephalopathy 8, MIM# 300607
Intellectual disability syndromic and non-syndromic v0.3920 ARHGEF9 Zornitza Stark Publications for gene: ARHGEF9 were set to
Intellectual disability syndromic and non-syndromic v0.3919 ARHGEF9 Zornitza Stark Mode of inheritance for gene: ARHGEF9 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 v0.3918 ARHGEF9 Zornitza Stark reviewed gene: ARHGEF9: Rating: GREEN; Mode of pathogenicity: None; Publications: 31942680, 30048823, 29130122, 28620718, 33600053, 32939676; Phenotypes: Developmental and epileptic encephalopathy 8, MIM# 300607; 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 v0.3918 DDX59 Zornitza Stark Mode of inheritance for gene: DDX59 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3917 CEP83 Zornitza Stark Marked gene: CEP83 as ready
Intellectual disability syndromic and non-syndromic v0.3917 CEP83 Zornitza Stark Gene: cep83 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3917 CEP83 Zornitza Stark Phenotypes for gene: CEP83 were changed from to Nephronophthisis 18, MIM# 615862; MONDO:0014374; Retinal dystrophy; ID
Intellectual disability syndromic and non-syndromic v0.3916 CEP83 Zornitza Stark Publications for gene: CEP83 were set to
Intellectual disability syndromic and non-syndromic v0.3915 CEP83 Zornitza Stark Mode of inheritance for gene: CEP83 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3914 CEP83 Zornitza Stark reviewed gene: CEP83: Rating: GREEN; Mode of pathogenicity: None; Publications: 24882706, 33938610; Phenotypes: Nephronophthisis 18, MIM# 615862, MONDO:0014374, Retinal dystrophy, ID; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3914 CEP164 Zornitza Stark Marked gene: CEP164 as ready
Intellectual disability syndromic and non-syndromic v0.3914 CEP164 Zornitza Stark Gene: cep164 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3914 CEP164 Zornitza Stark Classified gene: CEP164 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.3914 CEP164 Zornitza Stark Gene: cep164 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3913 CEP164 Zornitza Stark gene: CEP164 was added
gene: CEP164 was added to Intellectual disability syndromic and non-syndromic. Sources: Expert Review
Mode of inheritance for gene: CEP164 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CEP164 were set to 34132027; 34013113; 32055034; 27708425; 22863007
Phenotypes for gene: CEP164 were set to Bardet-Biedl syndrome; Nephronophthisis 15, MIM# 614845; Oro-facio-digital syndrome
Review for gene: CEP164 was set to GREEN
Added comment: More than 10 unrelated families reported. Although this is labelled as a nephronophthisis gene in OMIM, some of the reported individuals have had features such as retinal involvement, ID and polydactyly to suggest a more BBS-like phenotype. Also note one individual reported with OFD-like phenotype.
Sources: Expert Review
Intellectual disability syndromic and non-syndromic v0.3912 CEP104 Zornitza Stark Phenotypes for gene: CEP104 were changed from Joubert syndrome 25, MIM# 616781 to Joubert syndrome 25, MIM# 616781; MONDO:0014770
Intellectual disability syndromic and non-syndromic v0.3911 CEP104 Zornitza Stark edited their review of gene: CEP104: Changed phenotypes: Joubert syndrome 25, MIM# 616781, MONDO:0014770
Intellectual disability syndromic and non-syndromic v0.3911 C5orf42 Zornitza Stark Tag new gene name tag was added to gene: C5orf42.
Intellectual disability syndromic and non-syndromic v0.3911 C5orf42 Zornitza Stark Marked gene: C5orf42 as ready
Intellectual disability syndromic and non-syndromic v0.3911 C5orf42 Zornitza Stark Gene: c5orf42 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3911 C5orf42 Zornitza Stark Phenotypes for gene: C5orf42 were changed from to Joubert syndrome 17, MIM# 614615; MONDO:0013824; Orofaciodigital syndrome VI, MIM# 277170
Intellectual disability syndromic and non-syndromic v0.3910 C5orf42 Zornitza Stark Publications for gene: C5orf42 were set to
Intellectual disability syndromic and non-syndromic v0.3909 C5orf42 Zornitza Stark Mode of inheritance for gene: C5orf42 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3908 C5orf42 Zornitza Stark reviewed gene: C5orf42: Rating: GREEN; Mode of pathogenicity: None; Publications: 22425360, 24178751; Phenotypes: Joubert syndrome 17, MIM# 614615, MONDO:0013824, Orofaciodigital syndrome VI, MIM# 277170; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3908 BBS9 Zornitza Stark Phenotypes for gene: BBS9 were changed from Bardet-Biedl syndrome 9, MIM#615986; MONDO:0014437 to Bardet-Biedl syndrome 9, MIM#615986; MONDO:0014437
Intellectual disability syndromic and non-syndromic v0.3907 BBS9 Zornitza Stark Marked gene: BBS9 as ready
Intellectual disability syndromic and non-syndromic v0.3907 BBS9 Zornitza Stark Gene: bbs9 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3907 BBS9 Zornitza Stark Phenotypes for gene: BBS9 were changed from to Bardet-Biedl syndrome 9, MIM#615986; MONDO:0014437
Intellectual disability syndromic and non-syndromic v0.3906 BBS9 Zornitza Stark Publications for gene: BBS9 were set to
Intellectual disability syndromic and non-syndromic v0.3905 BBS9 Zornitza Stark Mode of inheritance for gene: BBS9 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3904 BBS9 Zornitza Stark reviewed gene: BBS9: Rating: GREEN; Mode of pathogenicity: None; Publications: 16380913, 22353939, 32686083, 32037757; Phenotypes: Bardet-Biedl syndrome 9, MIM#615986, MONDO:0014437; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3904 BBS7 Zornitza Stark Marked gene: BBS7 as ready
Intellectual disability syndromic and non-syndromic v0.3904 BBS7 Zornitza Stark Gene: bbs7 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3904 BBS7 Zornitza Stark Phenotypes for gene: BBS7 were changed from to Bardet-Biedl syndrome 7, MIM# 615984; MONDO:0014435
Intellectual disability syndromic and non-syndromic v0.3903 BBS7 Zornitza Stark Publications for gene: BBS7 were set to
Intellectual disability syndromic and non-syndromic v0.3902 BBS7 Zornitza Stark Mode of inheritance for gene: BBS7 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3901 BBS7 Zornitza Stark reviewed gene: BBS7: Rating: GREEN; Mode of pathogenicity: None; Publications: 12567324, 21937992, 19797195; Phenotypes: Bardet-Biedl syndrome 7, MIM# 615984, MONDO:0014435; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3901 BBS5 Zornitza Stark Marked gene: BBS5 as ready
Intellectual disability syndromic and non-syndromic v0.3901 BBS5 Zornitza Stark Gene: bbs5 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3901 BBS5 Zornitza Stark Phenotypes for gene: BBS5 were changed from to Bardet-Biedl syndrome 5, MIM#615983; MONDO:0014434
Intellectual disability syndromic and non-syndromic v0.3900 BBS5 Zornitza Stark Publications for gene: BBS5 were set to
Intellectual disability syndromic and non-syndromic v0.3899 BBS5 Zornitza Stark Mode of inheritance for gene: BBS5 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3898 BBS5 Zornitza Stark reviewed gene: BBS5: Rating: GREEN; Mode of pathogenicity: None; Publications: 19252258, 15137946, 10053027, 15637713; Phenotypes: Bardet-Biedl syndrome 5, MIM#615983, MONDO:0014434; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3898 BBS4 Zornitza Stark Marked gene: BBS4 as ready
Intellectual disability syndromic and non-syndromic v0.3898 BBS4 Zornitza Stark Gene: bbs4 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3898 BBS4 Zornitza Stark Phenotypes for gene: BBS4 were changed from to Bardet-Biedl syndrome 4, MIM#615982; MONDO:0014433
Intellectual disability syndromic and non-syndromic v0.3897 BBS4 Zornitza Stark Publications for gene: BBS4 were set to
Intellectual disability syndromic and non-syndromic v0.3896 BBS4 Zornitza Stark Mode of inheritance for gene: BBS4 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3895 BBS4 Zornitza Stark reviewed gene: BBS4: Rating: GREEN; Mode of pathogenicity: None; Publications: 12016587, 11381270; Phenotypes: Bardet-Biedl syndrome 4, MIM#615982, MONDO:0014433; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3895 ARL6 Zornitza Stark Marked gene: ARL6 as ready
Intellectual disability syndromic and non-syndromic v0.3895 ARL6 Zornitza Stark Gene: arl6 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3895 ARL6 Zornitza Stark Phenotypes for gene: ARL6 were changed from to Bardet-Biedl syndrome 3, MIM# 600151
Intellectual disability syndromic and non-syndromic v0.3894 ARL6 Zornitza Stark Publications for gene: ARL6 were set to
Intellectual disability syndromic and non-syndromic v0.3893 ARL6 Zornitza Stark Mode of inheritance for gene: ARL6 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3892 ARL6 Zornitza Stark changed review comment from: Multiple families reported and functional data.; to: Multiple families reported and functional data, ID is a key feature.
Intellectual disability syndromic and non-syndromic v0.3892 ARL6 Zornitza Stark reviewed gene: ARL6: Rating: GREEN; Mode of pathogenicity: None; Publications: 15258860, 32361989, 31888296, 25402481; Phenotypes: Bardet-Biedl syndrome 3, MIM# 600151; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3892 PPP2R1A Zornitza Stark Marked gene: PPP2R1A as ready
Intellectual disability syndromic and non-syndromic v0.3892 PPP2R1A Zornitza Stark Gene: ppp2r1a has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3892 PPP2R1A Zornitza Stark Phenotypes for gene: PPP2R1A were changed from to Mental retardation, autosomal dominant 36, MIM#616362; Microcephaly-corpus callosum hypoplasia-intellectual disability-facial dysmorphism syndrome, MONDO:0014605
Intellectual disability syndromic and non-syndromic v0.3891 PPP2R1A Zornitza Stark Publications for gene: PPP2R1A were set to
Intellectual disability syndromic and non-syndromic v0.3890 PPP2R1A Zornitza Stark Mode of inheritance for gene: PPP2R1A was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3889 PPP2R1A Zornitza Stark reviewed gene: PPP2R1A: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Mental retardation, autosomal dominant 36, MIM#616362, Microcephaly-corpus callosum hypoplasia-intellectual disability-facial dysmorphism syndrome, MONDO:0014605; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3889 CLPB Zornitza Stark Marked gene: CLPB as ready
Intellectual disability syndromic and non-syndromic v0.3889 CLPB Zornitza Stark Gene: clpb has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3889 CLPB Zornitza Stark Phenotypes for gene: CLPB were changed from to 3-methylglutaconic aciduria, type VII, with cataracts, neurologic involvement and neutropaenia, MIM# 616271
Intellectual disability syndromic and non-syndromic v0.3888 CLPB Zornitza Stark Publications for gene: CLPB were set to
Intellectual disability syndromic and non-syndromic v0.3887 CLPB Zornitza Stark Mode of inheritance for gene: CLPB was changed from Unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3886 CLPB Zornitza Stark reviewed gene: CLPB: Rating: GREEN; Mode of pathogenicity: None; Publications: 25597510, 34140661; Phenotypes: 3-methylglutaconic aciduria, type VII, with cataracts, neurologic involvement and neutropaenia, MIM# 616271; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3886 NCDN Zornitza Stark Phenotypes for gene: NCDN were changed from neurodevelopmental delay, intellectual disability, and epilepsy to Neurodevelopmental disorder with infantile epileptic spasms (NEDIES), MIM#619373
Intellectual disability syndromic and non-syndromic v0.3885 NCDN Zornitza Stark reviewed gene: NCDN: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with infantile epileptic spasms (NEDIES), MIM#619373; Mode of inheritance: None
Intellectual disability syndromic and non-syndromic v0.3885 ARCN1 Zornitza Stark Marked gene: ARCN1 as ready
Intellectual disability syndromic and non-syndromic v0.3885 ARCN1 Zornitza Stark Gene: arcn1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3885 ARCN1 Zornitza Stark Phenotypes for gene: ARCN1 were changed from to Short stature, rhizomelic, with microcephaly, micrognathia, and developmental delay (MIM#617164)
Intellectual disability syndromic and non-syndromic v0.3884 ARCN1 Zornitza Stark Publications for gene: ARCN1 were set to
Intellectual disability syndromic and non-syndromic v0.3883 ARCN1 Zornitza Stark Mode of inheritance for gene: ARCN1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3882 ARCN1 Zornitza Stark reviewed gene: ARCN1: Rating: GREEN; Mode of pathogenicity: None; Publications: 27476655, 33154040; Phenotypes: Short stature, rhizomelic, with microcephaly, micrognathia, and developmental delay (MIM#617164); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3882 SLC13A5 Zornitza Stark Marked gene: SLC13A5 as ready
Intellectual disability syndromic and non-syndromic v0.3882 SLC13A5 Zornitza Stark Gene: slc13a5 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3882 SLC13A5 Zornitza Stark Phenotypes for gene: SLC13A5 were changed from to Developmental and epileptic encephalopathy 25, with amelogenesis imperfecta MIM#615905; MONDO:0014392
Intellectual disability syndromic and non-syndromic v0.3881 SLC13A5 Zornitza Stark Publications for gene: SLC13A5 were set to
Intellectual disability syndromic and non-syndromic v0.3880 SLC13A5 Zornitza Stark Mode of inheritance for gene: SLC13A5 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3879 SLC13A5 Zornitza Stark reviewed gene: SLC13A5: Rating: GREEN; Mode of pathogenicity: None; Publications: 24995870, 26384929; Phenotypes: Developmental and epileptic encephalopathy 25, with amelogenesis imperfecta MIM#615905, MONDO:0014392; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3879 CTC1 Zornitza Stark Marked gene: CTC1 as ready
Intellectual disability syndromic and non-syndromic v0.3879 CTC1 Zornitza Stark Gene: ctc1 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.3879 CTC1 Zornitza Stark Phenotypes for gene: CTC1 were changed from to Cerebroretinal microangiopathy with calcifications and cysts, MIM# 612199
Intellectual disability syndromic and non-syndromic v0.3878 CTC1 Zornitza Stark Mode of inheritance for gene: CTC1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3877 CTC1 Zornitza Stark Classified gene: CTC1 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.3877 CTC1 Zornitza Stark Gene: ctc1 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.3876 CTC1 Zornitza Stark reviewed gene: CTC1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Cerebroretinal microangiopathy with calcifications and cysts, MIM# 612199; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3876 IFT74 Zornitza Stark Classified gene: IFT74 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.3876 IFT74 Zornitza Stark Gene: ift74 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3875 IFT74 Zornitza Stark gene: IFT74 was added
gene: IFT74 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: IFT74 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: IFT74 were set to 27486776; 32144365; 33531668
Phenotypes for gene: IFT74 were set to Bardet-Biedl syndrome 20, MIM# 617119; Joubert syndrome
Review for gene: IFT74 was set to GREEN
Added comment: Two individuals reported with BBS phenotype.

PMID 33531668: Identified IFT74 as a JBTS-associated gene in 3 unrelated families through WES. All the affected individuals carried truncated variants and shared one missense variant (p.Q179E) found only in East Asians. The expression of the human p.Q179E-IFT74 variant displayed compromised rescue effects in zebrafish ift74 morphants. Attenuated ciliogenesis; altered distribution of IFT proteins and ciliary membrane proteins, including ARL13B, INPP5E, and GPR161; and disrupted hedgehog signaling were observed in patient fibroblasts with IFT74 variants.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.3874 RFX4 Zornitza Stark Marked gene: RFX4 as ready
Intellectual disability syndromic and non-syndromic v0.3874 RFX4 Zornitza Stark Gene: rfx4 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3874 RFX3 Zornitza Stark Marked gene: RFX3 as ready
Intellectual disability syndromic and non-syndromic v0.3874 RFX3 Zornitza Stark Gene: rfx3 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3874 RFX7 Zornitza Stark Marked gene: RFX7 as ready
Intellectual disability syndromic and non-syndromic v0.3874 RFX7 Zornitza Stark Gene: rfx7 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3874 DLG4 Zornitza Stark Phenotypes for gene: DLG4 were changed from Intellectual developmental disorder 62 618793 to Intellectual developmental disorder 62, MIM# 618793
Intellectual disability syndromic and non-syndromic v0.3873 DLG4 Zornitza Stark Phenotypes for gene: DLG4 were changed from Intellectual disability; Marfanoid habitus to Intellectual developmental disorder 62 618793
Intellectual disability syndromic and non-syndromic v0.3872 DLG4 Zornitza Stark Publications for gene: DLG4 were set to 27479843; 25123844; 19617690; 29460436; 23020937; 28135719
Intellectual disability syndromic and non-syndromic v0.3871 GNAI1 Zornitza Stark Phenotypes for gene: GNAI1 were changed from Intellectual disability; seizures; hypotonia to Intellectual disability; seizures; hypotonia
Intellectual disability syndromic and non-syndromic v0.3870 GNAI1 Zornitza Stark Phenotypes for gene: GNAI1 were changed from Intellectual disability to Intellectual disability; seizures; hypotonia
Intellectual disability syndromic and non-syndromic v0.3869 GNAI1 Zornitza Stark Publications for gene: GNAI1 were set to 28135719
Intellectual disability syndromic and non-syndromic v0.3868 FARSA Zornitza Stark Marked gene: FARSA as ready
Intellectual disability syndromic and non-syndromic v0.3868 FARSA Zornitza Stark Gene: farsa has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3868 RFX7 Chirag Patel Classified gene: RFX7 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.3868 RFX7 Chirag Patel Gene: rfx7 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3868 RFX7 Chirag Patel Classified gene: RFX7 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.3868 RFX7 Chirag Patel Gene: rfx7 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3868 RFX7 Chirag Patel Classified gene: RFX7 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.3868 RFX7 Chirag Patel Gene: rfx7 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3867 RFX7 Chirag Patel Classified gene: RFX7 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.3867 RFX7 Chirag Patel Gene: rfx7 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3867 RFX7 Chirag Patel Classified gene: RFX7 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.3867 RFX7 Chirag Patel Gene: rfx7 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3867 RFX7 Chirag Patel Classified gene: RFX7 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.3867 RFX7 Chirag Patel Gene: rfx7 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3866 RFX4 Chirag Patel Classified gene: RFX4 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.3866 RFX4 Chirag Patel Gene: rfx4 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3866 RFX4 Chirag Patel Classified gene: RFX4 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.3866 RFX4 Chirag Patel Gene: rfx4 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3866 RFX4 Chirag Patel Classified gene: RFX4 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.3866 RFX4 Chirag Patel Gene: rfx4 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3866 RFX4 Chirag Patel Classified gene: RFX4 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.3866 RFX4 Chirag Patel Gene: rfx4 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3866 RFX4 Chirag Patel Classified gene: RFX4 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.3866 RFX4 Chirag Patel Gene: rfx4 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3865 RFX3 Chirag Patel Classified gene: RFX3 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.3865 RFX3 Chirag Patel Gene: rfx3 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3864 RFX4 Chirag Patel gene: RFX4 was added
gene: RFX4 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: RFX4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RFX4 were set to PMID: 33658631
Phenotypes for gene: RFX4 were set to ID, ASD, ADHD
Review for gene: RFX4 was set to GREEN
Added comment: Report of 38 individuals (from 33 unrelated families) with de novo or inherited loss of function variants in RFX3 (15 families), RFX4 (4 families), and RFX7 (14 families), identified through WES. Individuals share neurobehavioural features including ASD, intellectual disability, and/or ADHD; other frequent features include hypersensitivity to sensory stimuli and sleep problems. RFX3, RFX4, and RFX7 are strongly expressed in developing and adult human brain, and X-box binding motifs as well as RFX ChIP-seq peaks are enriched in the cis-regulatory regions of known ASD risk genes. These genes are potentially critical transcriptional regulators of neurobiological pathways associated with neurodevelopmental disease pathogenesis.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.3864 RFX3 Chirag Patel gene: RFX3 was added
gene: RFX3 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: RFX3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RFX3 were set to PMID: 33658631
Phenotypes for gene: RFX3 were set to ID, ASD, ADHD
Review for gene: RFX3 was set to GREEN
Added comment: Report of 38 individuals (from 33 unrelated families) with de novo or inherited loss of function variants in RFX3 (15 families), RFX4 (4 families), and RFX7 (14 families), identified through WES. Individuals share neurobehavioural features including ASD, intellectual disability, and/or ADHD; other frequent features include hypersensitivity to sensory stimuli and sleep problems. RFX3, RFX4, and RFX7 are strongly expressed in developing and adult human brain, and X-box binding motifs as well as RFX ChIP-seq peaks are enriched in the cis-regulatory regions of known ASD risk genes. These genes are potentially critical transcriptional regulators of neurobiological pathways associated with neurodevelopmental disease pathogenesis.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.3864 RFX7 Chirag Patel gene: RFX7 was added
gene: RFX7 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: RFX7 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RFX7 were set to PMID: 33658631
Phenotypes for gene: RFX7 were set to ID, ASD, ADHD
Review for gene: RFX7 was set to GREEN
Added comment: Report of 38 individuals (from 33 unrelated families) with de novo or inherited loss of function variants in RFX3 (15 families), RFX4 (4 families), and RFX7 (14 families), identified through WES. Individuals share neurobehavioural features including ASD, intellectual disability, and/or ADHD; other frequent features include hypersensitivity to sensory stimuli and sleep problems. RFX3, RFX4, and RFX7 are strongly expressed in developing and adult human brain, and X-box binding motifs as well as RFX ChIP-seq peaks are enriched in the cis-regulatory regions of known ASD risk genes. These genes are potentially critical transcriptional regulators of neurobiological pathways associated with neurodevelopmental disease pathogenesis.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.3863 DLG4 Chirag Patel reviewed gene: DLG4: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 33597769; Phenotypes: Intellectual developmental disorder 62; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3863 GNAI1 Chirag Patel reviewed gene: GNAI1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 33473207; Phenotypes: Developmental delay, seizures, and hypotonia; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3863 FARSA Chirag Patel Classified gene: FARSA as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.3863 FARSA Chirag Patel Gene: farsa has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3863 FARSA Chirag Patel Classified gene: FARSA as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.3863 FARSA Chirag Patel Gene: farsa has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3862 FARSA Chirag Patel gene: FARSA was added
gene: FARSA was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: FARSA was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FARSA were set to PMID: 33598926
Phenotypes for gene: FARSA were set to Rajab interstitial lung disease with brain calcifications 2
Review for gene: FARSA was set to GREEN
gene: FARSA was marked as current diagnostic
Added comment: FARSA is a subunit with FARSB to form FARS1 enzyme. Bi-allelic mutations in FARSB are well described.
Schuch et al. (2021) report 3 unrelated individuals with bi-allelic variants in FARSA. Identified through WES and variants segregated with disease. Functional evidence was obtained with reduced FARS1 enzyme activity levels in fibroblasts or EBV-transformed lymphoblastoid cell lines (EBV-LCLs) of patients. Common to all was a chronic interstitial lung disease starting early in life and characterized by bilateral ground-glass opacification on HR-CT, and cholesterol pneumonitis in lung histology. Additional abnormalities in other organ systems include liver disease, neurological manifestations, and growth restriction.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.3861 ZNF81 Zornitza Stark Marked gene: ZNF81 as ready
Intellectual disability syndromic and non-syndromic v0.3861 ZNF81 Zornitza Stark Gene: znf81 has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v0.3861 ZNF81 Zornitza Stark Tag disputed tag was added to gene: ZNF81.
Intellectual disability syndromic and non-syndromic v0.3861 ZNF81 Zornitza Stark Phenotypes for gene: ZNF81 were changed from to Intellectual disability
Intellectual disability syndromic and non-syndromic v0.3860 ZNF81 Zornitza Stark Publications for gene: ZNF81 were set to
Intellectual disability syndromic and non-syndromic v0.3859 ZNF81 Zornitza Stark Mode of inheritance for gene: ZNF81 was changed from Unknown to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability syndromic and non-syndromic v0.3858 ZNF81 Zornitza Stark Classified gene: ZNF81 as Red List (low evidence)
Intellectual disability syndromic and non-syndromic v0.3858 ZNF81 Zornitza Stark Gene: znf81 has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v0.3857 ZNF81 Zornitza Stark reviewed gene: ZNF81: Rating: RED; Mode of pathogenicity: None; Publications: 15121780; Phenotypes: Intellectual disability; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability syndromic and non-syndromic v0.3857 FOXP1 Zornitza Stark Publications for gene: FOXP1 were set to 26633542; 28741757
Intellectual disability syndromic and non-syndromic v0.3856 FOXP1 Zornitza Stark reviewed gene: FOXP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 34109629; Phenotypes: Mental retardation with language impairment and with or without autistic features 613670; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3856 PARP6 Zornitza Stark Publications for gene: PARP6 were set to Cells 2021, 10(6), 1289; https://doi.org/10.3390/cells10061289
Intellectual disability syndromic and non-syndromic v0.3855 PARP6 Zornitza Stark edited their review of gene: PARP6: Changed publications: 34067418
Intellectual disability syndromic and non-syndromic v0.3855 ATXN2L Zornitza Stark Marked gene: ATXN2L as ready
Intellectual disability syndromic and non-syndromic v0.3855 ATXN2L Zornitza Stark Gene: atxn2l has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.3855 SRCAP Zornitza Stark Phenotypes for gene: SRCAP were changed from to Floating-Harbor syndrome MIM#136140; Neurodevelopmental disorder, non-Floating Harbor
Intellectual disability syndromic and non-syndromic v0.3854 SRCAP Zornitza Stark Publications for gene: SRCAP were set to
Intellectual disability syndromic and non-syndromic v0.3853 SRCAP Zornitza Stark Mode of inheritance for gene: SRCAP was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3852 SRCAP Zornitza Stark reviewed gene: SRCAP: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder, non-Floating Harbor; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3852 EIF5A Zornitza Stark Phenotypes for gene: EIF5A were changed from Intellectual disability; microcephaly; dysmorphism to Faundes-Banka syndrome, MIM# 619376; Intellectual disability; microcephaly; dysmorphism
Intellectual disability syndromic and non-syndromic v0.3851 EIF5A Zornitza Stark edited their review of gene: EIF5A: Changed phenotypes: Faundes-Banka syndrome, MIM# 619376, Intellectual disability, microcephaly, dysmorphism
Intellectual disability syndromic and non-syndromic v0.3851 PIGF Zornitza Stark Phenotypes for gene: PIGF were changed from Glycosylphosphatidylinositol deficiency, onychodystrophy, osteodystrophy, intellectual disability, and seizures to Onychodystrophy, osteodystrophy, impaired intellectual development, and seizures syndrome, MIM# 619356
Intellectual disability syndromic and non-syndromic v0.3850 PIGF Zornitza Stark reviewed gene: PIGF: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Onychodystrophy, osteodystrophy, impaired intellectual development, and seizures syndrome, MIM# 619356; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3850 BCAS3 Seb Lunke Marked gene: BCAS3 as ready
Intellectual disability syndromic and non-syndromic v0.3850 BCAS3 Seb Lunke Gene: bcas3 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3850 BCAS3 Seb Lunke Classified gene: BCAS3 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.3850 BCAS3 Seb Lunke Gene: bcas3 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3849 PGM2L1 Sue White Marked gene: PGM2L1 as ready
Intellectual disability syndromic and non-syndromic v0.3849 PGM2L1 Sue White Gene: pgm2l1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3849 PGM2L1 Sue White Classified gene: PGM2L1 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.3849 PGM2L1 Sue White Gene: pgm2l1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3848 LTBP1 Sue White Classified gene: LTBP1 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.3848 LTBP1 Sue White Gene: ltbp1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3847 LTBP1 Chern Lim changed review comment from: PMID:33991472
- Premature truncating variants in multiple affected individuals from 4 unrelated consanguineous families.
- Affected individuals present with connective tissue features (cutis laxa and inguinal hernia), craniofacial dysmorphology, variable heart defects, and prominent skeletal features (craniosynostosis, short stature, brachydactyly, and syndactyly).
- Most of the affected individuals have developmental delay and other neurological features.
- Functional studies done on patient fibroblasts and zebrafish models.
Sources: Literature; to: PMID:33991472
- Premature truncating variants in multiple affected individuals from 4 unrelated consanguineous families.
- Affected individuals present with connective tissue features (cutis laxa and inguinal hernia), craniofacial dysmorphology, variable heart defects, and prominent skeletal features (craniosynostosis, short stature, brachydactyly, and syndactyly).
- Most of the affected individuals have developmental delay and other neurological features.
- Functional studies done on patient fibroblasts and zebrafish models.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.3847 LTBP1 Chern Lim gene: LTBP1 was added
gene: LTBP1 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: LTBP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LTBP1 were set to 33991472
Phenotypes for gene: LTBP1 were set to cutis laxa syndrome
Review for gene: LTBP1 was set to GREEN
gene: LTBP1 was marked as current diagnostic
Added comment: PMID:33991472
- Premature truncating variants in multiple affected individuals from 4 unrelated consanguineous families.
- Affected individuals present with connective tissue features (cutis laxa and inguinal hernia), craniofacial dysmorphology, variable heart defects, and prominent skeletal features (craniosynostosis, short stature, brachydactyly, and syndactyly).
- Most of the affected individuals have developmental delay and other neurological features.
- Functional studies done on patient fibroblasts and zebrafish models.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.3847 PGM2L1 Chern Lim gene: PGM2L1 was added
gene: PGM2L1 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: PGM2L1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PGM2L1 were set to 33979636
Phenotypes for gene: PGM2L1 were set to Neurodevelopmental disorder
Review for gene: PGM2L1 was set to GREEN
gene: PGM2L1 was marked as current diagnostic
Added comment: PMID: 33979636:
- Hom/chet PTVs in 4 unrelated individuals. All four affected individuals had severe developmental and speech delay, dysmorphic facial features, ear anomalies, high arched palate, strabismus, hypotonia, and keratosis pilaris. Early obesity and seizures were present in three individuals.
- Studies on patient fibroblasts and cell lines indicated that PGM2L1 deficiency causes a decrease, but not a disappearance, of the sugar bisphosphates needed for the formation of NDP-sugars and that there is no evidence that this leads to a glycosylation defect.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.3847 SRCAP Sue White Marked gene: SRCAP as ready
Intellectual disability syndromic and non-syndromic v0.3847 SRCAP Sue White Gene: srcap has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3847 ATXN2L Sue White Classified gene: ATXN2L as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.3847 ATXN2L Sue White Gene: atxn2l has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.3846 ATXN2L Sue White gene: ATXN2L was added
gene: ATXN2L was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: ATXN2L was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ATXN2L were set to 33283965; 33057194
Phenotypes for gene: ATXN2L were set to macrocephaly; intellectual disability
Penetrance for gene: ATXN2L were set to Complete
Review for gene: ATXN2L was set to AMBER
Added comment: Combined data from three large exome groups identified several de novo variants, including frameshift and missense, in ATXN2L in patients with developmental delay (Kaplanis et al., 2020). pLI=1.0
Single case report of a novel de novo missense variant in a child with macrocephaly and developmental delay. No functional work.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.3845 BCAS3 Paul De Fazio gene: BCAS3 was added
gene: BCAS3 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: BCAS3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BCAS3 were set to 34022130
Phenotypes for gene: BCAS3 were set to Syndromic neurodevelopmental disorder
Review for gene: BCAS3 was set to GREEN
gene: BCAS3 was marked as current diagnostic
Added comment: 15 individuals from eight unrelated families with germline bi-allelic loss-of-function variants in BCAS3. All probands share a global developmental delay accompanied by pyramidal tract involvement, microcephaly, short stature, strabismus, dysmorphic facial features, and seizures. Patient fibroblasts confirmed absence of BCAS3 protein.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.3845 SRCAP Paul De Fazio changed review comment from: Truncating variants in exons 33 and 34 of the SNF2-related CREBBP activator protein (SRCAP) gene cause the neurodevelopmental disorder Floating-Harbor syndrome (FLHS).

A cohort of 33 individuals with mostly de novo truncating variants both proximal and distal to the FLHS locus were found to have a distinct phenotype and DNA methylation pattern to FLHS.; to: Truncating variants in exons 33 and 34 of the SNF2-related CREBBP activator protein (SRCAP) gene cause the neurodevelopmental disorder (NDD) Floating-Harbor syndrome (FLHS).

A cohort of 33 individuals with mostly de novo truncating variants both proximal and distal to the FLHS locus were found to have a distinct phenotype and DNA methylation pattern to FLHS, referred to by the authors as "non-FLHS SRCAP-related NDD".
Intellectual disability syndromic and non-syndromic v0.3845 SRCAP Paul De Fazio reviewed gene: SRCAP: Rating: GREEN; Mode of pathogenicity: None; Publications: 33909990; Phenotypes: Floating-Harbor syndrome MIM#136140; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Intellectual disability syndromic and non-syndromic v0.3845 SYT1 Zornitza Stark reviewed gene: SYT1: Rating: GREEN; Mode of pathogenicity: None; Publications: 30107533; Phenotypes: Baker-Gordon syndrome, MIM# 618218, MONDO:0033864; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3845 SYT1 Zornitza Stark Phenotypes for gene: SYT1 were changed from Baker-Gordon syndrome; OMIM #618218 to Baker-Gordon syndrome, MIM# 618218; MONDO:0033864
Intellectual disability syndromic and non-syndromic v0.3844 UBTF Zornitza Stark Marked gene: UBTF as ready
Intellectual disability syndromic and non-syndromic v0.3844 UBTF Zornitza Stark Gene: ubtf has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3844 UBTF Zornitza Stark Phenotypes for gene: UBTF were changed from to Neurodegeneration, childhood-onset, with brain atrophy, MIM# 617672; MONDO:0044701
Intellectual disability syndromic and non-syndromic v0.3843 UBTF Zornitza Stark Publications for gene: UBTF were set to
Intellectual disability syndromic and non-syndromic v0.3842 UBTF Zornitza Stark Mode of inheritance for gene: UBTF was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3841 UBTF Zornitza Stark reviewed gene: UBTF: Rating: GREEN; Mode of pathogenicity: None; Publications: 28777933, 29300972; Phenotypes: Neurodegeneration, childhood-onset, with brain atrophy, MIM# 617672, MONDO:0044701; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3841 ZEB2 Zornitza Stark Phenotypes for gene: ZEB2 were changed from Mowat-Wilson syndrome (MIM#235730) to Mowat-Wilson syndrome, MIM# 235730; MONDO:0009341
Intellectual disability syndromic and non-syndromic v0.3840 ZEB2 Zornitza Stark Tag SV/CNV tag was added to gene: ZEB2.
Intellectual disability syndromic and non-syndromic v0.3840 ZEB2 Zornitza Stark edited their review of gene: ZEB2: Changed phenotypes: Mowat-Wilson syndrome, MIM# 235730, MONDO:0009341
Intellectual disability syndromic and non-syndromic v0.3840 SLC9A6 Zornitza Stark Marked gene: SLC9A6 as ready
Intellectual disability syndromic and non-syndromic v0.3840 SLC9A6 Zornitza Stark Gene: slc9a6 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3840 SLC9A6 Zornitza Stark Phenotypes for gene: SLC9A6 were changed from to Mental retardation, X-linked syndromic, Christianson type, MIM# 300243; MONDO:0010278
Intellectual disability syndromic and non-syndromic v0.3839 SLC9A6 Zornitza Stark Publications for gene: SLC9A6 were set to
Intellectual disability syndromic and non-syndromic v0.3838 SLC9A6 Zornitza Stark Mode of inheritance for gene: SLC9A6 was changed from Unknown to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability syndromic and non-syndromic v0.3837 SLC9A6 Zornitza Stark reviewed gene: SLC9A6: Rating: GREEN; Mode of pathogenicity: None; Publications: 18342287, 19377476, 25044251, 33278113, 32569089, 31879735; Phenotypes: Mental retardation, X-linked syndromic, Christianson type, MIM# 300243, MONDO:0010278; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability syndromic and non-syndromic v0.3837 SHANK3 Zornitza Stark Marked gene: SHANK3 as ready
Intellectual disability syndromic and non-syndromic v0.3837 SHANK3 Zornitza Stark Gene: shank3 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3837 SHANK3 Zornitza Stark Phenotypes for gene: SHANK3 were changed from to Phelan-McDermid syndrome, MIM# 606232; MONDO:0011652
Intellectual disability syndromic and non-syndromic v0.3836 SHANK3 Zornitza Stark Publications for gene: SHANK3 were set to
Intellectual disability syndromic and non-syndromic v0.3835 SHANK3 Zornitza Stark Mode of inheritance for gene: SHANK3 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3834 SHANK3 Zornitza Stark Tag SV/CNV tag was added to gene: SHANK3.
Intellectual disability syndromic and non-syndromic v0.3834 SHANK3 Zornitza Stark reviewed gene: SHANK3: Rating: GREEN; Mode of pathogenicity: None; Publications: 16284256, 17173049, 20186804, 22892527; Phenotypes: Phelan-McDermid syndrome, MIM# 606232, MONDO:0011652; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3834 SATB2 Zornitza Stark Marked gene: SATB2 as ready
Intellectual disability syndromic and non-syndromic v0.3834 SATB2 Zornitza Stark Gene: satb2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3834 SATB2 Zornitza Stark Phenotypes for gene: SATB2 were changed from to Glass syndrome, MIM# 612313; MONDO:0100147
Intellectual disability syndromic and non-syndromic v0.3833 SATB2 Zornitza Stark Publications for gene: SATB2 were set to
Intellectual disability syndromic and non-syndromic v0.3832 SATB2 Zornitza Stark Mode of inheritance for gene: SATB2 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3831 SATB2 Zornitza Stark reviewed gene: SATB2: Rating: GREEN; Mode of pathogenicity: None; Publications: 29023086, 28151491, 32446642; Phenotypes: Glass syndrome, MIM# 612313, MONDO:0100147; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3831 MEF2C Zornitza Stark Marked gene: MEF2C as ready
Intellectual disability syndromic and non-syndromic v0.3831 MEF2C Zornitza Stark Gene: mef2c has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3831 MEF2C Zornitza Stark Tag SV/CNV tag was added to gene: MEF2C.
Tag 5'UTR tag was added to gene: MEF2C.
Intellectual disability syndromic and non-syndromic v0.3831 MEF2C Zornitza Stark Phenotypes for gene: MEF2C were changed from to Mental retardation, stereotypic movements, epilepsy, and/or cerebral malformations, MIM# 613443; MONDO:0013266
Intellectual disability syndromic and non-syndromic v0.3830 MEF2C Zornitza Stark Publications for gene: MEF2C were set to
Intellectual disability syndromic and non-syndromic v0.3829 MEF2C Zornitza Stark Mode of inheritance for gene: MEF2C was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3828 MEF2C Zornitza Stark reviewed gene: MEF2C: Rating: GREEN; Mode of pathogenicity: None; Publications: 19876902, 19471318, 19592390, 19592390, 20513142, 34055696, 34022131; Phenotypes: Mental retardation, stereotypic movements, epilepsy, and/or cerebral malformations, MIM# 613443, MONDO:0013266 Edit; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3828 MBD5 Zornitza Stark edited their review of gene: MBD5: Changed phenotypes: Mental retardation, autosomal dominant 1, MIM# 156200, MONDO:0007974
Intellectual disability syndromic and non-syndromic v0.3828 MBD5 Zornitza Stark Marked gene: MBD5 as ready
Intellectual disability syndromic and non-syndromic v0.3828 MBD5 Zornitza Stark Gene: mbd5 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3828 MBD5 Zornitza Stark Tag SV/CNV tag was added to gene: MBD5.
Intellectual disability syndromic and non-syndromic v0.3828 MBD5 Zornitza Stark Phenotypes for gene: MBD5 were changed from to Mental retardation, autosomal dominant 1, MIM# 156200; MONDO:0007974
Intellectual disability syndromic and non-syndromic v0.3827 MBD5 Zornitza Stark Publications for gene: MBD5 were set to
Intellectual disability syndromic and non-syndromic v0.3826 MBD5 Zornitza Stark Mode of inheritance for gene: MBD5 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3825 MBD5 Zornitza Stark reviewed gene: MBD5: Rating: GREEN; Mode of pathogenicity: None; Publications: 18812405, 21981781, 23708187, 22726846, 33912662; Phenotypes: 18812405, 21981781, 23708187, 22726846, 33912662; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3825 IQSEC2 Zornitza Stark Marked gene: IQSEC2 as ready
Intellectual disability syndromic and non-syndromic v0.3825 IQSEC2 Zornitza Stark Gene: iqsec2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3825 IQSEC2 Zornitza Stark Phenotypes for gene: IQSEC2 were changed from to Mental retardation, X-linked 1/78, MIM# 309530, MONDO:0010656; Severe intellectual disability-progressive postnatal microcephaly- midline stereotypic hand movements syndrome MONDO:0018347
Intellectual disability syndromic and non-syndromic v0.3824 IQSEC2 Zornitza Stark Publications for gene: IQSEC2 were set to
Intellectual disability syndromic and non-syndromic v0.3823 IQSEC2 Zornitza Stark Mode of inheritance for gene: IQSEC2 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 v0.3822 IQSEC2 Zornitza Stark edited their review of gene: IQSEC2: Added comment: More than 20 unrelated families reported.; Changed publications: 31415821, 20473311, 30842726, 33368194, 23674175; Changed phenotypes: Mental retardation, X-linked 1/78, MIM# 309530, MONDO:0010656, Severe intellectual disability-progressive postnatal microcephaly- midline stereotypic hand movements syndrome MONDO:0018347
Intellectual disability syndromic and non-syndromic v0.3822 EHMT1 Zornitza Stark Phenotypes for gene: EHMT1 were changed from Kleefstra syndrome 1 (MIM#610253) to Kleefstra syndrome 1, MIM# 610253; MONDO:0027407
Intellectual disability syndromic and non-syndromic v0.3821 EHMT1 Zornitza Stark Publications for gene: EHMT1 were set to
Intellectual disability syndromic and non-syndromic v0.3820 EHMT1 Zornitza Stark edited their review of gene: EHMT1: Changed publications: 16826528, 19264732, 19293338, 22670143, 30448833
Intellectual disability syndromic and non-syndromic v0.3820 EHMT1 Zornitza Stark commented on gene: EHMT1: Well established gene-disease association. Deletions are common. Key features includeID/seizures/microcephaly/dysmorphism/congenital anomalies. More than 100 individuals reported.
Intellectual disability syndromic and non-syndromic v0.3820 EHMT1 Zornitza Stark edited their review of gene: EHMT1: Changed phenotypes: Kleefstra syndrome 1, MIM# 610253, MONDO:0027407
Intellectual disability syndromic and non-syndromic v0.3820 EEF1A2 Zornitza Stark Phenotypes for gene: EEF1A2 were changed from Epileptic encephalopathy, early infantile, 33, MIM# 616409; Mental retardation, autosomal dominant 38, MIM# 616393 to Mental retardation, autosomal dominant 38, MIM# 616393; MONDO:0014617; Developmental and epileptic encephalopathy 33, MIM# 616409; MONDO:0014625
Intellectual disability syndromic and non-syndromic v0.3819 EEF1A2 Zornitza Stark Publications for gene: EEF1A2 were set to 32160274
Intellectual disability syndromic and non-syndromic v0.3818 EEF1A2 Zornitza Stark edited their review of gene: EEF1A2: Changed phenotypes: Mental retardation, autosomal dominant 38, MIM# 616393, MONDO:0014617, Developmental and epileptic encephalopathy 33, MIM# 616409, MONDO:0014625
Intellectual disability syndromic and non-syndromic v0.3818 EEF1A2 Zornitza Stark edited their review of gene: EEF1A2: Changed publications: 24697219, 32196822, 32160274, 32062104, 31893083
Intellectual disability syndromic and non-syndromic v0.3818 MASP1 Zornitza Stark Marked gene: MASP1 as ready
Intellectual disability syndromic and non-syndromic v0.3818 MASP1 Zornitza Stark Gene: masp1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3818 MASP1 Zornitza Stark Phenotypes for gene: MASP1 were changed from to 3MC syndrome 1, MIM# 257920; MONDO:0009770
Intellectual disability syndromic and non-syndromic v0.3817 MASP1 Zornitza Stark Publications for gene: MASP1 were set to
Intellectual disability syndromic and non-syndromic v0.3816 MASP1 Zornitza Stark Mode of inheritance for gene: MASP1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3815 MASP1 Zornitza Stark reviewed gene: MASP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 26789649, 21258343, 21035106; Phenotypes: 3MC syndrome 1, MIM# 257920, MONDO:0009770; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3815 BRPF1 Zornitza Stark Marked gene: BRPF1 as ready
Intellectual disability syndromic and non-syndromic v0.3815 BRPF1 Zornitza Stark Gene: brpf1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3815 BRPF1 Zornitza Stark Phenotypes for gene: BRPF1 were changed from to Intellectual developmental disorder with dysmorphic facies and ptosis, MIM# 617333; MONDO:0015022
Intellectual disability syndromic and non-syndromic v0.3814 BRPF1 Zornitza Stark Publications for gene: BRPF1 were set to
Intellectual disability syndromic and non-syndromic v0.3813 BRPF1 Zornitza Stark Mode of inheritance for gene: BRPF1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3812 BRPF1 Zornitza Stark reviewed gene: BRPF1: Rating: GREEN; Mode of pathogenicity: None; Publications: 27939640, 27939639, 32652122; Phenotypes: Intellectual developmental disorder with dysmorphic facies and ptosis, MIM# 617333, MONDO:0015022; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3812 POGZ Zornitza Stark Marked gene: POGZ as ready
Intellectual disability syndromic and non-syndromic v0.3812 POGZ Zornitza Stark Gene: pogz has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3812 POGZ Zornitza Stark Phenotypes for gene: POGZ were changed from to White-Sutton syndrome, MIM# 616364; MONDO:0014606
Intellectual disability syndromic and non-syndromic v0.3811 POGZ Zornitza Stark Publications for gene: POGZ were set to
Intellectual disability syndromic and non-syndromic v0.3810 POGZ Zornitza Stark Mode of inheritance for gene: POGZ was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3809 POGZ Zornitza Stark reviewed gene: POGZ: Rating: GREEN; Mode of pathogenicity: None; Publications: 33098347, 31782611, 26942287; Phenotypes: White-Sutton syndrome, MIM# 616364, MONDO:0014606; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3809 UBE3B Zornitza Stark Marked gene: UBE3B as ready
Intellectual disability syndromic and non-syndromic v0.3809 UBE3B Zornitza Stark Gene: ube3b has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3809 UBE3B Zornitza Stark Phenotypes for gene: UBE3B were changed from to Kaufman oculocerebrofacial syndrome, MIM# 244450; MONDO:0009485
Intellectual disability syndromic and non-syndromic v0.3808 UBE3B Zornitza Stark Publications for gene: UBE3B were set to
Intellectual disability syndromic and non-syndromic v0.3807 UBE3B Zornitza Stark Mode of inheritance for gene: UBE3B was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3806 UBE3B Zornitza Stark reviewed gene: UBE3B: Rating: GREEN; Mode of pathogenicity: None; Publications: 23200864, 23200864, 34012380, 32949109; Phenotypes: Kaufman oculocerebrofacial syndrome, MIM# 244450, MONDO:0009485; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3806 TAF6 Zornitza Stark Marked gene: TAF6 as ready
Intellectual disability syndromic and non-syndromic v0.3806 TAF6 Zornitza Stark Gene: taf6 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3806 TAF6 Zornitza Stark Phenotypes for gene: TAF6 were changed from Alazami-Yuan syndrome, MIM# 617126 to Alazami-Yuan syndrome, MIM# 617126
Intellectual disability syndromic and non-syndromic v0.3806 TAF6 Zornitza Stark Phenotypes for gene: TAF6 were changed from to Alazami-Yuan syndrome, MIM# 617126
Intellectual disability syndromic and non-syndromic v0.3805 TAF6 Zornitza Stark Publications for gene: TAF6 were set to
Intellectual disability syndromic and non-syndromic v0.3804 TAF6 Zornitza Stark Mode of inheritance for gene: TAF6 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3803 TAF6 Zornitza Stark reviewed gene: TAF6: Rating: GREEN; Mode of pathogenicity: None; Publications: 25558065, 25574841, 32030742; Phenotypes: Alazami-Yuan syndrome, MIM# 617126; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3803 PSMC3 Zornitza Stark Marked gene: PSMC3 as ready
Intellectual disability syndromic and non-syndromic v0.3803 PSMC3 Zornitza Stark Gene: psmc3 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.3803 PSMC3 Zornitza Stark Classified gene: PSMC3 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.3803 PSMC3 Zornitza Stark Gene: psmc3 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.3802 PSMC3 Zornitza Stark gene: PSMC3 was added
gene: PSMC3 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: PSMC3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PSMC3 were set to 32500975
Phenotypes for gene: PSMC3 were set to Deafness, cataract, impaired intellectual development, and polyneuropathy, MIM#619354
Review for gene: PSMC3 was set to AMBER
Added comment: Three affected individuals from a single consanguineous family reported with homozygous intronic variant. Animal model.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.3801 GEMIN5 Zornitza Stark Marked gene: GEMIN5 as ready
Intellectual disability syndromic and non-syndromic v0.3801 GEMIN5 Zornitza Stark Gene: gemin5 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3801 GEMIN5 Zornitza Stark Classified gene: GEMIN5 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.3801 GEMIN5 Zornitza Stark Gene: gemin5 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3800 GEMIN5 Zornitza Stark gene: GEMIN5 was added
gene: GEMIN5 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: GEMIN5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GEMIN5 were set to 33963192
Phenotypes for gene: GEMIN5 were set to Neurodevelopmental disorder with cerebellar atrophy and motor dysfunction, MIM# 619333
Review for gene: GEMIN5 was set to GREEN
Added comment: Neurodevelopmental disorder with cerebellar atrophy and motor dysfunction (NEDCAM) is an autosomal recessive disorder characterized by global developmental delay with prominent motor abnormalities, mainly axial hypotonia, gait ataxia, and appendicular spasticity. Affected individuals have cognitive impairment and speech delay; brain imaging shows cerebellar atrophy.

30 individuals from 22 unrelated families reported.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.3799 NSF Zornitza Stark Phenotypes for gene: NSF were changed from Seizures; EEG with burst suppression; Global developmental delay; Intellectual disability to Developmental and epileptic encephalopathy 96, MIM# 619340; Seizures; EEG with burst suppression; Global developmental delay; Intellectual disability
Intellectual disability syndromic and non-syndromic v0.3798 NSF Zornitza Stark edited their review of gene: NSF: Changed phenotypes: Developmental and epileptic encephalopathy 96, MIM# 619340, Seizures, EEG with burst suppression, Global developmental delay, Intellectual disability
Intellectual disability syndromic and non-syndromic v0.3798 NFU1 Zornitza Stark Marked gene: NFU1 as ready
Intellectual disability syndromic and non-syndromic v0.3798 NFU1 Zornitza Stark Gene: nfu1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3798 NFU1 Zornitza Stark Phenotypes for gene: NFU1 were changed from to Multiple mitochondrial dysfunctions syndrome 1, MIM# 605711
Intellectual disability syndromic and non-syndromic v0.3797 NFU1 Zornitza Stark Publications for gene: NFU1 were set to
Intellectual disability syndromic and non-syndromic v0.3796 NFU1 Zornitza Stark Mode of inheritance for gene: NFU1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3795 NFU1 Zornitza Stark reviewed gene: NFU1: Rating: GREEN; Mode of pathogenicity: None; Publications: 21944046, 22077971, 32747156, 29441221; Phenotypes: Multiple mitochondrial dysfunctions syndrome 1, MIM# 605711; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3795 RAB11B Zornitza Stark Marked gene: RAB11B as ready
Intellectual disability syndromic and non-syndromic v0.3795 RAB11B Zornitza Stark Gene: rab11b has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3795 RAB11B Zornitza Stark Phenotypes for gene: RAB11B were changed from to Neurodevelopmental disorder with ataxic gait, absent speech, and decreased cortical white matter 617807
Intellectual disability syndromic and non-syndromic v0.3794 RAB11B Zornitza Stark Publications for gene: RAB11B were set to
Intellectual disability syndromic and non-syndromic v0.3793 RAB11B Zornitza Stark Mode of inheritance for gene: RAB11B was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3792 RAB11B Zornitza Stark reviewed gene: RAB11B: Rating: GREEN; Mode of pathogenicity: None; Publications: 29106825; Phenotypes: Neurodevelopmental disorder with ataxic gait, absent speech, and decreased cortical white matter 617807; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3792 UFSP2 Zornitza Stark Classified gene: UFSP2 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.3792 UFSP2 Zornitza Stark Gene: ufsp2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3791 UFSP2 Zornitza Stark Deleted their comment
Intellectual disability syndromic and non-syndromic v0.3791 UFSP2 Zornitza Stark edited their review of gene: UFSP2: Added comment: Additional cases identified in 100,000 Genomes project.; Changed rating: GREEN; Changed phenotypes: Abnormal muscle tone, Seizures, Global developmental delay, Delayed speech and language development, Intellectual disability, Strabismus; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3791 ADNP Zornitza Stark Marked gene: ADNP as ready
Intellectual disability syndromic and non-syndromic v0.3791 ADNP Zornitza Stark Gene: adnp has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3791 ADNP Zornitza Stark Phenotypes for gene: ADNP were changed from to Helsmoortel-van der Aa syndrome MIM#615873; MONDO:0014379
Intellectual disability syndromic and non-syndromic v0.3790 ADNP Zornitza Stark Publications for gene: ADNP were set to
Intellectual disability syndromic and non-syndromic v0.3789 ADNP Zornitza Stark Mode of inheritance for gene: ADNP was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3788 ADNP Zornitza Stark reviewed gene: ADNP: Rating: GREEN; Mode of pathogenicity: None; Publications: 24531329, 25057125, 25533962, 29724491, 29911927; Phenotypes: Helsmoortel-van der Aa syndrome MIM#615873, MONDO:0014379; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3788 PARP6 Zornitza Stark Marked gene: PARP6 as ready
Intellectual disability syndromic and non-syndromic v0.3788 PARP6 Zornitza Stark Gene: parp6 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3788 PARP6 Zornitza Stark Classified gene: PARP6 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.3788 PARP6 Zornitza Stark Gene: parp6 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3787 PARP6 Zornitza Stark gene: PARP6 was added
gene: PARP6 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: PARP6 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PARP6 were set to Cells 2021, 10(6), 1289; https://doi.org/10.3390/cells10061289
Phenotypes for gene: PARP6 were set to Intellectual disability; Epilepsy; Microcephaly
Review for gene: PARP6 was set to GREEN
Added comment: Four unrelated individuals reported with de novo variants in this gene and a neurodevelopmental phenotype. Supportive functional data. One pair of siblings with a homozygous missense: limited evidence for bi-allelic variants causing disease.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.3786 UFSP2 Konstantinos Varvagiannis changed review comment from: Ni et al (2021 - PMID: 33473208) describe the phenotype of 8 children (belonging to 4 families - 2 of which consanguineous) homozygous for a UFSP2 missense variant [NM_018359.5:c.344T>A; p.(Val115Glu)].

Members of a broader consanguineous pedigree from Pakistan with 3 affected children with epilepsy and DD and ID underwent exome sequencing. All affected individuals were homozygous for the specific SNV with their parents (2 parent pairs, in both cases first cousins) being heterozygous. An unaffected sib was homozygous for the wt allele. Through genematching platforms 3 additional families with similarly affected individuals and homozygosity for the same variant were recruited. These additional families were from Pakistan (1/3) and Afganistan (2/3).

Based on ROH analysis from the broader first pedigree and an additional family the authors concluded on a single shared region of homozygosity on chr 4q. Lack of ES data did not allow verification of whether 2/4 families shared the same haplotype with the other 2.

The authors calculated the probability of the genotype-phenotype cosegragation occurring by chance (0.009) and this was lower than the recommended criterion (0.06) for strong evidence of pathogenicity.

Shared features included abnormal tone in most (hypotonia 6/8, limb hypertonia 1/8), seizures (8/8 - onset 2d - 7m), severe DD with speech delay/absent speech (8/8), ID (8/8), strabismus (6/8).

UFSP2 encodes UFM1-specific protease 2 involved in UFmylation, a post-translational protein modification. As summarized by the authors the cysteine protease encoded by this gene (as is also the case for UFSP1) cleaves UFM1 in the initial step of UFMylation. Apart from producing mature UFM1, the 2 proteases have also the ability to release UFM1 from UFMylated proteins, in the process of de-UFMylation. [several refs. provided]

UFMylation is important in brain development with mutations in genes encoding other components of the pathway reported in other NDD disorders (incl. UFM1, UBA5, UFC1).

Additional studies were carried to provide evidence for pathogenicity of this variant.

Skin biopsies from 3 individuals were carried out to establish fibroblast cultures. Immunoblotting revealed reduced UFSP2 levels relative to controls. mRNA levels measured by qRT-PCR revealed no differences compared to controls altogether suggesting normal mRNA but reduced protein stability.

The authors demonstrated increased levels of UFM1-conjugated proteins (incl. DDRGK1, or TRIP4). Ectopic expression of wt UFSP2 normalized the levels of UFMylated proteins in the fibroblasts which was not the case for the V115E variant. Further the variant was difficult to detect by immunoblotting consistent with an effect on protein destabilization.

Although disruption of UFMylation induces ER stress, this was not shown to occur in patient fibroblast lines, when assessed for ER stress markers.

Evaluation of data from the GTEx project, concerning UFSP2 as well as well as DDRGK1 or TRIP4 - an UFMylation target - revealed relevant expression in multiple regions of the human brain.

Overall the authors provide evidence for defective de-UFMylation in patient fibroblasts (presence of increased UFMylation marks). The authors stress out that the effect of the variant in UFMylation in brain is unknown, as UFSP1 or other enzymes might compensate in the presence of hypomorphic UFSP2 mutants.

Biallelic UFSP2 variants have previously been reported in 2 skeletal dysplasias [# 142669. BEUKES HIP DYSPLASIA; BHD and # 617974. SPONDYLOEPIMETAPHYSEAL DYSPLASIA, DI ROCCO TYPE; SEMDDR]. These disorders are not characterized by neurological dysfunction or epilepsy. The authors underscore the fact that variants identified in these disorders (Y290H, D526A, H428R) localize within the C-terminal catalytic (peptidase) domain [aa 278 – 461] while the variant here identified lies in the N-terminal substrate binding domain affecting protein stability/abundance.

In OMIM, only the 2 aforementioned disorders are currently associated with biallelic UFSP2 mutations. There is no associated phenotype in G2P. SysID includes UFSP2 among the primary ID genes.

You may consider inclusion in the current panel with amber/green rating.
Sources: Literature; to: Ni et al (2021 - PMID: 33473208) describe the phenotype of 8 children (belonging to 4 families - 2 of which consanguineous) homozygous for a UFSP2 missense variant [NM_018359.5:c.344T>A; p.(Val115Glu)].

Members of a broader consanguineous pedigree from Pakistan with 3 affected children with epilepsy and DD and ID underwent exome sequencing. All affected individuals were homozygous for the specific SNV with their parents (2 parent pairs, in both cases first cousins) being heterozygous. An unaffected sib was homozygous for the wt allele. Through genematching platforms 3 additional families with similarly affected individuals and homozygosity for the same variant were recruited. These additional families were from Pakistan (1/3) and Afganistan (2/3).

Based on ROH analysis from the broader first pedigree and an additional family the authors concluded on a single shared region of homozygosity on chr 4q. Lack of ES data did not allow verification of whether 2/4 families shared the same haplotype with the other 2.

The authors calculated the probability of the genotype-phenotype cosegragation occurring by chance (0.009) and this was lower than the recommended criterion (0.06) for strong evidence of pathogenicity.

Shared features included abnormal tone in most (hypotonia 6/8, limb hypertonia 1/8), seizures (8/8 - onset 2d - 7m), severe DD with speech delay/absent speech (8/8), ID (8/8), strabismus (6/8).

UFSP2 encodes UFM1-specific protease 2 involved in UFmylation, a post-translational protein modification. As summarized by the authors the cysteine protease encoded by this gene (as is also the case for UFSP1) cleaves UFM1 in the initial step of UFMylation. Apart from producing mature UFM1, the 2 proteases have also the ability to release UFM1 from UFMylated proteins, in the process of de-UFMylation. [several refs. provided]

UFMylation is important in brain development with mutations in genes encoding other components of the pathway reported in other NDD disorders (incl. UFM1, UBA5, UFC1).

Additional studies were carried to provide evidence for pathogenicity of this variant.

Skin biopsies from 3 individuals were carried out to establish fibroblast cultures. Immunoblotting revealed reduced UFSP2 levels relative to controls. mRNA levels measured by qRT-PCR revealed no differences compared to controls altogether suggesting normal mRNA but reduced protein stability.

The authors demonstrated increased levels of UFM1-conjugated proteins (incl. DDRGK1, or TRIP4). Ectopic expression of wt UFSP2 normalized the levels of UFMylated proteins in the fibroblasts which was not the case for the V115E variant. Further the variant was difficult to detect by immunoblotting consistent with an effect on protein destabilization.

Although disruption of UFMylation induces ER stress, this was not shown to occur in patient fibroblast lines, when assessed for ER stress markers.

Evaluation of data from the GTEx project, concerning UFSP2 as well as well as DDRGK1 or TRIP4 - an UFMylation target - revealed relevant expression in multiple regions of the human brain.

Overall the authors provide evidence for defective de-UFMylation in patient fibroblasts (presence of increased UFMylation marks). The authors stress out that the effect of the variant in UFMylation in brain is unknown, as UFSP1 or other enzymes might compensate in the presence of hypomorphic UFSP2 mutants.

**Monoallelic** (correction to previous review) UFSP2 variants have previously been reported in 2 skeletal dysplasias [# 142669. BEUKES HIP DYSPLASIA; BHD and # 617974. SPONDYLOEPIMETAPHYSEAL DYSPLASIA, DI ROCCO TYPE; SEMDDR]. These disorders are not characterized by neurological dysfunction or epilepsy. The authors underscore the fact that variants identified in these disorders (Y290H, D526A, H428R) localize within the C-terminal catalytic (peptidase) domain [aa 278 – 461] while the variant here identified lies in the N-terminal substrate binding domain affecting protein stability/abundance.

In OMIM, only the 2 aforementioned disorders are currently associated with biallelic UFSP2 mutations. There is no associated phenotype in G2P. SysID includes UFSP2 among the primary ID genes.

You may consider inclusion in the current panel with amber/green rating.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.3786 UFSP2 Zornitza Stark Marked gene: UFSP2 as ready
Intellectual disability syndromic and non-syndromic v0.3786 UFSP2 Zornitza Stark Added comment: Comment when marking as ready: Amber rating as single, likely founder variant.
Intellectual disability syndromic and non-syndromic v0.3786 UFSP2 Zornitza Stark Gene: ufsp2 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.3786 UFSP2 Zornitza Stark Tag founder tag was added to gene: UFSP2.
Intellectual disability syndromic and non-syndromic v0.3786 UFSP2 Zornitza Stark Classified gene: UFSP2 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.3786 UFSP2 Zornitza Stark Gene: ufsp2 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.3785 UFSP2 Konstantinos Varvagiannis gene: UFSP2 was added
gene: UFSP2 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: UFSP2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: UFSP2 were set to 33473208
Phenotypes for gene: UFSP2 were set to Abnormal muscle tone; Seizures; Global developmental delay; Delayed speech and language development; Intellectual disability; Strabismus
Penetrance for gene: UFSP2 were set to Complete
Review for gene: UFSP2 was set to AMBER
Added comment: Ni et al (2021 - PMID: 33473208) describe the phenotype of 8 children (belonging to 4 families - 2 of which consanguineous) homozygous for a UFSP2 missense variant [NM_018359.5:c.344T>A; p.(Val115Glu)].

Members of a broader consanguineous pedigree from Pakistan with 3 affected children with epilepsy and DD and ID underwent exome sequencing. All affected individuals were homozygous for the specific SNV with their parents (2 parent pairs, in both cases first cousins) being heterozygous. An unaffected sib was homozygous for the wt allele. Through genematching platforms 3 additional families with similarly affected individuals and homozygosity for the same variant were recruited. These additional families were from Pakistan (1/3) and Afganistan (2/3).

Based on ROH analysis from the broader first pedigree and an additional family the authors concluded on a single shared region of homozygosity on chr 4q. Lack of ES data did not allow verification of whether 2/4 families shared the same haplotype with the other 2.

The authors calculated the probability of the genotype-phenotype cosegragation occurring by chance (0.009) and this was lower than the recommended criterion (0.06) for strong evidence of pathogenicity.

Shared features included abnormal tone in most (hypotonia 6/8, limb hypertonia 1/8), seizures (8/8 - onset 2d - 7m), severe DD with speech delay/absent speech (8/8), ID (8/8), strabismus (6/8).

UFSP2 encodes UFM1-specific protease 2 involved in UFmylation, a post-translational protein modification. As summarized by the authors the cysteine protease encoded by this gene (as is also the case for UFSP1) cleaves UFM1 in the initial step of UFMylation. Apart from producing mature UFM1, the 2 proteases have also the ability to release UFM1 from UFMylated proteins, in the process of de-UFMylation. [several refs. provided]

UFMylation is important in brain development with mutations in genes encoding other components of the pathway reported in other NDD disorders (incl. UFM1, UBA5, UFC1).

Additional studies were carried to provide evidence for pathogenicity of this variant.

Skin biopsies from 3 individuals were carried out to establish fibroblast cultures. Immunoblotting revealed reduced UFSP2 levels relative to controls. mRNA levels measured by qRT-PCR revealed no differences compared to controls altogether suggesting normal mRNA but reduced protein stability.

The authors demonstrated increased levels of UFM1-conjugated proteins (incl. DDRGK1, or TRIP4). Ectopic expression of wt UFSP2 normalized the levels of UFMylated proteins in the fibroblasts which was not the case for the V115E variant. Further the variant was difficult to detect by immunoblotting consistent with an effect on protein destabilization.

Although disruption of UFMylation induces ER stress, this was not shown to occur in patient fibroblast lines, when assessed for ER stress markers.

Evaluation of data from the GTEx project, concerning UFSP2 as well as well as DDRGK1 or TRIP4 - an UFMylation target - revealed relevant expression in multiple regions of the human brain.

Overall the authors provide evidence for defective de-UFMylation in patient fibroblasts (presence of increased UFMylation marks). The authors stress out that the effect of the variant in UFMylation in brain is unknown, as UFSP1 or other enzymes might compensate in the presence of hypomorphic UFSP2 mutants.

Biallelic UFSP2 variants have previously been reported in 2 skeletal dysplasias [# 142669. BEUKES HIP DYSPLASIA; BHD and # 617974. SPONDYLOEPIMETAPHYSEAL DYSPLASIA, DI ROCCO TYPE; SEMDDR]. These disorders are not characterized by neurological dysfunction or epilepsy. The authors underscore the fact that variants identified in these disorders (Y290H, D526A, H428R) localize within the C-terminal catalytic (peptidase) domain [aa 278 – 461] while the variant here identified lies in the N-terminal substrate binding domain affecting protein stability/abundance.

In OMIM, only the 2 aforementioned disorders are currently associated with biallelic UFSP2 mutations. There is no associated phenotype in G2P. SysID includes UFSP2 among the primary ID genes.

You may consider inclusion in the current panel with amber/green rating.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.3785 FAR1 Zornitza Stark Phenotypes for gene: FAR1 were changed from Peroxisomal fatty acyl-CoA reductase 1 disorder, MIM#616154; 33239752 to Peroxisomal fatty acyl-CoA reductase 1 disorder, MIM#616154; Cataracts, spastic paraparesis, and speech delay, MIM#619338
Intellectual disability syndromic and non-syndromic v0.3784 FAR1 Zornitza Stark edited their review of gene: FAR1: Changed phenotypes: Peroxisomal fatty acyl-CoA reductase 1 disorder, MIM#616154, Cataracts, spastic paraparesis, and speech delay, MIM#619338
Intellectual disability syndromic and non-syndromic v0.3784 BICRA Zornitza Stark Phenotypes for gene: BICRA were changed from Developmental delay, intellectual disability, autism spectrum disorder,behavioral abnormalities, dysmorphic features to Coffin-Siris syndrome-12, MIM#619325; Developmental delay, intellectual disability, autism spectrum disorder,behavioral abnormalities, dysmorphic features
Intellectual disability syndromic and non-syndromic v0.3783 BICRA Zornitza Stark reviewed gene: BICRA: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Coffin-Siris syndrome-12, MIM#619325; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3783 SBF1 Zornitza Stark Phenotypes for gene: SBF1 were changed from Charcot-Marie-Tooth disease, type 4B3, MIM# 615284 to Charcot-Marie-Tooth disease, type 4B3, MIM# 615284; MONDO:0014117
Intellectual disability syndromic and non-syndromic v0.3782 SBF1 Zornitza Stark edited their review of gene: SBF1: Changed phenotypes: Charcot-Marie-Tooth disease, type 4B3, MIM# 615284, MONDO:0014117
Intellectual disability syndromic and non-syndromic v0.3782 TBC1D2B Zornitza Stark Phenotypes for gene: TBC1D2B were changed from Global developmental delay; Intellectual disability; Seizures; Gingival overgrowth; Behavioral abnormality; Abnormality of the mandible; Abnormality of brain morphology; Abnormality of the eye; Hearing abnormality to Neurodevelopmental disorder with seizures and gingival overgrowth (NEDSGO), MIM#619323; Global developmental delay; Intellectual disability; Seizures; Gingival overgrowth; Behavioral abnormality; Abnormality of the mandible; Abnormality of brain morphology; Abnormality of the eye; Hearing abnormality
Intellectual disability syndromic and non-syndromic v0.3781 TBC1D2B Zornitza Stark reviewed gene: TBC1D2B: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with seizures and gingival overgrowth (NEDSGO), MIM#619323; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3781 SCN1A Zornitza Stark Marked gene: SCN1A as ready
Intellectual disability syndromic and non-syndromic v0.3781 SCN1A Zornitza Stark Gene: scn1a has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3781 SCN1A Zornitza Stark Phenotypes for gene: SCN1A were changed from to Epileptic encephalopathy, early infantile, 6 (Dravet syndrome) 607208 Developmental and epileptic encephalopathy 6B, non-Dravet, MIM# 619317
Intellectual disability syndromic and non-syndromic v0.3780 SCN1A Zornitza Stark reviewed gene: SCN1A: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Epileptic encephalopathy, early infantile, 6 (Dravet syndrome) 607208 Developmental and epileptic encephalopathy 6B, non-Dravet, MIM# 619317; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3780 KDM4B Zornitza Stark Phenotypes for gene: KDM4B were changed from Global developmental delay, intellectual disability and neuroanatomical defects to Intellectual developmental disorder, autosomal dominant 65, MIM# 619320; Global developmental delay, intellectual disability and neuroanatomical defects
Intellectual disability syndromic and non-syndromic v0.3779 KDM4B Zornitza Stark reviewed gene: KDM4B: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Intellectual developmental disorder, autosomal dominant 65, MIM# 619320; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3779 THOC2 Zornitza Stark Marked gene: THOC2 as ready
Intellectual disability syndromic and non-syndromic v0.3779 THOC2 Zornitza Stark Gene: thoc2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3779 THOC2 Zornitza Stark Phenotypes for gene: THOC2 were changed from to Mental retardation, X-linked 12/35 MIM#300957
Intellectual disability syndromic and non-syndromic v0.3778 THOC2 Zornitza Stark Publications for gene: THOC2 were set to
Intellectual disability syndromic and non-syndromic v0.3777 THOC2 Zornitza Stark Mode of inheritance for gene: THOC2 was changed from Unknown to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability syndromic and non-syndromic v0.3776 THOC2 Paul De Fazio reviewed gene: THOC2: Rating: GREEN; Mode of pathogenicity: None; Publications: 26166480, 32116545, 29851191, 32960281; Phenotypes: Mental retardation, X-linked 12/35 MIM#300957; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females; Current diagnostic: yes
Intellectual disability syndromic and non-syndromic v0.3776 CPE Zornitza Stark Marked gene: CPE as ready
Intellectual disability syndromic and non-syndromic v0.3776 CPE Zornitza Stark Gene: cpe has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.3776 CPE Zornitza Stark Classified gene: CPE as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.3776 CPE Zornitza Stark Gene: cpe has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.3775 CPE Zornitza Stark gene: CPE was added
gene: CPE was added to Intellectual disability syndromic and non-syndromic. Sources: Expert list
Mode of inheritance for gene: CPE was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CPE were set to 26120850; 32936766
Phenotypes for gene: CPE were set to Intellectual developmental disorder and hypogonadotropic hypogonadism, MIM# 619326
Review for gene: CPE was set to AMBER
Added comment: Four affected individuals from two unrelated families reported, bi-allelic LoF variants.
Sources: Expert list
Intellectual disability syndromic and non-syndromic v0.3774 SIAH1 Zornitza Stark Phenotypes for gene: SIAH1 were changed from Developmental delay; Infantile hypotonia; Dysmorphic features; Laryngomalacia to Buratti-Harel syndrome, MIM# 619314; Developmental delay; Infantile hypotonia; Dysmorphic features; Laryngomalacia
Intellectual disability syndromic and non-syndromic v0.3773 SIAH1 Zornitza Stark edited their review of gene: SIAH1: Changed phenotypes: Buratti-Harel syndrome, MIM# 619314, Developmental delay, Infantile hypotonia, Dysmorphic features, Laryngomalacia
Intellectual disability syndromic and non-syndromic v0.3773 FBXW7 Zornitza Stark Marked gene: FBXW7 as ready
Intellectual disability syndromic and non-syndromic v0.3773 FBXW7 Zornitza Stark Gene: fbxw7 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3773 FBXW7 Zornitza Stark Classified gene: FBXW7 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.3773 FBXW7 Zornitza Stark Gene: fbxw7 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3772 SMARCA5 Zornitza Stark Marked gene: SMARCA5 as ready
Intellectual disability syndromic and non-syndromic v0.3772 SMARCA5 Zornitza Stark Gene: smarca5 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3772 SMARCA5 Zornitza Stark Classified gene: SMARCA5 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.3772 SMARCA5 Zornitza Stark Gene: smarca5 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3771 SMARCA5 Zornitza Stark gene: SMARCA5 was added
gene: SMARCA5 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: SMARCA5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SMARCA5 were set to 33980485
Phenotypes for gene: SMARCA5 were set to Neurodevelopmental disorder; microcephaly; dysmorphic features
Review for gene: SMARCA5 was set to GREEN
Added comment: 12 individuals reported with either de novo or appropriately segregating variants in this gene and mild developmental delay, frequent postnatal short stature and microcephaly, and recurrent dysmorphic features. Functional data supports gene-disease association.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.3770 FBXW7 Zornitza Stark gene: FBXW7 was added
gene: FBXW7 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: FBXW7 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FBXW7 were set to 33057194
Phenotypes for gene: FBXW7 were set to FBXW7-related neurodevelopmental syndrome
Review for gene: FBXW7 was set to GREEN
Added comment: PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio developmental disorder study. 12 de novo missense and 1 de novo synonymous variant identified in ~10,000 cases with developmental disorders (no other phenotype info provided).

We are aware of additional cases pending publication.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.3769 SPG11 Zornitza Stark Marked gene: SPG11 as ready
Intellectual disability syndromic and non-syndromic v0.3769 SPG11 Zornitza Stark Gene: spg11 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3769 SPG11 Zornitza Stark Phenotypes for gene: SPG11 were changed from to Spastic paraplegia 11, autosomal recessive 604360
Intellectual disability syndromic and non-syndromic v0.3768 SPG11 Zornitza Stark Publications for gene: SPG11 were set to
Intellectual disability syndromic and non-syndromic v0.3767 SPG11 Zornitza Stark Mode of inheritance for gene: SPG11 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3766 SPG11 Zornitza Stark reviewed gene: SPG11: Rating: GREEN; Mode of pathogenicity: None; Publications: 33581793; Phenotypes: Spastic paraplegia 11, autosomal recessive 604360; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3766 SPTAN1 Zornitza Stark Marked gene: SPTAN1 as ready
Intellectual disability syndromic and non-syndromic v0.3766 SPTAN1 Zornitza Stark Gene: sptan1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3766 SPTAN1 Zornitza Stark Phenotypes for gene: SPTAN1 were changed from to Developmental and epileptic encephalopathy 5, MIM# 613477
Intellectual disability syndromic and non-syndromic v0.3765 SPTAN1 Zornitza Stark Publications for gene: SPTAN1 were set to
Intellectual disability syndromic and non-syndromic v0.3764 SPTAN1 Zornitza Stark Mode of inheritance for gene: SPTAN1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3763 SPTAN1 Zornitza Stark reviewed gene: SPTAN1: Rating: GREEN; Mode of pathogenicity: None; Publications: 20493457, 22258530, 32811770; Phenotypes: Developmental and epileptic encephalopathy 5, MIM# 613477; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3763 SPEN Zornitza Stark Publications for gene: SPEN were set to 33057194
Intellectual disability syndromic and non-syndromic v0.3762 SPEN Zornitza Stark Phenotypes for gene: SPEN were changed from Intellectual disability; autism; congenital anomalies to Radio-Tartaglia syndrome, MIM# 619312; Intellectual disability; autism; congenital anomalies
Intellectual disability syndromic and non-syndromic v0.3761 AFF3 Zornitza Stark Marked gene: AFF3 as ready
Intellectual disability syndromic and non-syndromic v0.3761 AFF3 Zornitza Stark Gene: aff3 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3761 AFF3 Zornitza Stark Phenotypes for gene: AFF3 were changed from to KINSSHIP syndrome, MIM# 619297
Intellectual disability syndromic and non-syndromic v0.3760 AFF3 Zornitza Stark Publications for gene: AFF3 were set to
Intellectual disability syndromic and non-syndromic v0.3759 AFF3 Zornitza Stark Mode of inheritance for gene: AFF3 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3758 AFF3 Zornitza Stark reviewed gene: AFF3: Rating: GREEN; Mode of pathogenicity: None; Publications: 31388108, 33961779; Phenotypes: KINSSHIP syndrome, MIM# 619297; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3758 RALA Zornitza Stark Phenotypes for gene: RALA were changed from Intellectual disability; short stature; dysmorphism to Hiatt-Neu-Cooper neurodevelopmental syndrome, MIM# 619311; Intellectual disability; short stature; dysmorphism
Intellectual disability syndromic and non-syndromic v0.3757 RALA Zornitza Stark edited their review of gene: RALA: Changed phenotypes: Hiatt-Neu-Cooper neurodevelopmental syndrome, MIM# 619311, Intellectual disability, short stature, dysmorphism
Intellectual disability syndromic and non-syndromic v0.3757 CAPN15 Zornitza Stark Marked gene: CAPN15 as ready
Intellectual disability syndromic and non-syndromic v0.3757 CAPN15 Zornitza Stark Gene: capn15 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3757 CAPN15 Zornitza Stark Classified gene: CAPN15 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.3757 CAPN15 Zornitza Stark Gene: capn15 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3756 CAPN15 Zornitza Stark gene: CAPN15 was added
gene: CAPN15 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: CAPN15 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CAPN15 were set to 33410501; 32885237
Phenotypes for gene: CAPN15 were set to Oculogastrointestinal neurodevelopmental syndrome, MIM# 619318
Review for gene: CAPN15 was set to GREEN
Added comment: 5 families reported, including DD/ID in 3. Profound in one family with bi-allelic LoF variant, PMID 33410501.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.3755 EXOC2 Zornitza Stark Phenotypes for gene: EXOC2 were changed from Global developmental delay; Intellectual disability; Abnormality of the face; Abnormality of brain morphology to Neurodevelopmental disorder with dysmorphic facies and cerebellar hypoplasia, MIM# 619306; Global developmental delay; Intellectual disability; Abnormality of the face; Abnormality of brain morphology
Intellectual disability syndromic and non-syndromic v0.3754 EXOC2 Zornitza Stark reviewed gene: EXOC2: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with dysmorphic facies and cerebellar hypoplasia, MIM# 619306; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3754 TMEM222 Zornitza Stark Classified gene: TMEM222 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.3754 TMEM222 Zornitza Stark Gene: tmem222 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3753 TMEM222 Konstantinos Varvagiannis gene: TMEM222 was added
gene: TMEM222 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: TMEM222 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TMEM222 were set to 33824500
Phenotypes for gene: TMEM222 were set to Motor delay; Delayed speech and language development; Intellectual disability; Generalized hypotonia; Broad-based gait; Abnormality of nervous system morphology; Seizures; Microcephaly; Behavioral abnormality
Penetrance for gene: TMEM222 were set to Complete
Review for gene: TMEM222 was set to GREEN
Added comment: Polla et al (2021 - PMID: 33824500) report 17 individuals from 9 unrelated families, with biallelic TMEM222 pathogenic variants.

The phenotype included motor, speech delay and moderate to severe ID (as universal features). Other manifestations included hypotonia (10/15), broad gait (5/12), seizures (7/17 - belonging to 6/9 families), MRI abnormalities (5/8). Variable behavioral abnormalities were observed (aggressive behavior, shy character, stereotypic movements etc). Abnormal OFC was a feature in several with microcephaly in 7 subjects from 4 families (measurements not available for all 17). Nonspecific facial features were reported in 10/17. Rare features incl. body tremors, decreased lower extremity muscle mass or disorder of motor neurons.

TMEM222 variants were identified following exome sequencing. Previous investigations incl. metabolic studies, FMR1, chromosomes by standard karyotype or CMA, SMA, CMT1A were reported to be normal (available for some individuals).

TMEM222 variants missense and pLoF ones mostly found in homozygosity (7/9 families were consanguineous, compound heterozygosity reported in a single case from the 9 families). Sanger sequencing was used for confirmation of variants, parental carrier state as well as testing of sibs (unaffected sibs tested in 4 families).

Few individuals had additional genetic findings in other genes, though classified as VUS (3 families).

The gene encodes transmembrane protein 222 (208 residues) which however has unknown function. The protein comprises 3 transmembrane domains and a domain of unknown function. TMEMs are a group of transmembrane proteins spanning membranes with - most commonly - unclear function.

The authors measured expression by qPCR mRNA analysis, demonstrating highest fetal and adult brain expression (incl. parietal and occipital cortex). Expression levels from GTEx data also support a role in neurodevelopment.

Immunocytochemistry revealed highest levels in mature human iPSC-derived glutaminergic cortical neurons and moderate in immature ones. Additional studies supported that the gene is highly expressed in dendrites and might play a role in postsynaptic vesicles (colocalization with postsynaptic and early endosomal markers).

A previous study by Riazuddin et al (2017 - PMID: 27457812) had identified TMEM222 as a candidate gene for ID. This family (PKMR213) however appears to be included as family 2 in the aforementioned publication (same pedigree, variant and phenotype in both articles).

In OMIM there is currently no associated phenotype.

The gene is listed among the primary ID genes in SysID.

Please consider inclusion in the ID panel with green (or amber) rating. This gene may also be included in other panels e.g. for epilepsy, microcephaly, etc.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.3753 CHD5 Zornitza Stark Marked gene: CHD5 as ready
Intellectual disability syndromic and non-syndromic v0.3753 CHD5 Zornitza Stark Gene: chd5 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3753 CHD5 Zornitza Stark Classified gene: CHD5 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.3753 CHD5 Zornitza Stark Gene: chd5 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3752 CHD5 Zornitza Stark gene: CHD5 was added
gene: CHD5 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: CHD5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CHD5 were set to 33944996
Phenotypes for gene: CHD5 were set to Intellectual disability; Epilepsy
Review for gene: CHD5 was set to GREEN
Added comment: 16 unrelated individuals reported with language deficits (81%), behavioral symptoms (69%), intellectual disability (64%), epilepsy (62%), and motor delay (56%).
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.3751 FBXO31 Zornitza Stark Phenotypes for gene: FBXO31 were changed from Mental retardation, autosomal recessive 45, MIM#615979; Cerebral palsy, intellectual disability, autosomal dominant to Mental retardation, autosomal recessive 45, MIM#615979; Spastic-dystonic cerebral palsy, de novo dominant
Intellectual disability syndromic and non-syndromic v0.3750 FBXO31 Zornitza Stark Publications for gene: FBXO31 were set to 24623383; 32989326
Intellectual disability syndromic and non-syndromic v0.3749 FBXO31 Zornitza Stark Mode of inheritance for gene: FBXO31 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3748 FBXO31 Zornitza Stark Classified gene: FBXO31 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.3748 FBXO31 Zornitza Stark Gene: fbxo31 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3747 FBXO31 Zornitza Stark changed review comment from: Single consanguineous family reported with homozygous truncating variant, limited functional evidence.; to: AR ID: Single consanguineous family reported with homozygous truncating variant, limited functional evidence.
Intellectual disability syndromic and non-syndromic v0.3747 FBXO31 Zornitza Stark edited their review of gene: FBXO31: Added comment: PMIDs 33675180; 32989326: three unrelated individuals with de novo missense variant, (p.Asp334Asn) and spastic-dystonic CP, including ID.; Changed rating: GREEN; Changed publications: 24623383, 33675180, 32989326; Changed phenotypes: Mental retardation, autosomal recessive 45, MIM#615979, Spastic-dystonic cerebral palsy, de novo dominant; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3747 DPYSL5 Zornitza Stark Marked gene: DPYSL5 as ready
Intellectual disability syndromic and non-syndromic v0.3747 DPYSL5 Zornitza Stark Gene: dpysl5 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3747 DPYSL5 Zornitza Stark Classified gene: DPYSL5 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.3747 DPYSL5 Zornitza Stark Gene: dpysl5 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3746 DPYSL5 Zornitza Stark gene: DPYSL5 was added
gene: DPYSL5 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: DPYSL5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: DPYSL5 were set to 33894126
Phenotypes for gene: DPYSL5 were set to Neurodevelopmental disorder with corpus callosum agenesis and cerebellar abnormalities
Review for gene: DPYSL5 was set to GREEN
Added comment: Nine individuals with brain malformations, including corpus callosum agenesis and/or posterior fossa abnormalities, associated with variable degrees of intellectual disability. The recurrent de novo p.Glu41Lys was found in eight unrelated patients, and a p.Gly47Arg variant was identified in one individual from the first family reported with Ritscher-Schinzel syndrome. Both impaired DPYSL5 function on dendritic outgrowth regulation by preventing the formation of the ternary complex with MAP2 and βIII-tubulin, ultimately leading to abnormal brain development.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.3745 SIN3B Zornitza Stark Marked gene: SIN3B as ready
Intellectual disability syndromic and non-syndromic v0.3745 SIN3B Zornitza Stark Gene: sin3b has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3745 SIN3B Zornitza Stark Mode of inheritance for gene: SIN3B was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3744 SIN3B Zornitza Stark Classified gene: SIN3B as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.3744 SIN3B Zornitza Stark Gene: sin3b has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3743 VPS41 Zornitza Stark Publications for gene: VPS41 were set to 32808683
Intellectual disability syndromic and non-syndromic v0.3742 VPS41 Zornitza Stark Classified gene: VPS41 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.3742 VPS41 Zornitza Stark Gene: vps41 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3741 VPS41 Zornitza Stark edited their review of gene: VPS41: Added comment: Another 9 individuals from 5 unrelated families reported.

Affected individuals were born after uneventful pregnancies and presented in most cases early in life with developmental delay. Various degrees of ataxia, hypotonia, and dystonia were present in all affected individuals, preventing independent ambulation. Likewise, nystagmus was commonly described. In addition, all affected individuals displayed intellectual disability and speech delay, and one sib pair had treatment-resistant epilepsy.; Changed rating: GREEN; Changed publications: 32808683, 33764426
Intellectual disability syndromic and non-syndromic v0.3741 ANKRD17 Zornitza Stark Publications for gene: ANKRD17 were set to
Intellectual disability syndromic and non-syndromic v0.3740 ANKRD17 Zornitza Stark Classified gene: ANKRD17 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.3740 ANKRD17 Zornitza Stark Gene: ankrd17 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3739 PTPN4 Bryony Thompson Marked gene: PTPN4 as ready
Intellectual disability syndromic and non-syndromic v0.3739 PTPN4 Bryony Thompson Gene: ptpn4 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3739 PTPN4 Bryony Thompson Classified gene: PTPN4 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.3739 PTPN4 Bryony Thompson Gene: ptpn4 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3738 PTPN4 Bryony Thompson gene: PTPN4 was added
gene: PTPN4 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: PTPN4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PTPN4 were set to 17953619; 25424712; 30238967; DOI: https://doi.org/10.1016/j.xhgg.2021.100033
Phenotypes for gene: PTPN4 were set to Intellectual disability; developmental delay
Review for gene: PTPN4 was set to GREEN
Added comment: >3 unrelated probands and supporting mouse model
PMID: 17953619 - knockout mouse model has impaired motor learning and cerebellar synaptic plasticity
PMID: 25424712 - twins with a de novo whole gene deletion and a Rett-like neurodevelopmental disorder
PMID: 30238967 - mosaic de novo variant (p.Leu72Ser) identified in a child with developmental delay, autistic features, hypotonia, increased immunoglobulin E and dental problems. Also supporting mouse assays demonstrating loss of protein expression in dendritic spines
DOI: https://doi.org/10.1016/j.xhgg.2021.100033 - missense and truncating variants in six unrelated individuals with varying degrees of intellectual disability or developmental delay. 5 were able to undergo segregation analysis and found to be de novo.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.3737 YWHAG Zornitza Stark Marked gene: YWHAG as ready
Intellectual disability syndromic and non-syndromic v0.3737 YWHAG Zornitza Stark Gene: ywhag has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3737 YWHAG Zornitza Stark Phenotypes for gene: YWHAG were changed from to Developmental and epileptic encephalopathy 56, (MIMI#617665)
Intellectual disability syndromic and non-syndromic v0.3736 YWHAG Zornitza Stark Publications for gene: YWHAG were set to
Intellectual disability syndromic and non-syndromic v0.3736 YWHAG Zornitza Stark Mode of inheritance for gene: YWHAG was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3735 YWHAG Zornitza Stark Mode of inheritance for gene: YWHAG was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3735 YWHAG Zornitza Stark Mode of inheritance for gene: YWHAG was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3734 YWHAG Zornitza Stark reviewed gene: YWHAG: Rating: GREEN; Mode of pathogenicity: None; Publications: 33393734, 33590706, 31926053, 33767733; Phenotypes: Developmental and epileptic encephalopathy 56, (MIMI#617665); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3734 HTT Zornitza Stark Publications for gene: HTT were set to 26740508; 27329733
Intellectual disability syndromic and non-syndromic v0.3733 HTT Zornitza Stark edited their review of gene: HTT: Added comment: PMID 33432339: Jung et al 2021 - further characterisation of the family previously reported in PMID: 27329733 (Rodan et al 2016) - using WGS they confirm they are the most likely cause of the LOMARS phenotype and clarify their locations as NM_002111.8(HTT): c.8157T>A (p.Phe2719Leu) and NM_002111.8(HTT)c.4469+1G>A (Note there are incorrect Clinvar entries). Functional studies show them each to be a hypomorphic mutation, resulting in severe deficiency of huntingtin in compound heterozygotes.

Still only 2 cases reported to date ((PMID: 27329733/33432339 and 26740508) with biallelic LOF variants in HTT associated with the LOMARS phenotype although this study add further weight with some functional data.; Changed publications: 26740508, 27329733, 33432339
Intellectual disability syndromic and non-syndromic v0.3733 MED25 Zornitza Stark Marked gene: MED25 as ready
Intellectual disability syndromic and non-syndromic v0.3733 MED25 Zornitza Stark Gene: med25 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3733 MED25 Zornitza Stark Phenotypes for gene: MED25 were changed from to Basel-Vanagait-Smirin-Yosef syndrome, MIM# 616449; Congenital cataract-microcephaly-naevus flammeus syndrome MONDO:0014643
Intellectual disability syndromic and non-syndromic v0.3732 MED25 Zornitza Stark Publications for gene: MED25 were set to
Intellectual disability syndromic and non-syndromic v0.3731 MED25 Zornitza Stark Mode of inheritance for gene: MED25 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3730 MED25 Zornitza Stark Tag founder tag was added to gene: MED25.
Intellectual disability syndromic and non-syndromic v0.3730 MED25 Zornitza Stark changed review comment from: Basel-Vanagaite-Smirin-Yosef syndrome is an autosomal recessive multiple congenital anomaly disorder characterized by severely delayed psychomotor development resulting in mental retardation, as well as variable eye, brain, cardiac, and palatal abnormalities. 7 individuals from 4 families reported initially, founder variant p.Tyr39Cys. Over 20 individuals reported since, including other variants.; to: Basel-Vanagaite-Smirin-Yosef syndrome is an autosomal recessive multiple congenital anomaly disorder characterized by severely delayed psychomotor development resulting in intellectual disability, as well as variable eye, brain, cardiac, and palatal abnormalities. 7 individuals from 4 families reported initially, founder variant p.Tyr39Cys. Over 20 individuals reported since, including other variants.
Intellectual disability syndromic and non-syndromic v0.3730 MED25 Zornitza Stark reviewed gene: MED25: Rating: GREEN; Mode of pathogenicity: None; Publications: 25792360, 32816121; Phenotypes: Basel-Vanagait-Smirin-Yosef syndrome, MIM# 616449, Congenital cataract-microcephaly-naevus flammeus syndrome MONDO:0014643; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3730 ANKRD17 Paul De Fazio reviewed gene: ANKRD17: Rating: GREEN; Mode of pathogenicity: None; Publications: 33909992; Phenotypes: Intellectual disability, speech delay, and dysmorphism; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Intellectual disability syndromic and non-syndromic v0.3730 SIN3B Elena Savva gene: SIN3B was added
gene: SIN3B was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: SIN3B was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SIN3B were set to PMID: 33811806
Phenotypes for gene: SIN3B were set to Syndromic intellectual disability/autism spectrum disorder
Review for gene: SIN3B was set to GREEN
Added comment: PMID: 33811806
- 9 affected patients, all de novo (2 PTCs, 2 missense, multigenic CNVs)
- syndrome hallmarked by intellectual disability, developmental delay, and dysmorphic facial features with variably penetrant ASD, congenital malformations, corpus callosum defects, and impaired growth.
- All SNV carriers had mild/mod ID
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.3730 PPIL1 Zornitza Stark Phenotypes for gene: PPIL1 were changed from Pontocerebellar hypoplasia; microcephaly; seizures to Pontocerebellar hypoplasia, type 14, MIM# 619301; microcephaly; seizures
Intellectual disability syndromic and non-syndromic v0.3729 PPIL1 Zornitza Stark edited their review of gene: PPIL1: Changed phenotypes: Pontocerebellar hypoplasia, type 14, MIM# 619301, microcephaly, seizures
Intellectual disability syndromic and non-syndromic v0.3729 SMARCA2 Zornitza Stark Phenotypes for gene: SMARCA2 were changed from Nicolaides-Baraitser syndrome, MIM #601358; Blepharophimosis-intellectual disability syndrome to Nicolaides-Baraitser syndrome, MIM #601358; Blepharophimosis-intellectual disability syndrome, MIM#619293
Intellectual disability syndromic and non-syndromic v0.3728 KCNQ5 Zornitza Stark Marked gene: KCNQ5 as ready
Intellectual disability syndromic and non-syndromic v0.3728 KCNQ5 Zornitza Stark Gene: kcnq5 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3728 KCNQ5 Zornitza Stark Phenotypes for gene: KCNQ5 were changed from to Mental retardation, autosomal dominant 46, MIM# 617601
Intellectual disability syndromic and non-syndromic v0.3727 KCNQ5 Zornitza Stark Publications for gene: KCNQ5 were set to
Intellectual disability syndromic and non-syndromic v0.3726 KCNQ5 Zornitza Stark Mode of inheritance for gene: KCNQ5 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3725 KCNQ5 Zornitza Stark reviewed gene: KCNQ5: Rating: GREEN; Mode of pathogenicity: None; Publications: 28669405, 30359776; Phenotypes: Mental retardation, autosomal dominant 46, MIM# 617601; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3725 KCNK9 Zornitza Stark Marked gene: KCNK9 as ready
Intellectual disability syndromic and non-syndromic v0.3725 KCNK9 Zornitza Stark Gene: kcnk9 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3725 KCNK9 Zornitza Stark Phenotypes for gene: KCNK9 were changed from to Birk-Barel syndrome, MIM# 612292; MONDO:0012856
Intellectual disability syndromic and non-syndromic v0.3724 KCNK9 Zornitza Stark Publications for gene: KCNK9 were set to
Intellectual disability syndromic and non-syndromic v0.3723 KCNK9 Zornitza Stark Mode of inheritance for gene: KCNK9 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, paternally imprinted (maternal allele expressed)
Intellectual disability syndromic and non-syndromic v0.3722 KCNK9 Zornitza Stark edited their review of gene: KCNK9: Changed phenotypes: Birk-Barel syndrome, MIM# 612292, MONDO:0012856
Intellectual disability syndromic and non-syndromic v0.3722 KCNK9 Zornitza Stark reviewed gene: KCNK9: Rating: GREEN; Mode of pathogenicity: None; Publications: 28333430, 27151206, 24980697, 18678320; Phenotypes: Birk-Barel syndrome, MIM# 612292; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, paternally imprinted (maternal allele expressed)
Intellectual disability syndromic and non-syndromic v0.3722 PPP2R5C Zornitza Stark Marked gene: PPP2R5C as ready
Intellectual disability syndromic and non-syndromic v0.3722 PPP2R5C Zornitza Stark Gene: ppp2r5c has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.3722 PPP2R5C Sue White Classified gene: PPP2R5C as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.3722 PPP2R5C Sue White Gene: ppp2r5c has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.3721 PPP2R5C Sue White gene: PPP2R5C was added
gene: PPP2R5C was added to Intellectual disability syndromic and non-syndromic. Sources: Research
Mode of inheritance for gene: PPP2R5C was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: PPP2R5C were set to macrocephaly; intellectual disability
Penetrance for gene: PPP2R5C were set to Complete
Review for gene: PPP2R5C was set to AMBER
Added comment: Emerging unpublished evidence of monoallelic missense variants causing intellectual disability and macrocephaly
Sources: Research
Intellectual disability syndromic and non-syndromic v0.3720 ADCY5 Zornitza Stark Publications for gene: ADCY5 were set to
Intellectual disability syndromic and non-syndromic v0.3719 ADCY5 Zornitza Stark Mode of inheritance for gene: ADCY5 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3718 ADCY5 Zornitza Stark changed review comment from: Variants in this gene cause a movement disorder, intellectual disability is not typically a feature.; to: 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.
Intellectual disability syndromic and non-syndromic v0.3718 ADCY5 Zornitza Stark edited their review of gene: ADCY5: Changed publications: 22782511, 24700542, 33051786, 32647899, 33704598; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3718 XPNPEP3 Zornitza Stark changed review comment from: 1 family with 3 sibs with a renal disease reminiscent of nephronophthisis.; to: Three families reported but phenotype is predominantly a renal ciliopathy.
Intellectual disability syndromic and non-syndromic v0.3718 KCNJ6 Zornitza Stark Publications for gene: KCNJ6 were set to 25620207
Intellectual disability syndromic and non-syndromic v0.3717 KCNJ6 Zornitza Stark changed review comment from: Keppen-Lubinsky syndrome characterised by severely delayed psychomotor development, hypertonia, hyperreflexia, generalized lipodystrophy giving an aged appearance, and distinctive dysmorphic features, including microcephaly, prominent eyes, narrow nasal bridge, and open mouth.

Three unrelated individuals reported with de novo variants in this gene (one recurred in 2), mouse model.; to: Keppen-Lubinsky syndrome characterised by severely delayed psychomotor development, hypertonia, hyperreflexia, generalized lipodystrophy giving an aged appearance, and distinctive dysmorphic features, including microcephaly, prominent eyes, narrow nasal bridge, and open mouth.

Four unrelated individuals reported with de novo variants in this gene (one recurred in 2), mouse model. One of the individuals did not have lipodystrophy but had a prominent hyperkinetic movement disorder.
Intellectual disability syndromic and non-syndromic v0.3717 KCNJ6 Zornitza Stark edited their review of gene: KCNJ6: Changed publications: 25620207, 29852244
Intellectual disability syndromic and non-syndromic v0.3717 KCNJ6 Zornitza Stark Marked gene: KCNJ6 as ready
Intellectual disability syndromic and non-syndromic v0.3717 KCNJ6 Zornitza Stark Gene: kcnj6 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3717 KCNJ6 Zornitza Stark Phenotypes for gene: KCNJ6 were changed from to Keppen-Lubinsky syndrome, MIM# 614098; MONDO:0013572
Intellectual disability syndromic and non-syndromic v0.3716 KCNJ6 Zornitza Stark Publications for gene: KCNJ6 were set to
Intellectual disability syndromic and non-syndromic v0.3715 KCNJ6 Zornitza Stark Mode of inheritance for gene: KCNJ6 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3714 KCNJ6 Zornitza Stark reviewed gene: KCNJ6: Rating: GREEN; Mode of pathogenicity: None; Publications: 25620207; Phenotypes: Keppen-Lubinsky syndrome, MIM# 614098, MONDO:0013572; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3714 JMJD1C Zornitza Stark Marked gene: JMJD1C as ready
Intellectual disability syndromic and non-syndromic v0.3714 JMJD1C Zornitza Stark Gene: jmjd1c has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3714 JMJD1C Zornitza Stark Classified gene: JMJD1C as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.3714 JMJD1C Zornitza Stark Gene: jmjd1c has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3713 JMJD1C Zornitza Stark reviewed gene: JMJD1C: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Intellectual disability; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3713 JMJD1C Chris Richmond gene: JMJD1C was added
gene: JMJD1C was added to Intellectual disability syndromic and non-syndromic. Sources: Expert Review
Mode of inheritance for gene: JMJD1C was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: JMJD1C were set to 26181491; 32996679
Phenotypes for gene: JMJD1C were set to Intellectual disability
Penetrance for gene: JMJD1C were set to unknown
Review for gene: JMJD1C was set to GREEN
Added comment: Reported in ID cohort (with Rett-like phenotypic overlap) with supporting functional studies (PMID: 26181491) "Functional study of the JMJD1C mutant Rett syndrome patient demonstrated that the altered protein had abnormal subcellular localization, diminished activity to demethylate the DNA damage-response protein MDC1, and reduced binding to MECP2. We confirmed that JMJD1C protein is widely expressed in brain regions and that its depletion compromises dendritic activity."

Splice-disrupting JMJD1C variant reported in association with learning disability and myoclonic epilepsy (PMID 32996679)

Disruption of gene due to balanced translocation (PMID 33591602) implicated in autism spectrum disease phenotype.
Sources: Expert Review
Intellectual disability syndromic and non-syndromic v0.3713 AFF4 Zornitza Stark edited their review of gene: AFF4: Changed mode of pathogenicity: Other; Changed publications: 25730767, 33248856, 31630891, 31058441; Changed phenotypes: CHOPS syndrome, MIM#616368, MONDO:0014609; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3713 AFF4 Zornitza Stark edited their review of gene: AFF4: Changed rating: GREEN
Intellectual disability syndromic and non-syndromic v0.3713 AFF4 Zornitza Stark changed review comment from: Comment when marking as ready: At least 15 unrelated individuals reported.; to: Comment when marking as ready: At least 15 unrelated individuals reported.

CdL-like, clinically recognisable phenotype, characterised by cognitive impairment, coarse facies, heart defects, obesity, pulmonary involvement, short stature, and skeletal dysplasia.
Intellectual disability syndromic and non-syndromic v0.3713 AFF4 Zornitza Stark Marked gene: AFF4 as ready
Intellectual disability syndromic and non-syndromic v0.3713 AFF4 Zornitza Stark Added comment: Comment when marking as ready: At least 15 unrelated individuals reported.
Intellectual disability syndromic and non-syndromic v0.3713 AFF4 Zornitza Stark Gene: aff4 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3713 AFF4 Zornitza Stark Phenotypes for gene: AFF4 were changed from CHOPS syndrome, MIM#616368 to CHOPS syndrome, MIM#616368; MONDO:0014609
Intellectual disability syndromic and non-syndromic v0.3712 AFF4 Zornitza Stark Publications for gene: AFF4 were set to 25730767
Intellectual disability syndromic and non-syndromic v0.3711 AFF4 Zornitza Stark Phenotypes for gene: AFF4 were changed from to CHOPS syndrome, MIM#616368
Intellectual disability syndromic and non-syndromic v0.3710 AFF4 Zornitza Stark Publications for gene: AFF4 were set to
Intellectual disability syndromic and non-syndromic v0.3709 AFF4 Zornitza Stark Mode of pathogenicity for gene: AFF4 was changed from to Other
Intellectual disability syndromic and non-syndromic v0.3708 AFF4 Zornitza Stark Mode of inheritance for gene: AFF4 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3707 AFF4 Teresa Zhao reviewed gene: AFF4: Rating: GREEN; Mode of pathogenicity: Other; Publications: 25730767; Phenotypes: CHOPS syndrome, MIM#616368; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability syndromic and non-syndromic v0.3707 VPS4A Zornitza Stark Phenotypes for gene: VPS4A were changed from Neurodevelopmental disorder to CIMDAG syndrome MIM# 619273
Intellectual disability syndromic and non-syndromic v0.3706 VPS4A Zornitza Stark reviewed gene: VPS4A: Rating: GREEN; Mode of pathogenicity: Other; Publications: ; Phenotypes: CIMDAG syndrome MIM# 619273; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3706 MED27 Zornitza Stark Phenotypes for gene: MED27 were changed from Intellectual disability; cerebellar hypoplasia; dystonia to Neurodevelopmental disorder with spasticity, cataracts, and cerebellar hypoplasia, MIM# 619286
Intellectual disability syndromic and non-syndromic v0.3705 MED27 Zornitza Stark reviewed gene: MED27: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with spasticity, cataracts, and cerebellar hypoplasia, MIM# 619286; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3705 TGIF1 Zornitza Stark Marked gene: TGIF1 as ready
Intellectual disability syndromic and non-syndromic v0.3705 TGIF1 Zornitza Stark Gene: tgif1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3705 TGIF1 Zornitza Stark Phenotypes for gene: TGIF1 were changed from to Holoprosencephaly 4, MIM# 142946; MONDO:0007734
Intellectual disability syndromic and non-syndromic v0.3704 TGIF1 Zornitza Stark Publications for gene: TGIF1 were set to
Intellectual disability syndromic and non-syndromic v0.3703 TGIF1 Zornitza Stark Mode of inheritance for gene: TGIF1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3702 TGIF1 Zornitza Stark reviewed gene: TGIF1: Rating: GREEN; Mode of pathogenicity: None; Publications: 10835638, 16323008; Phenotypes: Holoprosencephaly 4, MIM# 142946, MONDO:0007734; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3702 NEUROD2 Zornitza Stark Marked gene: NEUROD2 as ready
Intellectual disability syndromic and non-syndromic v0.3702 NEUROD2 Zornitza Stark Gene: neurod2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3702 NEUROD2 Zornitza Stark Phenotypes for gene: NEUROD2 were changed from Epileptic encephalopathy, early infantile, 72, MIM# 618374 to Epileptic encephalopathy, early infantile, 72, MIM# 618374; Intellectual disability
Intellectual disability syndromic and non-syndromic v0.3701 NEUROD2 Zornitza Stark Classified gene: NEUROD2 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.3701 NEUROD2 Zornitza Stark Gene: neurod2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3700 NEUROD2 Zornitza Stark gene: NEUROD2 was added
gene: NEUROD2 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: NEUROD2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: NEUROD2 were set to 33438828; 30323019
Phenotypes for gene: NEUROD2 were set to Epileptic encephalopathy, early infantile, 72, MIM# 618374
Review for gene: NEUROD2 was set to GREEN
Added comment: Four unrelated individuals altogether with de novo variants in this gene, two presenting predominantly with seizures, and two with ID.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.3699 MPLKIP Zornitza Stark Marked gene: MPLKIP as ready
Intellectual disability syndromic and non-syndromic v0.3699 MPLKIP Zornitza Stark Gene: mplkip has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3699 MPLKIP Zornitza Stark Phenotypes for gene: MPLKIP were changed from to Trichothiodystrophy 4, nonphotosensitive, MIM# 234050; MONDO:0021013
Intellectual disability syndromic and non-syndromic v0.3698 MPLKIP Zornitza Stark Publications for gene: MPLKIP were set to
Intellectual disability syndromic and non-syndromic v0.3697 MPLKIP Zornitza Stark Mode of inheritance for gene: MPLKIP was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3696 MPLKIP Zornitza Stark reviewed gene: MPLKIP: Rating: GREEN; Mode of pathogenicity: None; Publications: 15645389, 16977596; Phenotypes: Trichothiodystrophy 4, nonphotosensitive, MIM# 234050, MONDO:0021013; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3696 GTF2E2 Zornitza Stark Phenotypes for gene: GTF2E2 were changed from Trichothiodystrophy 6, nonphotosensitive; OMIM #616943 to Trichothiodystrophy 6, nonphotosensitive, MIM# 616943; MONDO:0014841
Intellectual disability syndromic and non-syndromic v0.3695 GTF2E2 Zornitza Stark Classified gene: GTF2E2 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.3695 GTF2E2 Zornitza Stark Gene: gtf2e2 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.3694 GTF2E2 Zornitza Stark Deleted their comment
Intellectual disability syndromic and non-syndromic v0.3694 SMG8 Zornitza Stark Phenotypes for gene: SMG8 were changed from Intellectual disability to Alzahrani-Kuwahara syndrome, MIM# 619268; Intellectual disability
Intellectual disability syndromic and non-syndromic v0.3693 ERCC5 Zornitza Stark Marked gene: ERCC5 as ready
Intellectual disability syndromic and non-syndromic v0.3693 ERCC5 Zornitza Stark Gene: ercc5 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3693 ERCC5 Zornitza Stark Phenotypes for gene: ERCC5 were changed from to Cerebrooculofacioskeletal syndrome 3, MIM# 616570; MONDO:0014696; Xeroderma pigmentosum, group G, MIM# 278780; MONDO:0010216
Intellectual disability syndromic and non-syndromic v0.3692 ERCC5 Zornitza Stark Publications for gene: ERCC5 were set to
Intellectual disability syndromic and non-syndromic v0.3691 ERCC5 Zornitza Stark Mode of inheritance for gene: ERCC5 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3690 ERCC5 Zornitza Stark reviewed gene: ERCC5: Rating: GREEN; Mode of pathogenicity: None; Publications: 7951246, 9096355, 9096355, 24700531, 33766032, 33219753; Phenotypes: Cerebrooculofacioskeletal syndrome 3, MIM# 616570, MONDO:0014696, Xeroderma pigmentosum, group G, MIM# 278780, MONDO:0010216; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3690 ERCC1 Zornitza Stark Marked gene: ERCC1 as ready
Intellectual disability syndromic and non-syndromic v0.3690 ERCC1 Zornitza Stark Gene: ercc1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3690 ERCC1 Zornitza Stark Phenotypes for gene: ERCC1 were changed from to Cerebrooculofacioskeletal syndrome 4, MIM# 610758; MONDO:0012554
Intellectual disability syndromic and non-syndromic v0.3689 ERCC1 Zornitza Stark Publications for gene: ERCC1 were set to
Intellectual disability syndromic and non-syndromic v0.3688 ERCC1 Zornitza Stark Mode of inheritance for gene: ERCC1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3687 ERCC1 Zornitza Stark reviewed gene: ERCC1: Rating: GREEN; Mode of pathogenicity: None; Publications: 17273966, 23623389, 32557569, 26085086, 33315086; Phenotypes: Cerebrooculofacioskeletal syndrome 4, MIM# 610758, MONDO:0012554; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3687 KCNH1 Zornitza Stark Marked gene: KCNH1 as ready
Intellectual disability syndromic and non-syndromic v0.3687 KCNH1 Zornitza Stark Gene: kcnh1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3687 KCNH1 Zornitza Stark Phenotypes for gene: KCNH1 were changed from to Temple-Baraitser syndrome, OMIM:611816; Zimmermann-Laband syndrome 1, OMIM:135500; Intellectual disability; Encephalopathy without features of TBS/ZLS
Intellectual disability syndromic and non-syndromic v0.3686 KCNH1 Zornitza Stark Publications for gene: KCNH1 were set to
Intellectual disability syndromic and non-syndromic v0.3685 KCNH1 Zornitza Stark Mode of inheritance for gene: KCNH1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3684 KCNH1 Arina Puzriakova reviewed gene: KCNH1: Rating: GREEN; Mode of pathogenicity: None; Publications: 33811134; Phenotypes: Temple-Baraitser syndrome, OMIM:611816, Zimmermann-Laband syndrome 1, OMIM:135500, Intellectual disability, Encephalopathy without features of TBS/ZLS; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3684 EMC10 Zornitza Stark Tag founder tag was added to gene: EMC10.
Intellectual disability syndromic and non-syndromic v0.3684 EMC10 Zornitza Stark Phenotypes for gene: EMC10 were changed from Developmental delay and intellectual disability, no OMIM# to Neurodevelopmental disorder with dysmorphic facies and variable seizures, MIM# 619264
Intellectual disability syndromic and non-syndromic v0.3683 EMC10 Zornitza Stark Marked gene: EMC10 as ready
Intellectual disability syndromic and non-syndromic v0.3683 EMC10 Zornitza Stark Gene: emc10 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3683 EMC10 Zornitza Stark Publications for gene: EMC10 were set to PMID: 32869858
Intellectual disability syndromic and non-syndromic v0.3682 EMC10 Zornitza Stark Classified gene: EMC10 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.3682 EMC10 Zornitza Stark Gene: emc10 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3681 EMC10 Zornitza Stark changed review comment from: Additional 12 individuals from 7 Middle Eastern families reported. Same variant in all, suggestive of founder effect.; to: Additional 12 individuals from 7 Middle Eastern families reported. Same variant in all, suggestive of founder effect (but different to the previously reported family).
Intellectual disability syndromic and non-syndromic v0.3681 EMC10 Zornitza Stark reviewed gene: EMC10: Rating: GREEN; Mode of pathogenicity: None; Publications: 33531666; Phenotypes: Neurodevelopmental disorder with dysmorphic facies and variable seizures, MIM# 619264; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3681 HDAC4 Bryony Thompson Publications for gene: HDAC4 were set to 24715439; 20691407; 31209962
Intellectual disability syndromic and non-syndromic v0.3680 HDAC4 Bryony Thompson edited their review of gene: HDAC4: Changed publications: 33537682
Intellectual disability syndromic and non-syndromic v0.3680 PLCH1 Zornitza Stark Marked gene: PLCH1 as ready
Intellectual disability syndromic and non-syndromic v0.3680 PLCH1 Zornitza Stark Gene: plch1 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.3680 PLCH1 Zornitza Stark Classified gene: PLCH1 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.3680 PLCH1 Zornitza Stark Gene: plch1 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.3679 PLCH1 Zornitza Stark gene: PLCH1 was added
gene: PLCH1 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: PLCH1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PLCH1 were set to 33820834
Phenotypes for gene: PLCH1 were set to Holoprosencephaly spectrum; Severe developmental delay; Brain malformations
Review for gene: PLCH1 was set to AMBER
Added comment: PMID: 33820834 (2021) - Two sibling pairs from two unrelated families with a holoprosencephaly spectrum phenotype and different homozygous PLCH1 variants (c.2065C>T, p.Arg689* and c.4235delA, p.Cys1079ValfsTer16, respectively). One family presented with congenital hydrocephalus, epilepsy, significant developmental delay and a monoventricle or fused thalami; while sibs from the second family had alobar holoprosencephaly and cyclopia. 3/4 individuals also displayed a cleft palate and congenital heart disease. Human embryo immunohistochemistry showed PLCH1 to be expressed in the notorcord, developing spinal cord (in a ventral to dorsal gradient), dorsal root ganglia, cerebellum and dermatomyosome.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.3678 PIGC Zornitza Stark Marked gene: PIGC as ready
Intellectual disability syndromic and non-syndromic v0.3678 PIGC Zornitza Stark Gene: pigc has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3678 PIGC Zornitza Stark Phenotypes for gene: PIGC were changed from to Glycosylphosphatidylinositol biosynthesis defect 16, MIM# 617816
Intellectual disability syndromic and non-syndromic v0.3677 PIGC Zornitza Stark Publications for gene: PIGC were set to
Intellectual disability syndromic and non-syndromic v0.3676 PIGC Zornitza Stark Mode of inheritance for gene: PIGC was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3675 DDX11 Zornitza Stark Marked gene: DDX11 as ready
Intellectual disability syndromic and non-syndromic v0.3675 DDX11 Zornitza Stark Gene: ddx11 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3675 DDX11 Zornitza Stark Phenotypes for gene: DDX11 were changed from to Warsaw breakage syndrome, MIM# 613398; MONDO:0013252
Intellectual disability syndromic and non-syndromic v0.3674 DDX11 Zornitza Stark Publications for gene: DDX11 were set to
Intellectual disability syndromic and non-syndromic v0.3673 DDX11 Zornitza Stark Mode of inheritance for gene: DDX11 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3672 DDX11 Zornitza Stark reviewed gene: DDX11: Rating: GREEN; Mode of pathogenicity: None; Publications: 20137776, 23033317, 30216658; Phenotypes: Warsaw breakage syndrome, MIM# 613398, MONDO:0013252; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3672 FAR1 Zornitza Stark Phenotypes for gene: FAR1 were changed from Peroxisomal fatty acyl-CoA reductase 1 disorder, MIM#616154 to Peroxisomal fatty acyl-CoA reductase 1 disorder, MIM#616154; 33239752
Intellectual disability syndromic and non-syndromic v0.3671 FAR1 Zornitza Stark Publications for gene: FAR1 were set to 25439727
Intellectual disability syndromic and non-syndromic v0.3670 FAR1 Zornitza Stark Mode of inheritance for gene: FAR1 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3669 FAR1 Zornitza Stark Classified gene: FAR1 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.3669 FAR1 Zornitza Stark Gene: far1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3668 FAR1 Zornitza Stark edited their review of gene: FAR1: Added comment: PMID 33239752: 12 patients with paediatric onset spastic paraparesis and bilateral congenital/juvenile cataracts. Most also had speech and gross motor developmental delay and truncal hypotonia. Exome sequencing identified de novo variants affecting the Arg480 residue in FAR1 (p.Arg480Cys/His/Leu). Further functional studies in fibroblasts showed that these variants cause a disruption of the plasmalogen-dependent feedback regulation of FAR1 protein levels leading to uncontrolled ether lipid production.; Changed rating: GREEN; Changed publications: 25439727, 33239752; Changed phenotypes: Peroxisomal fatty acyl-CoA reductase 1 disorder, MIM#616154, spastic paraparesis and bilateral cataracts; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3668 GRIA3 Zornitza Stark Marked gene: GRIA3 as ready
Intellectual disability syndromic and non-syndromic v0.3668 GRIA3 Zornitza Stark Gene: gria3 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3668 GRIA3 Zornitza Stark Phenotypes for gene: GRIA3 were changed from to Intellectual developmental disorder, X-linked, syndromic, Wu type (MIM#300699)
Intellectual disability syndromic and non-syndromic v0.3667 GRIA3 Zornitza Stark Publications for gene: GRIA3 were set to
Intellectual disability syndromic and non-syndromic v0.3666 GRIA3 Zornitza Stark Mode of inheritance for gene: GRIA3 was changed from Unknown to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability syndromic and non-syndromic v0.3665 GRIA3 Michelle Torres reviewed gene: GRIA3: Rating: GREEN; Mode of pathogenicity: None; Publications: 32977175, 17989220; Phenotypes: Intellectual developmental disorder, X-linked, syndromic, Wu type (MIM#300699); Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability syndromic and non-syndromic v0.3665 MAPKAPK5 Chirag Patel Classified gene: MAPKAPK5 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.3665 MAPKAPK5 Chirag Patel Gene: mapkapk5 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3664 MAPKAPK5 Chirag Patel gene: MAPKAPK5 was added
gene: MAPKAPK5 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: MAPKAPK5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MAPKAPK5 were set to PMID: 3344202
Phenotypes for gene: MAPKAPK5 were set to Developmental delay, variable brain anomalies, congenital heart defects, dysmorphic
Review for gene: MAPKAPK5 was set to GREEN
Added comment: 3 individuals from 2 families with severe developmental delay, variable brain anomalies, congenital heart defects, dysmorphic facial features, and a distinctive type of synpolydactyly with an additional hypoplastic digit between the fourth and fifth digits of hands and/or feet. Exome sequencing identified different homozygous truncating variants in MAPKAPK5 in both families, segregating with disease and unaffected parents as carriers.

Patient-derived cells showed no expression of MAPKAPK5 protein isoforms and reduced levels of the MAPKAPK5-interacting protein ERK3. F-actin recovery after latrunculin B treatment was found to be less efficient in patient-derived fibroblasts than in control cells, supporting a role of MAPKAPK5 in F-actin polymerization.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.3663 UBE4A Chirag Patel Classified gene: UBE4A as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.3663 UBE4A Chirag Patel Gene: ube4a has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3662 UBE4A Chirag Patel gene: UBE4A was added
gene: UBE4A was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: UBE4A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: UBE4A were set to PMID: 33420346
Phenotypes for gene: UBE4A were set to Intellectual disability and global developmental delay
Review for gene: UBE4A was set to GREEN
Added comment: 8 individuals, from 4 unrelated families, with syndromic intellectual disability and global developmental delay (other clinical features included hypotonia, short stature, seizures, and behaviour disorder. Exome sequencing identified biallelic loss-of-function variants in UBE4A in the 4 families, with variants segregating with disease and parents carriers. They demonstrated that UBE4A loss-of-function variants reduced RNA expression and protein levels in clinical samples. Mice generated to mimic patient-specific Ube4a loss-of-function variant exhibited muscular and neurological/behavioural abnormalities, some of which are suggestive of the clinical abnormalities seen in the affected individuals.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.3661 SGSH Zornitza Stark Marked gene: SGSH as ready
Intellectual disability syndromic and non-syndromic v0.3661 SGSH Zornitza Stark Gene: sgsh has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3661 SGSH Zornitza Stark Phenotypes for gene: SGSH were changed from to Mucopolysaccharidosis type IIIA (Sanfilippo A), MIM# 252900; MONDO:0009655
Intellectual disability syndromic and non-syndromic v0.3660 SGSH Zornitza Stark Publications for gene: SGSH were set to
Intellectual disability syndromic and non-syndromic v0.3659 SGSH Zornitza Stark Mode of inheritance for gene: SGSH was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3658 SGSH Zornitza Stark reviewed gene: SGSH: Rating: GREEN; Mode of pathogenicity: None; Publications: 7493035, 9158154, 9401012, 9554748; Phenotypes: Mucopolysaccharidosis type IIIA (Sanfilippo A), MIM# 252900, MONDO:0009655; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3658 SMPD1 Zornitza Stark Marked gene: SMPD1 as ready
Intellectual disability syndromic and non-syndromic v0.3658 SMPD1 Zornitza Stark Gene: smpd1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3658 SMPD1 Zornitza Stark Phenotypes for gene: SMPD1 were changed from to Niemann-Pick disease, type A, MIM# 257200; MONDO:0009756
Intellectual disability syndromic and non-syndromic v0.3657 SMPD1 Zornitza Stark Publications for gene: SMPD1 were set to
Intellectual disability syndromic and non-syndromic v0.3656 SMPD1 Zornitza Stark Mode of inheritance for gene: SMPD1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3655 SMPD1 Zornitza Stark reviewed gene: SMPD1: Rating: GREEN; Mode of pathogenicity: None; Publications: 32292456, 32280632, 28164782; Phenotypes: Niemann-Pick disease, type A, MIM# 257200, MONDO:0009756; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3655 MFSD8 Zornitza Stark Marked gene: MFSD8 as ready
Intellectual disability syndromic and non-syndromic v0.3655 MFSD8 Zornitza Stark Gene: mfsd8 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3655 MFSD8 Zornitza Stark Phenotypes for gene: MFSD8 were changed from to Ceroid lipofuscinosis, neuronal, 7, MIM# 610951; MONDO:0012588
Intellectual disability syndromic and non-syndromic v0.3654 MFSD8 Zornitza Stark Publications for gene: MFSD8 were set to
Intellectual disability syndromic and non-syndromic v0.3653 MFSD8 Zornitza Stark Mode of inheritance for gene: MFSD8 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3652 MFSD8 Zornitza Stark reviewed gene: MFSD8: Rating: GREEN; Mode of pathogenicity: None; Publications: 17564970, 19201763; Phenotypes: Ceroid lipofuscinosis, neuronal, 7, MIM# 610951, MONDO:0012588; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3652 MCOLN1 Zornitza Stark Tag SV/CNV tag was added to gene: MCOLN1.
Intellectual disability syndromic and non-syndromic v0.3652 MCOLN1 Zornitza Stark Marked gene: MCOLN1 as ready
Intellectual disability syndromic and non-syndromic v0.3652 MCOLN1 Zornitza Stark Gene: mcoln1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3652 MCOLN1 Zornitza Stark Phenotypes for gene: MCOLN1 were changed from to Mucolipidosis IV, MIM# 252650; MONDO:0009653
Intellectual disability syndromic and non-syndromic v0.3651 MCOLN1 Zornitza Stark Mode of inheritance for gene: MCOLN1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3650 MCOLN1 Zornitza Stark reviewed gene: MCOLN1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Mucolipidosis IV, MIM# 252650, MONDO:0009653; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3650 MANBA Zornitza Stark Marked gene: MANBA as ready
Intellectual disability syndromic and non-syndromic v0.3650 MANBA Zornitza Stark Gene: manba has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3650 MANBA Zornitza Stark Phenotypes for gene: MANBA were changed from to Mannosidosis, beta, MIM# 248510; MONDO:0009562
Intellectual disability syndromic and non-syndromic v0.3649 MANBA Zornitza Stark Mode of inheritance for gene: MANBA was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3648 MANBA Zornitza Stark reviewed gene: MANBA: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Mannosidosis, beta, MIM# 248510, MONDO:0009562; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3648 MAN2B1 Zornitza Stark Marked gene: MAN2B1 as ready
Intellectual disability syndromic and non-syndromic v0.3648 MAN2B1 Zornitza Stark Gene: man2b1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3648 MAN2B1 Zornitza Stark Phenotypes for gene: MAN2B1 were changed from to Mannosidosis, alpha-, types I and II, MIM# 248500; MONDO:0009561
Intellectual disability syndromic and non-syndromic v0.3647 MAN2B1 Zornitza Stark Mode of inheritance for gene: MAN2B1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3646 MAN2B1 Zornitza Stark reviewed gene: MAN2B1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Mannosidosis, alpha-, types I and II, MIM# 248500, MONDO:0009561; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3646 USP18 Zornitza Stark Marked gene: USP18 as ready
Intellectual disability syndromic and non-syndromic v0.3646 USP18 Zornitza Stark Gene: usp18 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3646 USP18 Zornitza Stark Phenotypes for gene: USP18 were changed from to Pseudo-TORCH syndrome 2; OMIM #617397
Intellectual disability syndromic and non-syndromic v0.3645 USP18 Zornitza Stark Publications for gene: USP18 were set to
Intellectual disability syndromic and non-syndromic v0.3644 USP18 Zornitza Stark Mode of inheritance for gene: USP18 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3643 TSPOAP1 Alison Yeung Marked gene: TSPOAP1 as ready
Intellectual disability syndromic and non-syndromic v0.3643 TSPOAP1 Alison Yeung Gene: tspoap1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3643 TSPOAP1 Alison Yeung Classified gene: TSPOAP1 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.3643 TSPOAP1 Alison Yeung Gene: tspoap1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3642 TSPOAP1 Ain Roesley gene: TSPOAP1 was added
gene: TSPOAP1 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: TSPOAP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TSPOAP1 were set to 33539324
Phenotypes for gene: TSPOAP1 were set to Dystonia, intellectual disability and cerebellar atrophy
Penetrance for gene: TSPOAP1 were set to unknown
Review for gene: TSPOAP1 was set to GREEN
Added comment: 7 affecteds from 3 families (1 consanguineous)
2x null, 1x missense

Affecteds with the null variants presented with juvenile-onset progressive generalized dystonia, associated with intellectual disability and cerebellar atrophy while those with the missense p.(Gly1808Ser) presented with isolated adult-onset focal dystonia (mild cognitive impairment noted)

mice KO models were investigated
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.3642 NCDN Alison Yeung Marked gene: NCDN as ready
Intellectual disability syndromic and non-syndromic v0.3642 NCDN Alison Yeung Gene: ncdn has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3642 NCDN Alison Yeung Classified gene: NCDN as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.3642 NCDN Alison Yeung Gene: ncdn has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3641 NCDN Ain Roesley gene: NCDN was added
gene: NCDN was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: NCDN was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: NCDN were set to 33711248
Phenotypes for gene: NCDN were set to neurodevelopmental delay, intellectual disability, and epilepsy
Penetrance for gene: NCDN were set to unknown
Added comment: 4x families all missense and de novo except for 1 consag family where 3 affecteds were homozygous and carrier parents unaffected

ID ranged from mild to severe
3/4 probands had seizures
only 3 affecteds had MRI done, with 1 delayed myelination

in vitro studies were done
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.3641 TBX1 Zornitza Stark Marked gene: TBX1 as ready
Intellectual disability syndromic and non-syndromic v0.3641 TBX1 Zornitza Stark Gene: tbx1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3641 TBX1 Zornitza Stark Phenotypes for gene: TBX1 were changed from to DiGeorge syndrome, MIM# 188400
Intellectual disability syndromic and non-syndromic v0.3640 TBX1 Zornitza Stark Mode of inheritance for gene: TBX1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3639 TBX1 Zornitza Stark Tag SV/CNV tag was added to gene: TBX1.
Intellectual disability syndromic and non-syndromic v0.3639 TBX1 Zornitza Stark reviewed gene: TBX1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: DiGeorge syndrome, MIM# 188400; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3639 SLC5A5 Zornitza Stark Marked gene: SLC5A5 as ready
Intellectual disability syndromic and non-syndromic v0.3639 SLC5A5 Zornitza Stark Gene: slc5a5 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.3639 SLC5A5 Zornitza Stark Phenotypes for gene: SLC5A5 were changed from to Thyroid dyshormonogenesis 1, MIM# 274400
Intellectual disability syndromic and non-syndromic v0.3638 SLC5A5 Zornitza Stark Mode of inheritance for gene: SLC5A5 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3637 SLC5A5 Zornitza Stark Classified gene: SLC5A5 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.3637 SLC5A5 Zornitza Stark Gene: slc5a5 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.3636 SLC5A5 Zornitza Stark reviewed gene: SLC5A5: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Thyroid dyshormonogenesis 1, MIM# 274400; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3636 SLC45A1 Zornitza Stark Marked gene: SLC45A1 as ready
Intellectual disability syndromic and non-syndromic v0.3636 SLC45A1 Zornitza Stark Gene: slc45a1 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.3636 SLC45A1 Zornitza Stark Phenotypes for gene: SLC45A1 were changed from to Intellectual developmental disorder with neuropsychiatric features, MIM# 617532
Intellectual disability syndromic and non-syndromic v0.3635 SLC45A1 Zornitza Stark Publications for gene: SLC45A1 were set to
Intellectual disability syndromic and non-syndromic v0.3634 SLC45A1 Zornitza Stark Mode of inheritance for gene: SLC45A1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3633 SLC45A1 Zornitza Stark Classified gene: SLC45A1 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.3633 SLC45A1 Zornitza Stark Gene: slc45a1 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.3632 SLC45A1 Zornitza Stark reviewed gene: SLC45A1: Rating: AMBER; Mode of pathogenicity: None; Publications: 28434495; Phenotypes: Intellectual developmental disorder with neuropsychiatric features, MIM# 617532; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3632 SLC2A2 Zornitza Stark Marked gene: SLC2A2 as ready
Intellectual disability syndromic and non-syndromic v0.3632 SLC2A2 Zornitza Stark Gene: slc2a2 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.3632 SLC2A2 Zornitza Stark Phenotypes for gene: SLC2A2 were changed from to Fanconi-Bickel syndrome, MIM# 227810
Intellectual disability syndromic and non-syndromic v0.3631 SLC2A2 Zornitza Stark Mode of inheritance for gene: SLC2A2 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3630 SLC2A2 Zornitza Stark Classified gene: SLC2A2 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.3630 SLC2A2 Zornitza Stark Gene: slc2a2 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.3629 SLC2A2 Zornitza Stark reviewed gene: SLC2A2: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Fanconi-Bickel syndrome, MIM# 227810; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3629 PIK3R2 Zornitza Stark Marked gene: PIK3R2 as ready
Intellectual disability syndromic and non-syndromic v0.3629 PIK3R2 Zornitza Stark Gene: pik3r2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3629 PIK3R2 Zornitza Stark Phenotypes for gene: PIK3R2 were changed from to Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 1, MIM# 603387
Intellectual disability syndromic and non-syndromic v0.3628 PIK3R2 Zornitza Stark Publications for gene: PIK3R2 were set to
Intellectual disability syndromic and non-syndromic v0.3627 PIK3R2 Zornitza Stark Mode of inheritance for gene: PIK3R2 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3626 PIK3R2 Zornitza Stark reviewed gene: PIK3R2: Rating: GREEN; Mode of pathogenicity: None; Publications: 22729224, 23745724, 33604570; Phenotypes: Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 1, MIM# 603387; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3626 NPHP3 Zornitza Stark Marked gene: NPHP3 as ready
Intellectual disability syndromic and non-syndromic v0.3626 NPHP3 Zornitza Stark Gene: nphp3 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3626 NPHP3 Zornitza Stark Phenotypes for gene: NPHP3 were changed from to Meckel syndrome 7, MIM# 267010
Intellectual disability syndromic and non-syndromic v0.3625 NPHP3 Zornitza Stark Publications for gene: NPHP3 were set to 18371931
Intellectual disability syndromic and non-syndromic v0.3625 NPHP3 Zornitza Stark Publications for gene: NPHP3 were set to
Intellectual disability syndromic and non-syndromic v0.3624 NPHP3 Zornitza Stark Mode of inheritance for gene: NPHP3 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3623 FGFR2 Zornitza Stark Marked gene: FGFR2 as ready
Intellectual disability syndromic and non-syndromic v0.3623 FGFR2 Zornitza Stark Gene: fgfr2 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.3623 FGFR2 Zornitza Stark Phenotypes for gene: FGFR2 were changed from to Antley-Bixler syndrome without genital anomalies or disordered steroidogenesis, MIM# 207410; Apert syndrome, MIM# 101200
Intellectual disability syndromic and non-syndromic v0.3622 FGFR2 Zornitza Stark Mode of inheritance for gene: FGFR2 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3621 FGFR2 Zornitza Stark Classified gene: FGFR2 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.3621 FGFR2 Zornitza Stark Gene: fgfr2 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.3620 FGFR2 Zornitza Stark reviewed gene: FGFR2: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Antley-Bixler syndrome without genital anomalies or disordered steroidogenesis, MIM# 207410, Apert syndrome, MIM# 101200; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3620 CYP27A1 Zornitza Stark Marked gene: CYP27A1 as ready
Intellectual disability syndromic and non-syndromic v0.3620 CYP27A1 Zornitza Stark Gene: cyp27a1 has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v0.3620 CYP27A1 Zornitza Stark Phenotypes for gene: CYP27A1 were changed from to Cerebrotendinous xanthomatosis, MIM# 213700
Intellectual disability syndromic and non-syndromic v0.3619 CYP27A1 Zornitza Stark Mode of inheritance for gene: CYP27A1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3618 CYP27A1 Zornitza Stark Classified gene: CYP27A1 as Red List (low evidence)
Intellectual disability syndromic and non-syndromic v0.3618 CYP27A1 Zornitza Stark Gene: cyp27a1 has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v0.3617 CYP27A1 Zornitza Stark reviewed gene: CYP27A1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Cerebrotendinous xanthomatosis, MIM# 213700; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3617 HGSNAT Zornitza Stark Marked gene: HGSNAT as ready
Intellectual disability syndromic and non-syndromic v0.3617 HGSNAT Zornitza Stark Gene: hgsnat has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3617 HGSNAT Zornitza Stark Phenotypes for gene: HGSNAT were changed from to Mucopolysaccharidosis type IIIC (Sanfilippo C), MIM# 252930; MONDO:0009657
Intellectual disability syndromic and non-syndromic v0.3616 HGSNAT Zornitza Stark Publications for gene: HGSNAT were set to
Intellectual disability syndromic and non-syndromic v0.3615 HGSNAT Zornitza Stark Mode of inheritance for gene: HGSNAT was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3614 HGSNAT Zornitza Stark reviewed gene: HGSNAT: Rating: GREEN; Mode of pathogenicity: None; Publications: 19479962, 31228227, 20825431, 20583299; Phenotypes: Mucopolysaccharidosis type IIIC (Sanfilippo C), MIM# 252930, MONDO:0009657; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3614 GUSB Zornitza Stark Marked gene: GUSB as ready
Intellectual disability syndromic and non-syndromic v0.3614 GUSB Zornitza Stark Gene: gusb has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3614 GUSB Zornitza Stark Phenotypes for gene: GUSB were changed from to Mucopolysaccharidosis VII, MIM# 253220; MONDO:0009662
Intellectual disability syndromic and non-syndromic v0.3613 GUSB Zornitza Stark Mode of inheritance for gene: GUSB was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3612 GUSB Zornitza Stark reviewed gene: GUSB: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Mucopolysaccharidosis VII, MIM# 253220, MONDO:0009662; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3612 GNPTG Zornitza Stark Marked gene: GNPTG as ready
Intellectual disability syndromic and non-syndromic v0.3612 GNPTG Zornitza Stark Gene: gnptg has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3612 GNPTG Zornitza Stark Phenotypes for gene: GNPTG were changed from to Mucolipidosis III gamma, MIM# 252605; MONDO:0009652
Intellectual disability syndromic and non-syndromic v0.3611 GNPTG Zornitza Stark Publications for gene: GNPTG were set to
Intellectual disability syndromic and non-syndromic v0.3610 GNPTG Zornitza Stark Mode of inheritance for gene: GNPTG was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3609 GNPTG Zornitza Stark reviewed gene: GNPTG: Rating: GREEN; Mode of pathogenicity: None; Publications: 10712439, 19370764, 19659762, 33507475, 33023972, 32651481; Phenotypes: Mucolipidosis III gamma, MIM# 252605, MONDO:0009652; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3609 CDH11 Zornitza Stark Marked gene: CDH11 as ready
Intellectual disability syndromic and non-syndromic v0.3609 CDH11 Zornitza Stark Gene: cdh11 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3609 CDH11 Zornitza Stark Phenotypes for gene: CDH11 were changed from to Elsahy-Waters syndrome, MIM# 211380; Teebi hypertelorism syndrome
Intellectual disability syndromic and non-syndromic v0.3608 CDH11 Zornitza Stark Publications for gene: CDH11 were set to
Intellectual disability syndromic and non-syndromic v0.3607 CDH11 Zornitza Stark Mode of inheritance for gene: CDH11 was changed from Unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3606 CDH11 Zornitza Stark reviewed gene: CDH11: Rating: GREEN; Mode of pathogenicity: None; Publications: 33811546, 27431290, 28988429, 29271567; Phenotypes: Elsahy-Waters syndrome, MIM# 211380, Teebi hypertelorism syndrome; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3606 CDH11 Chirag Patel reviewed gene: CDH11: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 33811546; Phenotypes: Teebi hypertelorism syndrome; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3606 NMNAT1 Zornitza Stark edited their review of gene: NMNAT1: Changed phenotypes: Spondyloepiphyseal dysplasia, sensorineural hearing loss, intellectual disability, and Leber congenital amaurosis (SHILCA), MIM#619260
Intellectual disability syndromic and non-syndromic v0.3606 NMNAT1 Zornitza Stark Phenotypes for gene: NMNAT1 were changed from Spondyloepiphyseal dysplasia, sensorineural hearing loss, intellectual disability, and Leber congenital amaurosis (SHILCA), MIM#619260; Leber congenital amaurosis 9, MIM# 608553 to Spondyloepiphyseal dysplasia, sensorineural hearing loss, intellectual disability, and Leber congenital amaurosis (SHILCA), MIM#619260
Intellectual disability syndromic and non-syndromic v0.3605 NMNAT1 Zornitza Stark Marked gene: NMNAT1 as ready
Intellectual disability syndromic and non-syndromic v0.3605 NMNAT1 Zornitza Stark Gene: nmnat1 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.3605 NMNAT1 Zornitza Stark Classified gene: NMNAT1 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.3605 NMNAT1 Zornitza Stark Gene: nmnat1 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.3604 NMNAT1 Zornitza Stark gene: NMNAT1 was added
gene: NMNAT1 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
SV/CNV, founder tags were added to gene: NMNAT1.
Mode of inheritance for gene: NMNAT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NMNAT1 were set to 32533184; 33668384
Phenotypes for gene: NMNAT1 were set to Spondyloepiphyseal dysplasia, sensorineural hearing loss, intellectual disability, and Leber congenital amaurosis (SHILCA), MIM#619260; Leber congenital amaurosis 9, MIM# 608553
Review for gene: NMNAT1 was set to AMBER
Added comment: Three families reported, but two are distantly related (shared haplotype). The affected children in those two families were homozygous for 7.4-kb duplication involving the last 2 exons of the NMNAT1 gene, spanning the beginning of intron 3 to the middle of the 3-prime UTR (chr1:10,036,359-10,043,727, GRCh37). The third affected individual was compound het for the duplication and a splicing variant.

Note bi-allelic variants in this gene are associated with non-syndromic LCA, multiple families.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.3603 CLN5 Zornitza Stark Marked gene: CLN5 as ready
Intellectual disability syndromic and non-syndromic v0.3603 CLN5 Zornitza Stark Gene: cln5 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3603 CLN5 Zornitza Stark Phenotypes for gene: CLN5 were changed from to Ceroid lipofuscinosis, neuronal, 5, MIM# 256731; MONDO:0009745
Intellectual disability syndromic and non-syndromic v0.3602 CLN5 Zornitza Stark Publications for gene: CLN5 were set to
Intellectual disability syndromic and non-syndromic v0.3601 CLN5 Zornitza Stark Mode of inheritance for gene: CLN5 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3600 CLN5 Zornitza Stark reviewed gene: CLN5: Rating: GREEN; Mode of pathogenicity: None; Publications: 20157158; Phenotypes: Ceroid lipofuscinosis, neuronal, 5, MIM# 256731, MONDO:0009745; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3600 ARSB Zornitza Stark Marked gene: ARSB as ready
Intellectual disability syndromic and non-syndromic v0.3600 ARSB Zornitza Stark Gene: arsb has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3600 ARSB Zornitza Stark Phenotypes for gene: ARSB were changed from to Mucopolysaccharidosis type VI (Maroteaux-Lamy), MIM# 253200; MONDO:0009661
Intellectual disability syndromic and non-syndromic v0.3599 ARSB Zornitza Stark Publications for gene: ARSB were set to
Intellectual disability syndromic and non-syndromic v0.3598 ARSB Zornitza Stark Mode of inheritance for gene: ARSB was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3597 ARSB Zornitza Stark reviewed gene: ARSB: Rating: GREEN; Mode of pathogenicity: None; Publications: 11668612; Phenotypes: Mucopolysaccharidosis type VI (Maroteaux-Lamy), MIM# 253200, MONDO:0009661; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3597 COPB1 Zornitza Stark Phenotypes for gene: COPB1 were changed from Severe intellectual disability; variable microcephaly; cataracts to Baralle-Macken syndrome, MIM# 619255; Severe intellectual disability; variable microcephaly; cataracts
Intellectual disability syndromic and non-syndromic v0.3596 COPB1 Zornitza Stark edited their review of gene: COPB1: Changed phenotypes: Baralle-Macken syndrome, MIM# 619255, Severe intellectual disability, variable microcephaly, cataracts
Intellectual disability syndromic and non-syndromic v0.3596 TTC5 Zornitza Stark Phenotypes for gene: TTC5 were changed from Central hypotonia; Global developmental delay; Intellectual disability; Abnormality of nervous system morphology; Microcephaly; Abnormality of the face; Behavioral abnormality; Abnormality of the genitourinary system to Neurodevelopmental disorder with cerebral atrophy and variable facial dysmorphism , MIM#619244; Central hypotonia; Global developmental delay; Intellectual disability; Abnormality of nervous system morphology; Microcephaly; Abnormality of the face; Behavioral abnormality; Abnormality of the genitourinary system
Intellectual disability syndromic and non-syndromic v0.3595 TTC5 Zornitza Stark reviewed gene: TTC5: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with cerebral atrophy and variable facial dysmorphism , MIM#619244; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3595 WDR62 Zornitza Stark Marked gene: WDR62 as ready
Intellectual disability syndromic and non-syndromic v0.3595 WDR62 Zornitza Stark Gene: wdr62 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3595 WDR62 Zornitza Stark Phenotypes for gene: WDR62 were changed from to Microcephaly 2, primary, autosomal recessive, with or without cortical malformations, MIM# 604317; MONDO:0011435
Intellectual disability syndromic and non-syndromic v0.3594 WDR62 Zornitza Stark Publications for gene: WDR62 were set to
Intellectual disability syndromic and non-syndromic v0.3593 WDR62 Zornitza Stark Mode of inheritance for gene: WDR62 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3592 WDR62 Zornitza Stark reviewed gene: WDR62: Rating: GREEN; Mode of pathogenicity: None; Publications: 20890279, 20729831, 20890278, 21496009, 21834044, 22775483, 32677750, 31788460; Phenotypes: Microcephaly 2, primary, autosomal recessive, with or without cortical malformations, MIM# 604317, MONDO:0011435; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3592 TRMT10A Zornitza Stark Marked gene: TRMT10A as ready
Intellectual disability syndromic and non-syndromic v0.3592 TRMT10A Zornitza Stark Gene: trmt10a has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3592 TRMT10A Zornitza Stark Phenotypes for gene: TRMT10A were changed from to Microcephaly, short stature, and impaired glucose metabolism 1, MIM# 616033; MONDO:0000208
Intellectual disability syndromic and non-syndromic v0.3591 TRMT10A Zornitza Stark Publications for gene: TRMT10A were set to
Intellectual disability syndromic and non-syndromic v0.3590 TRMT10A Zornitza Stark Mode of inheritance for gene: TRMT10A was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3589 TRMT10A Zornitza Stark reviewed gene: TRMT10A: Rating: GREEN; Mode of pathogenicity: None; Publications: 24204302, 25053765, 33448213, 33067246, 26535115, 26526202, 26297882; Phenotypes: Microcephaly, short stature, and impaired glucose metabolism 1, MIM# 616033, MONDO:0000208; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3589 TRAIP Zornitza Stark Publications for gene: TRAIP were set to
Intellectual disability syndromic and non-syndromic v0.3588 TRAIP Zornitza Stark edited their review of gene: TRAIP: Added comment: Three families reported, though two distantly related (founder); functional data.; Changed publications: 26595769
Intellectual disability syndromic and non-syndromic v0.3588 STIL Zornitza Stark Marked gene: STIL as ready
Intellectual disability syndromic and non-syndromic v0.3588 STIL Zornitza Stark Gene: stil has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3588 STIL Zornitza Stark Phenotypes for gene: STIL were changed from to Microcephaly 7, primary, autosomal recessive, MIM# 612703; MONDO:0012989
Intellectual disability syndromic and non-syndromic v0.3587 STIL Zornitza Stark Publications for gene: STIL were set to
Intellectual disability syndromic and non-syndromic v0.3586 STIL Zornitza Stark Mode of inheritance for gene: STIL was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3585 STIL Zornitza Stark reviewed gene: STIL: Rating: GREEN; Mode of pathogenicity: None; Publications: 19215732, 22989186, 25218063, 33132204, 32677750, 29230157; Phenotypes: Microcephaly 7, primary, autosomal recessive, MIM# 612703, MONDO:0012989; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3585 STAMBP Zornitza Stark Marked gene: STAMBP as ready
Intellectual disability syndromic and non-syndromic v0.3585 STAMBP Zornitza Stark Gene: stambp has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3585 STAMBP Zornitza Stark Phenotypes for gene: STAMBP were changed from to Microcephaly-capillary malformation syndrome, MIM# 614261; MONDO:0013659
Intellectual disability syndromic and non-syndromic v0.3584 STAMBP Zornitza Stark Publications for gene: STAMBP were set to
Intellectual disability syndromic and non-syndromic v0.3583 STAMBP Zornitza Stark Mode of inheritance for gene: STAMBP was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3582 STAMBP Zornitza Stark reviewed gene: STAMBP: Rating: GREEN; Mode of pathogenicity: None; Publications: 23542699, 31638258, 29907875, 27531570, 25692795, 25266620; Phenotypes: Microcephaly-capillary malformation syndrome, MIM# 614261, MONDO:0013659; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3582 RTTN Zornitza Stark Marked gene: RTTN as ready
Intellectual disability syndromic and non-syndromic v0.3582 RTTN Zornitza Stark Gene: rttn has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3582 RTTN Zornitza Stark Phenotypes for gene: RTTN were changed from to Microcephaly, short stature, and polymicrogyria with seizures, MIM# 614833; Microcephalic primordial dwarfism due to RTTN deficiency MONDO:0018764
Intellectual disability syndromic and non-syndromic v0.3581 RTTN Zornitza Stark Publications for gene: RTTN were set to
Intellectual disability syndromic and non-syndromic v0.3580 RTTN Zornitza Stark Mode of inheritance for gene: RTTN was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3579 RTTN Zornitza Stark reviewed gene: RTTN: Rating: GREEN; Mode of pathogenicity: None; Publications: 22939636, 26608784, 26940245, 30121372, 29967526, 30927481, 30121372; Phenotypes: Microcephaly, short stature, and polymicrogyria with seizures, MIM# 614833, Microcephalic primordial dwarfism due to RTTN deficiency MONDO:0018764; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3579 BRD4 Chirag Patel Classified gene: BRD4 as Red List (low evidence)
Intellectual disability syndromic and non-syndromic v0.3579 BRD4 Chirag Patel Gene: brd4 has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v0.3578 BRD4 Chirag Patel reviewed gene: BRD4: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability syndromic and non-syndromic v0.3578 NDE1 Zornitza Stark Marked gene: NDE1 as ready
Intellectual disability syndromic and non-syndromic v0.3578 NDE1 Zornitza Stark Gene: nde1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3578 NDE1 Zornitza Stark Phenotypes for gene: NDE1 were changed from to Lissencephaly 4 (with microcephaly), MIM# 614019; MONDO:0013527; Microhydranencephaly, MIM# 605013; MONDO:0011504
Intellectual disability syndromic and non-syndromic v0.3577 NDE1 Zornitza Stark Publications for gene: NDE1 were set to
Intellectual disability syndromic and non-syndromic v0.3576 NDE1 Zornitza Stark Mode of inheritance for gene: NDE1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3575 NDE1 Zornitza Stark reviewed gene: NDE1: Rating: GREEN; Mode of pathogenicity: None; Publications: 21529752, 21529751, 30637988, 15473967; Phenotypes: Lissencephaly 4 (with microcephaly), MIM# 614019, MONDO:0013527, Microhydranencephaly, MIM# 605013, MONDO:0011504; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3575 MSMO1 Zornitza Stark Marked gene: MSMO1 as ready
Intellectual disability syndromic and non-syndromic v0.3575 MSMO1 Zornitza Stark Gene: msmo1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3575 MSMO1 Zornitza Stark Phenotypes for gene: MSMO1 were changed from to Microcephaly, congenital cataract, and psoriasiform dermatitis, MIM# 616834; MONDO:0014793
Intellectual disability syndromic and non-syndromic v0.3574 MSMO1 Zornitza Stark Publications for gene: MSMO1 were set to
Intellectual disability syndromic and non-syndromic v0.3573 MSMO1 Zornitza Stark Mode of inheritance for gene: MSMO1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3572 MSMO1 Zornitza Stark reviewed gene: MSMO1: Rating: GREEN; Mode of pathogenicity: None; Publications: 27604308, 21285510, 24144731, 33161406, 28673550, 33161406; Phenotypes: Microcephaly, congenital cataract, and psoriasiform dermatitis, MIM# 616834, MONDO:0014793; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3572 MCPH1 Zornitza Stark Marked gene: MCPH1 as ready
Intellectual disability syndromic and non-syndromic v0.3572 MCPH1 Zornitza Stark Gene: mcph1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3572 MCPH1 Zornitza Stark Phenotypes for gene: MCPH1 were changed from to Microcephaly 1, primary, autosomal recessive, MIM# 251200; MONDO:0009617
Intellectual disability syndromic and non-syndromic v0.3571 MCPH1 Zornitza Stark Publications for gene: MCPH1 were set to
Intellectual disability syndromic and non-syndromic v0.3570 MCPH1 Zornitza Stark Mode of inheritance for gene: MCPH1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3569 MCPH1 Zornitza Stark reviewed gene: MCPH1: Rating: GREEN; Mode of pathogenicity: None; Publications: 12046007, 15199523, 16311745, 20978018, 32294449, 30351297, 29026105; Phenotypes: Microcephaly 1, primary, autosomal recessive, MIM# 251200, MONDO:0009617; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3569 LARP7 Zornitza Stark Marked gene: LARP7 as ready
Intellectual disability syndromic and non-syndromic v0.3569 LARP7 Zornitza Stark Gene: larp7 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3569 LARP7 Zornitza Stark Phenotypes for gene: LARP7 were changed from to Alazami syndrome, MIM# 615071; Microcephalic primordial dwarfism, Alazami type MONDO:0014031
Intellectual disability syndromic and non-syndromic v0.3568 LARP7 Zornitza Stark Publications for gene: LARP7 were set to
Intellectual disability syndromic and non-syndromic v0.3567 LARP7 Zornitza Stark Mode of inheritance for gene: LARP7 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3566 LARP7 Zornitza Stark reviewed gene: LARP7: Rating: GREEN; Mode of pathogenicity: None; Publications: 22865833, 21937992, 30006060, 33569879; Phenotypes: Alazami syndrome, MIM# 615071, Microcephalic primordial dwarfism, Alazami type MONDO:0014031; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3566 KNL1 Zornitza Stark Marked gene: KNL1 as ready
Intellectual disability syndromic and non-syndromic v0.3566 KNL1 Zornitza Stark Gene: knl1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3566 KNL1 Zornitza Stark Phenotypes for gene: KNL1 were changed from to Microcephaly 4, primary, autosomal recessive, MIM# 604321; MONDO:0011437
Intellectual disability syndromic and non-syndromic v0.3565 KNL1 Zornitza Stark Publications for gene: KNL1 were set to
Intellectual disability syndromic and non-syndromic v0.3564 KNL1 Zornitza Stark Mode of inheritance for gene: KNL1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3563 KNL1 Zornitza Stark reviewed gene: KNL1: Rating: GREEN; Mode of pathogenicity: None; Publications: 22983954, 26626498, 27149178, 30304678, 27784895; Phenotypes: Microcephaly 4, primary, autosomal recessive, MIM# 604321, MONDO:0011437; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3563 TNRC6B Zornitza Stark Phenotypes for gene: TNRC6B were changed from Global developmental delay; Intellectual disability; Autistic behavior to Global developmental delay with speech and behavioural abnormalities, MIM# 619243
Intellectual disability syndromic and non-syndromic v0.3562 TNRC6B Zornitza Stark edited their review of gene: TNRC6B: Changed rating: GREEN; Changed phenotypes: Global developmental delay with speech and behavioural abnormalities, MIM# 619243; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3562 KIF11 Zornitza Stark Phenotypes for gene: KIF11 were changed from Microcephaly with or without chorioretinopathy, lymphoedema, or mental retardation, MIM# 152950; MONDO:0007918 to Microcephaly with or without chorioretinopathy, lymphoedema, or mental retardation, MIM# 152950; MONDO:0007918
Intellectual disability syndromic and non-syndromic v0.3561 KIF11 Zornitza Stark Phenotypes for gene: KIF11 were changed from Microcephaly with or without chorioretinopathy, lymphedema, or mental retardation MIM#152950 to Microcephaly with or without chorioretinopathy, lymphoedema, or mental retardation, MIM# 152950; MONDO:0007918
Intellectual disability syndromic and non-syndromic v0.3560 KIF11 Zornitza Stark Publications for gene: KIF11 were set to 24281367
Intellectual disability syndromic and non-syndromic v0.3559 KIF11 Zornitza Stark reviewed gene: KIF11: Rating: GREEN; Mode of pathogenicity: None; Publications: 22284827, 25115524, 25124931, 27212378, 32730767, 31993640, 25996076; Phenotypes: Microcephaly with or without chorioretinopathy, lymphoedema, or mental retardation, MIM# 152950, MONDO:0007918; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3559 IER3IP1 Zornitza Stark Marked gene: IER3IP1 as ready
Intellectual disability syndromic and non-syndromic v0.3559 IER3IP1 Zornitza Stark Gene: ier3ip1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3559 IER3IP1 Zornitza Stark Phenotypes for gene: IER3IP1 were changed from to Microcephaly, epilepsy, and diabetes syndrome, MIM# 614231; Primary microcephaly-epilepsy-permanent neonatal diabetes syndrome, MONDO:0013647
Intellectual disability syndromic and non-syndromic v0.3558 IER3IP1 Zornitza Stark Publications for gene: IER3IP1 were set to
Intellectual disability syndromic and non-syndromic v0.3557 IER3IP1 Zornitza Stark Mode of inheritance for gene: IER3IP1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3556 IER3IP1 Zornitza Stark reviewed gene: IER3IP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 21835305, 22991235, 24138066, 28711742; Phenotypes: Microcephaly, epilepsy, and diabetes syndrome, MIM# 614231, Primary microcephaly-epilepsy-permanent neonatal diabetes syndrome, MONDO:0013647; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3556 EFTUD2 Zornitza Stark Marked gene: EFTUD2 as ready
Intellectual disability syndromic and non-syndromic v0.3556 EFTUD2 Zornitza Stark Gene: eftud2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3556 EFTUD2 Zornitza Stark Phenotypes for gene: EFTUD2 were changed from to Mandibulofacial dysostosis, Guion-Almeida type, MIM# 610536; Mandibulofacial dysostosis-microcephaly syndrome MONDO:0012516
Intellectual disability syndromic and non-syndromic v0.3555 EFTUD2 Zornitza Stark Publications for gene: EFTUD2 were set to
Intellectual disability syndromic and non-syndromic v0.3554 EFTUD2 Zornitza Stark Mode of inheritance for gene: EFTUD2 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3553 EFTUD2 Zornitza Stark reviewed gene: EFTUD2: Rating: GREEN; Mode of pathogenicity: None; Publications: 22305528, 23188108, 33601405, 33262786, 26507355; Phenotypes: Mandibulofacial dysostosis, Guion-Almeida type, MIM# 610536, Mandibulofacial dysostosis-microcephaly syndrome MONDO:0012516; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3553 CEP152 Zornitza Stark Marked gene: CEP152 as ready
Intellectual disability syndromic and non-syndromic v0.3553 CEP152 Zornitza Stark Gene: cep152 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3553 CEP152 Zornitza Stark Phenotypes for gene: CEP152 were changed from to Microcephaly 9, primary, autosomal recessive, MIM# 614852; MONDO:0013923; Seckel syndrome 5, MIM# 613823; MONDO:0013443
Intellectual disability syndromic and non-syndromic v0.3552 CEP152 Zornitza Stark Publications for gene: CEP152 were set to
Intellectual disability syndromic and non-syndromic v0.3551 CEP152 Zornitza Stark Mode of inheritance for gene: CEP152 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3550 CEP152 Zornitza Stark reviewed gene: CEP152: Rating: GREEN; Mode of pathogenicity: None; Publications: 20598275, 22775483, 21131973, 23199753; Phenotypes: Microcephaly 9, primary, autosomal recessive, MIM# 614852, MONDO:0013923, Seckel syndrome 5, MIM# 613823, MONDO:0013443; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3550 CUL3 Zornitza Stark Phenotypes for gene: CUL3 were changed from Global developmental delay; Intellectual disability; Seizures; Abnormality of cardiovascular system morphology; Abnormality of the palate to Neurodevelopmental disorder with or without autism or seizures, MIM# 619239; Global developmental delay; Intellectual disability; Seizures; Abnormality of cardiovascular system morphology; Abnormality of the palate
Intellectual disability syndromic and non-syndromic v0.3549 CUL3 Zornitza Stark reviewed gene: CUL3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with or without autism or seizures, MIM# 619239; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3549 DDB1 Zornitza Stark Publications for gene: DDB1 were set to
Intellectual disability syndromic and non-syndromic v0.3548 DDB1 Sue White reviewed gene: DDB1: Rating: GREEN; Mode of pathogenicity: None; Publications: 33743206; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3548 ZNF711 Zornitza Stark Mode of inheritance for gene: ZNF711 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 v0.3547 ZNF711 Zornitza Stark Marked gene: ZNF711 as ready
Intellectual disability syndromic and non-syndromic v0.3547 ZNF711 Zornitza Stark Gene: znf711 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3547 ZNF711 Zornitza Stark Phenotypes for gene: ZNF711 were changed from to Mental retardation, X-linked 97; OMIM #300803
Intellectual disability syndromic and non-syndromic v0.3546 ZNF711 Zornitza Stark Publications for gene: ZNF711 were set to
Intellectual disability syndromic and non-syndromic v0.3545 ZNF711 Zornitza Stark Mode of inheritance for gene: ZNF711 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 v0.3544 ZNF711 Chirag Patel reviewed gene: ZNF711: Rating: GREEN; Mode of pathogenicity: None; Publications: PubMed: 27993705, 19377476; Phenotypes: Mental retardation, X-linked 97, OMIM #300803; 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 v0.3544 DM1 Bryony Thompson Marked STR: DM1 as ready
Intellectual disability syndromic and non-syndromic v0.3544 DM1 Bryony Thompson Str: dm1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3544 DM1 Bryony Thompson Classified STR: DM1 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.3544 DM1 Bryony Thompson Str: dm1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3543 DM1 Bryony Thompson STR: DM1 was added
STR: DM1 was added to Intellectual disability syndromic and non-syndromic. Sources: Expert list
Mode of inheritance for STR: DM1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for STR: DM1 were set to 20301344; 29325606
Phenotypes for STR: DM1 were set to Myotonic dystrophy 1 MIM#160900
Review for STR: DM1 was set to GREEN
STR: DM1 was marked as clinically relevant
Added comment: HGVS nomenclature: NM_001081560.2:c.*224_*226CTG[X]
RNA toxic gain of function is mechanism of disease
Premutation: 35-49 repeats, no clinical signs
Mild: 50-~150 repeats, age of onset 20-70 yrs, clinical signs - cataracts, mild myotonia
Classic: ~100-~1,000 repeats, age of onset 10-30 yrs, clinical signs - weakness, myotonia, cataracts, balding, cardiac arrhythmia
Congenital: >1,000 repeats, age of onset birth-10 yrs , clinical signs - infantile hypotonia, respiratory deficits, intellectual disability, classic signs in adults
Sources: Expert list
Intellectual disability syndromic and non-syndromic v0.3542 DMPK Bryony Thompson Classified gene: DMPK as No list
Intellectual disability syndromic and non-syndromic v0.3542 DMPK Bryony Thompson Added comment: Comment on list classification: STR is the only cause of condition for this gene and is present in STRs for this panel.
Intellectual disability syndromic and non-syndromic v0.3542 DMPK Bryony Thompson Gene: dmpk has been removed from the panel.
Intellectual disability syndromic and non-syndromic v0.3541 INPP4A Zornitza Stark Marked gene: INPP4A as ready
Intellectual disability syndromic and non-syndromic v0.3541 INPP4A Zornitza Stark Gene: inpp4a has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.3541 INPP4A Zornitza Stark Classified gene: INPP4A as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.3541 INPP4A Zornitza Stark Gene: inpp4a has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.3540 INPP4A Zornitza Stark gene: INPP4A was added
gene: INPP4A was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: INPP4A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: INPP4A were set to 31978615; 31938306; 25338135; 20011524
Phenotypes for gene: INPP4A were set to Intellectual disability
Review for gene: INPP4A was set to AMBER
Added comment: Two families reported with bi-allelic variants and a neurological phenotype. Supportive mouse model and expression data.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.3539 SATB1 Zornitza Stark Phenotypes for gene: SATB1 were changed from Developmental delay with dysmorphic facies and dental anomalies, MIM# 619228; Neurodevelopmental disorder; intellectual disability; epilepsy; microcephaly to Kohlschutter-Tonz syndrome-like, MIM# 619229; Developmental delay with dysmorphic facies and dental anomalies, MIM# 619228; Neurodevelopmental disorder; intellectual disability; epilepsy; microcephaly
Intellectual disability syndromic and non-syndromic v0.3538 SATB1 Zornitza Stark edited their review of gene: SATB1: Changed rating: GREEN
Intellectual disability syndromic and non-syndromic v0.3538 SATB1 Zornitza Stark edited their review of gene: SATB1: Added comment: Kohlschutter-Tonz syndrome-like (KTZSL) is characterized by global developmental delay with moderately to severely impaired intellectual development, poor or absent speech, and delayed motor skills. Although the severity of the disorder varies, many patients are nonverbal and have hypotonia with inability to sit or walk. Early-onset epilepsy is common and may be refractory to treatment, leading to epileptic encephalopathy and further interruption of developmental progress. Most patients have feeding difficulties with poor overall growth and dysmorphic facial features, as well as significant dental anomalies resembling amelogenesis imperfecta. This phenotype was reported in 28 patients (patients 13 to 40, PMID 33513338), including 9 patients from 3 families. Most variants were de novo, though some were inherited, suggestive of incomplete penetrance and variable expressivity.

Developmental delay with dysmorphic facies and dental anomalies (DEFDA) is characterized by generally mild global developmental delay with variably impaired intellectual development, walking by 2 to 3 years, and slow language acquisition. The severity of the disorder ranges from moderate cognitive deficits to mild learning difficulties or behavioral abnormalities. Most patients have dysmorphic facial features, often with abnormal dentition and nonspecific visual defects, such as myopia, astigmatism, and strabismus. Although rare, involvement of other systems, such as skeletal, cardiac, and gastrointestinal, may be present. 12 individuals from 11 families reported (one inherited variant, affected parent).; Changed phenotypes: Kohlschutter-Tonz syndrome-like, MIM# 619229, Developmental delay with dysmorphic facies and dental anomalies, MIM# 619228, Developmental disorders
Intellectual disability syndromic and non-syndromic v0.3538 SATB1 Zornitza Stark Phenotypes for gene: SATB1 were changed from Neurodevelopmental disorder; intellectual disability; epilepsy; microcephaly to Developmental delay with dysmorphic facies and dental anomalies, MIM# 619228; Neurodevelopmental disorder; intellectual disability; epilepsy; microcephaly
Intellectual disability syndromic and non-syndromic v0.3537 SATB1 Zornitza Stark edited their review of gene: SATB1: Changed phenotypes: Developmental delay with dysmorphic facies and dental anomalies, MIM# 619228, Developmental disorders
Intellectual disability syndromic and non-syndromic v0.3537 INPP5E Zornitza Stark Publications for gene: INPP5E were set to 19668216; 32139166; 29230161; 29052317; 27998989; 27401686
Intellectual disability syndromic and non-syndromic v0.3536 INPP5E Zornitza Stark edited their review of gene: INPP5E: Changed publications: 19668216, 32139166, 29230161, 29052317, 27998989, 27401686, 19668215
Intellectual disability syndromic and non-syndromic v0.3536 INPP5E Zornitza Stark Marked gene: INPP5E as ready
Intellectual disability syndromic and non-syndromic v0.3536 INPP5E Zornitza Stark Gene: inpp5e has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3536 INPP5E Zornitza Stark Phenotypes for gene: INPP5E were changed from to Joubert syndrome 1, MIM# 213300; MONDO:0008944; Mental retardation, truncal obesity, retinal dystrophy, and micropenis, MIM# 610156; MONDO:0012423
Intellectual disability syndromic and non-syndromic v0.3535 INPP5E Zornitza Stark Publications for gene: INPP5E were set to
Intellectual disability syndromic and non-syndromic v0.3534 INPP5E Zornitza Stark Mode of inheritance for gene: INPP5E was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3533 INPP5E Zornitza Stark reviewed gene: INPP5E: Rating: GREEN; Mode of pathogenicity: None; Publications: 19668216, 32139166, 29230161, 29052317, 27998989, 27401686; Phenotypes: Joubert syndrome 1, MIM# 213300, MONDO:0008944, Mental retardation, truncal obesity, retinal dystrophy, and micropenis, MIM# 610156, MONDO:0012423; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3533 CSPP1 Zornitza Stark Marked gene: CSPP1 as ready
Intellectual disability syndromic and non-syndromic v0.3533 CSPP1 Zornitza Stark Gene: cspp1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3533 CSPP1 Zornitza Stark Phenotypes for gene: CSPP1 were changed from to Joubert syndrome 21, MIM# 615636; MONDO:0014288
Intellectual disability syndromic and non-syndromic v0.3532 CSPP1 Zornitza Stark Publications for gene: CSPP1 were set to
Intellectual disability syndromic and non-syndromic v0.3531 CSPP1 Zornitza Stark Mode of inheritance for gene: CSPP1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3530 CSPP1 Zornitza Stark reviewed gene: CSPP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 24360808, 24360803, 24360807, 25997910; Phenotypes: Joubert syndrome 21, MIM# 615636, MONDO:0014288; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3530 KDM5B Zornitza Stark edited their review of gene: KDM5B: Changed phenotypes: Mental retardation, autosomal recessive 65 MIM#618109, Intellectual disability and/or autism, autosomal dominant
Intellectual disability syndromic and non-syndromic v0.3530 KDM5B Zornitza Stark Marked gene: KDM5B as ready
Intellectual disability syndromic and non-syndromic v0.3530 KDM5B Zornitza Stark Gene: kdm5b has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3530 KDM5B Zornitza Stark Phenotypes for gene: KDM5B were changed from to Mental retardation, autosomal recessive 65 MIM#618109; Intellectual disability and/or autism, autosomal dominant
Intellectual disability syndromic and non-syndromic v0.3529 KDM5B Zornitza Stark Publications for gene: KDM5B were set to
Intellectual disability syndromic and non-syndromic v0.3528 KDM5B Zornitza Stark Mode of inheritance for gene: KDM5B 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 v0.3527 KDM5B Zornitza Stark reviewed gene: KDM5B: Rating: GREEN; Mode of pathogenicity: None; Publications: 29276005, 30217758, 30409806; Phenotypes: Mental retardation, autosomal recessive 65 MIM#618109, autosomal dominant autism spectrum disorder or intellectual disability; 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 v0.3527 TPP2 Zornitza Stark Marked gene: TPP2 as ready
Intellectual disability syndromic and non-syndromic v0.3527 TPP2 Zornitza Stark Gene: tpp2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3527 TPP2 Zornitza Stark Classified gene: TPP2 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.3527 TPP2 Zornitza Stark Gene: tpp2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3526 TPP2 Zornitza Stark gene: TPP2 was added
gene: TPP2 was added to Intellectual disability syndromic and non-syndromic. Sources: Expert list
Mode of inheritance for gene: TPP2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TPP2 were set to 25525876; 25414442; 33586135; 18362329
Phenotypes for gene: TPP2 were set to Immunodeficiency 78 with autoimmunity and developmental delay, MIM# 619220
Review for gene: TPP2 was set to GREEN
Added comment: Immunodeficiency-78 with autoimmunity and developmental delay (IMD78) is an autosomal recessive systemic disorder characterized by onset of symptoms in early childhood. Affected individuals present with features of immune deficiency, such as recurrent sinopulmonary or skin infections, as well as autoimmunity, including autoimmune cytopenias, hemolytic anemia, and thrombocytopenia. Autoimmune hepatitis or thyroid disease and central nervous system vasculitis with stroke may also occur. There is increased susceptibility to bacterial, viral, and fungal infections. Laboratory studies show lymphopenia with advanced differentiation and premature senescence of CD8+ T cells and B cells; some patients may have hypergammaglobulinemia. The findings indicate immune dysregulation. Patients also have global developmental delay with speech delay and variable intellectual disability. Five unrelated families and a mouse model.
Sources: Expert list
Intellectual disability syndromic and non-syndromic v0.3525 DOCK7 Zornitza Stark Marked gene: DOCK7 as ready
Intellectual disability syndromic and non-syndromic v0.3525 DOCK7 Zornitza Stark Gene: dock7 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3525 DOCK7 Zornitza Stark Phenotypes for gene: DOCK7 were changed from Developmental and epileptic encephalopathy 23 MIM#615859 to Developmental and epileptic encephalopathy 23 MIM#615859; MONDO:0014371
Intellectual disability syndromic and non-syndromic v0.3524 DOCK7 Zornitza Stark Phenotypes for gene: DOCK7 were changed from to Developmental and epileptic encephalopathy 23 MIM#615859
Intellectual disability syndromic and non-syndromic v0.3523 DOCK7 Zornitza Stark Publications for gene: DOCK7 were set to
Intellectual disability syndromic and non-syndromic v0.3522 DOCK7 Zornitza Stark Mode of inheritance for gene: DOCK7 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3521 DOCK7 Paul De Fazio reviewed gene: DOCK7: Rating: GREEN; Mode of pathogenicity: None; Publications: 24814191, 30771731, 30807358; Phenotypes: Developmental and epileptic encephalopathy 23 MIM#615859; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability syndromic and non-syndromic v0.3521 COPB1 Zornitza Stark Marked gene: COPB1 as ready
Intellectual disability syndromic and non-syndromic v0.3521 COPB1 Zornitza Stark Gene: copb1 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.3521 COPB1 Zornitza Stark Classified gene: COPB1 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.3521 COPB1 Zornitza Stark Gene: copb1 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.3520 COPB1 Zornitza Stark gene: COPB1 was added
gene: COPB1 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: COPB1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COPB1 were set to 33632302
Phenotypes for gene: COPB1 were set to Severe intellectual disability; variable microcephaly; cataracts
Review for gene: COPB1 was set to AMBER
Added comment: Two unrelated families, some supportive functional data.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.3519 SLC1A4 Zornitza Stark Phenotypes for gene: SLC1A4 were changed from Spastic tetraplegia, thin corpus callosum, and progressive microcephaly, MIM# 616657 to Spastic tetraplegia, thin corpus callosum, and progressive microcephaly, MIM# 616657; MONDO:0014725
Intellectual disability syndromic and non-syndromic v0.3518 SLC1A4 Zornitza Stark Tag founder tag was added to gene: SLC1A4.
Intellectual disability syndromic and non-syndromic v0.3518 WDR45B Zornitza Stark Marked gene: WDR45B as ready
Intellectual disability syndromic and non-syndromic v0.3518 WDR45B Zornitza Stark Gene: wdr45b has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3518 WDR45B Zornitza Stark Phenotypes for gene: WDR45B were changed from to Neurodevelopmental disorder with spastic quadriplegia and brain abnormalities with or without seizures, MIM# 617977
Intellectual disability syndromic and non-syndromic v0.3517 WDR45B Zornitza Stark Publications for gene: WDR45B were set to
Intellectual disability syndromic and non-syndromic v0.3516 WDR45B Zornitza Stark Mode of inheritance for gene: WDR45B was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3515 WDR45B Zornitza Stark reviewed gene: WDR45B: Rating: GREEN; Mode of pathogenicity: None; Publications: 21937992, 28503735, 27431290; Phenotypes: Neurodevelopmental disorder with spastic quadriplegia and brain abnormalities with or without seizures, MIM# 617977; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3515 NT5C2 Zornitza Stark Marked gene: NT5C2 as ready
Intellectual disability syndromic and non-syndromic v0.3515 NT5C2 Zornitza Stark Gene: nt5c2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3515 NT5C2 Zornitza Stark Phenotypes for gene: NT5C2 were changed from to Spastic paraplegia 45, autosomal recessive, MIM# 613162; MONDO:0013165
Intellectual disability syndromic and non-syndromic v0.3514 NT5C2 Zornitza Stark Publications for gene: NT5C2 were set to
Intellectual disability syndromic and non-syndromic v0.3513 NT5C2 Zornitza Stark Mode of inheritance for gene: NT5C2 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3512 NT5C2 Zornitza Stark reviewed gene: NT5C2: Rating: GREEN; Mode of pathogenicity: None; Publications: 24482476, 32153630, 29123918, 28884889, 28327087; Phenotypes: Spastic paraplegia 45, autosomal recessive, MIM# 613162, MONDO:0013165; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3512 HACE1 Zornitza Stark Marked gene: HACE1 as ready
Intellectual disability syndromic and non-syndromic v0.3512 HACE1 Zornitza Stark Gene: hace1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3512 HACE1 Zornitza Stark Phenotypes for gene: HACE1 were changed from to Spastic paraplegia and psychomotor retardation with or without seizures, 616756; MONDO:0014764
Intellectual disability syndromic and non-syndromic v0.3511 HACE1 Zornitza Stark Publications for gene: HACE1 were set to
Intellectual disability syndromic and non-syndromic v0.3510 HACE1 Zornitza Stark Mode of inheritance for gene: HACE1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3509 HACE1 Zornitza Stark reviewed gene: HACE1: Rating: GREEN; Mode of pathogenicity: None; Publications: 26424145, 26437029, 31321300; Phenotypes: Spastic paraplegia and psychomotor retardation with or without seizures, 616756, MONDO:0014764; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3509 KIDINS220 Zornitza Stark Marked gene: KIDINS220 as ready
Intellectual disability syndromic and non-syndromic v0.3509 KIDINS220 Zornitza Stark Gene: kidins220 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3509 KIDINS220 Zornitza Stark Phenotypes for gene: KIDINS220 were changed from to Spastic paraplegia, intellectual disability, nystagmus, and obesity, MIM# 617296; MONDO:0015007
Intellectual disability syndromic and non-syndromic v0.3508 KIDINS220 Zornitza Stark Publications for gene: KIDINS220 were set to
Intellectual disability syndromic and non-syndromic v0.3507 KIDINS220 Zornitza Stark Mode of inheritance for gene: KIDINS220 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3506 KIDINS220 Zornitza Stark reviewed gene: KIDINS220: Rating: GREEN; Mode of pathogenicity: None; Publications: 27005418, 29667355; Phenotypes: Spastic paraplegia, intellectual disability, nystagmus, and obesity, MIM# 617296, MONDO:0015007; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3506 KDM5C Zornitza Stark Marked gene: KDM5C as ready
Intellectual disability syndromic and non-syndromic v0.3506 KDM5C Zornitza Stark Gene: kdm5c has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3506 KDM5C Zornitza Stark Phenotypes for gene: KDM5C were changed from to Mental retardation, X-linked, syndromic, Claes-Jensen type, MIM# 300534; MONDO:0010355
Intellectual disability syndromic and non-syndromic v0.3505 KDM5C Zornitza Stark Publications for gene: KDM5C were set to
Intellectual disability syndromic and non-syndromic v0.3504 KDM5C Zornitza Stark Mode of inheritance for gene: KDM5C 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 v0.3503 KDM5C Zornitza Stark reviewed gene: KDM5C: Rating: GREEN; Mode of pathogenicity: None; Publications: 15586325, 32279304; Phenotypes: Mental retardation, X-linked, syndromic, Claes-Jensen type, MIM# 300534, MONDO:0010355; 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 v0.3503 AP4M1 Zornitza Stark Marked gene: AP4M1 as ready
Intellectual disability syndromic and non-syndromic v0.3503 AP4M1 Zornitza Stark Gene: ap4m1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3503 AP4M1 Zornitza Stark Phenotypes for gene: AP4M1 were changed from to Spastic paraplegia 50, autosomal recessive, MIM# 612936
Intellectual disability syndromic and non-syndromic v0.3502 AP4M1 Zornitza Stark Publications for gene: AP4M1 were set to
Intellectual disability syndromic and non-syndromic v0.3501 AP4M1 Zornitza Stark Mode of inheritance for gene: AP4M1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3500 AP4M1 Zornitza Stark reviewed gene: AP4M1: Rating: GREEN; Mode of pathogenicity: None; Publications: 19559397, 21937992, 21937992, 32979048, 31915823, 29096665, 28464862, 25496299; Phenotypes: Spastic paraplegia 50, autosomal recessive, MIM# 612936; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3500 AP4B1 Zornitza Stark Marked gene: AP4B1 as ready
Intellectual disability syndromic and non-syndromic v0.3500 AP4B1 Zornitza Stark Gene: ap4b1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3500 AP4B1 Zornitza Stark Phenotypes for gene: AP4B1 were changed from to Spastic paraplegia 47, autosomal recessive, MIM# 614066
Intellectual disability syndromic and non-syndromic v0.3499 AP4B1 Zornitza Stark Publications for gene: AP4B1 were set to
Intellectual disability syndromic and non-syndromic v0.3498 AP4B1 Zornitza Stark Mode of inheritance for gene: AP4B1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3497 AP4B1 Zornitza Stark reviewed gene: AP4B1: Rating: GREEN; Mode of pathogenicity: None; Publications: 21620353, 22290197, 24700674, 24781758, 32979048, 32171285, 32166732, 31525725, 31525725; Phenotypes: Spastic paraplegia 47, autosomal recessive, MIM# 614066; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3497 AP4S1 Zornitza Stark Marked gene: AP4S1 as ready
Intellectual disability syndromic and non-syndromic v0.3497 AP4S1 Zornitza Stark Gene: ap4s1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3497 AP4S1 Zornitza Stark Phenotypes for gene: AP4S1 were changed from to Spastic paraplegia 52, autosomal recessive, MIM# 614067
Intellectual disability syndromic and non-syndromic v0.3496 AP4S1 Zornitza Stark Publications for gene: AP4S1 were set to
Intellectual disability syndromic and non-syndromic v0.3495 AP4S1 Zornitza Stark Mode of inheritance for gene: AP4S1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3494 AP4S1 Zornitza Stark reviewed gene: AP4S1: Rating: GREEN; Mode of pathogenicity: None; Publications: 21620353, 25552650, 32979048, 32216065, 31915823, 30283821, 27444738; Phenotypes: Spastic paraplegia 52, autosomal recessive, MIM# 614067; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3494 AIMP1 Zornitza Stark Marked gene: AIMP1 as ready
Intellectual disability syndromic and non-syndromic v0.3494 AIMP1 Zornitza Stark Gene: aimp1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3494 AIMP1 Zornitza Stark Phenotypes for gene: AIMP1 were changed from to Intellectual disability; Leukodystrophy, hypomyelinating, 3, MIM# 260600
Intellectual disability syndromic and non-syndromic v0.3493 AIMP1 Zornitza Stark Publications for gene: AIMP1 were set to
Intellectual disability syndromic and non-syndromic v0.3492 AIMP1 Zornitza Stark Mode of inheritance for gene: AIMP1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3491 AIMP1 Zornitza Stark reviewed gene: AIMP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 26173967, 21092922, 24958424, 33402283, 32531460, 30486714, 30477741; Phenotypes: Intellectual disability, Leukodystrophy, hypomyelinating, 3, MIM# 260600; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3491 CC2D1A Zornitza Stark Marked gene: CC2D1A as ready
Intellectual disability syndromic and non-syndromic v0.3491 CC2D1A Zornitza Stark Gene: cc2d1a has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3491 CC2D1A Zornitza Stark Phenotypes for gene: CC2D1A were changed from to Autosomal recessive mental retardation, (MIM#608443)
Intellectual disability syndromic and non-syndromic v0.3490 CC2D1A Zornitza Stark Publications for gene: CC2D1A were set to
Intellectual disability syndromic and non-syndromic v0.3489 CC2D1A Zornitza Stark Mode of inheritance for gene: CC2D1A was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3488 CC2D1A Michelle Torres edited their review of gene: CC2D1A: Added comment: 7 NMD predicted reported, no missense (ClinVar, Decipher, LOVD, PMID: 25066123). Severity of ID and presence of cognitive and social features, as well as seizures is variable inter and intra-familial (PMID: 25066123).; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3488 CC2D1A Michelle Torres reviewed gene: CC2D1A: Rating: GREEN; Mode of pathogenicity: None; Publications: 25066123; Phenotypes: Autosomal recessive mental retardation, (MIM#608443), AR; Mode of inheritance: None
Intellectual disability syndromic and non-syndromic v0.3488 CDK5RAP2 Zornitza Stark Marked gene: CDK5RAP2 as ready
Intellectual disability syndromic and non-syndromic v0.3488 CDK5RAP2 Zornitza Stark Gene: cdk5rap2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3488 CDK5RAP2 Zornitza Stark Phenotypes for gene: CDK5RAP2 were changed from to Microcephaly 3, primary, autosomal recessive, MIM# 604804; MONDO:0011488
Intellectual disability syndromic and non-syndromic v0.3487 CDK5RAP2 Zornitza Stark Publications for gene: CDK5RAP2 were set to
Intellectual disability syndromic and non-syndromic v0.3486 CDK5RAP2 Zornitza Stark Mode of inheritance for gene: CDK5RAP2 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3485 CDK5RAP2 Zornitza Stark reviewed gene: CDK5RAP2: Rating: GREEN; Mode of pathogenicity: None; Publications: 15793586, 22887808, 23995685, 23726037, 27761245, 20460369, 32677750, 32015000; Phenotypes: Microcephaly 3, primary, autosomal recessive, MIM# 604804, MONDO:0011488; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3485 PGK1 Zornitza Stark Marked gene: PGK1 as ready
Intellectual disability syndromic and non-syndromic v0.3485 PGK1 Zornitza Stark Gene: pgk1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3485 PGK1 Zornitza Stark Phenotypes for gene: PGK1 were changed from to Phosphoglycerate kinase 1 deficiency, MIM# 300653; MONDO:0010392
Intellectual disability syndromic and non-syndromic v0.3484 PGK1 Zornitza Stark Mode of inheritance for gene: PGK1 was changed from Unknown to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability syndromic and non-syndromic v0.3483 PGK1 Zornitza Stark reviewed gene: PGK1: Rating: GREEN; Mode of pathogenicity: None; Publications: 6933565, 1547346, 7577653, 9512313; Phenotypes: Phosphoglycerate kinase 1 deficiency, MIM# 300653; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability syndromic and non-syndromic v0.3483 SIAH1 Zornitza Stark Marked gene: SIAH1 as ready
Intellectual disability syndromic and non-syndromic v0.3483 SIAH1 Zornitza Stark Gene: siah1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3483 SIAH1 Zornitza Stark Classified gene: SIAH1 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.3483 SIAH1 Zornitza Stark Gene: siah1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3482 SIAH1 Zornitza Stark gene: SIAH1 was added
gene: SIAH1 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: SIAH1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SIAH1 were set to 32430360
Phenotypes for gene: SIAH1 were set to Developmental delay; Infantile hypotonia; Dysmorphic features; Laryngomalacia
Review for gene: SIAH1 was set to GREEN
Added comment: - PMID: 32430360 (2021) - Five unrelated individuals with shared features of developmental delay, infantile hypotonia, dysmorphic features and laryngomalacia. All had speech delay and where cognitive assessment was age appropriate individuals exhibited learning difficulties. Trio WES revealed distinct de novo variants in SIAH1. In vitro assays demonstrated that SIAH1 mutants induce loss of Wnt stimulatory activity.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.3481 EEF2 Zornitza Stark Marked gene: EEF2 as ready
Intellectual disability syndromic and non-syndromic v0.3481 EEF2 Zornitza Stark Gene: eef2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3481 EEF2 Zornitza Stark Classified gene: EEF2 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.3481 EEF2 Zornitza Stark Gene: eef2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3480 EEF2 Zornitza Stark gene: EEF2 was added
gene: EEF2 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: EEF2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: EEF2 were set to 33355653
Phenotypes for gene: EEF2 were set to Neurodevelopmental disorder; macrocephaly; hydrocephalus
Review for gene: EEF2 was set to GREEN
Added comment: De novo EEF2 missense variants reported in 3 unrelated children (3, 6 and 9 years of age) with a mild neurodevelopmental phenotype comprising motor delay and relative macrocephaly associated with ventriculomegaly.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.3479 DLK1 Zornitza Stark Marked gene: DLK1 as ready
Intellectual disability syndromic and non-syndromic v0.3479 DLK1 Zornitza Stark Added comment: Comment when marking as ready: Association with central precocious puberty but not ID.
Intellectual disability syndromic and non-syndromic v0.3479 DLK1 Zornitza Stark Gene: dlk1 has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v0.3479 DLK1 Zornitza Stark Classified gene: DLK1 as Red List (low evidence)
Intellectual disability syndromic and non-syndromic v0.3479 DLK1 Zornitza Stark Gene: dlk1 has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v0.3478 DLK1 Zornitza Stark Publications for gene: DLK1 were set to PMID: 28324015
Intellectual disability syndromic and non-syndromic v0.3477 DLK1 Zornitza Stark Classified gene: DLK1 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.3477 DLK1 Zornitza Stark Gene: dlk1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3476 DLK1 Natasha Brown reviewed gene: DLK1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 28324015, PMID: 30462238; Phenotypes: central precocious puberty; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, maternally imprinted (paternal allele expressed)
Intellectual disability syndromic and non-syndromic v0.3476 DLK1 Natasha Brown Source Genetic Health Queensland was removed from DLK1.
Source Literature was added to DLK1.
Mode of inheritance for gene DLK1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, maternally imprinted (paternal allele expressed)
Phenotypes for gene: DLK1 were changed from to central precocious puberty
Penetrance for gene DLK1 was set from to None
Publications for gene DLK1 were changed from PMID: 28324015 to PMID: 28324015
Intellectual disability syndromic and non-syndromic v0.3475 EIF5A Zornitza Stark Marked gene: EIF5A as ready
Intellectual disability syndromic and non-syndromic v0.3475 EIF5A Zornitza Stark Gene: eif5a has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3475 EIF5A Zornitza Stark Classified gene: EIF5A as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.3475 EIF5A Zornitza Stark Gene: eif5a has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3474 EIF5A Zornitza Stark gene: EIF5A was added
gene: EIF5A was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: EIF5A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: EIF5A were set to 33547280
Phenotypes for gene: EIF5A were set to Intellectual disability; microcephaly; dysmorphism
Review for gene: EIF5A was set to GREEN
Added comment: 7 unrelated individuals reported with de novo variants in this gene and variable combinations of developmental delay, microcephaly, micrognathia and dysmorphism.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.3473 POLRMT Zornitza Stark Marked gene: POLRMT as ready
Intellectual disability syndromic and non-syndromic v0.3473 POLRMT Zornitza Stark Gene: polrmt has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3473 POLRMT Zornitza Stark Classified gene: POLRMT as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.3473 POLRMT Zornitza Stark Gene: polrmt has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3472 POLRMT Zornitza Stark gene: POLRMT was added
gene: POLRMT was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: POLRMT was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: POLRMT were set to 33602924
Phenotypes for gene: POLRMT were set to Mitochondrial disorder; intellectual disability; hypotonia
Review for gene: POLRMT was set to GREEN
Added comment: 8 individuals from 7 families reported. 5 families with bi-allelic variants and 2 with heterozygous variants. Affected individuals presented with global developmental delay, hypotonia, short stature, and speech/intellectual disability in childhood; one subject displayed an indolent progressive external ophthalmoplegia phenotype.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.3471 KARS Zornitza Stark Phenotypes for gene: KARS were changed from Leukoencephalopathy with or without deafness (LEPID), MIM#619147; Combined mitochondrial oxidative phosphorylation deficiency; epilepsy; intellectual disability; microcephaly to Leukoencephalopathy with or without deafness (LEPID), MIM#619147; Combined mitochondrial oxidative phosphorylation deficiency; epilepsy; intellectual disability; microcephaly
Intellectual disability syndromic and non-syndromic v0.3471 KARS Zornitza Stark Phenotypes for gene: KARS were changed from Combined mitochondrial oxidative phosphorylation deficiency; epilepsy; intellectual disability; microcephaly to Leukoencephalopathy with or without deafness (LEPID), MIM#619147; Combined mitochondrial oxidative phosphorylation deficiency; epilepsy; intellectual disability; microcephaly
Intellectual disability syndromic and non-syndromic v0.3470 KARS Zornitza Stark edited their review of gene: KARS: Changed phenotypes: Leukoencephalopathy with or without deafness (LEPID), MIM#619147, Combined mitochondrial oxidative phosphorylation deficiency, epilepsy, intellectual disability, microcephaly
Intellectual disability syndromic and non-syndromic v0.3470 SPEN Zornitza Stark Phenotypes for gene: SPEN were changed from Developmental disorders to Intellectual disability; autism; congenital anomalies
Intellectual disability syndromic and non-syndromic v0.3469 SPEN Alison Yeung Classified gene: SPEN as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.3469 SPEN Alison Yeung Gene: spen has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3469 SPEN Alison Yeung Classified gene: SPEN as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.3469 SPEN Alison Yeung Gene: spen has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3468 MED27 Alison Yeung Marked gene: MED27 as ready
Intellectual disability syndromic and non-syndromic v0.3468 MED27 Alison Yeung Gene: med27 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3468 MED27 Alison Yeung Classified gene: MED27 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.3468 MED27 Alison Yeung Gene: med27 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3467 MED27 Alison Yeung gene: MED27 was added
gene: MED27 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: MED27 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MED27 were set to 33443317
Phenotypes for gene: MED27 were set to Intellectual disability; cerebellar hypoplasia; dystonia
Review for gene: MED27 was set to GREEN
gene: MED27 was marked as current diagnostic
Added comment: 16 patients from 11 families reported
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.3466 SPEN Chern Lim reviewed gene: SPEN: Rating: GREEN; Mode of pathogenicity: None; Publications: 33596411; Phenotypes: Developmental delay/intellectual disability, autism spectrum disorder, anxiety, aggressive behavior, attention deficit disorder, hypotonia, brain and spine anomalies, congenital heart defects, high/narrow palate, facial dysmorphisms, and obesity/increased BMI; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Intellectual disability syndromic and non-syndromic v0.3466 FOXP2 Zornitza Stark Marked gene: FOXP2 as ready
Intellectual disability syndromic and non-syndromic v0.3466 FOXP2 Zornitza Stark Gene: foxp2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3466 FOXP2 Zornitza Stark Phenotypes for gene: FOXP2 were changed from to Speech-language disorder-1, MIM# 602081
Intellectual disability syndromic and non-syndromic v0.3465 FOXP2 Zornitza Stark Publications for gene: FOXP2 were set to
Intellectual disability syndromic and non-syndromic v0.3464 FOXP2 Zornitza Stark Mode of inheritance for gene: FOXP2 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3463 FOXP2 Zornitza Stark reviewed gene: FOXP2: Rating: GREEN; Mode of pathogenicity: None; Publications: 15877281, 15983371, 27336128; Phenotypes: Speech-language disorder-1, MIM# 602081; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3463 TOGARAM1 Zornitza Stark Marked gene: TOGARAM1 as ready
Intellectual disability syndromic and non-syndromic v0.3463 TOGARAM1 Zornitza Stark Gene: togaram1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3463 TOGARAM1 Zornitza Stark Classified gene: TOGARAM1 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.3463 TOGARAM1 Zornitza Stark Gene: togaram1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3462 TOGARAM1 Zornitza Stark gene: TOGARAM1 was added
gene: TOGARAM1 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: TOGARAM1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TOGARAM1 were set to 32747439; 32453716
Phenotypes for gene: TOGARAM1 were set to Joubert syndrome 37, MIM# 619185
Review for gene: TOGARAM1 was set to GREEN
Added comment: Six families reported with features of ciliopathy, including molar tooth sign consistent with Joubert syndrome. In some of the families the disorder presented prenatally; however, severe ID in survivors including absent speech.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.3461 HS2ST1 Zornitza Stark Phenotypes for gene: HS2ST1 were changed from Intellectual disability; dysmorphic features; congenital anomalies to Neurofacioskeletal syndrome with or without renal agenesis, MIM#619194; Intellectual disability; dysmorphic features; congenital anomalies
Intellectual disability syndromic and non-syndromic v0.3460 HS2ST1 Zornitza Stark reviewed gene: HS2ST1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurofacioskeletal syndrome with or without renal agenesis, MIM#619194; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3460 UBR7 Zornitza Stark Phenotypes for gene: UBR7 were changed from Intellectual disability; epilepsy; hypothyroidism; congenital anomalies; dysmorphic features to Li-Campeau syndrome, MIM# 619189; Intellectual disability; epilepsy; hypothyroidism; congenital anomalies; dysmorphic features
Intellectual disability syndromic and non-syndromic v0.3459 UBR7 Zornitza Stark edited their review of gene: UBR7: Changed phenotypes: Li-Campeau syndrome, MIM# 619189, Intellectual disability, epilepsy, hypothyroidism, congenital anomalies, dysmorphic features
Intellectual disability syndromic and non-syndromic v0.3459 ZNF292 Zornitza Stark Phenotypes for gene: ZNF292 were changed from Intellectual disability; autism; ADHD to Intellectual developmental disorder, autosomal dominant 63, MIM# 619188; Intellectual disability; autism; ADHD
Intellectual disability syndromic and non-syndromic v0.3458 ZNF292 Zornitza Stark Deleted their comment
Intellectual disability syndromic and non-syndromic v0.3458 ZNF292 Zornitza Stark edited their review of gene: ZNF292: Changed rating: GREEN; Changed phenotypes: Intellectual developmental disorder, autosomal dominant 63, MIM# 619188; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3458 LMNB2 Zornitza Stark Phenotypes for gene: LMNB2 were changed from Congenital microcephaly; Global developmental delay; Intellectual disability to Microcephaly 27, primary, autosomal dominant, MIM# 619180; Congenital microcephaly; Global developmental delay; Intellectual disability
Intellectual disability syndromic and non-syndromic v0.3457 LMNB2 Zornitza Stark reviewed gene: LMNB2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Microcephaly 27, primary, autosomal dominant, MIM# 619180; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3457 LMNB1 Zornitza Stark Phenotypes for gene: LMNB1 were changed from Global developmental delay, Intellectual disability, Microcephaly, Short stature, Seizures, Abnormality of the corpus callosum, Cortical gyral simplification, Feeding difficulties, Scoliosis; Leukodystrophy, adult-onset, autosomal dominant, MIM#169500 to Microcephaly 26, primary, autosomal dominant, MIM# 619179; Global developmental delay, Intellectual disability, Microcephaly, Short stature, Seizures, Abnormality of the corpus callosum, Cortical gyral simplification, Feeding difficulties, Scoliosis; Leukodystrophy, adult-onset, autosomal dominant, MIM#169500
Intellectual disability syndromic and non-syndromic v0.3456 FGF13 Zornitza Stark Phenotypes for gene: FGF13 were changed from Intellectual disability; epilepsy to Developmental and epileptic encephalopathy 90, MIM# 301058; Intellectual disability; epilepsy
Intellectual disability syndromic and non-syndromic v0.3455 FGF13 Zornitza Stark edited their review of gene: FGF13: Changed phenotypes: Developmental and epileptic encephalopathy 90, MIM# 301058, Intellectual disability, epilepsy
Intellectual disability syndromic and non-syndromic v0.3455 MSL3 Zornitza Stark Marked gene: MSL3 as ready
Intellectual disability syndromic and non-syndromic v0.3455 MSL3 Zornitza Stark Gene: msl3 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3455 MSL3 Zornitza Stark Phenotypes for gene: MSL3 were changed from to Basilicata-Akhtar syndrome, OMIM # 301032
Intellectual disability syndromic and non-syndromic v0.3454 MSL3 Zornitza Stark Publications for gene: MSL3 were set to
Intellectual disability syndromic and non-syndromic v0.3453 MSL3 Zornitza Stark Mode of inheritance for gene: MSL3 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 v0.3452 MSL3 Zornitza Stark Deleted their comment
Intellectual disability syndromic and non-syndromic v0.3452 MSL3 Zornitza Stark commented on gene: MSL3: Well established ID gene. 2021 paper documents findings in 25 individuals. Variants found to be clustering in the terminal eight exons suggesting that truncating variants in the first five exons might be compensated by an alternative MSL3 transcript. Three-dimensional modeling of missense and splice variants indicated that these have a deleterious effect. The main clinical findings comprised developmental delay and intellectual disability ranging from mild to severe. Autism spectrum disorder, muscle tone abnormalities, and macrocephaly were common as well as hearing impairment and gastrointestinal problems. Hypoplasia of the cerebellar vermis emerged as a consistent magnetic resonance image (MRI) finding.
Intellectual disability syndromic and non-syndromic v0.3452 MSL3 Zornitza Stark reviewed gene: MSL3: Rating: GREEN; Mode of pathogenicity: None; Publications: 33173220; Phenotypes: Basilicata-Akhtar syndrome, OMIM # 301032; 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 v0.3452 TOE1 Zornitza Stark Marked gene: TOE1 as ready
Intellectual disability syndromic and non-syndromic v0.3452 TOE1 Zornitza Stark Gene: toe1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3452 TOE1 Zornitza Stark Phenotypes for gene: TOE1 were changed from to Pontocerebellar hypoplasia, type 7, MIM# 614969
Intellectual disability syndromic and non-syndromic v0.3451 TOE1 Zornitza Stark Publications for gene: TOE1 were set to
Intellectual disability syndromic and non-syndromic v0.3450 TOE1 Zornitza Stark Mode of inheritance for gene: TOE1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3449 TOE1 Zornitza Stark reviewed gene: TOE1: Rating: GREEN; Mode of pathogenicity: None; Publications: 28092684; Phenotypes: Pontocerebellar hypoplasia, type 7, MIM# 614969; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3449 CLP1 Zornitza Stark Marked gene: CLP1 as ready
Intellectual disability syndromic and non-syndromic v0.3449 CLP1 Zornitza Stark Gene: clp1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3449 CLP1 Zornitza Stark Phenotypes for gene: CLP1 were changed from to Pontocerebellar hypoplasia type 10, MIM# 615803
Intellectual disability syndromic and non-syndromic v0.3448 CLP1 Zornitza Stark Publications for gene: CLP1 were set to
Intellectual disability syndromic and non-syndromic v0.3447 CLP1 Zornitza Stark Mode of inheritance for gene: CLP1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3446 CLP1 Zornitza Stark Tag founder tag was added to gene: CLP1.
Intellectual disability syndromic and non-syndromic v0.3446 CLP1 Zornitza Stark reviewed gene: CLP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 24766809, 29307788; Phenotypes: Pontocerebellar hypoplasia type 10, MIM# 615803; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3446 CHMP1A Zornitza Stark Marked gene: CHMP1A as ready
Intellectual disability syndromic and non-syndromic v0.3446 CHMP1A Zornitza Stark Gene: chmp1a has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3446 CHMP1A Zornitza Stark Phenotypes for gene: CHMP1A were changed from to Pontocerebellar hypoplasia, type 8, MIM# 614961
Intellectual disability syndromic and non-syndromic v0.3445 CHMP1A Zornitza Stark Publications for gene: CHMP1A were set to
Intellectual disability syndromic and non-syndromic v0.3444 CHMP1A Zornitza Stark Mode of inheritance for gene: CHMP1A was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3443 CHMP1A Zornitza Stark reviewed gene: CHMP1A: Rating: GREEN; Mode of pathogenicity: None; Publications: 23023333; Phenotypes: Pontocerebellar hypoplasia, type 8, MIM# 614961; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3443 BRF1 Zornitza Stark Marked gene: BRF1 as ready
Intellectual disability syndromic and non-syndromic v0.3443 BRF1 Zornitza Stark Gene: brf1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3443 BRF1 Zornitza Stark Phenotypes for gene: BRF1 were changed from to Cerebellofaciodental syndrome, MIM# 616202
Intellectual disability syndromic and non-syndromic v0.3442 BRF1 Zornitza Stark Publications for gene: BRF1 were set to
Intellectual disability syndromic and non-syndromic v0.3441 BRF1 Zornitza Stark Mode of inheritance for gene: BRF1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3440 BRF1 Zornitza Stark reviewed gene: BRF1: Rating: GREEN; Mode of pathogenicity: None; Publications: 25561519, 25561519, 27748960; Phenotypes: Cerebellofaciodental syndrome, MIM# 616202; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3440 CLCN6 Zornitza Stark Phenotypes for gene: CLCN6 were changed from Developmental delay; neurodegeneration to Neurodegeneration, childhood-onset, hypotonia, respiratory insufficiency and brain imaging abnormalities, MIM# 619173; Developmental delay; neurodegeneration
Intellectual disability syndromic and non-syndromic v0.3439 CLCN6 Zornitza Stark edited their review of gene: CLCN6: Changed phenotypes: Neurodegeneration, childhood-onset, hypotonia, respiratory insufficiency and brain imaging abnormalities, MIM# 619173, Developmental delay, neurodegeneration
Intellectual disability syndromic and non-syndromic v0.3439 OTUD5 Zornitza Stark Phenotypes for gene: OTUD5 were changed from X-linked severe neurodevelopmental delay, hydrocephalus, and early lethality to Multiple congenital anomalies-neurodevelopmental syndrome, X-linked, MIM# 301056
Intellectual disability syndromic and non-syndromic v0.3438 OTUD5 Zornitza Stark Publications for gene: OTUD5 were set to PMID: 33131077
Intellectual disability syndromic and non-syndromic v0.3437 OTUD5 Zornitza Stark Classified gene: OTUD5 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.3437 OTUD5 Zornitza Stark Gene: otud5 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3436 OTUD5 Zornitza Stark reviewed gene: OTUD5: Rating: GREEN; Mode of pathogenicity: None; Publications: 33523931; Phenotypes: Multiple congenital anomalies-neurodevelopmental syndrome, X-linked, MIM# 301056; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability syndromic and non-syndromic v0.3436 SLC46A1 Zornitza Stark Marked gene: SLC46A1 as ready
Intellectual disability syndromic and non-syndromic v0.3436 SLC46A1 Zornitza Stark Gene: slc46a1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3436 SLC46A1 Zornitza Stark Phenotypes for gene: SLC46A1 were changed from to Folate malabsorption, hereditary, MIM# 229050
Intellectual disability syndromic and non-syndromic v0.3435 SLC46A1 Zornitza Stark Publications for gene: SLC46A1 were set to
Intellectual disability syndromic and non-syndromic v0.3434 SLC46A1 Zornitza Stark Mode of inheritance for gene: SLC46A1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3433 SLC46A1 Zornitza Stark reviewed gene: SLC46A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 17446347, 17129779, 21333572; Phenotypes: Folate malabsorption, hereditary, MIM# 229050; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3433 PRUNE1 Zornitza Stark Marked gene: PRUNE1 as ready
Intellectual disability syndromic and non-syndromic v0.3433 PRUNE1 Zornitza Stark Gene: prune1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3433 PRUNE1 Zornitza Stark Phenotypes for gene: PRUNE1 were changed from to Neurodevelopmental disorder with microcephaly, hypotonia, and variable brain anomalies , MIM#617481
Intellectual disability syndromic and non-syndromic v0.3432 PRUNE1 Zornitza Stark Publications for gene: PRUNE1 were set to
Intellectual disability syndromic and non-syndromic v0.3431 PRUNE1 Zornitza Stark Mode of inheritance for gene: PRUNE1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3430 PRUNE1 Zornitza Stark reviewed gene: PRUNE1: Rating: GREEN; Mode of pathogenicity: None; Publications: 26539891, 28334956, 33105479; Phenotypes: Neurodevelopmental disorder with microcephaly, hypotonia, and variable brain anomalies , MIM#617481; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3430 TRIM8 Zornitza Stark Phenotypes for gene: TRIM8 were changed from Intellectual disability; Seizures to Intellectual disability; Seizures; FSGS
Intellectual disability syndromic and non-syndromic v0.3429 TRIM8 Zornitza Stark Publications for gene: TRIM8 were set to 30244534; 27346735; 23934111
Intellectual disability syndromic and non-syndromic v0.3428 TRIM8 Zornitza Stark edited their review of gene: TRIM8: Added comment: Further 10 families reported.; Changed publications: 30244534, 27346735, 23934111, 33508234; Changed phenotypes: Intellectual disability, Seizures, FSGS
Intellectual disability syndromic and non-syndromic v0.3428 PIGF Zornitza Stark Marked gene: PIGF as ready
Intellectual disability syndromic and non-syndromic v0.3428 PIGF Zornitza Stark Gene: pigf has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v0.3428 PIGF Zornitza Stark Classified gene: PIGF as Red List (low evidence)
Intellectual disability syndromic and non-syndromic v0.3428 PIGF Zornitza Stark Gene: pigf has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v0.3427 PIGF Paul De Fazio gene: PIGF was added
gene: PIGF was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: PIGF was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PIGF were set to 33386993
Phenotypes for gene: PIGF were set to Glycosylphosphatidylinositol deficiency, onychodystrophy, osteodystrophy, intellectual disability, and seizures
Review for gene: PIGF was set to RED
gene: PIGF was marked as current diagnostic
Added comment: The same homozygous missense variant identified in 2 individuals from different families from the same region of India. Individuals had a phenotype similar to DOORS syndrome without deafness. Impaired glycosylphosphatidylinositol (GPI) biosynthesis was demonstrated.

Rated Red as the two families are likely to be related (founder mutation?).
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.3427 HIRA Zornitza Stark Marked gene: HIRA as ready
Intellectual disability syndromic and non-syndromic v0.3427 HIRA Zornitza Stark Gene: hira has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3427 HIRA Zornitza Stark Classified gene: HIRA as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.3427 HIRA Zornitza Stark Gene: hira has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3426 HIRA Paul De Fazio gene: HIRA was added
gene: HIRA was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: HIRA was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: HIRA were set to 33417013; 28135719; 25363760
Phenotypes for gene: HIRA were set to Neurodevelopmental disorder
Review for gene: HIRA was set to GREEN
gene: HIRA was marked as current diagnostic
Added comment: Two unrelated patients with different de novo loss of function variants identified in PMID 33417013:

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

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

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

Rated Green due to 4 unrelated individuals (albeit 2 in large cohort studies) and a mouse model. NB: HIRA is within the common 22q deletion region.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.3426 OTUD5 Zornitza Stark Marked gene: OTUD5 as ready
Intellectual disability syndromic and non-syndromic v0.3426 OTUD5 Zornitza Stark Gene: otud5 has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v0.3426 METAP1 Sebastian Lunke Marked gene: METAP1 as ready
Intellectual disability syndromic and non-syndromic v0.3426 METAP1 Sebastian Lunke Gene: metap1 has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v0.3426 METAP1 Sebastian Lunke Classified gene: METAP1 as Red List (low evidence)
Intellectual disability syndromic and non-syndromic v0.3426 METAP1 Sebastian Lunke Gene: metap1 has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v0.3425 SATB1 Zornitza Stark Phenotypes for gene: SATB1 were changed from Developmental disorders to Neurodevelopmental disorder; intellectual disability; epilepsy; microcephaly
Intellectual disability syndromic and non-syndromic v0.3424 KCNN2 Sebastian Lunke Marked gene: KCNN2 as ready
Intellectual disability syndromic and non-syndromic v0.3424 KCNN2 Sebastian Lunke Gene: kcnn2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3424 KCNN2 Sebastian Lunke Phenotypes for gene: KCNN2 were changed from neurodevelopmental movement disorders to Neurodevelopmental movement disorders; Developmental Delay; Seizures
Intellectual disability syndromic and non-syndromic v0.3423 KCNN2 Sebastian Lunke Classified gene: KCNN2 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.3423 KCNN2 Sebastian Lunke Gene: kcnn2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3422 SATB1 Zornitza Stark Publications for gene: SATB1 were set to 33057194
Intellectual disability syndromic and non-syndromic v0.3421 SATB1 Zornitza Stark Classified gene: SATB1 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.3421 SATB1 Zornitza Stark Gene: satb1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3420 METAP1 Paul De Fazio gene: METAP1 was added
gene: METAP1 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: METAP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: METAP1 were set to 32764695
Phenotypes for gene: METAP1 were set to Intellectual disability, aggression, neurodevelopmental delay
Review for gene: METAP1 was set to RED
gene: METAP1 was marked as current diagnostic
Added comment: Biallelic nonsense (NMD-predicted) variant identified in 4 sibs in a consanguineous family with dev delay. One sib had bilateral clinodactyly of her toes and her left 3rd finger, other sibs were not dysmorphic. Rated red due to single consanguineous family.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.3420 SATB1 Elena Savva reviewed gene: SATB1: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID: 33513338, 33057194; Phenotypes: Neurodevelopmental disorders; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability syndromic and non-syndromic v0.3420 KCNN2 Ain Roesley gene: KCNN2 was added
gene: KCNN2 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: KCNN2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: KCNN2 were set to 33242881
Phenotypes for gene: KCNN2 were set to neurodevelopmental movement disorders
Penetrance for gene: KCNN2 were set to unknown
Review for gene: KCNN2 was set to GREEN
Added comment: - 11 probands all de novo except for 1 mother-daughter pair.
- a mix of null and missense variants
- 2/11 with microcephaly, 10/11 motor delay, 7/11 language delay (excluding 2 with regression), all with varying degrees of ID, 3/11 seizures, 7/11 movement disorder, 4/11 cerebellar ataxia, 6/11 MRI anomalies

additional variants were noted in 2 patients: 1x cHet for variants in MED12L and 1x de novo TNK2 variant

patch clamp functional studies were also done
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.3420 OTUD5 Chirag Patel gene: OTUD5 was added
gene: OTUD5 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: OTUD5 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: OTUD5 were set to PMID: 33131077
Phenotypes for gene: OTUD5 were set to X-linked severe neurodevelopmental delay, hydrocephalus, and early lethality
Review for gene: OTUD5 was set to RED
Added comment: 13 male patients from a single family with three generations affected. Patients presented prenatally or during the neonatal period with IUGR, ventriculomegaly, hydrocephalus, hypotonia, congenital heart defects, hypospadias, and severe neurodevelopmental delay. The disease is typically fatal during infancy, mainly due to sepsis (pneumonias). Female carriers are asymptomatic. WGS in four individuals identified a unique candidate variant in the OTUD5 gene (NM_017602.3:c.598G > A, p.Glu200Lys). The variant cosegregated with the disease in 10 tested individuals. No functional studies.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.3419 PDE2A Zornitza Stark Phenotypes for gene: PDE2A were changed from Paroxysmal dyskinesia to Paroxysmal dyskinesia; Intellectual developmental disorder with paroxysmal dyskinesia or seizures, MIM# 619150
Intellectual disability syndromic and non-syndromic v0.3418 PDE2A Zornitza Stark edited their review of gene: PDE2A: Changed phenotypes: Paroxysmal dyskinesia, Intellectual developmental disorder with paroxysmal dyskinesia or seizures, MIM# 619150
Intellectual disability syndromic and non-syndromic v0.3418 NBEA Zornitza Stark Phenotypes for gene: NBEA were changed from Intellectual disability; Seizures to Neurodevelopmental disorder with or without early-onset generalized epilepsy, MIM# 619157; Intellectual disability; Seizures
Intellectual disability syndromic and non-syndromic v0.3417 NBEA Zornitza Stark edited their review of gene: NBEA: Changed phenotypes: Neurodevelopmental disorder with or without early-onset generalized epilepsy, MIM# 619157, Intellectual disability, Seizures
Intellectual disability syndromic and non-syndromic v0.3417 SDHAF1 Zornitza Stark Phenotypes for gene: SDHAF1 were changed from Mitochondrial complex II deficiency, nuclear type 2, MIM# 619166 to Mitochondrial complex II deficiency, nuclear type 2, MIM# 619166
Intellectual disability syndromic and non-syndromic v0.3417 SDHAF1 Zornitza Stark Phenotypes for gene: SDHAF1 were changed from Mitochondrial complex II deficiency, nuclear type 2, MIM# 619166 to Mitochondrial complex II deficiency, nuclear type 2, MIM# 619166
Intellectual disability syndromic and non-syndromic v0.3417 SDHAF1 Zornitza Stark Marked gene: SDHAF1 as ready
Intellectual disability syndromic and non-syndromic v0.3417 SDHAF1 Zornitza Stark Gene: sdhaf1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3417 SDHAF1 Zornitza Stark Phenotypes for gene: SDHAF1 were changed from to Mitochondrial complex II deficiency, nuclear type 2, MIM# 619166
Intellectual disability syndromic and non-syndromic v0.3416 SDHAF1 Zornitza Stark Publications for gene: SDHAF1 were set to
Intellectual disability syndromic and non-syndromic v0.3415 SDHAF1 Zornitza Stark Mode of inheritance for gene: SDHAF1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3414 SDHAF1 Zornitza Stark reviewed gene: SDHAF1: Rating: GREEN; Mode of pathogenicity: None; Publications: 19465911, 26749241, 22995659; Phenotypes: Mitochondrial complex II deficiency, nuclear type 2, MIM# 619166; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3414 UPB1 Zornitza Stark Marked gene: UPB1 as ready
Intellectual disability syndromic and non-syndromic v0.3414 UPB1 Zornitza Stark Gene: upb1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3414 UPB1 Zornitza Stark Phenotypes for gene: UPB1 were changed from to Beta-ureidopropionase deficiency, OMIM #613161
Intellectual disability syndromic and non-syndromic v0.3413 UPB1 Zornitza Stark Publications for gene: UPB1 were set to
Intellectual disability syndromic and non-syndromic v0.3412 UPB1 Zornitza Stark Mode of inheritance for gene: UPB1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3411 UPB1 Zornitza Stark Classified gene: UPB1 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.3411 UPB1 Zornitza Stark Gene: upb1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3410 UPB1 Zornitza Stark reviewed gene: UPB1: Rating: GREEN; Mode of pathogenicity: None; Publications: 27604308, 24526388, 25638458, 22525402, 15385443, 17964839; Phenotypes: Beta-ureidopropionase deficiency, MIM# 613161; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3410 UROC1 Zornitza Stark Marked gene: UROC1 as ready
Intellectual disability syndromic and non-syndromic v0.3410 UROC1 Zornitza Stark Gene: uroc1 has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v0.3410 UROC1 Zornitza Stark Phenotypes for gene: UROC1 were changed from to Urocanase deficiency, MIM#276880
Intellectual disability syndromic and non-syndromic v0.3409 UROC1 Zornitza Stark Publications for gene: UROC1 were set to
Intellectual disability syndromic and non-syndromic v0.3408 UROC1 Zornitza Stark Mode of inheritance for gene: UROC1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3407 UROC1 Zornitza Stark Classified gene: UROC1 as Red List (low evidence)
Intellectual disability syndromic and non-syndromic v0.3407 UROC1 Zornitza Stark Gene: uroc1 has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v0.3406 UROC1 Zornitza Stark reviewed gene: UROC1: Rating: RED; Mode of pathogenicity: None; Publications: 19304569, 30619714; Phenotypes: Urocanase deficiency, MIM#276880; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3406 HNRNPU Zornitza Stark Marked gene: HNRNPU as ready
Intellectual disability syndromic and non-syndromic v0.3406 HNRNPU Zornitza Stark Gene: hnrnpu has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3406 HNRNPU Zornitza Stark Phenotypes for gene: HNRNPU were changed from Epileptic encephalopathy, early infantile, 54, MIM#617391 to Developmental and epileptic encephalopathy 54 MIM# 617391
Intellectual disability syndromic and non-syndromic v0.3405 LAS1L Zornitza Stark Publications for gene: LAS1L were set to 25644381; 25644381
Intellectual disability syndromic and non-syndromic v0.3404 LAS1L Zornitza Stark Classified gene: LAS1L as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.3404 LAS1L Zornitza Stark Gene: las1l has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.3403 LAS1L Zornitza Stark changed review comment from: Three unrelated families.; to: Three unrelated families, however note the pathogenicity of the variant reported in PMID 26358559 is questionable.
Intellectual disability syndromic and non-syndromic v0.3403 LAS1L Zornitza Stark edited their review of gene: LAS1L: Changed rating: AMBER; Changed publications: 25644381, 26358559
Intellectual disability syndromic and non-syndromic v0.3403 AGO2 Zornitza Stark Phenotypes for gene: AGO2 were changed from Intellectual disability to Lessel-Kreienkamp syndrome (LESKRES), MIM#619149; Intellectual disability
Intellectual disability syndromic and non-syndromic v0.3402 AGO2 Zornitza Stark edited their review of gene: AGO2: Changed phenotypes: Lessel-Kreienkamp syndrome (LESKRES), MIM#619149, Intellectual disability
Intellectual disability syndromic and non-syndromic v0.3402 CBY1 Bryony Thompson Marked gene: CBY1 as ready
Intellectual disability syndromic and non-syndromic v0.3402 CBY1 Bryony Thompson Gene: cby1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3402 CBY1 Bryony Thompson Classified gene: CBY1 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.3402 CBY1 Bryony Thompson Gene: cby1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3401 CBY1 Bryony Thompson gene: CBY1 was added
gene: CBY1 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: CBY1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CBY1 were set to 33131181; 25103236; 25220153
Phenotypes for gene: CBY1 were set to intellectual disability; cerebellar ataxia; molar tooth sign; polydactyly; Joubert syndrome
Review for gene: CBY1 was set to GREEN
Added comment: Three cases in two unrelated consanguineous families with homozygous loss of function variants, with ID as a feature of the phenotype. Multiple null model organisms recapitulate the human phenotype: Null mouse model had cystic kidneys, a phenotype common to ciliopathies. Reducing Cby levels in Xenopus laevis model reduced the density of multiciliated cells, the number of basal bodies per multiciliated cell, and the numbers of neural tube primary cilia; it also led to abnormal development of the neural crest, central nervous system, and pronephros. Depletion of cby1 in zebrafish results in ciliopathy‐related phenotypes.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.3400 LAMB1 Zornitza Stark Marked gene: LAMB1 as ready
Intellectual disability syndromic and non-syndromic v0.3400 LAMB1 Zornitza Stark Gene: lamb1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3400 LAMB1 Zornitza Stark Phenotypes for gene: LAMB1 were changed from to Lissencephaly 5, MIM# 615191; Cystic leukoencephalopathy
Intellectual disability syndromic and non-syndromic v0.3399 LAMB1 Zornitza Stark Publications for gene: LAMB1 were set to
Intellectual disability syndromic and non-syndromic v0.3398 LAMB1 Zornitza Stark Mode of inheritance for gene: LAMB1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3397 LAMB1 Zornitza Stark reviewed gene: LAMB1: Rating: GREEN; Mode of pathogenicity: None; Publications: 23472759, 25925986, 29888467, 25925986; Phenotypes: Lissencephaly 5, MIM# 615191, Cystic leukoencephalopathy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3397 HIST1H1E Zornitza Stark Marked gene: HIST1H1E as ready
Intellectual disability syndromic and non-syndromic v0.3397 HIST1H1E Zornitza Stark Gene: hist1h1e has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3397 HIST1H1E Zornitza Stark Phenotypes for gene: HIST1H1E were changed from to Rahman syndrome, MIM# 617537
Intellectual disability syndromic and non-syndromic v0.3396 HIST1H1E Zornitza Stark Publications for gene: HIST1H1E were set to
Intellectual disability syndromic and non-syndromic v0.3395 HIST1H1E Zornitza Stark Mode of inheritance for gene: HIST1H1E was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3394 HIST1H1E Zornitza Stark reviewed gene: HIST1H1E: Rating: GREEN; Mode of pathogenicity: None; Publications: 28475857, 33270410, 31910894, 31400068; Phenotypes: Rahman syndrome, MIM# 617537; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3394 EED Zornitza Stark Marked gene: EED as ready
Intellectual disability syndromic and non-syndromic v0.3394 EED Zornitza Stark Gene: eed has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3394 EED Zornitza Stark Phenotypes for gene: EED were changed from to Cohen-Gibson syndrome, MIM# 617561
Intellectual disability syndromic and non-syndromic v0.3393 EED Zornitza Stark Publications for gene: EED were set to
Intellectual disability syndromic and non-syndromic v0.3392 EED Zornitza Stark Mode of inheritance for gene: EED was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3391 EED Zornitza Stark reviewed gene: EED: Rating: GREEN; Mode of pathogenicity: None; Publications: 25787343, 27193220, 27868325, 28229514; Phenotypes: Cohen-Gibson syndrome, MIM# 617561; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3391 PPP2R5D Zornitza Stark Marked gene: PPP2R5D as ready
Intellectual disability syndromic and non-syndromic v0.3391 PPP2R5D Zornitza Stark Gene: ppp2r5d has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3391 PPP2R5D Zornitza Stark Phenotypes for gene: PPP2R5D were changed from to Mental retardation, autosomal dominant 35, MIM#616355
Intellectual disability syndromic and non-syndromic v0.3390 PPP2R5D Zornitza Stark Publications for gene: PPP2R5D were set to
Intellectual disability syndromic and non-syndromic v0.3389 PPP2R5D Zornitza Stark Mode of pathogenicity for gene: PPP2R5D was changed from to Other
Intellectual disability syndromic and non-syndromic v0.3388 PPP2R5D Zornitza Stark Mode of inheritance for gene: PPP2R5D was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3387 PPP2R5D Zornitza Stark reviewed gene: PPP2R5D: Rating: GREEN; Mode of pathogenicity: Other; Publications: 32074998, 26168268; Phenotypes: Mental retardation, autosomal dominant 35, MIM#616355; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3387 SCAMP5 Zornitza Stark Mode of pathogenicity for gene: SCAMP5 was changed from None to Other
Intellectual disability syndromic and non-syndromic v0.3386 SCAMP5 Zornitza Stark edited their review of gene: SCAMP5: Changed mode of pathogenicity: Other
Intellectual disability syndromic and non-syndromic v0.3386 SCAMP5 Zornitza Stark Phenotypes for gene: SCAMP5 were changed from no OMIM number yet to Intellectual disability; seizures; autism
Intellectual disability syndromic and non-syndromic v0.3385 SCAMP5 Zornitza Stark Publications for gene: SCAMP5 were set to PMID: 31439720
Intellectual disability syndromic and non-syndromic v0.3384 SCAMP5 Zornitza Stark edited their review of gene: SCAMP5: Added comment: PMID 33390987: Four unrelated individuals reported with same de novo missense variant, p. Gly180Trp. The onset age of seizures was ranged from 6 to 15 months. Patients had different types of seizures, including focal seizures, generalized tonic-clonic seizures and tonic seizure. One patient showed typical autism spectrum disorder (ASD) symptoms. Electroencephalogram (EEG) findings presented as focal or multifocal discharges, sometimes spreading to generalization. Brain magnetic resonance imaging (MRI) abnormalities were present in each patient. Severe intellectual disability and language and motor developmental disorders were found in our patients, with all patients having poor language development and were nonverbal at last follow-up. All but one of the patients could walk independently in childhood, but the ability to walk independently in one patient had deteriorated with age. All patients had abnormal neurological exam findings, mostly signs of extrapyramidal system involvement. Dysmorphic features were found in 2/4 patients, mainly in the face and trunk.; Changed rating: GREEN; Changed publications: 33390987; Changed phenotypes: Intellectual disability, seizures, autism; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3384 ZNF526 Zornitza Stark Marked gene: ZNF526 as ready
Intellectual disability syndromic and non-syndromic v0.3384 ZNF526 Zornitza Stark Gene: znf526 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3384 ZNF526 Zornitza Stark Classified gene: ZNF526 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.3384 ZNF526 Zornitza Stark Gene: znf526 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3383 ZNF526 Zornitza Stark gene: ZNF526 was added
gene: ZNF526 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: ZNF526 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZNF526 were set to 21937992; 25558065; 33397746
Phenotypes for gene: ZNF526 were set to Intellectual disability; Microcephaly; Cataracts; Epilepsy; Hypertonia; Dystonia
Review for gene: ZNF526 was set to GREEN
Added comment: Currently not associated with any phenotype in OMIM (last updated on 09/12/2011), but has a 'possible' disease confidence rating for 'Autosomal Recessive Mental Retardation' in Gene2Phenotype.

- PMID: 21937992 (2011) - Two unrelated families (with 4 affected individuals in each) with non-syndromic ID (mild or moderate, respectively) identified harbouring different biallelic missense variants in the ZNF526 gene.

- PMID: 25558065 (2015) - One family with ID, Noonan-like facies, pulmonary stenosis and a homozygous missense variant in this gene. No further details provided.

- PMID: 33397746 (2021) - Five individuals from four unrelated families with homozygous ZNF526 variants. Four harboured truncating variants, and were all affected by profound DD and severe ID, microcephaly (ranging from -4 SD to -8 SD), bilateral progressive cataracts, hypertonic-dystonic movements, epilepsy and brain MRI anomalies. The fifth patient had a homozygous missense variant and a slightly less severe disorder, with postnatal microcephaly (-2 SD), progressive bilateral cataracts, severe ID, and normal brain MRI. Zebrafish model demonstrated brain and eye malformations resembling findings seen in the human holoprosencephaly spectrum
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.3382 MORC2 Zornitza Stark Phenotypes for gene: MORC2 were changed from Charcot-Marie-Tooth disease, axonal, type 2Z, MIM #616688; Intellectual disability to Developmental delay, impaired growth, dysmorphic facies, and axonal neuropathy, MIM# 619090; Intellectual disability
Intellectual disability syndromic and non-syndromic v0.3381 MORC2 Zornitza Stark edited their review of gene: MORC2: Changed phenotypes: Developmental delay, impaired growth, dysmorphic facies, and axonal neuropathy, MIM# 619090, Intellectual disability
Intellectual disability syndromic and non-syndromic v0.3381 CELF2 Zornitza Stark Marked gene: CELF2 as ready
Intellectual disability syndromic and non-syndromic v0.3381 CELF2 Zornitza Stark Gene: celf2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3381 CELF2 Zornitza Stark Classified gene: CELF2 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.3381 CELF2 Zornitza Stark Gene: celf2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3380 CELF2 Zornitza Stark gene: CELF2 was added
gene: CELF2 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: CELF2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CELF2 were set to 33131106
Phenotypes for gene: CELF2 were set to Developmental and epileptic encephalopathy
Review for gene: CELF2 was set to GREEN
Added comment: Five unrelated individuals reported. Four with de novo variants, and one inherited from a mosaic mother. Notably, all identified variants, except for c.272‐1G>C, were clustered within 20 amino acid residues of the C‐terminus, which might be a nuclear localization signal.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.3379 FGF13 Zornitza Stark Marked gene: FGF13 as ready
Intellectual disability syndromic and non-syndromic v0.3379 FGF13 Zornitza Stark Gene: fgf13 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3379 FGF13 Zornitza Stark Classified gene: FGF13 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.3379 FGF13 Zornitza Stark Gene: fgf13 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3378 FGF13 Zornitza Stark gene: FGF13 was added
gene: FGF13 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: FGF13 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: FGF13 were set to 33245860
Phenotypes for gene: FGF13 were set to Intellectual disability; epilepsy
Mode of pathogenicity for gene: FGF13 was set to Other
Review for gene: FGF13 was set to GREEN
Added comment: Two sibling pairs and three unrelated males reported who presented in infancy with intractable focal seizures and severe developmental delay. The variants were located in the N-terminal domain of the A isoform of FGF13/FHF2 (FHF2A). The X-linked FHF2 gene (also known as FGF13) has alternative first exons which produce multiple protein isoforms that differ in their N-terminal sequence. The variants were located at highly conserved residues in the FHF2A inactivation particle that competes with the intrinsic fast inactivation mechanism of Nav channels. Functional characterization of mutant FHF2A co-expressed with wild-type Nav1.6 (SCN8A) revealed that mutant FHF2A proteins lost the ability to induce rapid-onset, long-term blockade of the channel while retaining pro-excitatory properties. These gain-of-function effects are likely to increase neuronal excitability consistent with the epileptic potential of FHF2 variants.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.3377 UBR7 Zornitza Stark Marked gene: UBR7 as ready
Intellectual disability syndromic and non-syndromic v0.3377 UBR7 Zornitza Stark Gene: ubr7 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3377 UBR7 Zornitza Stark Classified gene: UBR7 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.3377 UBR7 Zornitza Stark Gene: ubr7 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3376 UBR7 Zornitza Stark gene: UBR7 was added
gene: UBR7 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: UBR7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: UBR7 were set to 33340455
Phenotypes for gene: UBR7 were set to Intellectual disability; epilepsy; hypothyroidism; congenital anomalies; dysmorphic features
Review for gene: UBR7 was set to GREEN
Added comment: Seven individuals from 6 unrelated families. All had developmental delay, and all males had urogenital anomalies, namely cryptorchidism in 5/6 and small penis in 1/6. Six individuals had seizures and hypotonia. Hypothyroidism was present in 4/7 individuals, and ptosis was noted in 6/7 individuals. Five individuals exhibited cardiac abnormalities: two had ventricular septal defect, one had atrial septal defect, one had a patent ductus arteriosus requiring surgery, and the other had a patent ductus arteriosus and a patent foramen ovale that both closed spontaneously. Five individuals had short stature (height < 3rd percentile). Physical examination revealed various dysmorphic features, including prominent forehead (3/7), hypertelorism (4/7), telecanthus (1/7), epicanthus(1/7), downslanting palpebral fissures (3/7), thick eyebrow (1/7), low-set ears (3/7), long philtrum (2/7), unilateral single transverse palmar crease (1/7), and hypertrichosis (1/7).
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.3375 RALGAPB Zornitza Stark Marked gene: RALGAPB as ready
Intellectual disability syndromic and non-syndromic v0.3375 RALGAPB Zornitza Stark Gene: ralgapb has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v0.3375 RALGAPB Zornitza Stark Classified gene: RALGAPB as Red List (low evidence)
Intellectual disability syndromic and non-syndromic v0.3375 RALGAPB Zornitza Stark Gene: ralgapb has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v0.3374 RNU7-1 Zornitza Stark Marked gene: RNU7-1 as ready
Intellectual disability syndromic and non-syndromic v0.3374 RNU7-1 Zornitza Stark Gene: rnu7-1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3374 RNU7-1 Zornitza Stark Classified gene: RNU7-1 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.3374 RNU7-1 Zornitza Stark Gene: rnu7-1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3373 LSM11 Zornitza Stark Marked gene: LSM11 as ready
Intellectual disability syndromic and non-syndromic v0.3373 LSM11 Zornitza Stark Gene: lsm11 has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v0.3373 LSM11 Zornitza Stark Classified gene: LSM11 as Red List (low evidence)
Intellectual disability syndromic and non-syndromic v0.3373 LSM11 Zornitza Stark Gene: lsm11 has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v0.3372 DPH2 Zornitza Stark Marked gene: DPH2 as ready
Intellectual disability syndromic and non-syndromic v0.3372 DPH2 Zornitza Stark Gene: dph2 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.3372 DPH2 Zornitza Stark Classified gene: DPH2 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.3372 DPH2 Zornitza Stark Gene: dph2 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.3371 EIF2AK2 Zornitza Stark Marked gene: EIF2AK2 as ready
Intellectual disability syndromic and non-syndromic v0.3371 EIF2AK2 Zornitza Stark Gene: eif2ak2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3371 FBRSL1 Zornitza Stark Marked gene: FBRSL1 as ready
Intellectual disability syndromic and non-syndromic v0.3371 FBRSL1 Zornitza Stark Gene: fbrsl1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3371 CAMK2B Zornitza Stark Marked gene: CAMK2B as ready
Intellectual disability syndromic and non-syndromic v0.3371 CAMK2B Zornitza Stark Gene: camk2b has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3371 CAMK2B Zornitza Stark Phenotypes for gene: CAMK2B were changed from to Mental retardation, autosomal dominant 54, MIM# 617799
Intellectual disability syndromic and non-syndromic v0.3370 CAMK2B Zornitza Stark Publications for gene: CAMK2B were set to
Intellectual disability syndromic and non-syndromic v0.3369 CAMK2B Zornitza Stark Mode of inheritance for gene: CAMK2B was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3368 CAMK2B Zornitza Stark reviewed gene: CAMK2B: Rating: GREEN; Mode of pathogenicity: None; Publications: 29100089, 29560374, 32875707; Phenotypes: Mental retardation, autosomal dominant 54, MIM# 617799; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3368 RALGAPB Elena Savva gene: RALGAPB was added
gene: RALGAPB was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: RALGAPB was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: RALGAPB were set to PMID: 32853829
Phenotypes for gene: RALGAPB were set to Neurodevelopmental disorders, autism
Review for gene: RALGAPB was set to RED
Added comment: PMID: 32853829 - Reviews previous publications and identifies 10 de novo variants (5 PTCs, 5 missense) in patients with ASD (7/10), epilepsy (2/10) and developmental delay (1/10).
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.3368 RNU7-1 Paul De Fazio gene: RNU7-1 was added
gene: RNU7-1 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: RNU7-1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RNU7-1 were set to 33230297
Phenotypes for gene: RNU7-1 were set to Aicardi–Goutières syndrome-like
Review for gene: RNU7-1 was set to GREEN
gene: RNU7-1 was marked as current diagnostic
Added comment: Review originally submitted by Ming Wong
- 16 affected individuals from 11 families
- Compared to control fibroblasts, patient fibroblasts were enriched for misprocessed forms of
replication-dependent histone (RDH) mRNAs
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.3368 LSM11 Ee Ming Wong gene: LSM11 was added
gene: LSM11 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: LSM11 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LSM11 were set to PMID: 33230297
Phenotypes for gene: LSM11 were set to type I interferonopathy Aicardi–Goutières syndrome
Review for gene: LSM11 was set to RED
gene: LSM11 was marked as current diagnostic
Added comment: - Two affected siblings from a consanguineous family carrying a homozygous variant in LSM11
- Compared to control fibroblasts, patient fibroblasts were enriched for misprocessed forms of
replication-dependent histone (RDH) mRNAs
- Knockdown of LSM11 in THP-1 cells results in an increase in misprocessed RDH mRNA and
interferon signaling

(added as Red as per discussion with Seb)
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.3368 FBRSL1 Sue White Classified gene: FBRSL1 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.3368 FBRSL1 Sue White Gene: fbrsl1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3367 DPH2 Paul De Fazio gene: DPH2 was added
gene: DPH2 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: DPH2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DPH2 were set to 32576952; 27421267
Phenotypes for gene: DPH2 were set to Diphthamide-deficiency syndrome
Review for gene: DPH2 was set to AMBER
gene: DPH2 was marked as current diagnostic
Added comment: One 19 month old reported (PMID:32576952) with biallelic (one missense, one nonsense) variants in DPH2, with phenotype similar to DPH1 deficiency (gross motor delay, not walking, fine motor and expressive language delays, macrocephaly)

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

In vitro functional assays support reduced diphthamide synthesis activity for the variants identified in PMID:32576952.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.3367 EIF2AK2 Seb Lunke reviewed gene: EIF2AK2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability syndromic and non-syndromic v0.3367 FBRSL1 Elena Savva gene: FBRSL1 was added
gene: FBRSL1 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: FBRSL1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: FBRSL1 were set to PMID: 32424618
Phenotypes for gene: FBRSL1 were set to Malformation and intellectual disability syndrome
Review for gene: FBRSL1 was set to GREEN
Added comment: Three children with de novo PTCs that escape NMD, and an overlapping syndromic phenotype with respiratory insufficiency, postnatal growth restriction, microcephaly, global developmental delay and other malformations. 2/3 had heart defects, cleft palate and hearing impairement.
Supported by Xenopus oocyte functional studies
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.3367 MLYCD Zornitza Stark Marked gene: MLYCD as ready
Intellectual disability syndromic and non-syndromic v0.3367 MLYCD Zornitza Stark Gene: mlycd has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3367 MLYCD Zornitza Stark Phenotypes for gene: MLYCD were changed from to Malonyl-CoA decarboxylase deficiency, MIM# 248360
Intellectual disability syndromic and non-syndromic v0.3366 MLYCD Zornitza Stark Publications for gene: MLYCD were set to
Intellectual disability syndromic and non-syndromic v0.3365 MLYCD Zornitza Stark Mode of inheritance for gene: MLYCD was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3364 MLYCD Zornitza Stark reviewed gene: MLYCD: Rating: GREEN; Mode of pathogenicity: None; Publications: 12955715; Phenotypes: Malonyl-CoA decarboxylase deficiency, MIM# 248360; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3364 KCNQ3 Zornitza Stark Marked gene: KCNQ3 as ready
Intellectual disability syndromic and non-syndromic v0.3364 KCNQ3 Zornitza Stark Gene: kcnq3 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3364 KCNQ3 Zornitza Stark Phenotypes for gene: KCNQ3 were changed from to Seizures, benign neonatal, 2, MIM# 121201
Intellectual disability syndromic and non-syndromic v0.3363 KCNQ3 Zornitza Stark Publications for gene: KCNQ3 were set to
Intellectual disability syndromic and non-syndromic v0.3362 KCNQ3 Zornitza Stark Mode of inheritance for gene: KCNQ3 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3361 KCNQ3 Zornitza Stark reviewed gene: KCNQ3: Rating: GREEN; Mode of pathogenicity: None; Publications: 33337327, 25524373, 24851285; Phenotypes: Seizures, benign neonatal, 2, MIM# 121201; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3361 PRKACB Zornitza Stark Phenotypes for gene: PRKACB were changed from Postaxial hand polydactyly; Postaxial foot polydactyly; Common atrium; Atrioventricular canal defect; Narrow chest; Abnormality of the teeth; Intellectual disability to Cardioacrofacial dysplasia 2, MIM# 619143; Postaxial hand polydactyly; Postaxial foot polydactyly; Common atrium; Atrioventricular canal defect; Narrow chest; Abnormality of the teeth; Intellectual disability
Intellectual disability syndromic and non-syndromic v0.3360 PRKACB Zornitza Stark reviewed gene: PRKACB: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Cardioacrofacial dysplasia 2, MIM# 619143; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3360 YIF1B Zornitza Stark Phenotypes for gene: YIF1B were changed from Central hypotonia; Failure to thrive; Microcephaly; Global developmental delay; Intellectual disability; Seizures; Spasticity; Abnormality of movement to Kaya-Barakat-Masson syndrome, MIM# 619125; Central hypotonia; Failure to thrive; Microcephaly; Global developmental delay; Intellectual disability; Seizures; Spasticity; Abnormality of movement
Intellectual disability syndromic and non-syndromic v0.3359 YIF1B Zornitza Stark reviewed gene: YIF1B: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Kaya-Barakat-Masson syndrome, MIM# 619125, Central hypotonia, Failure to thrive, Microcephaly, Global developmental delay, Intellectual disability, Seizures, Spasticity, Abnormality of movement; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3359 ATIC Zornitza Stark Marked gene: ATIC as ready
Intellectual disability syndromic and non-syndromic v0.3359 ATIC Zornitza Stark Gene: atic has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3359 ATIC Zornitza Stark Phenotypes for gene: ATIC were changed from to AICA-ribosiduria due to ATIC deficiency, MIM# 608688
Intellectual disability syndromic and non-syndromic v0.3358 ATIC Zornitza Stark Publications for gene: ATIC were set to
Intellectual disability syndromic and non-syndromic v0.3357 ATIC Zornitza Stark Mode of inheritance for gene: ATIC was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3356 ATIC Zornitza Stark reviewed gene: ATIC: Rating: GREEN; Mode of pathogenicity: None; Publications: 15114530, 32557644; Phenotypes: AICA-ribosiduria due to ATIC deficiency, MIM# 608688; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3356 SOX2 Zornitza Stark Phenotypes for gene: SOX2 were changed from Microphthalmia, syndromic 3, MIM# 206900; Optic nerve hypoplasia and abnormalities of the central nervous system, MIM# 206900 to Microphthalmia, syndromic 3, MIM# 206900; Optic nerve hypoplasia and abnormalities of the central nervous system, MIM# 206900
Intellectual disability syndromic and non-syndromic v0.3356 SOX2 Zornitza Stark Phenotypes for gene: SOX2 were changed from to Microphthalmia, syndromic 3, MIM# 206900; Optic nerve hypoplasia and abnormalities of the central nervous system, MIM# 206900
Intellectual disability syndromic and non-syndromic v0.3355 SOX2 Zornitza Stark Publications for gene: SOX2 were set to
Intellectual disability syndromic and non-syndromic v0.3354 SOX2 Zornitza Stark Mode of inheritance for gene: SOX2 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3353 SOX2 Zornitza Stark reviewed gene: SOX2: Rating: GREEN; Mode of pathogenicity: None; Publications: 30450772, 28121235, 25542770, 24498598, 24211324, 24033328, 21326281; Phenotypes: Microphthalmia, syndromic 3, MIM# 206900, Optic nerve hypoplasia and abnormalities of the central nervous system, MIM# 206900; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3353 RERE Zornitza Stark Marked gene: RERE as ready
Intellectual disability syndromic and non-syndromic v0.3353 RERE Zornitza Stark Gene: rere has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3353 RERE Zornitza Stark Phenotypes for gene: RERE were changed from to Neurodevelopmental disorder with or without anomalies of the brain, eye, or heart, MIM# 616975
Intellectual disability syndromic and non-syndromic v0.3352 RERE Zornitza Stark Publications for gene: RERE were set to
Intellectual disability syndromic and non-syndromic v0.3351 RERE Zornitza Stark Mode of inheritance for gene: RERE was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3350 RERE Zornitza Stark reviewed gene: RERE: Rating: GREEN; Mode of pathogenicity: None; Publications: 27087320, 23451234, 30896913, 30061196; Phenotypes: Neurodevelopmental disorder with or without anomalies of the brain, eye, or heart, MIM# 616975; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3350 RARB Zornitza Stark Marked gene: RARB as ready
Intellectual disability syndromic and non-syndromic v0.3350 RARB Zornitza Stark Gene: rarb has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3350 RARB Zornitza Stark Phenotypes for gene: RARB were changed from to Microphthalmia, syndromic 12, MIM# 615524
Intellectual disability syndromic and non-syndromic v0.3349 RARB Zornitza Stark Publications for gene: RARB were set to
Intellectual disability syndromic and non-syndromic v0.3348 RARB Zornitza Stark Mode of inheritance for gene: RARB was changed from Unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3347 RARB Zornitza Stark reviewed gene: RARB: Rating: GREEN; Mode of pathogenicity: None; Publications: 30880327, 30281527, 24075189, 27120018, 25457163, 17506106; Phenotypes: Microphthalmia, syndromic 12, MIM# 615524; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3347 SMOC1 Zornitza Stark Marked gene: SMOC1 as ready
Intellectual disability syndromic and non-syndromic v0.3347 SMOC1 Zornitza Stark Gene: smoc1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3347 SMOC1 Zornitza Stark Phenotypes for gene: SMOC1 were changed from to Microphthalmia with limb anomalies, MIM# 206920
Intellectual disability syndromic and non-syndromic v0.3346 SMOC1 Zornitza Stark Publications for gene: SMOC1 were set to
Intellectual disability syndromic and non-syndromic v0.3345 SMOC1 Zornitza Stark Mode of inheritance for gene: SMOC1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3344 SMOC1 Zornitza Stark reviewed gene: SMOC1: Rating: GREEN; Mode of pathogenicity: None; Publications: 21194678, 21194680, 30445150; Phenotypes: Microphthalmia with limb anomalies, MIM# 206920; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3344 MAB21L2 Zornitza Stark Marked gene: MAB21L2 as ready
Intellectual disability syndromic and non-syndromic v0.3344 MAB21L2 Zornitza Stark Gene: mab21l2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3344 MAB21L2 Zornitza Stark Phenotypes for gene: MAB21L2 were changed from to Microphthalmia/coloboma and skeletal dysplasia syndrome, MIM# 615877
Intellectual disability syndromic and non-syndromic v0.3343 MAB21L2 Zornitza Stark Publications for gene: MAB21L2 were set to
Intellectual disability syndromic and non-syndromic v0.3342 MAB21L2 Zornitza Stark Mode of inheritance for gene: MAB21L2 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3341 MAB21L2 Zornitza Stark reviewed gene: MAB21L2: Rating: GREEN; Mode of pathogenicity: None; Publications: 24906020, 25719200, 31037784, 30375740, 30073347, 26116559; Phenotypes: Microphthalmia/coloboma and skeletal dysplasia syndrome, MIM# 615877; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3341 PDSS1 Zornitza Stark Marked gene: PDSS1 as ready
Intellectual disability syndromic and non-syndromic v0.3341 PDSS1 Zornitza Stark Gene: pdss1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3341 PDSS1 Zornitza Stark Phenotypes for gene: PDSS1 were changed from to Coenzyme Q10 deficiency, primary, 2 MIM#614651
Intellectual disability syndromic and non-syndromic v0.3340 PDSS1 Zornitza Stark Publications for gene: PDSS1 were set to
Intellectual disability syndromic and non-syndromic v0.3339 PDSS1 Zornitza Stark Mode of inheritance for gene: PDSS1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3338 PDSS1 Paul De Fazio reviewed gene: PDSS1: Rating: GREEN; Mode of pathogenicity: None; Publications: 17332895, 22494076, 33285023; Phenotypes: Coenzyme Q10 deficiency, primary, 2 MIM#614651; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability syndromic and non-syndromic v0.3338 C16orf62 Zornitza Stark Phenotypes for gene: C16orf62 were changed from 3C/Ritscher-Schinzel-like syndrome to Ritscher-Schinzel syndrome-3 (RTSC3), MIM#619135
Intellectual disability syndromic and non-syndromic v0.3337 C16orf62 Zornitza Stark edited their review of gene: C16orf62: Changed phenotypes: Ritscher-Schinzel syndrome-3 (RTSC3), MIM#619135
Intellectual disability syndromic and non-syndromic v0.3337 GAD1 Zornitza Stark Phenotypes for gene: GAD1 were changed from Cerebral palsy, spastic quadriplegic, 1, MIM#603513; Developmental and epileptic encephalopathy to Cerebral palsy, spastic quadriplegic, 1, MIM#603513; Developmental and epileptic encephalopathy 89, MIM# 619124
Intellectual disability syndromic and non-syndromic v0.3336 GAD1 Zornitza Stark edited their review of gene: GAD1: Changed phenotypes: Cerebral palsy, spastic quadriplegic, 1, MIM#603513, Developmental and epileptic encephalopathy 89, MIM# 619124
Intellectual disability syndromic and non-syndromic v0.3336 XYLT1 Zornitza Stark Phenotypes for gene: XYLT1 were changed from Desbuquois dysplasia 2; OMIM# 615777 to Desbuquois dysplasia 2, MIM# 615777; Baratela-Scott syndrome
Intellectual disability syndromic and non-syndromic v0.3335 XYLT1 Zornitza Stark Tag SV/CNV tag was added to gene: XYLT1.
Tag STR tag was added to gene: XYLT1.
Intellectual disability syndromic and non-syndromic v0.3335 XYLT1 Zornitza Stark reviewed gene: XYLT1: Rating: GREEN; Mode of pathogenicity: None; Publications: 30554721, 24581741, 23982343; Phenotypes: Desbuquois dysplasia 2, MIM# 615777, Baratela-Scott syndrome; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3335 TUSC3 Zornitza Stark Tag SV/CNV tag was added to gene: TUSC3.
Intellectual disability syndromic and non-syndromic v0.3335 TUSC3 Zornitza Stark Marked gene: TUSC3 as ready
Intellectual disability syndromic and non-syndromic v0.3335 TUSC3 Zornitza Stark Gene: tusc3 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3335 TUSC3 Zornitza Stark Phenotypes for gene: TUSC3 were changed from to Mental retardation, autosomal recessive 7, MIM# 611093, MONDO:0012615; TUSC3-CDG (Disorders of protein N-glycosylation)
Intellectual disability syndromic and non-syndromic v0.3334 TUSC3 Zornitza Stark Publications for gene: TUSC3 were set to
Intellectual disability syndromic and non-syndromic v0.3333 TUSC3 Zornitza Stark Mode of inheritance for gene: TUSC3 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3332 TUSC3 Zornitza Stark reviewed gene: TUSC3: Rating: GREEN; Mode of pathogenicity: None; Publications: 18452889, 18455129, 21739581, 27148795, 31606977; Phenotypes: Mental retardation, autosomal recessive 7, MIM# 611093, MONDO:0012615, TUSC3-CDG (Disorders of protein N-glycosylation); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3332 TMEM165 Zornitza Stark Marked gene: TMEM165 as ready
Intellectual disability syndromic and non-syndromic v0.3332 TMEM165 Zornitza Stark Gene: tmem165 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3332 TMEM165 Zornitza Stark Phenotypes for gene: TMEM165 were changed from to Congenital disorder of glycosylation, type IIk, MIM# 614727; TMEM165-CDG, MONDO:0013870
Intellectual disability syndromic and non-syndromic v0.3331 TMEM165 Zornitza Stark Publications for gene: TMEM165 were set to
Intellectual disability syndromic and non-syndromic v0.3330 TMEM165 Zornitza Stark Mode of inheritance for gene: TMEM165 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3329 TMEM165 Zornitza Stark reviewed gene: TMEM165: Rating: GREEN; Mode of pathogenicity: None; Publications: 22683087, 28323990, 27401145, 27008884, 26238249, 25609749; Phenotypes: Congenital disorder of glycosylation, type IIk, MIM# 614727, TMEM165-CDG, MONDO:0013870; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3329 EXT2 Zornitza Stark Publications for gene: EXT2 were set to
Intellectual disability syndromic and non-syndromic v0.3328 EXT2 Zornitza Stark edited their review of gene: EXT2: Changed publications: 30288735, 30075207, 26246518
Intellectual disability syndromic and non-syndromic v0.3328 ST3GAL5 Zornitza Stark Phenotypes for gene: ST3GAL5 were changed from Salt and pepper developmental regression syndrome; OMIM #609056 to Salt and pepper developmental regression syndrome 609056; GM3 synthase deficiency, MONDO:0018274; Lactosylceramide alpha-2,3-sialyltransferase deficiency (Disorders of glycosphingolipid and glycosylphosphatidylinositol anchor glycosylation)
Intellectual disability syndromic and non-syndromic v0.3327 ST3GAL5 Zornitza Stark Publications for gene: ST3GAL5 were set to PubMed: 15502825; 22990144; 24026681; 27232954; 30185102; 24026681
Intellectual disability syndromic and non-syndromic v0.3326 ST3GAL5 Zornitza Stark Tag founder tag was added to gene: ST3GAL5.
Intellectual disability syndromic and non-syndromic v0.3326 ST3GAL5 Zornitza Stark reviewed gene: ST3GAL5: Rating: GREEN; Mode of pathogenicity: None; Publications: 23436467, 22990144, 15502825, 27232954, 30691927, 30688114, 30576498; Phenotypes: Salt and pepper developmental regression syndrome 609056, GM3 synthase deficiency, MONDO:0018274, Lactosylceramide alpha-2,3-sialyltransferase deficiency (Disorders of glycosphingolipid and glycosylphosphatidylinositol anchor glycosylation); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3326 DPYD Ain Roesley reviewed gene: DPYD: Rating: AMBER; Mode of pathogenicity: None; Publications: 10071185, 25565930, 30349988, 28275972, 17065071, 21114665, 22003227, 28123791; Phenotypes: Dihydropyrimidine dehydrogenase deficiency (MIM#274270); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3326 RFT1 Zornitza Stark Marked gene: RFT1 as ready
Intellectual disability syndromic and non-syndromic v0.3326 RFT1 Zornitza Stark Gene: rft1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3326 RFT1 Zornitza Stark Phenotypes for gene: RFT1 were changed from to Congenital disorder of glycosylation, type In, MIM# 612015; RFT1-CDG, MONDO:0012783
Intellectual disability syndromic and non-syndromic v0.3325 RFT1 Zornitza Stark Publications for gene: RFT1 were set to
Intellectual disability syndromic and non-syndromic v0.3324 RFT1 Zornitza Stark Mode of inheritance for gene: RFT1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3323 RFT1 Zornitza Stark reviewed gene: RFT1: Rating: GREEN; Mode of pathogenicity: None; Publications: 18313027, 19701946, 19856127, 23111317, 30071302, 29923091, 27927990, 26892341; Phenotypes: Congenital disorder of glycosylation, type In, MIM# 612015, RFT1-CDG, MONDO:0012783; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3323 MGAT2 Zornitza Stark Marked gene: MGAT2 as ready
Intellectual disability syndromic and non-syndromic v0.3323 MGAT2 Zornitza Stark Gene: mgat2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3323 MGAT2 Zornitza Stark Phenotypes for gene: MGAT2 were changed from to Congenital disorder of glycosylation, type IIa, MIM# 212066; MGAT2-CDG, MONDO:0008908
Intellectual disability syndromic and non-syndromic v0.3322 MGAT2 Zornitza Stark Publications for gene: MGAT2 were set to
Intellectual disability syndromic and non-syndromic v0.3321 MGAT2 Zornitza Stark Mode of inheritance for gene: MGAT2 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3320 MGAT2 Zornitza Stark reviewed gene: MGAT2: Rating: GREEN; Mode of pathogenicity: None; Publications: 8808595, 11228641, 22105986, 33044030, 31420886; Phenotypes: Congenital disorder of glycosylation, type IIa, MIM# 212066, MGAT2-CDG, MONDO:0008908; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3320 MPI Zornitza Stark Marked gene: MPI as ready
Intellectual disability syndromic and non-syndromic v0.3320 MPI Zornitza Stark Gene: mpi has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v0.3320 MPI Zornitza Stark Phenotypes for gene: MPI were changed from to Congenital disorder of glycosylation, type Ib, MIM# 602579; MPI-CDG MONDO:0011257
Intellectual disability syndromic and non-syndromic v0.3319 MPI Zornitza Stark Publications for gene: MPI were set to
Intellectual disability syndromic and non-syndromic v0.3318 MPI Zornitza Stark Mode of inheritance for gene: MPI was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3317 MPI Zornitza Stark Classified gene: MPI as Red List (low evidence)
Intellectual disability syndromic and non-syndromic v0.3317 MPI Zornitza Stark Gene: mpi has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v0.3316 MPI Zornitza Stark reviewed gene: MPI: Rating: RED; Mode of pathogenicity: None; Publications: 12414827, 9585601, 10980531, 33098580, 33204592, 32905087, 32266963, 30242110; Phenotypes: Congenital disorder of glycosylation, type Ib, MIM# 602579, MPI-CDG MONDO:0011257; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3316 PGM3 Zornitza Stark Marked gene: PGM3 as ready
Intellectual disability syndromic and non-syndromic v0.3316 PGM3 Zornitza Stark Gene: pgm3 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3316 PGM3 Zornitza Stark Phenotypes for gene: PGM3 were changed from to Immunodeficiency 23, MIM# 615816; PGM3-CDG, MONDO:0014353
Intellectual disability syndromic and non-syndromic v0.3315 PGM3 Zornitza Stark Publications for gene: PGM3 were set to
Intellectual disability syndromic and non-syndromic v0.3314 PGM3 Zornitza Stark Mode of inheritance for gene: PGM3 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3313 PGM3 Zornitza Stark reviewed gene: PGM3: Rating: GREEN; Mode of pathogenicity: None; Publications: 30578875, 31231132, 33098103, 30157810, 28704707; Phenotypes: Immunodeficiency 23, MIM# 615816, PGM3-CDG, MONDO:0014353; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3313 PGAP3 Zornitza Stark Marked gene: PGAP3 as ready
Intellectual disability syndromic and non-syndromic v0.3313 PGAP3 Zornitza Stark Gene: pgap3 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3313 PGAP3 Zornitza Stark Phenotypes for gene: PGAP3 were changed from to Hyperphosphatasia with mental retardation syndrome 4, MIM# 615716, MONDO:0014318
Intellectual disability syndromic and non-syndromic v0.3312 PGAP3 Zornitza Stark Publications for gene: PGAP3 were set to 24439110; 29620724; 30345601; 30217754
Intellectual disability syndromic and non-syndromic v0.3311 PGAP3 Zornitza Stark Publications for gene: PGAP3 were set to
Intellectual disability syndromic and non-syndromic v0.3310 PGAP3 Zornitza Stark Mode of inheritance for gene: PGAP3 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3309 PGAP3 Zornitza Stark reviewed gene: PGAP3: Rating: GREEN; Mode of pathogenicity: None; Publications: 24439110, 29620724, 30345601, 30217754; Phenotypes: Hyperphosphatasia with mental retardation syndrome 4, MIM# 615716, MONDO:0014318; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3309 PGAP2 Zornitza Stark Marked gene: PGAP2 as ready
Intellectual disability syndromic and non-syndromic v0.3309 PGAP2 Zornitza Stark Gene: pgap2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3309 PGAP2 Zornitza Stark Phenotypes for gene: PGAP2 were changed from to Hyperphosphatasia with mental retardation syndrome 3, MIM# 614207, MONDO:0013628
Intellectual disability syndromic and non-syndromic v0.3308 PGAP2 Zornitza Stark Publications for gene: PGAP2 were set to
Intellectual disability syndromic and non-syndromic v0.3307 PGAP2 Zornitza Stark Mode of inheritance for gene: PGAP2 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3306 PGAP2 Zornitza Stark reviewed gene: PGAP2: Rating: GREEN; Mode of pathogenicity: None; Publications: 23561846, 23561847, 31805394, 29119105, 27871432; Phenotypes: Hyperphosphatasia with mental retardation syndrome 3, MIM# 614207, MONDO:0013628; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3306 PIGV Zornitza Stark Marked gene: PIGV as ready
Intellectual disability syndromic and non-syndromic v0.3306 PIGV Zornitza Stark Gene: pigv has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3306 PIGV Zornitza Stark Phenotypes for gene: PIGV were changed from to Hyperphosphatasia with mental retardation syndrome 1, MIM# 239300, MONDO:0009398
Intellectual disability syndromic and non-syndromic v0.3305 PIGV Zornitza Stark Publications for gene: PIGV were set to
Intellectual disability syndromic and non-syndromic v0.3304 PIGV Zornitza Stark Mode of inheritance for gene: PIGV was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3303 PIGV Zornitza Stark reviewed gene: PIGV: Rating: GREEN; Mode of pathogenicity: None; Publications: 20802478, 22315194, 28817240, 24129430; Phenotypes: Hyperphosphatasia with mental retardation syndrome 1, MIM# 239300, MONDO:0009398; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3303 PIGT Zornitza Stark Phenotypes for gene: PIGT were changed from Multiple congenital anomalies-hypotonia-seizures syndrome 3, MIM# 615398 to Multiple congenital anomalies-hypotonia-seizures syndrome 3, MIM# 615398, MONDO:0014165
Intellectual disability syndromic and non-syndromic v0.3302 PIGT Zornitza Stark edited their review of gene: PIGT: Changed phenotypes: Multiple congenital anomalies-hypotonia-seizures syndrome 3, MIM# 615398, MONDO:0014165
Intellectual disability syndromic and non-syndromic v0.3302 PIGO Zornitza Stark Marked gene: PIGO as ready
Intellectual disability syndromic and non-syndromic v0.3302 PIGO Zornitza Stark Gene: pigo has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3302 PIGO Zornitza Stark Phenotypes for gene: PIGO were changed from to Hyperphosphatasia with mental retardation syndrome 2, MIM# 614749, MONDO:0013882
Intellectual disability syndromic and non-syndromic v0.3301 PIGO Zornitza Stark Publications for gene: PIGO were set to
Intellectual disability syndromic and non-syndromic v0.3300 PIGO Zornitza Stark Mode of inheritance for gene: PIGO was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3299 PIGO Zornitza Stark reviewed gene: PIGO: Rating: GREEN; Mode of pathogenicity: None; Publications: 22683086, 31698102, 28900819, 28545593, 28337824; Phenotypes: Hyperphosphatasia with mental retardation syndrome 2, MIM# 614749, MONDO:0013882; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3299 PIGN Zornitza Stark Marked gene: PIGN as ready
Intellectual disability syndromic and non-syndromic v0.3299 PIGN Zornitza Stark Gene: pign has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3299 PIGN Zornitza Stark Phenotypes for gene: PIGN were changed from to Multiple congenital anomalies-hypotonia-seizures syndrome 1, MIM# 614080, MONDO:0013563
Intellectual disability syndromic and non-syndromic v0.3298 PIGN Zornitza Stark Publications for gene: PIGN were set to
Intellectual disability syndromic and non-syndromic v0.3297 PIGN Zornitza Stark Mode of inheritance for gene: PIGN was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3296 PIGN Zornitza Stark reviewed gene: PIGN: Rating: GREEN; Mode of pathogenicity: None; Publications: 21493957, 24253414, 26364997, 26394714, 33193741, 32585529, 29330547; Phenotypes: Multiple congenital anomalies-hypotonia-seizures syndrome 1, MIM# 614080, MONDO:0013563; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3296 PIGL Zornitza Stark Marked gene: PIGL as ready
Intellectual disability syndromic and non-syndromic v0.3296 PIGL Zornitza Stark Gene: pigl has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3296 PIGL Zornitza Stark Phenotypes for gene: PIGL were changed from to CHIME syndrome, MIM# 280000, MONDO:0010221
Intellectual disability syndromic and non-syndromic v0.3295 PIGL Zornitza Stark Publications for gene: PIGL were set to
Intellectual disability syndromic and non-syndromic v0.3294 PIGL Zornitza Stark Tag SV/CNV tag was added to gene: PIGL.
Tag founder tag was added to gene: PIGL.
Intellectual disability syndromic and non-syndromic v0.3294 PIGL Zornitza Stark Mode of inheritance for gene: PIGL was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3293 PIGL Zornitza Stark reviewed gene: PIGL: Rating: GREEN; Mode of pathogenicity: None; Publications: 22444671, 31535386, 30023290, 29473937, 28371479, 25706356; Phenotypes: CHIME syndrome, MIM# 280000, MONDO:0010221; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3293 B3GALNT2 Zornitza Stark Marked gene: B3GALNT2 as ready
Intellectual disability syndromic and non-syndromic v0.3293 B3GALNT2 Zornitza Stark Gene: b3galnt2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3293 B3GALNT2 Zornitza Stark Phenotypes for gene: B3GALNT2 were changed from to Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies, type A, 11, MIM# 615181; MONDO:0014071
Intellectual disability syndromic and non-syndromic v0.3292 B3GALNT2 Zornitza Stark Publications for gene: B3GALNT2 were set to
Intellectual disability syndromic and non-syndromic v0.3291 B3GALNT2 Zornitza Stark Mode of inheritance for gene: B3GALNT2 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3290 B3GALNT2 Zornitza Stark reviewed gene: B3GALNT2: Rating: GREEN; Mode of pathogenicity: None; Publications: 23453667, 33290285, 29791932, 29273094, 28688748, 28303321; Phenotypes: Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies, type A, 11, MIM# 615181, MONDO:0014071; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3290 MPDU1 Zornitza Stark Marked gene: MPDU1 as ready
Intellectual disability syndromic and non-syndromic v0.3290 MPDU1 Zornitza Stark Gene: mpdu1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3290 MPDU1 Zornitza Stark Phenotypes for gene: MPDU1 were changed from to Congenital disorder of glycosylation, type If, MIM# 609180; MPDU1-CDG, MONDO:0012211
Intellectual disability syndromic and non-syndromic v0.3289 MPDU1 Zornitza Stark Publications for gene: MPDU1 were set to
Intellectual disability syndromic and non-syndromic v0.3288 MPDU1 Zornitza Stark Mode of inheritance for gene: MPDU1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3287 MPDU1 Zornitza Stark reviewed gene: MPDU1: Rating: GREEN; Mode of pathogenicity: None; Publications: 11733564, 11733556, 31741824, 29721919; Phenotypes: Congenital disorder of glycosylation, type If, MIM# 609180, MPDU1-CDG, MONDO:0012211; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3287 DPAGT1 Zornitza Stark Marked gene: DPAGT1 as ready
Intellectual disability syndromic and non-syndromic v0.3287 DPAGT1 Zornitza Stark Gene: dpagt1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3287 DPAGT1 Zornitza Stark Phenotypes for gene: DPAGT1 were changed from to Congenital disorder of glycosylation, type Ij, MIM# 608093; DPAGT1-CDG MONDO:0011964
Intellectual disability syndromic and non-syndromic v0.3286 DPAGT1 Zornitza Stark Publications for gene: DPAGT1 were set to
Intellectual disability syndromic and non-syndromic v0.3285 DPAGT1 Zornitza Stark Mode of inheritance for gene: DPAGT1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3284 DPAGT1 Zornitza Stark reviewed gene: DPAGT1: Rating: GREEN; Mode of pathogenicity: None; Publications: 12872255, 22492991, 22304930, 31153949, 30653653, 30117111; Phenotypes: Congenital disorder of glycosylation, type Ij, MIM# 608093, DPAGT1-CDG MONDO:0011964; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3284 DOLK Zornitza Stark Marked gene: DOLK as ready
Intellectual disability syndromic and non-syndromic v0.3284 DOLK Zornitza Stark Gene: dolk has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3284 DOLK Zornitza Stark Phenotypes for gene: DOLK were changed from to DK1-CDG, MONDO:0012556; Congenital disorder of glycosylation, type Im, MIM# 610768
Intellectual disability syndromic and non-syndromic v0.3283 DOLK Zornitza Stark Publications for gene: DOLK were set to
Intellectual disability syndromic and non-syndromic v0.3282 DOLK Zornitza Stark Mode of inheritance for gene: DOLK was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3281 DOLK Zornitza Stark reviewed gene: DOLK: Rating: GREEN; Mode of pathogenicity: None; Publications: 17273964, 22242004, 23890587, 30653653, 28816422, 24144945; Phenotypes: DK1-CDG, MONDO:0012556, Congenital disorder of glycosylation, type Im, MIM# 610768; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3281 DPYD Elena Savva Deleted their review
Intellectual disability syndromic and non-syndromic v0.3281 EZH2 Zornitza Stark Marked gene: EZH2 as ready
Intellectual disability syndromic and non-syndromic v0.3281 EZH2 Zornitza Stark Gene: ezh2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3281 EZH2 Zornitza Stark Phenotypes for gene: EZH2 were changed from to Weaver syndrome MIM#277590
Intellectual disability syndromic and non-syndromic v0.3280 EZH2 Zornitza Stark Publications for gene: EZH2 were set to
Intellectual disability syndromic and non-syndromic v0.3279 EZH2 Zornitza Stark Mode of inheritance for gene: EZH2 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3278 EZH2 Zornitza Stark reviewed gene: EZH2: Rating: GREEN; Mode of pathogenicity: None; Publications: 29244146, 23865096; Phenotypes: Weaver syndrome MIM#277590; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3278 DPYD Elena Savva reviewed gene: DPYD: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 29152729; Phenotypes: 5-fluorouracil toxicity MIM#274270, Dihydropyrimidine dehydrogenase deficiency MIM#274270; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3278 COG5 Zornitza Stark Marked gene: COG5 as ready
Intellectual disability syndromic and non-syndromic v0.3278 COG5 Zornitza Stark Gene: cog5 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3278 COG5 Zornitza Stark Phenotypes for gene: COG5 were changed from to Congenital disorder of glycosylation, type IIi, MIM# 613612
Intellectual disability syndromic and non-syndromic v0.3277 COG5 Zornitza Stark Publications for gene: COG5 were set to
Intellectual disability syndromic and non-syndromic v0.3276 COG5 Zornitza Stark Mode of inheritance for gene: COG5 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3275 COG5 Zornitza Stark reviewed gene: COG5: Rating: GREEN; Mode of pathogenicity: None; Publications: 23228021, 31572517, 32174980; Phenotypes: Congenital disorder of glycosylation, type IIi, MIM# 613612; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3275 SHMT2 Zornitza Stark Phenotypes for gene: SHMT2 were changed from Congenital microcephaly; Infantile axial hypotonia; Spastic paraparesis; Global developmental delay; Intellectual disability; Abnormality of the corpus callosum; Abnormal cortical gyration; Hypertrophic cardiomyopathy; Abnormality of the face; Proximal placement of thumb; 2-3 toe syndactyly to Neurodevelopmental disorder with cardiomyopathy, spasticity, and brain abnormalities (NEDCASB), MIM#619121; Congenital microcephaly; Infantile axial hypotonia; Spastic paraparesis; Global developmental delay; Intellectual disability; Abnormality of the corpus callosum; Abnormal cortical gyration; Hypertrophic cardiomyopathy; Abnormality of the face; Proximal placement of thumb; 2-3 toe syndactyly
Intellectual disability syndromic and non-syndromic v0.3274 SHMT2 Zornitza Stark reviewed gene: SHMT2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with cardiomyopathy, spasticity, and brain abnormalities (NEDCASB), MIM#619121, Congenital microcephaly, Infantile axial hypotonia, Spastic paraparesis, Global developmental delay, Intellectual disability, Abnormality of the corpus callosum, Abnormal cortical gyration, Hypertrophic cardiomyopathy, Abnormality of the face, Proximal placement of thumb, 2-3 toe syndactylyCongenital microcephaly, Infantile axial hypotonia, Spastic paraparesis, Global developmental delay, Intellectual disability, Abnormality of the corpus callosum, Abnormal cortical gyration, Hypertrophic cardiomyopathy, Abnormality of the face, Proximal placement of thumb, 2-3 toe syndactyly; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3274 PPIL1 Zornitza Stark Marked gene: PPIL1 as ready
Intellectual disability syndromic and non-syndromic v0.3274 PPIL1 Zornitza Stark Gene: ppil1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3274 PPIL1 Zornitza Stark Classified gene: PPIL1 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.3274 PPIL1 Zornitza Stark Gene: ppil1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3273 PPIL1 Zornitza Stark gene: PPIL1 was added
gene: PPIL1 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: PPIL1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PPIL1 were set to 33220177
Phenotypes for gene: PPIL1 were set to Pontocerebellar hypoplasia; microcephaly; seizures
Review for gene: PPIL1 was set to GREEN
Added comment: 17 individuals from 9 unrelated families reported with bi-allelic variants in the gene and PCH, microcephaly, hypotonia, seizures, severe DD/ID. Mouse models support gene-disease association.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.3272 DIP2B Bryony Thompson Classified gene: DIP2B as No list
Intellectual disability syndromic and non-syndromic v0.3272 DIP2B Bryony Thompson Added comment: Comment on list classification: Only repeat expansion reported. Added as an STR
Intellectual disability syndromic and non-syndromic v0.3272 DIP2B Bryony Thompson Gene: dip2b has been removed from the panel.
Intellectual disability syndromic and non-syndromic v0.3271 FRA12A Bryony Thompson Marked STR: FRA12A as ready
Intellectual disability syndromic and non-syndromic v0.3271 FRA12A Bryony Thompson Str: fra12a has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.3271 FRA12A Bryony Thompson Classified STR: FRA12A as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.3271 FRA12A Bryony Thompson Str: fra12a has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.3270 FRA12A Bryony Thompson STR: FRA12A was added
STR: FRA12A was added to Intellectual disability syndromic and non-syndromic. Sources: Other
5'UTR tags were added to STR: FRA12A.
Mode of inheritance for STR: FRA12A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for STR: FRA12A were set to 17236128
Phenotypes for STR: FRA12A were set to Mental retardation, FRA12A type MIM#136630
Review for STR: FRA12A was set to AMBER
Added comment: NM_173602.2:c.-137CGG[X]
All individuals expressing FRA12A had CGG-repeat expansion. The length of the expanded allele in 3 unaffected FRA12A carriers was 650–850 bp. In the two affected patients from 2 families with FRA12A, the length of the expanded allele was ∼1,050-1,150 bp.
70 controls used to determine the "normal" repeat range.
Sources: Other
Intellectual disability syndromic and non-syndromic v0.3269 FRAXE Bryony Thompson Classified STR: FRAXE as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.3269 FRAXE Bryony Thompson Str: fraxe has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3268 FRAXE Bryony Thompson STR: FRAXE was added
STR: FRAXE was added to Intellectual disability syndromic and non-syndromic. Sources: Expert list
Mode of inheritance for STR: FRAXE was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for STR: FRAXE were set to 8334699; 8673085; 11388762
Phenotypes for STR: FRAXE were set to Fragile X syndrome, FRAXE type (OMIM 309548)
Review for STR: FRAXE was set to GREEN
STR: FRAXE was marked as clinically relevant
STR: FRAXE was marked as current diagnostic
Added comment: NM_001169122.1(AFF2):c.-460_-458GCC(6_25)
Loss of function through methylation silencing is the mechanism of disease
Normal - 5-44 repeats
Inconclusive - 45-54 repeats
Premutation - 55-200 repeats
Abnormal - >200 or >230 repeats
Sources: Expert list
Intellectual disability syndromic and non-syndromic v0.3267 RAP1B Zornitza Stark Publications for gene: RAP1B were set to PMID: 32627184
Intellectual disability syndromic and non-syndromic v0.3266 RAP1B Zornitza Stark Classified gene: RAP1B as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.3266 RAP1B Zornitza Stark Gene: rap1b has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3265 RAP1B Zornitza Stark edited their review of gene: RAP1B: Added comment: Another individual with de novo missense variant from a Kabuki-like cohort but note facial gestalt was not typical, had DD.; Changed rating: GREEN; Changed publications: 32627184, 26280580
Intellectual disability syndromic and non-syndromic v0.3265 RAP1B Zornitza Stark reviewed gene: RAP1B: Rating: AMBER; Mode of pathogenicity: None; Publications: 32627184; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3265 RAP1B Zornitza Stark Marked gene: RAP1B as ready
Intellectual disability syndromic and non-syndromic v0.3265 RAP1B Zornitza Stark Gene: rap1b has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.3265 RAP1B Zornitza Stark Classified gene: RAP1B as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.3265 RAP1B Zornitza Stark Gene: rap1b has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.3264 RAP1B Chirag Patel gene: RAP1B was added
gene: RAP1B was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: RAP1B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RAP1B were set to PMID: 32627184
Phenotypes for gene: RAP1B were set to RAP1B‐associated phenotype, no OMIM #
Review for gene: RAP1B was set to RED
Added comment: De novo variants in the RAP1B gene (c.35G>T p.(Gly12Val) and c.178G>C p.(Gly60Arg)) in two unrelated patients with thrombocytopenia, microcephaly, learning difficulties, renal malformations, structural anomalies of the brain and other features (not Kabuki like).

RAP1B is a member of the RAS superfamily of small GTPases. There is strong evidence that the p.Gly12Val and p.Gly60Arg variants in the RAP1B gene lead into a dysregulation of the downstream pathway. Both substitutions have been described previously as dominant constitutively active in RAS‐related proteins (gain of function variants).
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.3263 EMC10 Chirag Patel gene: EMC10 was added
gene: EMC10 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: EMC10 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EMC10 were set to PMID: 32869858
Phenotypes for gene: EMC10 were set to Developmental delay and intellectual disability, no OMIM#
Review for gene: EMC10 was set to RED
Added comment: Homozygous variants of EMC1 are associated with GDD, scoliosis, and cerebellar atrophy, indicating the relevance of this pathway for neurogenetic disorders.

One Saudi family with 2 affected individuals with mild ID, speech delay, and GDD.
WES and Sanger sequencing revealed a homozygous splice acceptor site variant (c.679‐1G>A) in EMC10 . Variant segregated within the family. RT‐qPCR showed a substantial decrease in the relative EMC10 gene expression in the patients.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.3262 FBXO28 Zornitza Stark changed review comment from: Nine new individuals with FBXO28 pathogenic variants (four missense, including one recurrent, three nonsense, and one frameshift) and all 10 known cases reviewed to delineate the phenotypic spectrum. All patients had epilepsy and 9 of 10 had DEE, including infantile spasms (3) and a progressive myoclonic epilepsy (1). Median age at seizure onset was 22.5 months (range 8 months to 5 years). Nine of 10 patients had intellectual disability, which was profound in six of nine and severe in three of nine. Movement disorders occurred in eight of 10 patients, six of 10 had hypotonia, four of 10 had acquired microcephaly, and five of 10 had dysmorphic features.
Sources: Literature; to: Nine new individuals with FBXO28 pathogenic variants (four missense, including one recurrent, three nonsense, and one frameshift) and all 10 known cases reviewed to delineate the phenotypic spectrum. All had epilepsy and 9 of 10 had DEE, including infantile spasms (3) and a progressive myoclonic epilepsy (1). Median age at seizure onset was 22.5 months (range 8 months to 5 years). Nine of 10 patients had intellectual disability, which was profound in six of nine and severe in three of nine. Movement disorders occurred in eight of 10 patients, six of 10 had hypotonia, four of 10 had acquired microcephaly, and five of 10 had dysmorphic features.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.3262 FBXO28 Zornitza Stark Marked gene: FBXO28 as ready
Intellectual disability syndromic and non-syndromic v0.3262 FBXO28 Zornitza Stark Gene: fbxo28 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3262 FBXO28 Zornitza Stark Classified gene: FBXO28 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.3262 FBXO28 Zornitza Stark Gene: fbxo28 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3261 FBXO28 Zornitza Stark gene: FBXO28 was added
gene: FBXO28 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: FBXO28 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FBXO28 were set to 33280099
Phenotypes for gene: FBXO28 were set to Developmental and epileptic encephalopathy
Review for gene: FBXO28 was set to GREEN
Added comment: Nine new individuals with FBXO28 pathogenic variants (four missense, including one recurrent, three nonsense, and one frameshift) and all 10 known cases reviewed to delineate the phenotypic spectrum. All patients had epilepsy and 9 of 10 had DEE, including infantile spasms (3) and a progressive myoclonic epilepsy (1). Median age at seizure onset was 22.5 months (range 8 months to 5 years). Nine of 10 patients had intellectual disability, which was profound in six of nine and severe in three of nine. Movement disorders occurred in eight of 10 patients, six of 10 had hypotonia, four of 10 had acquired microcephaly, and five of 10 had dysmorphic features.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.3260 RLIM Zornitza Stark Publications for gene: RLIM were set to 29728705; 25735484; 25644381
Intellectual disability syndromic and non-syndromic v0.3259 RLIM Zornitza Stark Mode of pathogenicity for gene: RLIM was changed from to Other
Intellectual disability syndromic and non-syndromic v0.3258 RLIM Zornitza Stark changed review comment from: 14 males from 9 families reported with duplications involving RLIM gene, suggesting dosage effect.; to: 14 males from 9 families reported with duplications involving RLIM gene and intellectual disability, suggesting dosage effect.
Intellectual disability syndromic and non-syndromic v0.3258 RLIM Zornitza Stark edited their review of gene: RLIM: Added comment: 14 males from 9 families reported with duplications involving RLIM gene, suggesting dosage effect.; Changed mode of pathogenicity: Other; Changed publications: 29728705, 25735484, 25644381, 33159883
Intellectual disability syndromic and non-syndromic v0.3258 CLCN6 Zornitza Stark Marked gene: CLCN6 as ready
Intellectual disability syndromic and non-syndromic v0.3258 CLCN6 Zornitza Stark Gene: clcn6 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3258 CLCN6 Zornitza Stark Classified gene: CLCN6 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.3258 CLCN6 Zornitza Stark Gene: clcn6 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3257 CLCN6 Zornitza Stark gene: CLCN6 was added
gene: CLCN6 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: CLCN6 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CLCN6 were set to 33217309
Phenotypes for gene: CLCN6 were set to Developmental delay; neurodegeneration
Review for gene: CLCN6 was set to GREEN
Added comment: Three unrelated families reported with recurrent GOF de novo c.1658A>G (p.Tyr553Cys) and severe developmental delay with pronounced generalized hypotonia, respiratory insufficiency, and variable neurodegeneration and diffusion restriction in cerebral peduncles, midbrain, and/or brainstem in MRI scans.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.3256 HS2ST1 Zornitza Stark Phenotypes for gene: HS2ST1 were changed from to Intellectual disability; dysmorphic features; congenital anomalies
Intellectual disability syndromic and non-syndromic v0.3255 KDM4B Zornitza Stark Marked gene: KDM4B as ready
Intellectual disability syndromic and non-syndromic v0.3255 KDM4B Zornitza Stark Gene: kdm4b has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3255 KDM4B Zornitza Stark Classified gene: KDM4B as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.3255 KDM4B Zornitza Stark Gene: kdm4b has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3254 SMG8 Zornitza Stark Publications for gene: SMG8 were set to 31130284
Intellectual disability syndromic and non-syndromic v0.3253 SMG8 Zornitza Stark Classified gene: SMG8 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.3253 SMG8 Zornitza Stark Gene: smg8 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3252 HS2ST1 Elena Savva Mode of pathogenicity for gene: HS2ST1 was changed from None to None
Intellectual disability syndromic and non-syndromic v0.3252 HS2ST1 Elena Savva Classified gene: HS2ST1 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.3252 HS2ST1 Elena Savva Gene: hs2st1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3251 HS2ST1 Elena Savva Marked gene: HS2ST1 as ready
Intellectual disability syndromic and non-syndromic v0.3251 HS2ST1 Elena Savva Added comment: Comment when marking as ready: - 4 affected from 3 unrelated families - 3 unique missense and 2 PTCs - Developmental Delay, Corpus Callosum Hypoplasia or Aplasia, and Skeletal and Renal Abnormalities
Intellectual disability syndromic and non-syndromic v0.3251 HS2ST1 Elena Savva Gene: hs2st1 has been removed from the panel.
Intellectual disability syndromic and non-syndromic v0.3251 VPS4A Elena Savva changed review comment from: Comment when marking as ready: PMID: 33186543 - 2x de novo hetorozygous missense variants in the AAA (large ATPase) domain. 1x homozygous missense in the MIT domain (milder phenotype and unaffected parents - possibly just a simple LoF mechanism for AR inheritance). Demonstrated defective CD71 trafficking in all 3 patients. PMID: 33186545 - 6x probands with de novo missense variants in the AAA domain. 5 of the variants were at amino acid position 284 (changes to Trp and Gly). Demonstrated that the variants had a dominant-negative effect on VPS4A function. "The six probands with de novo substitutions affecting Glu206 or Arg284 had a consistent phenotype characterized by severe DD, profound ID, and dystonia. Children were very delayed in establishing head control and none achieved independent walking. Other common findings were cerebellar hypoplasia (five individuals out of six, the other showing uncharacterized severe cerebral atrophy) with a variable degree of corpus callosum hypoplasia. One individual also had bilateral polymicrogyria. Epilepsy was present in three and dystonia in five subjects. Eye involvement was also a common finding, including congenital cataract, retinal dystrophy, and in one case congenital Leber amaurosis. Four individuals were diagnosed with hepatosplenomegaly and/or steatosis. Three subjects had anemia, which was characterized as dyserythropoietic in two. Severe feeding difficulties were present in four individuals, requiring assisted feeding in three. Two had sensorineural deafness. Severe growth retardation, generally for all parameters, was present in most cases. Notably, severe microcephaly (typically with Z scores < −5) was universal. Overall, the disorder seems to have a poor prognosis as two affected individuals died in childhood or early adult life."; to: PMID: 33186543 - 2x de novo hetorozygous missense variants in the AAA (large ATPase) domain. 1x homozygous missense in the MIT domain (milder phenotype and unaffected parents - possibly just a simple LoF mechanism for AR inheritance). Demonstrated defective CD71 trafficking in all 3 patients.

PMID: 33186545 - 6x probands with de novo missense variants in the AAA domain. 5 of the variants were at amino acid position 284 (changes to Trp and Gly). Demonstrated that the variants had a dominant-negative effect on VPS4A function. "The six probands with de novo substitutions affecting Glu206 or Arg284 had a consistent phenotype characterized by severe DD, profound ID, and dystonia. Children were very delayed in establishing head control and none achieved independent walking. Other common findings were cerebellar hypoplasia (five individuals out of six, the other showing uncharacterized severe cerebral atrophy) with a variable degree of corpus callosum hypoplasia. One individual also had bilateral polymicrogyria. Epilepsy was present in three and dystonia in five subjects. Eye involvement was also a common finding, including congenital cataract, retinal dystrophy, and in one case congenital Leber amaurosis. Four individuals were diagnosed with hepatosplenomegaly and/or steatosis. Three subjects had anemia, which was characterized as dyserythropoietic in two. Severe feeding difficulties were present in four individuals, requiring assisted feeding in three. Two had sensorineural deafness. Severe growth retardation, generally for all parameters, was present in most cases. Notably, severe microcephaly (typically with Z scores < −5) was universal. Overall, the disorder seems to have a poor prognosis as two affected individuals died in childhood or early adult life."
Intellectual disability syndromic and non-syndromic v0.3251 VPS4A Elena Savva Added comment: Comment on mode of pathogenicity: Dominant negative
Intellectual disability syndromic and non-syndromic v0.3251 VPS4A Elena Savva Mode of pathogenicity for gene: VPS4A was changed from None to Other
Intellectual disability syndromic and non-syndromic v0.3251 VPS4A Elena Savva Marked gene: VPS4A as ready
Intellectual disability syndromic and non-syndromic v0.3251 VPS4A Elena Savva Added comment: Comment when marking as ready: PMID: 33186543 - 2x de novo hetorozygous missense variants in the AAA (large ATPase) domain. 1x homozygous missense in the MIT domain (milder phenotype and unaffected parents - possibly just a simple LoF mechanism for AR inheritance). Demonstrated defective CD71 trafficking in all 3 patients. PMID: 33186545 - 6x probands with de novo missense variants in the AAA domain. 5 of the variants were at amino acid position 284 (changes to Trp and Gly). Demonstrated that the variants had a dominant-negative effect on VPS4A function. "The six probands with de novo substitutions affecting Glu206 or Arg284 had a consistent phenotype characterized by severe DD, profound ID, and dystonia. Children were very delayed in establishing head control and none achieved independent walking. Other common findings were cerebellar hypoplasia (five individuals out of six, the other showing uncharacterized severe cerebral atrophy) with a variable degree of corpus callosum hypoplasia. One individual also had bilateral polymicrogyria. Epilepsy was present in three and dystonia in five subjects. Eye involvement was also a common finding, including congenital cataract, retinal dystrophy, and in one case congenital Leber amaurosis. Four individuals were diagnosed with hepatosplenomegaly and/or steatosis. Three subjects had anemia, which was characterized as dyserythropoietic in two. Severe feeding difficulties were present in four individuals, requiring assisted feeding in three. Two had sensorineural deafness. Severe growth retardation, generally for all parameters, was present in most cases. Notably, severe microcephaly (typically with Z scores < −5) was universal. Overall, the disorder seems to have a poor prognosis as two affected individuals died in childhood or early adult life."
Intellectual disability syndromic and non-syndromic v0.3251 VPS4A Elena Savva Gene: vps4a has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3251 VPS4A Elena Savva Classified gene: VPS4A as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.3251 VPS4A Elena Savva Gene: vps4a has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3250 VPS4A Kristin Rigbye gene: VPS4A was added
gene: VPS4A was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: VPS4A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: VPS4A were set to 33186543; 33186545
Phenotypes for gene: VPS4A were set to Neurodevelopmental disorder
Review for gene: VPS4A was set to GREEN
Added comment: PMID: 33186543 - 2x de novo hetorozygous missense variants in the AAA (large ATPase) domain.
1x homozygous missense in the MIT domain (milder phenotype and unaffected parents - possibly just a simple LoF mechanism for AR inheritance).
Demonstrated defective CD71 trafficking in all 3 patients.

PMID: 33186545 - 6x probands with de novo missense variants in the AAA domain. 5 of the variants were at amino acid position 284 (changes to Trp and Gly).
Demonstrated that the variants had a dominant-negative effect on VPS4A function.

"The six probands with de novo substitutions affecting Glu206 or Arg284 had a consistent phenotype characterized by severe DD, profound ID, and dystonia. Children were very delayed in establishing head control and none achieved independent walking. Other common findings were cerebellar hypoplasia (five individuals out of six, the other showing uncharacterized severe cerebral atrophy) with a variable degree of corpus callosum hypoplasia. One individual also had bilateral polymicrogyria. Epilepsy was present in three and dystonia in five subjects. Eye involvement was also a common finding, including congenital cataract, retinal dystrophy, and in one case congenital Leber amaurosis. Four individuals were diagnosed with hepatosplenomegaly and/or steatosis. Three subjects had anemia, which was characterized as dyserythropoietic in two. Severe feeding difficulties were present in four individuals, requiring assisted feeding in three. Two had sensorineural deafness. Severe growth retardation, generally for all parameters, was present in most cases. Notably, severe microcephaly (typically with Z scores < −5) was universal. Overall, the disorder seems to have a poor prognosis as two affected individuals died in childhood or early adult life."
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.3250 BICRA Elena Savva Classified gene: BICRA as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.3250 BICRA Elena Savva Gene: bicra has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3250 BICRA Elena Savva Classified gene: BICRA as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.3250 BICRA Elena Savva Gene: bicra has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3250 BICRA Elena Savva Classified gene: BICRA as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.3250 BICRA Elena Savva Gene: bicra has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3250 BICRA Elena Savva Classified gene: BICRA as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.3250 BICRA Elena Savva Gene: bicra has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3250 BICRA Elena Savva Classified gene: BICRA as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.3250 BICRA Elena Savva Gene: bicra has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3249 BICRA Elena Savva Classified gene: BICRA as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.3249 BICRA Elena Savva Gene: bicra has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3250 BICRA Elena Savva Classified gene: BICRA as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.3250 BICRA Elena Savva Gene: bicra has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3249 BICRA Elena Savva Classified gene: BICRA as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.3249 BICRA Elena Savva Gene: bicra has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3249 BICRA Elena Savva Classified gene: BICRA as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.3249 BICRA Elena Savva Gene: bicra has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3249 HS2ST1 Ain Roesley gene: HS2ST1 was added
gene: HS2ST1 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: HS2ST1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HS2ST1 were set to 33159882
Penetrance for gene: HS2ST1 were set to unknown
Added comment: - 4 affected from 3 unrelated families
- 3 unique missense and 2 PTCs
- Developmental Delay, Corpus Callosum Hypoplasia or Aplasia, and Skeletal and Renal Abnormalities
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.3249 BICRA Elena Savva Classified gene: BICRA as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.3249 BICRA Elena Savva Gene: bicra has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3248 BICRA Elena Savva Marked gene: BICRA as ready
Intellectual disability syndromic and non-syndromic v0.3248 BICRA Elena Savva Added comment: Comment when marking as ready: 12 individuals reported, 11 de novo (1 not resolved), "with neurodevelopmental phenotypes—developmental delay (HP:0001263), intellectual disability (HP:0001249), autism spectrum disorder (HP:0000729), and/or behavioral phenotypes (HP:0000708)—and variable structural birth defects and dysmorphic features". Mostly LoF or gene deletions, but 2 missense reported. Zebrafish model supports the gene-disease association.
Intellectual disability syndromic and non-syndromic v0.3248 BICRA Elena Savva Gene: bicra has been removed from the panel.
Intellectual disability syndromic and non-syndromic v0.3248 KDM4B Kristin Rigbye gene: KDM4B was added
gene: KDM4B was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: KDM4B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KDM4B were set to PMID: 33232677
Phenotypes for gene: KDM4B were set to Global developmental delay, intellectual disability and neuroanatomical defects
Review for gene: KDM4B was set to GREEN
Added comment: Nine individuals with mono-allelic de novo or inherited variants in KDM4B.

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

In a knockout mouse the total brain volume was significantly reduced with decreased
size of the hippocampal dentate gyrus, partial agenesis of the corpus callosum, and ventriculomegaly.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.3248 SMG8 Kristin Rigbye reviewed gene: SMG8: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 33242396; Phenotypes: Neuorodevelopmental disorder; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3248 BICRA Paul De Fazio gene: BICRA was added
gene: BICRA was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: BICRA was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: BICRA were set to 33232675
Phenotypes for gene: BICRA were set to Developmental delay, intellectual disability, autism spectrum disorder,behavioral abnormalities, dysmorphic features
Review for gene: BICRA was set to GREEN
gene: BICRA was marked as current diagnostic
Added comment: 12 individuals reported, 11 de novo (1 not resolved), "with neurodevelopmental phenotypes—developmental delay (HP:0001263), intellectual disability (HP:0001249), autism spectrum disorder (HP:0000729), and/or behavioral phenotypes (HP:0000708)—and variable structural birth defects and dysmorphic features". Mostly LoF or gene deletions, but 2 missense reported. Zebrafish model supports the gene-disease association.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.3248 AGO2 Zornitza Stark Classified gene: AGO2 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.3248 AGO2 Zornitza Stark Gene: ago2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3247 AGO2 Zornitza Stark Classified gene: AGO2 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.3247 AGO2 Zornitza Stark Gene: ago2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3246 AGO2 Zornitza Stark Marked gene: AGO2 as ready
Intellectual disability syndromic and non-syndromic v0.3246 AGO2 Zornitza Stark Gene: ago2 has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v0.3246 AGO2 Zornitza Stark gene: AGO2 was added
gene: AGO2 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: AGO2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: AGO2 were set to 33199684
Phenotypes for gene: AGO2 were set to Intellectual disability
Review for gene: AGO2 was set to GREEN
Added comment: 21 individuals reported, five variants (p.L192P, p.G201V, p.T357M, p.M364T, p.C751Y) were recurrent. Variable ID.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.3245 KAT5 Zornitza Stark Deleted their comment
Intellectual disability syndromic and non-syndromic v0.3245 KAT5 Zornitza Stark Phenotypes for gene: KAT5 were changed from Severe global developmental delay; Intellectual disability; Seizures; Microcephaly; Behavioral abnormality; Sleep disturbance; Morphological abnormality of the central nervous system; Short stature; Oral cleft; Abnormality of the face to Neurodevelopmental disorder with dysmorphic facies, sleep disturbance, and brain abnormalities (NEDFASB), MIM#619103; Severe global developmental delay; Intellectual disability; Seizures; Microcephaly; Behavioral abnormality; Sleep disturbance; Morphological abnormality of the central nervous system; Short stature; Oral cleft; Abnormality of the face
Intellectual disability syndromic and non-syndromic v0.3244 KAT5 Zornitza Stark edited their review of gene: KAT5: Changed rating: GREEN; Changed phenotypes: Neurodevelopmental disorder with dysmorphic facies, sleep disturbance, and brain abnormalities (NEDFASB), MIM#619103; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3244 H3F3B Zornitza Stark Phenotypes for gene: H3F3B were changed from to Intellectual disability; regression; seizures
Intellectual disability syndromic and non-syndromic v0.3243 H3F3B Zornitza Stark Publications for gene: H3F3B were set to
Intellectual disability syndromic and non-syndromic v0.3242 H3F3B Zornitza Stark Mode of inheritance for gene: H3F3B was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3241 H3F3B Zornitza Stark Classified gene: H3F3B as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.3241 H3F3B Zornitza Stark Gene: h3f3b has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3240 H3F3B Zornitza Stark edited their review of gene: H3F3B: Added comment: 13 unrelated individuals reported with missense variants in H3F3B. Phenotype primarily comprised intellectual disability and minor congenital anomalies, regression in significant proportion. Seizures in 50%.; Changed rating: GREEN; Changed publications: 33268356; Changed phenotypes: Intellectual disability, regression, seizures; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3240 H3F3A Zornitza Stark Phenotypes for gene: H3F3A were changed from to Intellectual disability; regression; seizures
Intellectual disability syndromic and non-syndromic v0.3239 H3F3A Zornitza Stark Publications for gene: H3F3A were set to
Intellectual disability syndromic and non-syndromic v0.3238 H3F3A Zornitza Stark Mode of inheritance for gene: H3F3A was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3237 H3F3A Zornitza Stark Classified gene: H3F3A as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.3237 H3F3A Zornitza Stark Gene: h3f3a has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3236 H3F3A Zornitza Stark edited their review of gene: H3F3A: Added comment: 33 unrelated individuals reported with missense variants in H3F3A. Phenotype primarily comprised intellectual disability and minor congenital anomalies, regression in significant proportion. Seizures in 50%.; Changed rating: GREEN; Changed publications: 33268356; Changed phenotypes: Intellectual disability, regression, seizures; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3236 HIVEP2 Zornitza Stark Marked gene: HIVEP2 as ready
Intellectual disability syndromic and non-syndromic v0.3236 HIVEP2 Zornitza Stark Gene: hivep2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3236 HIVEP2 Zornitza Stark Phenotypes for gene: HIVEP2 were changed from to Mental retardation, autosomal dominant 43, MIM# 616977
Intellectual disability syndromic and non-syndromic v0.3235 HIVEP2 Zornitza Stark Publications for gene: HIVEP2 were set to
Intellectual disability syndromic and non-syndromic v0.3234 HIVEP2 Zornitza Stark Mode of inheritance for gene: HIVEP2 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3233 HIVEP2 Zornitza Stark reviewed gene: HIVEP2: Rating: GREEN; Mode of pathogenicity: None; Publications: 26153216, 27003583, 16836985, 31602191, 31207095; Phenotypes: Mental retardation, autosomal dominant 43, MIM# 616977; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3233 TFE3 Zornitza Stark Mode of inheritance for gene: TFE3 was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Intellectual disability syndromic and non-syndromic v0.3232 TFE3 Zornitza Stark Publications for gene: TFE3 were set to 30595499; 31833172
Intellectual disability syndromic and non-syndromic v0.3231 TFE3 Zornitza Stark Mode of pathogenicity for gene: TFE3 was changed from None to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Intellectual disability syndromic and non-syndromic v0.3230 TFE3 Zornitza Stark Mode of inheritance for gene: TFE3 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability syndromic and non-syndromic v0.3229 USP7 Zornitza Stark Phenotypes for gene: USP7 were changed from ID; Autism to Hao-Fountain syndrome, MIM# 616863; ID; Autism
Intellectual disability syndromic and non-syndromic v0.3228 USP7 Zornitza Stark Publications for gene: USP7 were set to 30679821
Intellectual disability syndromic and non-syndromic v0.3227 USP7 Zornitza Stark edited their review of gene: USP7: Changed publications: 26365382, 30679821
Intellectual disability syndromic and non-syndromic v0.3227 USP7 Zornitza Stark reviewed gene: USP7: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Hao-Fountain syndrome, MIM# 616863; Mode of inheritance: None
Intellectual disability syndromic and non-syndromic v0.3227 TFE3 Arina Puzriakova reviewed gene: TFE3: 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: 32409512; Phenotypes: TFE3-related intellectual disability with pigmentary mosaicism; 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 v0.3227 PIGK Zornitza Stark Marked gene: PIGK as ready
Intellectual disability syndromic and non-syndromic v0.3227 PIGK Zornitza Stark Gene: pigk has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3227 PIGK Zornitza Stark Phenotypes for gene: PIGK were changed from Intellectual disability; seizures; cerebellar atrophy to Neurodevelopmental disorder with hypotonia and cerebellar atrophy, with or without seizures, MIM# 618879
Intellectual disability syndromic and non-syndromic v0.3226 PIGK Zornitza Stark edited their review of gene: PIGK: Changed phenotypes: Neurodevelopmental disorder with hypotonia and cerebellar atrophy, with or without seizures, MIM# 618879
Intellectual disability syndromic and non-syndromic v0.3226 PIGB Zornitza Stark Phenotypes for gene: PIGB were changed from Epileptic encephalopathy, early infantile, 80; OMIM #618580 to Developmental and epileptic encephalopathy 80, MIM# 618580
Intellectual disability syndromic and non-syndromic v0.3225 PIGB Zornitza Stark reviewed gene: PIGB: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Developmental and epileptic encephalopathy 80, MIM# 618580; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3225 GPAA1 Zornitza Stark Marked gene: GPAA1 as ready
Intellectual disability syndromic and non-syndromic v0.3225 GPAA1 Zornitza Stark Gene: gpaa1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3225 GPAA1 Zornitza Stark Phenotypes for gene: GPAA1 were changed from to Glycosylphosphatidylinositol biosynthesis defect 15, MIM# 617810
Intellectual disability syndromic and non-syndromic v0.3224 GPAA1 Zornitza Stark Publications for gene: GPAA1 were set to
Intellectual disability syndromic and non-syndromic v0.3223 GPAA1 Zornitza Stark Mode of inheritance for gene: GPAA1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3222 GPAA1 Zornitza Stark reviewed gene: GPAA1: Rating: GREEN; Mode of pathogenicity: None; Publications: 29100095; Phenotypes: Glycosylphosphatidylinositol biosynthesis defect 15, MIM# 617810; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3222 HDAC4 Bryony Thompson Classified gene: HDAC4 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.3222 HDAC4 Bryony Thompson Gene: hdac4 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3221 HDAC4 Bryony Thompson reviewed gene: HDAC4: Rating: GREEN; Mode of pathogenicity: None; Publications: https://doi.org/10.1016/j.xhgg.2020.100015; Phenotypes: Intellectual disability, hypotonia, dysmorphism; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3221 OGT Zornitza Stark Marked gene: OGT as ready
Intellectual disability syndromic and non-syndromic v0.3221 OGT Zornitza Stark Gene: ogt has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3221 OGT Zornitza Stark Phenotypes for gene: OGT were changed from to Mental retardation, X-linked 106, MIM# 300997
Intellectual disability syndromic and non-syndromic v0.3220 OGT Zornitza Stark Publications for gene: OGT were set to
Intellectual disability syndromic and non-syndromic v0.3219 OGT Zornitza Stark Mode of inheritance for gene: OGT was changed from Unknown to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability syndromic and non-syndromic v0.3218 OGT Zornitza Stark reviewed gene: OGT: Rating: GREEN; Mode of pathogenicity: None; Publications: 28302723, 28584052, 31296563, 31627256, 29769320, 29606577; Phenotypes: Mental retardation, X-linked 106, MIM# 300997; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability syndromic and non-syndromic v0.3218 DPM2 Zornitza Stark Classified gene: DPM2 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.3218 DPM2 Zornitza Stark Gene: dpm2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3217 DPM2 Zornitza Stark edited their review of gene: DPM2: Added comment: Further unrelated individual reported, main clinical features were truncal hypotonia, hypertonicity, congenital heart defects, intellectual disability, and generalized muscle wasting.; Changed rating: GREEN; Changed publications: 23109149, 33129689
Intellectual disability syndromic and non-syndromic v0.3217 ALG9 Zornitza Stark Marked gene: ALG9 as ready
Intellectual disability syndromic and non-syndromic v0.3217 ALG9 Zornitza Stark Gene: alg9 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3217 ALG9 Zornitza Stark Phenotypes for gene: ALG9 were changed from to Congenital disorder of glycosylation, type Il, MIM#608776
Intellectual disability syndromic and non-syndromic v0.3216 ALG9 Zornitza Stark Publications for gene: ALG9 were set to
Intellectual disability syndromic and non-syndromic v0.3215 ALG9 Zornitza Stark Mode of inheritance for gene: ALG9 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3214 ALG8 Zornitza Stark Marked gene: ALG8 as ready
Intellectual disability syndromic and non-syndromic v0.3214 ALG8 Zornitza Stark Gene: alg8 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3214 ALG8 Zornitza Stark Phenotypes for gene: ALG8 were changed from to Congenital disorder of glycosylation, type Ih, MIM# 608104
Intellectual disability syndromic and non-syndromic v0.3213 ALG8 Zornitza Stark Publications for gene: ALG8 were set to
Intellectual disability syndromic and non-syndromic v0.3212 ALG8 Zornitza Stark Mode of inheritance for gene: ALG8 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3211 ALG8 Zornitza Stark reviewed gene: ALG8: Rating: GREEN; Mode of pathogenicity: None; Publications: 26066342; Phenotypes: Congenital disorder of glycosylation, type Ih, MIM# 608104; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3211 ALG3 Zornitza Stark Marked gene: ALG3 as ready
Intellectual disability syndromic and non-syndromic v0.3211 ALG3 Zornitza Stark Gene: alg3 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3211 ALG3 Zornitza Stark Phenotypes for gene: ALG3 were changed from to Congenital disorder of glycosylation, type Id, MIM# 601110
Intellectual disability syndromic and non-syndromic v0.3210 ALG3 Zornitza Stark Publications for gene: ALG3 were set to
Intellectual disability syndromic and non-syndromic v0.3209 ALG3 Zornitza Stark Mode of inheritance for gene: ALG3 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3208 ALG3 Zornitza Stark reviewed gene: ALG3: Rating: GREEN; Mode of pathogenicity: None; Publications: 31067009; Phenotypes: Congenital disorder of glycosylation, type Id, MIM# 601110; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3208 USP9X Zornitza Stark Marked gene: USP9X as ready
Intellectual disability syndromic and non-syndromic v0.3208 USP9X Zornitza Stark Gene: usp9x has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3208 USP9X Zornitza Stark Phenotypes for gene: USP9X were changed from to Mental retardation, X-linked 99, XLR (MIM#300919) and XLD (MIM#300968)
Intellectual disability syndromic and non-syndromic v0.3207 USP9X Zornitza Stark Publications for gene: USP9X were set to
Intellectual disability syndromic and non-syndromic v0.3206 USP9X Zornitza Stark Mode of inheritance for gene: USP9X 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 v0.3205 ALG6 Zornitza Stark Marked gene: ALG6 as ready
Intellectual disability syndromic and non-syndromic v0.3205 ALG6 Zornitza Stark Gene: alg6 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3205 ALG6 Zornitza Stark Phenotypes for gene: ALG6 were changed from to Congenital disorder of glycosylation, type Ic (MIM#603147)
Intellectual disability syndromic and non-syndromic v0.3204 ALG6 Zornitza Stark Publications for gene: ALG6 were set to
Intellectual disability syndromic and non-syndromic v0.3203 ALG6 Zornitza Stark Mode of inheritance for gene: ALG6 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3202 ALG6 Zornitza Stark reviewed gene: ALG6: Rating: GREEN; Mode of pathogenicity: None; Publications: 10914684, 27498540; Phenotypes: Congenital disorder of glycosylation, type Ic (MIM#603147); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3202 MOGS Zornitza Stark Marked gene: MOGS as ready
Intellectual disability syndromic and non-syndromic v0.3202 MOGS Zornitza Stark Gene: mogs has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3202 MOGS Zornitza Stark Phenotypes for gene: MOGS were changed from to Congenital disorder of glycosylation, type IIb, MIM# 606056
Intellectual disability syndromic and non-syndromic v0.3201 MOGS Zornitza Stark Publications for gene: MOGS were set to
Intellectual disability syndromic and non-syndromic v0.3200 MOGS Zornitza Stark Mode of inheritance for gene: MOGS was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3199 MOGS Zornitza Stark reviewed gene: MOGS: Rating: GREEN; Mode of pathogenicity: None; Publications: 31925597, 30587846, 33058492; Phenotypes: Congenital disorder of glycosylation, type IIb, MIM# 606056; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3199 USP9X Paul De Fazio reviewed gene: USP9X: Rating: GREEN; Mode of pathogenicity: None; Publications: 31443933, 26833328; Phenotypes: Mental retardation, X-linked 99, XLR (MIM#300919) and XLD (MIM#300968); 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 v0.3199 NEMF Zornitza Stark Phenotypes for gene: NEMF were changed from Intellectual disability; neuropathy to Intellectual developmental disorder with speech delay and axonal peripheral neuropathy, MIM# 619099; Intellectual disability; neuropathy
Intellectual disability syndromic and non-syndromic v0.3198 NEMF Zornitza Stark edited their review of gene: NEMF: Changed phenotypes: Intellectual developmental disorder with speech delay and axonal peripheral neuropathy, MIM# 619099, Intellectual disability, neuropathy
Intellectual disability syndromic and non-syndromic v0.3198 NARS Zornitza Stark Phenotypes for gene: NARS were changed from Neurodevelopmental disorder with microcephaly, impaired language, and gait abnormalities (NEDMILG), MIM#619091; Neurodevelopmental disorder with microcephaly, impaired language, epilepsy, and gait abnormalities (NEDMILEG), MIM#619092; Abnormal muscle tone; Microcephaly; Global developmental delay; Intellectual disability; Seizures; Ataxia; Abnormality of the face; Demyelinating peripheral neuropathy to Neurodevelopmental disorder with microcephaly, impaired language, and gait abnormalities (NEDMILG), MIM#619091; Neurodevelopmental disorder with microcephaly, impaired language, epilepsy, and gait abnormalities (NEDMILEG), MIM#619092; Abnormal muscle tone; Microcephaly; Global developmental delay; Intellectual disability; Seizures; Ataxia; Abnormality of the face; Demyelinating peripheral neuropathy
Intellectual disability syndromic and non-syndromic v0.3197 NARS Zornitza Stark Phenotypes for gene: NARS were changed from Abnormal muscle tone; Microcephaly; Global developmental delay; Intellectual disability; Seizures; Ataxia; Abnormality of the face; Demyelinating peripheral neuropathy to Neurodevelopmental disorder with microcephaly, impaired language, and gait abnormalities (NEDMILG), MIM#619091; Neurodevelopmental disorder with microcephaly, impaired language, epilepsy, and gait abnormalities (NEDMILEG), MIM#619092; Abnormal muscle tone; Microcephaly; Global developmental delay; Intellectual disability; Seizures; Ataxia; Abnormality of the face; Demyelinating peripheral neuropathy
Intellectual disability syndromic and non-syndromic v0.3196 NARS Zornitza Stark reviewed gene: NARS: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with microcephaly, impaired language, and gait abnormalities (NEDMILG), MIM#619091, Neurodevelopmental disorder with microcephaly, impaired language, epilepsy, and gait abnormalities (NEDMILEG), MIM#619092, Abnormal muscle tone, Microcephaly, Global developmental delay, Intellectual disability, Seizures, Ataxia, Abnormality of the face, Demyelinating peripheral neuropathy; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3196 RLIM Zornitza Stark Marked gene: RLIM as ready
Intellectual disability syndromic and non-syndromic v0.3196 RLIM Zornitza Stark Gene: rlim has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3196 RLIM Zornitza Stark Phenotypes for gene: RLIM were changed from to Tonne-Kalscheuer syndrome, MIM# 300978
Intellectual disability syndromic and non-syndromic v0.3195 RLIM Zornitza Stark Publications for gene: RLIM were set to
Intellectual disability syndromic and non-syndromic v0.3194 RLIM Zornitza Stark Mode of inheritance for gene: RLIM was changed from Unknown to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability syndromic and non-syndromic v0.3193 RLIM Zornitza Stark reviewed gene: RLIM: Rating: GREEN; Mode of pathogenicity: None; Publications: 29728705, 25735484, 25644381; Phenotypes: Tonne-Kalscheuer syndrome, MIM# 300978; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability syndromic and non-syndromic v0.3193 B4GALT7 Zornitza Stark Marked gene: B4GALT7 as ready
Intellectual disability syndromic and non-syndromic v0.3193 B4GALT7 Zornitza Stark Gene: b4galt7 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3193 B4GALT7 Zornitza Stark Phenotypes for gene: B4GALT7 were changed from to Ehlers-Danlos syndrome, spondylodysplastic type, 1, MIM# 130070
Intellectual disability syndromic and non-syndromic v0.3192 B4GALT7 Zornitza Stark Publications for gene: B4GALT7 were set to
Intellectual disability syndromic and non-syndromic v0.3191 B4GALT7 Zornitza Stark Mode of inheritance for gene: B4GALT7 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3190 B4GALT7 Zornitza Stark reviewed gene: B4GALT7: Rating: AMBER; Mode of pathogenicity: None; Publications: 23956117, 24755949, 31278392, 31614862, 31862401; Phenotypes: Ehlers-Danlos syndrome, spondylodysplastic type, 1, MIM# 130070; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3190 MAPK1 Zornitza Stark Phenotypes for gene: MAPK1 were changed from Global developmental delay; Intellectual disability; Behavioral abnormality; Growth delay; Abnormality of the face; Abnormality of the neck; Abnormality of the cardiovascular system; Abnormality of the skin to Noonan syndrome 13, MIM#619087; Global developmental delay; Intellectual disability; Behavioral abnormality; Growth delay; Abnormality of the face; Abnormality of the neck; Abnormality of the cardiovascular system; Abnormality of the skin
Intellectual disability syndromic and non-syndromic v0.3189 MAPK1 Zornitza Stark reviewed gene: MAPK1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Noonan syndrome 13, MIM#619087, Global developmental delay, Intellectual disability, Behavioral abnormality, Growth delay, Abnormality of the face, Abnormality of the neck, Abnormality of the cardiovascular system, Abnormality of the skin; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3189 SLC12A2 Zornitza Stark Phenotypes for gene: SLC12A2 were changed from Kilquist syndrome, MIM#619080; deafness; intellectual disability; dysmorphic features; absent salivation; ectodermal dysplasia; constipation; intestinal malrotation; multiple congenital anomalies to Delpire-McNeill syndrome, MIM# 619083; Kilquist syndrome, MIM#619080; deafness; intellectual disability; dysmorphic features; absent salivation; ectodermal dysplasia; constipation; intestinal malrotation; multiple congenital anomalies
Intellectual disability syndromic and non-syndromic v0.3188 SLC12A2 Zornitza Stark edited their review of gene: SLC12A2: Changed phenotypes: Delpire-McNeill syndrome, MIM# 619083, Kilquist syndrome, MIM#619080, deafness, intellectual disability, dysmorphic features, absent salivation, ectodermal dysplasia, constipation, intestinal malrotation, multiple congenital anomalies
Intellectual disability syndromic and non-syndromic v0.3188 SLC12A2 Zornitza Stark Phenotypes for gene: SLC12A2 were changed from Kilquist syndrome; deafness; intellectual disability; dysmorphic features; absent salivation; ectodermal dysplasia; constipation; intestinal malrotation; multiple congenital anomalies to Kilquist syndrome, MIM#619080; deafness; intellectual disability; dysmorphic features; absent salivation; ectodermal dysplasia; constipation; intestinal malrotation; multiple congenital anomalies
Intellectual disability syndromic and non-syndromic v0.3187 SLC12A2 Zornitza Stark edited their review of gene: SLC12A2: Changed phenotypes: Kilquist syndrome, MIM#619080, deafness, intellectual disability, dysmorphic features, absent salivation, ectodermal dysplasia, constipation, intestinal malrotation, multiple congenital anomalies
Intellectual disability syndromic and non-syndromic v0.3187 JAM3 Zornitza Stark Marked gene: JAM3 as ready
Intellectual disability syndromic and non-syndromic v0.3187 JAM3 Zornitza Stark Gene: jam3 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3187 JAM3 Zornitza Stark Phenotypes for gene: JAM3 were changed from to Hemorrhagic destruction of the brain, subependymal calcification, and cataracts, MIM# 613730
Intellectual disability syndromic and non-syndromic v0.3186 JAM3 Zornitza Stark Publications for gene: JAM3 were set to
Intellectual disability syndromic and non-syndromic v0.3185 JAM3 Zornitza Stark Mode of inheritance for gene: JAM3 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3184 JAM3 Zornitza Stark reviewed gene: JAM3: Rating: GREEN; Mode of pathogenicity: None; Publications: 23255084, 21109224; Phenotypes: Hemorrhagic destruction of the brain, subependymal calcification, and cataracts, MIM# 613730; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3184 NCKAP1 Zornitza Stark Marked gene: NCKAP1 as ready
Intellectual disability syndromic and non-syndromic v0.3184 NCKAP1 Zornitza Stark Gene: nckap1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3184 NCKAP1 Zornitza Stark Phenotypes for gene: NCKAP1 were changed from to Intellectual disability; autism
Intellectual disability syndromic and non-syndromic v0.3183 NCKAP1 Zornitza Stark Publications for gene: NCKAP1 were set to
Intellectual disability syndromic and non-syndromic v0.3182 NCKAP1 Zornitza Stark Mode of inheritance for gene: NCKAP1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3181 NCKAP1 Zornitza Stark reviewed gene: NCKAP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 33157009; Phenotypes: Intellectual disability, autism; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3181 ACAD9 Zornitza Stark Marked gene: ACAD9 as ready
Intellectual disability syndromic and non-syndromic v0.3181 ACAD9 Zornitza Stark Gene: acad9 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3181 ACAD9 Zornitza Stark Phenotypes for gene: ACAD9 were changed from to Mitochondrial complex I deficiency, nuclear type 20 MIM#611126
Intellectual disability syndromic and non-syndromic v0.3180 ACAD9 Zornitza Stark Publications for gene: ACAD9 were set to
Intellectual disability syndromic and non-syndromic v0.3179 ACAD9 Zornitza Stark Mode of inheritance for gene: ACAD9 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3178 ACAD9 Zornitza Stark reviewed gene: ACAD9: Rating: GREEN; Mode of pathogenicity: None; Publications: 30025539; Phenotypes: Mitochondrial complex I deficiency, nuclear type 20 MIM#611126; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3178 ITFG2 Zornitza Stark Publications for gene: ITFG2 were set to 28397838; https://doi.org/10.1038/s41525-020-00150-z
Intellectual disability syndromic and non-syndromic v0.3177 ITFG2 Zornitza Stark edited their review of gene: ITFG2: Changed rating: AMBER; Changed publications: 33083013; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3177 UNC80 Zornitza Stark Marked gene: UNC80 as ready
Intellectual disability syndromic and non-syndromic v0.3177 UNC80 Zornitza Stark Gene: unc80 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3177 UNC80 Zornitza Stark Phenotypes for gene: UNC80 were changed from to Hypotonia, infantile, with psychomotor retardation and characteristic facies 2, MIM# 616801; MONDO:0014777
Intellectual disability syndromic and non-syndromic v0.3176 UNC80 Zornitza Stark Publications for gene: UNC80 were set to 26708751; 26708753; 26545877; 32620897; 30167850; 30167850
Intellectual disability syndromic and non-syndromic v0.3176 UNC80 Zornitza Stark Publications for gene: UNC80 were set to
Intellectual disability syndromic and non-syndromic v0.3175 UNC80 Zornitza Stark edited their review of gene: UNC80: Changed phenotypes: Hypotonia, infantile, with psychomotor retardation and characteristic facies 2, MIM# 616801, MONDO:0014777
Intellectual disability syndromic and non-syndromic v0.3175 UNC80 Zornitza Stark Mode of inheritance for gene: UNC80 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3174 UNC80 Zornitza Stark reviewed gene: UNC80: Rating: GREEN; Mode of pathogenicity: None; Publications: 26708751, 26708753, 26545877, 32620897, 30167850, 30167850; Phenotypes: Hypotonia, infantile, with psychomotor retardation and characteristic facies 2, MIM# 616801; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3174 ZFHX4 Zornitza Stark Tag SV/CNV tag was added to gene: ZFHX4.
Intellectual disability syndromic and non-syndromic v0.3174 ZFHX4 Zornitza Stark Classified gene: ZFHX4 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.3174 ZFHX4 Zornitza Stark Gene: zfhx4 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3173 ZFHX4 Zornitza Stark gene: ZFHX4 was added
gene: ZFHX4 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: ZFHX4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ZFHX4 were set to 33057194; 24038936; 21802062
Phenotypes for gene: ZFHX4 were set to Developmental disorders; intellectual disability, dysmorphic features
Review for gene: ZFHX4 was set to GREEN
Added comment: PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio study from the Deciphering Developmental Disorders study. 16 de novo variants (5 frameshift, 5 missense, 4 stopgain, 2 synonymous) identified in ~10,000 cases with developmental disorders (no other phenotype info provided).
PMID: 24038936 - a single case with developmental delay, macrocephaly, ventriculomegaly, hypermetropia, recurrent infections, dysmorphism and a de novo deletion of the last 7 exons of the gene.
PMID:21802062 (2011) report 8 individuals with ID and overlapping deletions of 8q21.11 (0.66-13.55 Mb in size); the smallest region of overlap encompasses 3 genes including ZFHX4.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.3172 UPF1 Zornitza Stark Marked gene: UPF1 as ready
Intellectual disability syndromic and non-syndromic v0.3172 UPF1 Zornitza Stark Gene: upf1 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.3172 UPF1 Zornitza Stark Classified gene: UPF1 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.3172 UPF1 Zornitza Stark Gene: upf1 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.3171 UPF1 Zornitza Stark gene: UPF1 was added
gene: UPF1 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: UPF1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: UPF1 were set to 33057194
Phenotypes for gene: UPF1 were set to Developmental disorders
Review for gene: UPF1 was set to AMBER
Added comment: PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio study from the Deciphering Developmental Disorders study. 16 de novo variants (1 frameshift, 11 missense, 4 synonymous) identified in ~10,000 cases with developmental disorders (no other phenotype info provided, hence Amber rating).
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.3170 U2AF2 Zornitza Stark Marked gene: U2AF2 as ready
Intellectual disability syndromic and non-syndromic v0.3170 U2AF2 Zornitza Stark Gene: u2af2 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.3170 U2AF2 Zornitza Stark Classified gene: U2AF2 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.3170 U2AF2 Zornitza Stark Gene: u2af2 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.3169 U2AF2 Zornitza Stark gene: U2AF2 was added
gene: U2AF2 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: U2AF2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: U2AF2 were set to 33057194
Phenotypes for gene: U2AF2 were set to Developmental disorders
Review for gene: U2AF2 was set to AMBER
Added comment: PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio study from the Deciphering Developmental Disorders study. 10 de novo variants (1 in-frame, 8 missense, 1 synoymous) identified in ~10,000 cases with developmental disorders (no other phenotype info provided, hence Amber rating).
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.3168 TCF7L2 Zornitza Stark Marked gene: TCF7L2 as ready
Intellectual disability syndromic and non-syndromic v0.3168 TCF7L2 Zornitza Stark Gene: tcf7l2 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.3168 TCF7L2 Zornitza Stark Classified gene: TCF7L2 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.3168 TCF7L2 Zornitza Stark Gene: tcf7l2 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.3167 TCF7L2 Zornitza Stark gene: TCF7L2 was added
gene: TCF7L2 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: TCF7L2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TCF7L2 were set to 33057194
Phenotypes for gene: TCF7L2 were set to Developmental disorders
Review for gene: TCF7L2 was set to AMBER
Added comment: A diabetes susceptibility locus associated with common SNVs, see OMIM for details.

PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio study from the Deciphering Developmental Disorders study. 12 de novo variants (2 frameshift, 6 missense, 1 splice acceptor, 2 stopgain, 1 synonymous) identified in ~10,000 cases with developmental disorders (no other phenotype info provided, hence Amber rating).
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.3166 SRRM2 Zornitza Stark Marked gene: SRRM2 as ready
Intellectual disability syndromic and non-syndromic v0.3166 SRRM2 Zornitza Stark Gene: srrm2 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.3166 SRRM2 Zornitza Stark Classified gene: SRRM2 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.3166 SRRM2 Zornitza Stark Gene: srrm2 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.3165 SRRM2 Zornitza Stark gene: SRRM2 was added
gene: SRRM2 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: SRRM2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SRRM2 were set to 33057194
Phenotypes for gene: SRRM2 were set to Developmental disorders
Review for gene: SRRM2 was set to AMBER
Added comment: PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio study from the Deciphering Developmental Disorders study. 28 de novo variants (11 frameshift, 7 missense, 1 splice acceptor, 5 stopgain, 4 synonymous) identified in ~10,000 cases with developmental disorders (no other phenotype info provided hence Amber rating).
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.3164 SPEN Zornitza Stark Marked gene: SPEN as ready
Intellectual disability syndromic and non-syndromic v0.3164 SPEN Zornitza Stark Gene: spen has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.3164 SPEN Zornitza Stark Classified gene: SPEN as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.3164 SPEN Zornitza Stark Gene: spen has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.3163 SPEN Zornitza Stark gene: SPEN was added
gene: SPEN was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: SPEN was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SPEN were set to 33057194
Phenotypes for gene: SPEN were set to Developmental disorders
Review for gene: SPEN was set to AMBER
Added comment: PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio study from the Deciphering Developmental Disorders study. 25 de novo variants (6 frameshift, 1 in-frame, 7 missense, 8 stopgain, 3 synonymous) identified in ~10,000 cases with developmental disorders (no other phenotype info provided hence Amber rating).
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.3162 SATB1 Zornitza Stark Marked gene: SATB1 as ready
Intellectual disability syndromic and non-syndromic v0.3162 SATB1 Zornitza Stark Gene: satb1 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.3162 SATB1 Zornitza Stark Classified gene: SATB1 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.3162 SATB1 Zornitza Stark Gene: satb1 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.3161 SATB1 Zornitza Stark gene: SATB1 was added
gene: SATB1 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: SATB1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SATB1 were set to 33057194
Phenotypes for gene: SATB1 were set to Developmental disorders
Review for gene: SATB1 was set to AMBER
Added comment: PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio study from the Deciphering Developmental Disorders study. 12 de novo (2 frameshift, 7 missense, 1 stopgain, 2 synonymous) identified in ~10,000 cases with developmental disorders (no other phenotype info provided hence Amber rating).
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.3160 RAB14 Zornitza Stark Marked gene: RAB14 as ready
Intellectual disability syndromic and non-syndromic v0.3160 RAB14 Zornitza Stark Gene: rab14 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.3160 RAB14 Zornitza Stark Classified gene: RAB14 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.3160 RAB14 Zornitza Stark Gene: rab14 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.3159 RAB14 Zornitza Stark gene: RAB14 was added
gene: RAB14 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: RAB14 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RAB14 were set to 33057194
Phenotypes for gene: RAB14 were set to Developmental disorders
Review for gene: RAB14 was set to AMBER
Added comment: PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio study from the Deciphering Developmental Disorders study. 8 de novo variants (1 in-frame, 7 missense) identified in ~10,000 cases with developmental disorders (no other phenotype info provided hence Amber rating).
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.3158 PSMC5 Zornitza Stark Marked gene: PSMC5 as ready
Intellectual disability syndromic and non-syndromic v0.3158 PSMC5 Zornitza Stark Gene: psmc5 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.3158 PSMC5 Zornitza Stark Classified gene: PSMC5 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.3158 PSMC5 Zornitza Stark Gene: psmc5 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.3157 PSMC5 Zornitza Stark gene: PSMC5 was added
gene: PSMC5 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: PSMC5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PSMC5 were set to 33057194
Phenotypes for gene: PSMC5 were set to Developmental disorders
Review for gene: PSMC5 was set to AMBER
Added comment: PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio study from the Deciphering Developmental Disorders study. 10 de novo variants (1 in-frame, 9 missense) identified in ~10,000 cases with developmental disorders (no other phenotype info provided hence Amber rating).
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.3156 MSL2 Zornitza Stark Marked gene: MSL2 as ready
Intellectual disability syndromic and non-syndromic v0.3156 MSL2 Zornitza Stark Gene: msl2 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.3156 MSL2 Zornitza Stark Classified gene: MSL2 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.3156 MSL2 Zornitza Stark Gene: msl2 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.3155 MSL2 Zornitza Stark gene: MSL2 was added
gene: MSL2 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: MSL2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MSL2 were set to 31332282; 33057194
Phenotypes for gene: MSL2 were set to Developmental disorders; autism
Review for gene: MSL2 was set to AMBER
Added comment: PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio study from the Deciphering Developmental Disorders study. 13 de novo variants (9 frameshift, 4 missense) identified in ~10,000 cases with developmental disorders (no other phenotype info provided hence Amber rating).
PMID: 31332282 - candidate gene in a single autism study, with recurrent de novo variants in a potential oligogenic model
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.3154 MMGT1 Zornitza Stark Marked gene: MMGT1 as ready
Intellectual disability syndromic and non-syndromic v0.3154 MMGT1 Zornitza Stark Gene: mmgt1 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.3154 MMGT1 Zornitza Stark Classified gene: MMGT1 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.3154 MMGT1 Zornitza Stark Gene: mmgt1 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.3153 MMGT1 Zornitza Stark gene: MMGT1 was added
gene: MMGT1 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: MMGT1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MMGT1 were set to 33057194
Phenotypes for gene: MMGT1 were set to Developmental disorders
Review for gene: MMGT1 was set to AMBER
Added comment: PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio study from the Deciphering Developmental Disorders study. 3 de novo missense identified in ~10,000 cases with developmental disorders (no other phenotype info provided hence Amber rating).
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.3152 HNRNPD Zornitza Stark Marked gene: HNRNPD as ready
Intellectual disability syndromic and non-syndromic v0.3152 HNRNPD Zornitza Stark Gene: hnrnpd has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.3152 HNRNPD Zornitza Stark Classified gene: HNRNPD as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.3152 HNRNPD Zornitza Stark Gene: hnrnpd has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.3151 HNRNPD Zornitza Stark gene: HNRNPD was added
gene: HNRNPD was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: HNRNPD was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: HNRNPD were set to 33057194
Phenotypes for gene: HNRNPD were set to Developmental disorders
Review for gene: HNRNPD was set to AMBER
Added comment: PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio study from the Deciphering Developmental Disorders study. 8 de novo variants (5 frameshift, 1 missense, 1 splice acceptor, 1 synonymous) identified in ~10,000 cases with developmental disorders (no other phenotype info provided hence Amber rating).
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.3150 GIGYF1 Zornitza Stark Marked gene: GIGYF1 as ready
Intellectual disability syndromic and non-syndromic v0.3150 GIGYF1 Zornitza Stark Gene: gigyf1 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.3150 GIGYF1 Zornitza Stark Classified gene: GIGYF1 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.3150 GIGYF1 Zornitza Stark Gene: gigyf1 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.3149 GIGYF1 Zornitza Stark gene: GIGYF1 was added
gene: GIGYF1 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: GIGYF1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: GIGYF1 were set to 33057194
Phenotypes for gene: GIGYF1 were set to Developmental disorder
Review for gene: GIGYF1 was set to AMBER
Added comment: PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio study from the Deciphering Developmental Disorders study. 14 de novo variants (4 frameshift, 5 missense, 1 splice donor, 3 stopgain, 1 synonymous) identified in ~10,000 cases with developmental disorders (no other phenotype info provided, hence Amber rating).
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.3148 AP2S1 Zornitza Stark Marked gene: AP2S1 as ready
Intellectual disability syndromic and non-syndromic v0.3148 AP2S1 Zornitza Stark Gene: ap2s1 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.3148 AP2S1 Zornitza Stark Classified gene: AP2S1 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.3148 AP2S1 Zornitza Stark Gene: ap2s1 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.3147 AP2S1 Zornitza Stark gene: AP2S1 was added
gene: AP2S1 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: AP2S1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: AP2S1 were set to 33057194
Phenotypes for gene: AP2S1 were set to Developmental disorder
Review for gene: AP2S1 was set to AMBER
Added comment: Established hypercalcaemia gene. PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio developmental disorder study. 5 de novo missense identified in ~10,000 cases with developmental disorders (no other phenotype info provided, hence Amber rating).
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.3146 ARHGAP35 Zornitza Stark Marked gene: ARHGAP35 as ready
Intellectual disability syndromic and non-syndromic v0.3146 ARHGAP35 Zornitza Stark Gene: arhgap35 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.3146 ARHGAP35 Zornitza Stark Classified gene: ARHGAP35 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.3146 ARHGAP35 Zornitza Stark Gene: arhgap35 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.3145 ARHGAP35 Zornitza Stark gene: ARHGAP35 was added
gene: ARHGAP35 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: ARHGAP35 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ARHGAP35 were set to 33057194
Phenotypes for gene: ARHGAP35 were set to Developmental disorder
Review for gene: ARHGAP35 was set to AMBER
Added comment: Has been identified as a gene with significant de novo enrichment in a large trio developmental disorder study. 16 de novo variants (3 frameshift, 2 in-frame, 10 missense, 1 stopgain) identified in ~10,000 cases with developmental disorders (no other phenotype info provided hence Amber rating).
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.3144 ATP6V0A1 Zornitza Stark Marked gene: ATP6V0A1 as ready
Intellectual disability syndromic and non-syndromic v0.3144 ATP6V0A1 Zornitza Stark Gene: atp6v0a1 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.3144 ATP6V0A1 Zornitza Stark Classified gene: ATP6V0A1 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.3144 ATP6V0A1 Zornitza Stark Gene: atp6v0a1 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.3143 ATP6V0A1 Zornitza Stark gene: ATP6V0A1 was added
gene: ATP6V0A1 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: ATP6V0A1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ATP6V0A1 were set to 30842224; 33057194
Phenotypes for gene: ATP6V0A1 were set to Developmental disorder; Rett syndrome-like
Review for gene: ATP6V0A1 was set to AMBER
Added comment: PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio developmental disorder study. 11 de novo missense identified in ~10,000 cases with developmental disorders (no other phenotype info provided, hence Amber rating).
PMID: 30842224 - identified a de novo missense variant in a single individual with atypical Rett syndrome phenotype
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.3142 DDX23 Zornitza Stark Marked gene: DDX23 as ready
Intellectual disability syndromic and non-syndromic v0.3142 DDX23 Zornitza Stark Gene: ddx23 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.3142 DDX23 Zornitza Stark Classified gene: DDX23 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.3142 DDX23 Zornitza Stark Gene: ddx23 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.3141 DDX23 Zornitza Stark gene: DDX23 was added
gene: DDX23 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: DDX23 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: DDX23 were set to 33057194
Phenotypes for gene: DDX23 were set to Developmental disorder
Review for gene: DDX23 was set to AMBER
Added comment: PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio developmental disorder study. 6 de novo missense identified in ~10,000 cases with developmental disorders. Rated Amber as no other phenotype info provided.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.3140 FOXP4 Zornitza Stark Marked gene: FOXP4 as ready
Intellectual disability syndromic and non-syndromic v0.3140 FOXP4 Zornitza Stark Gene: foxp4 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.3140 FOXP4 Zornitza Stark Classified gene: FOXP4 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.3140 FOXP4 Zornitza Stark Gene: foxp4 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.3139 FOXP4 Zornitza Stark edited their review of gene: FOXP4: Changed rating: AMBER
Intellectual disability syndromic and non-syndromic v0.3139 FOXP4 Zornitza Stark changed review comment from: Eight unrelated individuals reported, seven de novo missense, and one individual with a truncating variant. Detailed phenotypic information available on 6. Overlapping features included speech and language delays, growth abnormalities, congenital diaphragmatic hernia (2/6), cervical spine abnormalities, and ptosis. Intellectual disability described as mild in 2, some had normal intellect despite the early challenges.
Sources: Literature; to: Eight unrelated individuals reported, seven de novo missense, and one individual with a truncating variant. Detailed phenotypic information available on 6. Overlapping features included speech and language delays, growth abnormalities, congenital diaphragmatic hernia (2/6), cervical spine abnormalities, and ptosis. Intellectual disability described as mild in 2, some had normal intellect despite the early speech and language delays.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.3139 FOXP4 Zornitza Stark changed review comment from: Six unrelated individuals reported, 5 with missense variants in the forkhead box DNA-binding domain of FOXP4, and one individual with a truncating variant. Overlapping features included speech and language delays, growth abnormalities, congenital diaphragmatic hernia, cervical spine abnormalities, and ptosis.
Sources: Literature; to: Eight unrelated individuals reported, seven de novo missense, and one individual with a truncating variant. Detailed phenotypic information available on 6. Overlapping features included speech and language delays, growth abnormalities, congenital diaphragmatic hernia (2/6), cervical spine abnormalities, and ptosis. Intellectual disability described as mild in 2, some had normal intellect despite the early challenges.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.3139 FOXP4 Zornitza Stark gene: FOXP4 was added
gene: FOXP4 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: FOXP4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FOXP4 were set to 33110267
Phenotypes for gene: FOXP4 were set to Neurodevelopmental disorder; multiple congenital abnormalities
Review for gene: FOXP4 was set to GREEN
Added comment: Six unrelated individuals reported, 5 with missense variants in the forkhead box DNA-binding domain of FOXP4, and one individual with a truncating variant. Overlapping features included speech and language delays, growth abnormalities, congenital diaphragmatic hernia, cervical spine abnormalities, and ptosis.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.3138 DHX32 Zornitza Stark Marked gene: DHX32 as ready
Intellectual disability syndromic and non-syndromic v0.3138 DHX32 Zornitza Stark Gene: dhx32 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.3138 DHX32 Zornitza Stark Classified gene: DHX32 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.3138 DHX32 Zornitza Stark Gene: dhx32 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.3137 FBXO31 Zornitza Stark Phenotypes for gene: FBXO31 were changed from Mental retardation, autosomal recessive 45, MIM#615979; Cerebral palsy, intellectual disability, autosomal dominant to Mental retardation, autosomal recessive 45, MIM#615979; Cerebral palsy, intellectual disability, autosomal dominant
Intellectual disability syndromic and non-syndromic v0.3136 FBXO31 Zornitza Stark Phenotypes for gene: FBXO31 were changed from Mental retardation, autosomal recessive 45, MIM#615979 to Mental retardation, autosomal recessive 45, MIM#615979; Cerebral palsy, intellectual disability, autosomal dominant
Intellectual disability syndromic and non-syndromic v0.3135 FBXO31 Zornitza Stark Publications for gene: FBXO31 were set to 24623383
Intellectual disability syndromic and non-syndromic v0.3134 FBXO31 Zornitza Stark Mode of pathogenicity for gene: FBXO31 was changed from to Other
Intellectual disability syndromic and non-syndromic v0.3133 FBXO31 Zornitza Stark Classified gene: FBXO31 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.3133 FBXO31 Zornitza Stark Gene: fbxo31 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.3132 DHX32 Dean Phelan gene: DHX32 was added
gene: DHX32 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: DHX32 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: DHX32 were set to PMID: 32989326
Phenotypes for gene: DHX32 were set to Intellectual disability, spastic diplegia, dystonia, brain abnormalities
Review for gene: DHX32 was set to AMBER
Added comment: PMID: 32989326 - Large cohort study of cerebral palsy cases identified two de novo variants in two unrelated patients with intellectual disability, one with spastic diplegia, and the other characterised as generalised dystonia. Brain abnormalities were identified also.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.3132 FBXO31 Kristin Rigbye reviewed gene: FBXO31: Rating: AMBER; Mode of pathogenicity: Other; Publications: PMID: 32989326; Phenotypes: Mental retardation, autosomal recessive 45, MIM#615979, Cerebral palsy; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3132 STN1 Sue White Classified gene: STN1 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.3132 STN1 Sue White Gene: stn1 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.3131 STN1 Sue White gene: STN1 was added
gene: STN1 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: STN1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: STN1 were set to 32627942; 27432940
Phenotypes for gene: STN1 were set to cerebral calcification; premature ageing; bone marrow failure; retinal telangiactasia; hepatic fibrosis
Penetrance for gene: STN1 were set to Complete
Added comment: 3 unrelated patients reported with Coats-plus syndrome. Developmental delay noted in two.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.3130 TKFC Zornitza Stark Phenotypes for gene: TKFC were changed from Developmental delay; cataracts; liver dysfunction to Triokinase and FMN cyclase deficiency syndrome, MIM#618805; Developmental delay; cataracts; liver dysfunction
Intellectual disability syndromic and non-syndromic v0.3129 TKFC Zornitza Stark edited their review of gene: TKFC: Changed phenotypes: Triokinase and FMN cyclase deficiency syndrome, MIM#618805, Developmental delay, cataracts, liver dysfunction
Intellectual disability syndromic and non-syndromic v0.3129 PRKAR1B Zornitza Stark Marked gene: PRKAR1B as ready
Intellectual disability syndromic and non-syndromic v0.3129 PRKAR1B Zornitza Stark Gene: prkar1b has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3129 PRKAR1B Zornitza Stark Classified gene: PRKAR1B as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.3129 PRKAR1B Zornitza Stark Gene: prkar1b has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3128 PRKAR1B Konstantinos Varvagiannis edited their review of gene: PRKAR1B: Changed publications: https://doi.org/10.1101/2020.09.10.20190314, 25414040
Intellectual disability syndromic and non-syndromic v0.3128 PRKAR1B Konstantinos Varvagiannis gene: PRKAR1B was added
gene: PRKAR1B was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: PRKAR1B was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: PRKAR1B were set to https://doi.org/10.1101/2020.09.10.20190314; 33057194
Phenotypes for gene: PRKAR1B were set to Global developmental delay; Intellectual disability; Autism; Attention deficit hyperactivity disorder; Aggressive behavior; Abnormality of movement; Upslanted palpebral fissure
Penetrance for gene: PRKAR1B were set to unknown
Review for gene: PRKAR1B was set to AMBER
Added comment: Please consider inclusion of this gene with amber rating pending publication of the preprint and/or additional evidence.

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

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

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

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

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

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

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

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

Please note that a specific PRKAR1B variant (NM_002735.2:c.149T>G - p.Leu50Arg) has been previous reported to segregate with a late-onset neurodegenerative disorder characterized by dementia and/or parkinsonism within a large pedigree with 12 affected individuals [Wong et al 2014 - PMID: 25414040].
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.3128 MPP5 Zornitza Stark Marked gene: MPP5 as ready
Intellectual disability syndromic and non-syndromic v0.3128 MPP5 Zornitza Stark Gene: mpp5 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3128 MPP5 Zornitza Stark Classified gene: MPP5 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.3128 MPP5 Zornitza Stark Gene: mpp5 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3127 MPP5 Konstantinos Varvagiannis gene: MPP5 was added
gene: MPP5 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: MPP5 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: MPP5 were set to 33073849
Phenotypes for gene: MPP5 were set to Global developmental delay; Intellectual disability; Delayed speech and language development; Developmental regression; Behavioral abnormality
Penetrance for gene: MPP5 were set to unknown
Review for gene: MPP5 was set to GREEN
Added comment: Sterling et al (2020 - PMID: 33073849) provide information on the phenotype of 3 individuals with de novo MPP5 variants.

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

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

One subject was found to harbor a de novo mosaic (5/25 reads) stopgain variant, further confirmed by Sanger sequencing [NM_022474.4:c.1555C>T - p.(Arg519Ter). The specific variant is reported once in gnomAD (1/251338). Two de novo missense variants were identified in the remaining individuals [c.1289A>G - p.Glu430Gly / c.974A>C - p.His325Pro). All variants had in silico predictions in favor of a deleterious effect (CADD score >24).

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

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

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

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

Haploinsufficiency (rather than a dominant negative effect) is favored as the underlying disease mechanism. This is also in line with a dose dependent effect observed in mice.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.3127 ODC1 Zornitza Stark Publications for gene: ODC1 were set to 30475435
Intellectual disability syndromic and non-syndromic v0.3126 ODC1 Zornitza Stark edited their review of gene: ODC1: Added comment: Fifth individual reported in PMID 30239107: de novo nonsense variant identified, molecular modeling suggested that due to lack of a C terminus in the mutant protein, antizyme binding does not induce ODC degradation, leading to accumulation of active protein.; Changed publications: 30475435, 30239107
Intellectual disability syndromic and non-syndromic v0.3126 ODC1 Zornitza Stark Phenotypes for gene: ODC1 were changed from Intellectual disability; macrocephaly; dysmorphism to Neurodevelopmental disorder with alopecia and brain imaging abnormalities (NEDABIA), MIM#619075
Intellectual disability syndromic and non-syndromic v0.3125 ODC1 Zornitza Stark edited their review of gene: ODC1: Changed phenotypes: Neurodevelopmental disorder with alopecia and brain imaging abnormalities (NEDABIA), MIM#619075
Intellectual disability syndromic and non-syndromic v0.3125 ODC1 Zornitza Stark edited their review of gene: ODC1: Changed phenotypes: neurodevelopmental disorder with alopecia and brain imaging abnormalities (NEDABIA), MIM#619075
Intellectual disability syndromic and non-syndromic v0.3125 LRRC32 Zornitza Stark Phenotypes for gene: LRRC32 were changed from Intellectual disability; cleft palate; proliferative retinopathy to Cleft palate, proliferative retinopathy, and developmental delay (CPPRDD) syndrome, MIM# 619074
Intellectual disability syndromic and non-syndromic v0.3124 LRRC32 Zornitza Stark edited their review of gene: LRRC32: Changed phenotypes: Cleft palate, proliferative retinopathy, and developmental delay (CPPRDD) syndrome, MIM# 619074
Intellectual disability syndromic and non-syndromic v0.3124 NUS1 Zornitza Stark Phenotypes for gene: NUS1 were changed from Epilepsy; intellectual disability to Mental retardation, autosomal dominant 55, with seizures, MIM# 617831
Intellectual disability syndromic and non-syndromic v0.3123 NUS1 Zornitza Stark edited their review of gene: NUS1: Changed phenotypes: Mental retardation, autosomal dominant 55, with seizures, MIM# 617831
Intellectual disability syndromic and non-syndromic v0.3123 COG8 Zornitza Stark Marked gene: COG8 as ready
Intellectual disability syndromic and non-syndromic v0.3123 COG8 Zornitza Stark Gene: cog8 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3123 COG8 Zornitza Stark Phenotypes for gene: COG8 were changed from to Congenital disorder of glycosylation, type IIh, MIM# 611182
Intellectual disability syndromic and non-syndromic v0.3122 COG8 Zornitza Stark Publications for gene: COG8 were set to
Intellectual disability syndromic and non-syndromic v0.3121 COG8 Zornitza Stark Mode of inheritance for gene: COG8 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3120 COG8 Zornitza Stark changed review comment from: Four unrelated families reported with bi-allelic LOF variants and a broad range of predominantly neurological features (ID, seizures, arthrogryposis, brain malformations).

ID present in 3/4, presentation in the 4th family was antenatal but with severe neurological phenotype that would have been expected to result in ID.; to: Four unrelated families reported with bi-allelic LOF variants and a broad range of predominantly neurological features (ID, seizures, arthrogryposis, brain malformations).

ID reported in 3/4, presentation in the 4th family was antenatal but with severe neurological phenotype that would have been expected to result in ID.
Intellectual disability syndromic and non-syndromic v0.3120 COG8 Zornitza Stark reviewed gene: COG8: Rating: GREEN; Mode of pathogenicity: None; Publications: 17220172, 28619360, 30690882, 17331980; Phenotypes: Congenital disorder of glycosylation, type IIh, MIM# 611182; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3120 SLC35A3 Zornitza Stark Phenotypes for gene: SLC35A3 were changed from ?Arthrogryposis, mental retardation, and seizures; OMIM #615553 to Arthrogryposis, mental retardation, and seizures OMIM #615553; Skeletal dysplasia
Intellectual disability syndromic and non-syndromic v0.3119 SLC35A3 Zornitza Stark Publications for gene: SLC35A3 were set to PMID: 28328131; 24031089
Intellectual disability syndromic and non-syndromic v0.3118 SLC35A3 Zornitza Stark reviewed gene: SLC35A3: Rating: AMBER; Mode of pathogenicity: None; Publications: 28777481; Phenotypes: Skeletal dysplasia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3118 APOPT1 Zornitza Stark Marked gene: APOPT1 as ready
Intellectual disability syndromic and non-syndromic v0.3118 APOPT1 Zornitza Stark Gene: apopt1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3118 APOPT1 Zornitza Stark Phenotypes for gene: APOPT1 were changed from Mitochondrial complex IV deficiency, nuclear type 17, MIM#619061 to Mitochondrial complex IV deficiency, nuclear type 17, MIM#619061
Intellectual disability syndromic and non-syndromic v0.3117 APOPT1 Zornitza Stark Phenotypes for gene: APOPT1 were changed from to Mitochondrial complex IV deficiency, nuclear type 17, MIM#619061
Intellectual disability syndromic and non-syndromic v0.3116 APOPT1 Zornitza Stark Publications for gene: APOPT1 were set to
Intellectual disability syndromic and non-syndromic v0.3115 APOPT1 Zornitza Stark Mode of inheritance for gene: APOPT1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3114 APOPT1 Zornitza Stark reviewed gene: APOPT1: Rating: GREEN; Mode of pathogenicity: None; Publications: 25175347; Phenotypes: Mitochondrial complex IV deficiency, nuclear type 17, MIM#619061; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3114 COA3 Zornitza Stark Phenotypes for gene: COA3 were changed from Mitochondrial complex IV deficiency to Mitochondrial complex IV deficiency, nuclear type 14, MIM# 619058
Intellectual disability syndromic and non-syndromic v0.3113 COA3 Zornitza Stark edited their review of gene: COA3: Changed phenotypes: Mitochondrial complex IV deficiency, nuclear type 14, MIM# 619058
Intellectual disability syndromic and non-syndromic v0.3113 PET100 Zornitza Stark Phenotypes for gene: PET100 were changed from Mitochondrial complex IV deficiency, MIM# 220110 to Mitochondrial complex IV deficiency, nuclear type 12, MIM# 619055
Intellectual disability syndromic and non-syndromic v0.3112 PET100 Zornitza Stark Tag founder tag was added to gene: PET100.
Intellectual disability syndromic and non-syndromic v0.3112 PET100 Zornitza Stark edited their review of gene: PET100: Changed phenotypes: Mitochondrial complex IV deficiency, nuclear type 12, MIM# 619055
Intellectual disability syndromic and non-syndromic v0.3112 COX14 Zornitza Stark Phenotypes for gene: COX14 were changed from Mitochondrial complex IV deficiency, MIM#220110 to Mitochondrial complex IV deficiency, nuclear type 10, MIM#619053
Intellectual disability syndromic and non-syndromic v0.3111 COX14 Zornitza Stark edited their review of gene: COX14: Changed phenotypes: Mitochondrial complex IV deficiency, nuclear type 10, MIM#619053
Intellectual disability syndromic and non-syndromic v0.3111 PRKACB Zornitza Stark Marked gene: PRKACB as ready
Intellectual disability syndromic and non-syndromic v0.3111 PRKACB Zornitza Stark Gene: prkacb has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.3111 PRKACB Zornitza Stark Classified gene: PRKACB as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.3111 PRKACB Zornitza Stark Gene: prkacb has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.3110 COX6B1 Zornitza Stark Marked gene: COX6B1 as ready
Intellectual disability syndromic and non-syndromic v0.3110 COX6B1 Zornitza Stark Gene: cox6b1 has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v0.3110 COX6B1 Zornitza Stark Phenotypes for gene: COX6B1 were changed from to Mitochondrial complex IV deficiency, nuclear type 7, MIM# 619051
Intellectual disability syndromic and non-syndromic v0.3109 COX6B1 Zornitza Stark Publications for gene: COX6B1 were set to
Intellectual disability syndromic and non-syndromic v0.3108 COX6B1 Zornitza Stark Mode of inheritance for gene: COX6B1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3107 COX6B1 Zornitza Stark Classified gene: COX6B1 as Red List (low evidence)
Intellectual disability syndromic and non-syndromic v0.3107 COX6B1 Zornitza Stark Gene: cox6b1 has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v0.3106 COX6B1 Zornitza Stark reviewed gene: COX6B1: Rating: RED; Mode of pathogenicity: None; Publications: 18499082, 24781756; Phenotypes: Mitochondrial complex IV deficiency, nuclear type 7, MIM# 619051; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3106 SCO1 Zornitza Stark Marked gene: SCO1 as ready
Intellectual disability syndromic and non-syndromic v0.3106 SCO1 Zornitza Stark Gene: sco1 has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v0.3106 SCO1 Zornitza Stark Phenotypes for gene: SCO1 were changed from to Mitochondrial complex IV deficiency, nuclear type 4, MIM# 619048
Intellectual disability syndromic and non-syndromic v0.3105 SCO1 Zornitza Stark Publications for gene: SCO1 were set to
Intellectual disability syndromic and non-syndromic v0.3104 SCO1 Zornitza Stark Mode of inheritance for gene: SCO1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3103 SCO1 Zornitza Stark Classified gene: SCO1 as Red List (low evidence)
Intellectual disability syndromic and non-syndromic v0.3103 SCO1 Zornitza Stark Gene: sco1 has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v0.3102 SCO1 Zornitza Stark reviewed gene: SCO1: Rating: RED; Mode of pathogenicity: None; Publications: 11013136, 19295170, 31352446, 23878101; Phenotypes: Mitochondrial complex IV deficiency, nuclear type 4, MIM# 619048; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3102 PRKACB Konstantinos Varvagiannis edited their review of gene: PRKACB: Changed mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Intellectual disability syndromic and non-syndromic v0.3102 PRKACB Konstantinos Varvagiannis gene: PRKACB was added
gene: PRKACB was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: PRKACB was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: PRKACB were set to 33058759
Phenotypes for gene: PRKACB were set to Postaxial hand polydactyly; Postaxial foot polydactyly; Common atrium; Atrioventricular canal defect; Narrow chest; Abnormality of the teeth; Intellectual disability
Penetrance for gene: PRKACB were set to Complete
Review for gene: PRKACB was set to AMBER
Added comment: ID was a feature in 2/4 individuals with PRKACB pathogenic variant reported to date.
------
Palencia-Campos et al (2020 - PMID: 33058759) report on the phenotype of 3 individuals heterozygous for PRKACA and 4 individuals heterozygous for PRKACB pathogenic variants.

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

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

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

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

WES was carried out in all.

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

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

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

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

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

As for PRKACA, the authors cite another study where a 31-month old female with EvC syndrome diagnosis was found to harbor the aforementioned variant (NM_001304349.1:c.637G>A:p.Gly213Arg corresponding to NM_002730.4:c.409G>A / p.Gly137Arg) as a de novo event. Without additional evidence at the time, the variant was considered to be a candidate for this subject's phenotype (Monies et al 2019 – PMID: 31130284).
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.3102 COX10 Zornitza Stark Marked gene: COX10 as ready
Intellectual disability syndromic and non-syndromic v0.3102 COX10 Zornitza Stark Gene: cox10 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3102 COX10 Zornitza Stark Phenotypes for gene: COX10 were changed from to Mitochondrial complex IV deficiency, nuclear type 3, MIM# 619046
Intellectual disability syndromic and non-syndromic v0.3101 COX10 Zornitza Stark Publications for gene: COX10 were set to
Intellectual disability syndromic and non-syndromic v0.3100 COX10 Zornitza Stark Mode of inheritance for gene: COX10 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3099 COX10 Zornitza Stark reviewed gene: COX10: Rating: GREEN; Mode of pathogenicity: None; Publications: 10767350, 12928484, 15455402, 27290639; Phenotypes: Mitochondrial complex IV deficiency, nuclear type 3, MIM# 619046; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3099 DPH1 Zornitza Stark Publications for gene: DPH1 were set to 25558065; 26220823
Intellectual disability syndromic and non-syndromic v0.3098 DPH1 Zornitza Stark edited their review of gene: DPH1: Added comment: Four unrelated families reported, 11 affected individuals. Common clinical features include abnormal skull shape (trigonocephaly, scaphocephaly, or prominent forehead accompanied with metopic ridge), distinctive face (downslanted palpebral fissures, low set ears, depressed nasal bridge, and sparse hair on the scalp, eyelashes, and/or eyebrows), short stature, developmental delay, and intellectual disability. Heart and brain malformations are also frequently observed.; Changed publications: 29362492, 29410513, 25558065, 26220823
Intellectual disability syndromic and non-syndromic v0.3098 SETD1A Zornitza Stark changed review comment from: OMIM has assigned a second phenotype in relation to the syndromic ID cohort reported in PMID 32346159. All variants were predicted to disrupt or delete the SET catalytic domain, and LOF is the established mechanism.

In addition, there are 3 families reported with a predominantly seizure phenotype without ID, PMID 31197650. All the variants are missense and mechanism of pathogenicity is not clearly established, hence it is difficult to know whether these are two distinct conditions or part of a spectrum of severity for SETD1A-related disorders.; to: OMIM has assigned a second phenotype in relation to the syndromic ID cohort reported in PMID 32346159. All variants were predicted to disrupt or delete the SET catalytic domain, and LOF is the established mechanism.

In addition, there are 4 families reported with a predominantly seizure phenotype without ID, PMID 31197650. All the variants are missense and mechanism of pathogenicity is not clearly established, hence it is difficult to know whether these are two distinct conditions or part of a spectrum of severity for SETD1A-related disorders.
Intellectual disability syndromic and non-syndromic v0.3098 SETD1A Zornitza Stark Phenotypes for gene: SETD1A were changed from Epilepsy, early-onset, with or without developmental delay, MIM# 618832 to Epilepsy, early-onset, with or without developmental delay, MIM# 618832; Neurodevelopmental disorder with speech impairment and dysmorphic facies, MIM# 619056
Intellectual disability syndromic and non-syndromic v0.3097 SETD1A Zornitza Stark edited their review of gene: SETD1A: Added comment: OMIM has assigned a second phenotype in relation to the syndromic ID cohort reported in PMID 32346159. All variants were predicted to disrupt or delete the SET catalytic domain, and LOF is the established mechanism.

In addition, there are 3 families reported with a predominantly seizure phenotype without ID, PMID 31197650. All the variants are missense and mechanism of pathogenicity is not clearly established, hence it is difficult to know whether these are two distinct conditions or part of a spectrum of severity for SETD1A-related disorders.; Changed phenotypes: Epilepsy, early-onset, with or without developmental delay, MIM# 618832, Neurodevelopmental disorder with speech impairment and dysmorphic facies, MIM# 619056
Intellectual disability syndromic and non-syndromic v0.3097 JARID2 Zornitza Stark Publications for gene: JARID2 were set to 23294540
Intellectual disability syndromic and non-syndromic v0.3096 JARID2 Zornitza Stark Tag SV/CNV tag was added to gene: JARID2.
Intellectual disability syndromic and non-syndromic v0.3096 JARID2 Zornitza Stark Classified gene: JARID2 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.3096 JARID2 Zornitza Stark Gene: jarid2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3095 JARID2 Zornitza Stark changed review comment from: 13 additional individuals reported, note CNVs common.; to: 13 additional individuals reported, note CNVs common but LOF sequence variants identified too.
Intellectual disability syndromic and non-syndromic v0.3095 JARID2 Zornitza Stark edited their review of gene: JARID2: Added comment: 13 additional individuals reported, note CNVs common.; Changed rating: GREEN; Changed publications: 23294540, 33077894
Intellectual disability syndromic and non-syndromic v0.3095 NUDT2 Zornitza Stark Phenotypes for gene: NUDT2 were changed from Muscular hypotonia; Global developmental delay; Intellectual disability to Muscular hypotonia; Global developmental delay; Intellectual disability; Polyneuropathy
Intellectual disability syndromic and non-syndromic v0.3094 NUDT2 Zornitza Stark Publications for gene: NUDT2 were set to 27431290; 30059600
Intellectual disability syndromic and non-syndromic v0.3093 NUDT2 Zornitza Stark Classified gene: NUDT2 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.3093 NUDT2 Zornitza Stark Gene: nudt2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3092 NUDT2 Zornitza Stark changed review comment from: Two additional families reported with a different homozygous variant and ID/polyneuropathy phenotype. Upgrade to Green.; to: Three individuals from two additional families reported with a different homozygous variant and ID/polyneuropathy phenotype. Upgrade to Green.
Intellectual disability syndromic and non-syndromic v0.3092 NUDT2 Zornitza Stark edited their review of gene: NUDT2: Added comment: Two additional families reported with a different homozygous variant and ID/polyneuropathy phenotype. Upgrade to Green.; Changed rating: GREEN; Changed publications: 27431290, 30059600, 33058507; Changed phenotypes: Muscular hypotonia, Global developmental delay, Intellectual disability, Polyneuropathy
Intellectual disability syndromic and non-syndromic v0.3092 AFF2 Zornitza Stark Marked gene: AFF2 as ready
Intellectual disability syndromic and non-syndromic v0.3092 AFF2 Zornitza Stark Gene: aff2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3092 AFF2 Zornitza Stark Phenotypes for gene: AFF2 were changed from to Mental retardation, X-linked, FRAXE type 309548
Intellectual disability syndromic and non-syndromic v0.3091 AFF2 Zornitza Stark Publications for gene: AFF2 were set to
Intellectual disability syndromic and non-syndromic v0.3090 AFF2 Zornitza Stark Mode of inheritance for gene: AFF2 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3089 AFF2 Zornitza Stark reviewed gene: AFF2: Rating: GREEN; Mode of pathogenicity: None; Publications: 8334699, 21739600, 22773736; Phenotypes: Mental retardation, X-linked, FRAXE type 309548; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3089 KANSL1 Zornitza Stark Tag SV/CNV tag was added to gene: KANSL1.
Intellectual disability syndromic and non-syndromic v0.3089 AUTS2 Zornitza Stark Marked gene: AUTS2 as ready
Intellectual disability syndromic and non-syndromic v0.3089 AUTS2 Zornitza Stark Gene: auts2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3089 AUTS2 Zornitza Stark Phenotypes for gene: AUTS2 were changed from to Mental retardation, autosomal dominant 26, MIM#615834
Intellectual disability syndromic and non-syndromic v0.3088 AUTS2 Zornitza Stark Publications for gene: AUTS2 were set to
Intellectual disability syndromic and non-syndromic v0.3087 AUTS2 Zornitza Stark Mode of inheritance for gene: AUTS2 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3086 AUTS2 Zornitza Stark Tag SV/CNV tag was added to gene: AUTS2.
Intellectual disability syndromic and non-syndromic v0.3086 AUTS2 Zornitza Stark reviewed gene: AUTS2: Rating: GREEN; Mode of pathogenicity: None; Publications: 23332918, 25205402, 31474318; Phenotypes: Mental retardation, autosomal dominant 26, MIM#615834; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3086 ZEB2 Zornitza Stark Marked gene: ZEB2 as ready
Intellectual disability syndromic and non-syndromic v0.3086 ZEB2 Zornitza Stark Gene: zeb2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3086 ZEB2 Zornitza Stark Phenotypes for gene: ZEB2 were changed from to Mowat-Wilson syndrome (MIM#235730)
Intellectual disability syndromic and non-syndromic v0.3085 ZEB2 Zornitza Stark Publications for gene: ZEB2 were set to
Intellectual disability syndromic and non-syndromic v0.3084 ZEB2 Zornitza Stark Mode of inheritance for gene: ZEB2 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3083 ZEB2 Zornitza Stark reviewed gene: ZEB2: Rating: GREEN; Mode of pathogenicity: None; Publications: 29300384; Phenotypes: Mowat-Wilson syndrome (MIM#235730); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3083 HECW2 Zornitza Stark Publications for gene: HECW2 were set to 27389779
Intellectual disability syndromic and non-syndromic v0.3082 HECW2 Zornitza Stark Mode of pathogenicity for gene: HECW2 was changed from to Other
Intellectual disability syndromic and non-syndromic v0.3081 HECW2 Zornitza Stark reviewed gene: HECW2: Rating: GREEN; Mode of pathogenicity: Other; Publications: 29807643, 29395664, 27334371, 27389779; Phenotypes: Neurodevelopmental disorder with hypotonia, seizures, and absent language, MIM# 617268, intellectual disability, epilepsy, regression, microcephaly; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3081 CSNK1G1 Zornitza Stark Marked gene: CSNK1G1 as ready
Intellectual disability syndromic and non-syndromic v0.3081 CSNK1G1 Zornitza Stark Added comment: Comment when marking as ready: Borderline Green/Amber rating.
Intellectual disability syndromic and non-syndromic v0.3081 CSNK1G1 Zornitza Stark Gene: csnk1g1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3081 CSNK1G1 Zornitza Stark Classified gene: CSNK1G1 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.3081 CSNK1G1 Zornitza Stark Gene: csnk1g1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3080 LMNB2 Zornitza Stark Marked gene: LMNB2 as ready
Intellectual disability syndromic and non-syndromic v0.3080 LMNB2 Zornitza Stark Gene: lmnb2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3080 LMNB2 Zornitza Stark Classified gene: LMNB2 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.3080 LMNB2 Zornitza Stark Gene: lmnb2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3079 LMNB1 Zornitza Stark changed review comment from: Adult-onset neurodegenerative condition, not truly ID.; to: Adult-onset neurodegenerative condition, not truly ID. Associated with CNV of this gene, suggestive of haploinsufficiency.
Intellectual disability syndromic and non-syndromic v0.3079 LMNB1 Zornitza Stark Publications for gene: LMNB1 were set to 32910914
Intellectual disability syndromic and non-syndromic v0.3078 CSNK1G1 Konstantinos Varvagiannis changed review comment from: Gold et al (2020 - PMID: 33009664) report 5 individuals with CSNK1G1 variants, including updated information on a previously reported subject (Martin et al 2014 - PMID: 24463883).

Features included DD (5/5) with associated expressive language delay, ASD (in at least 3/5), seizures (2/5), dysmorphic facial features (4/5 arched eyebrows, 3/5 prominent central incisors, 2/5 epicanthus) and limb anomalies (2/5 - proximally placed thumb, 5th f. clinodactyly, asymmetric overgrowth - the other individual had tapering fingers). GI problems were observed in 4/5. Two individuals had macrocephaly and one had microcephaly. There was no formal developmental assessment although ID might be implied in at least 3 individuals (p1: 20y - single words/regression in walking following a seizure episode, p2: 8y - first words at 5y, assistance to feed, dress and bathe, ASD, p4: 13y - regression, assistance to feed and dress).

CSNK1G1 encodes the gamma-1 isoform of casein kinase 1, a protein involved in growth and cell morphogenesis. The gene has ubiquitous expression, incl. brain. As commented, in brain it regulates phosphorylation of NMDA receptors, playing a role in synaptic transmission (4 articles cited).

One individual had a 1.2 kb deletion spanning exon 3 of CSNK1G1 [chr15:64550952-64552120 - GRCh37]. Parental samples were unavailable for this individual. Four individuals were found to harbor de novo CSNK1G1 variants [NM_022048.3: c.688C>T - p.(Arg230Trp) dn | c.1255C>T - p.(Gln419*) dn | c.1214+5G>A dn with in silico predictions in favor of splice disruption | c.419C>T - p.(Thr140Met) dn].

Arg230Trp is however present once in gnomAD. The stopgain variant is located in the last exon and predicted to skip NMD.

There were no variant studies performed.

The Drosophila gish gene encodes a CK1γ homolog with preferential expression in the mushroom body. Heterozygous and homozygous mutants exhibit impairment in memory retention, more severe in homozygous flies. gish was also identified as a seizure modifier in a fly epilepsy model (heterozygous para mt flies).

The authors also speculate that impaired transduction of LRP6 (and WNT signaling) might be implicated.

Finally the authors discuss the phenotype of individuals in Decipher one of whom (327861) harbors a frameshift variant and presenting ID, epilepsy and progressive spasticity. [NB. Inheritance of this variant is not specified, while this individual has a further inherited SCN2A missense SNV]. Two further Decipher cases with microdeletions spanning CSNK1G1 (and additional variants) are also discussed.

Overall, this gene can be considered for inclusion with probably amber rating.
Sources: Literature; to: Gold et al (2020 - PMID: 33009664) report 5 individuals with CSNK1G1 variants, including updated information on a previously reported subject (Martin et al 2014 - PMID: 24463883).

Features included DD (5/5) with associated expressive language delay, ASD (in at least 3/5), seizures (2/5), dysmorphic facial features (4/5 arched eyebrows, 3/5 prominent central incisors, 2/5 epicanthus) and limb anomalies (2/5 - proximally placed thumb, 5th f. clinodactyly, asymmetric overgrowth - the other individual had tapering fingers). GI problems were observed in 4/5. Two individuals had macrocephaly and one had microcephaly. There was no formal developmental assessment although ID might be implied in at least 3 individuals (p1: 20y - single words/regression in walking following a seizure episode, p2: 8y - first words at 5y, assistance to feed, dress and bathe, ASD, p4: 13y - regression, assistance to feed and dress).

CSNK1G1 encodes the gamma-1 isoform of casein kinase 1, a protein involved in growth and cell morphogenesis. The gene has ubiquitous expression, incl. brain. As commented, in brain it regulates phosphorylation of NMDA receptors, playing a role in synaptic transmission (4 articles cited).

One individual had a 1.2 kb deletion spanning exon 3 of CSNK1G1 [chr15:64550952-64552120 - GRCh37]. Parental samples were unavailable for this individual. Four individuals were found to harbor de novo CSNK1G1 variants [NM_022048.3: c.688C>T - p.(Arg230Trp) dn | c.1255C>T - p.(Gln419*) dn | c.1214+5G>A dn with in silico predictions in favor of splice disruption | c.419C>T - p.(Thr140Met) dn].

Arg230Trp is however present once in gnomAD. The stopgain variant is located in the last exon and predicted to skip NMD.

There were no variant studies performed.

The Drosophila gish gene encodes a CK1γ homolog with preferential expression in the mushroom body. Heterozygous and homozygous mutants exhibit impairment in memory retention, more severe in homozygous flies. gish was also identified as a seizure modifier in a fly epilepsy model (heterozygous para mt flies).

The authors also speculate that impaired transduction of LRP6 (and WNT signaling) might be implicated.

Finally the authors discuss the phenotype of individuals in Decipher one of whom (327861) harbors a frameshift variant and presented ID, epilepsy and progressive spasticity. [NB. Inheritance of this variant is not specified, while this individual has a further inherited SCN2A missense SNV]. Two further Decipher cases with microdeletions spanning CSNK1G1 (and additional variants) are also discussed.

Overall, this gene can be considered for inclusion with probably amber rating.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.3078 CSNK1G1 Konstantinos Varvagiannis changed review comment from: Gold et al (2020 - PMID: 33009664) report 5 individuals with CSNK1G1 variants, including updated information on a previously reported subject (Martin et al 2014 - PMID: 24463883).

Features included DD (5/5) with associated expressive language delay, ASD (in at least 3/5), seizures (2/5), dysmorphic facial features (4/5 arched eyebrows, 3/5 prominent central incisors, 2/5 epicanthus) and limb anomalies (2/5 - proximally placed thumb, 5th f. clinodactyly, asymmetric overgrowth - the other individual had tapering fingers). GI problems were observed in 4/5. Two individuals had macrocephaly and one had microcephaly. There was no formal developmental assessment although ID might be implied in at least 3 individuals (p1: 20y - single words/regression in walking following a seizure episode, p2: 8y - first words at 5y, assistance to feed, dress and bathe, ASD, p4: 13y - regression, assistance to feed and dress).

CSNK1G1 encodes the gamma-1 isoform of casein kinase 1, a protein involved in growth and cell morphogenesis. The gene has ubiquitous expression, incl. brain. As commented, in brain it regulates phosphorylation of NMDA receptors, playing a role in synaptic transmission (4 articles cited).

One individual had a 1.2 kb deletion spanning exon 3 of CSNK1G1 [chr15:64550952-64552120 - GRCh37]. Parental samples were unavailable for this individual. Four individuals were found to harbor de novo CSNK1G1 variants [NM_022048.3: c.688C>T - p.(Arg230Trp) dn | c.1255C>T - p.(Gln419*) dn | c.1214+5G>A dn with in silico predictions in favor of splice disruption | c.419C>T - p.(Thr140Met) dn].

Arg230Trp is however present once in gnomAD. The stopgain variant is located in the last exon and predicted to skip NMD.

There were no variant studies performed.

The Drosophila gish gene encodes a CK1γ homolog with preferential expression in the mushroom body. Heterozygous and homozygous mutants exhibit impairment in memory retention, more severe in homozygous flies. gish was also identified as a seizure modifier in a fly epilepsy model (heterozygous para mt flies).

The authors also speculate that impaired transduction of LRP6 (and WNT signaling) might be implicated.

Finally the authors discuss the phenotype of individuals in Decipher one of whom (327861) harbors a frameshift variant and presenting ID, epilepsy and progressive spasticity. [NB. Inheritance of this variant is not specified, while this individual has a further inherited SCN2A missense SNV]. Two further Decipher cases with microdeletions spanning CSNK1G1 (and additional variants) also discussed.

Overall, this gene can be considered for inclusion with probably amber rating.
Sources: Literature; to: Gold et al (2020 - PMID: 33009664) report 5 individuals with CSNK1G1 variants, including updated information on a previously reported subject (Martin et al 2014 - PMID: 24463883).

Features included DD (5/5) with associated expressive language delay, ASD (in at least 3/5), seizures (2/5), dysmorphic facial features (4/5 arched eyebrows, 3/5 prominent central incisors, 2/5 epicanthus) and limb anomalies (2/5 - proximally placed thumb, 5th f. clinodactyly, asymmetric overgrowth - the other individual had tapering fingers). GI problems were observed in 4/5. Two individuals had macrocephaly and one had microcephaly. There was no formal developmental assessment although ID might be implied in at least 3 individuals (p1: 20y - single words/regression in walking following a seizure episode, p2: 8y - first words at 5y, assistance to feed, dress and bathe, ASD, p4: 13y - regression, assistance to feed and dress).

CSNK1G1 encodes the gamma-1 isoform of casein kinase 1, a protein involved in growth and cell morphogenesis. The gene has ubiquitous expression, incl. brain. As commented, in brain it regulates phosphorylation of NMDA receptors, playing a role in synaptic transmission (4 articles cited).

One individual had a 1.2 kb deletion spanning exon 3 of CSNK1G1 [chr15:64550952-64552120 - GRCh37]. Parental samples were unavailable for this individual. Four individuals were found to harbor de novo CSNK1G1 variants [NM_022048.3: c.688C>T - p.(Arg230Trp) dn | c.1255C>T - p.(Gln419*) dn | c.1214+5G>A dn with in silico predictions in favor of splice disruption | c.419C>T - p.(Thr140Met) dn].

Arg230Trp is however present once in gnomAD. The stopgain variant is located in the last exon and predicted to skip NMD.

There were no variant studies performed.

The Drosophila gish gene encodes a CK1γ homolog with preferential expression in the mushroom body. Heterozygous and homozygous mutants exhibit impairment in memory retention, more severe in homozygous flies. gish was also identified as a seizure modifier in a fly epilepsy model (heterozygous para mt flies).

The authors also speculate that impaired transduction of LRP6 (and WNT signaling) might be implicated.

Finally the authors discuss the phenotype of individuals in Decipher one of whom (327861) harbors a frameshift variant and presenting ID, epilepsy and progressive spasticity. [NB. Inheritance of this variant is not specified, while this individual has a further inherited SCN2A missense SNV]. Two further Decipher cases with microdeletions spanning CSNK1G1 (and additional variants) are also discussed.

Overall, this gene can be considered for inclusion with probably amber rating.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.3078 CSNK1G1 Konstantinos Varvagiannis gene: CSNK1G1 was added
gene: CSNK1G1 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: CSNK1G1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CSNK1G1 were set to 33009664
Phenotypes for gene: CSNK1G1 were set to Global developmental delay; Intellectual disability; Autism; Seizures; Abnormality of the face; Abnromality of limbs
Penetrance for gene: CSNK1G1 were set to unknown
Review for gene: CSNK1G1 was set to AMBER
Added comment: Gold et al (2020 - PMID: 33009664) report 5 individuals with CSNK1G1 variants, including updated information on a previously reported subject (Martin et al 2014 - PMID: 24463883).

Features included DD (5/5) with associated expressive language delay, ASD (in at least 3/5), seizures (2/5), dysmorphic facial features (4/5 arched eyebrows, 3/5 prominent central incisors, 2/5 epicanthus) and limb anomalies (2/5 - proximally placed thumb, 5th f. clinodactyly, asymmetric overgrowth - the other individual had tapering fingers). GI problems were observed in 4/5. Two individuals had macrocephaly and one had microcephaly. There was no formal developmental assessment although ID might be implied in at least 3 individuals (p1: 20y - single words/regression in walking following a seizure episode, p2: 8y - first words at 5y, assistance to feed, dress and bathe, ASD, p4: 13y - regression, assistance to feed and dress).

CSNK1G1 encodes the gamma-1 isoform of casein kinase 1, a protein involved in growth and cell morphogenesis. The gene has ubiquitous expression, incl. brain. As commented, in brain it regulates phosphorylation of NMDA receptors, playing a role in synaptic transmission (4 articles cited).

One individual had a 1.2 kb deletion spanning exon 3 of CSNK1G1 [chr15:64550952-64552120 - GRCh37]. Parental samples were unavailable for this individual. Four individuals were found to harbor de novo CSNK1G1 variants [NM_022048.3: c.688C>T - p.(Arg230Trp) dn | c.1255C>T - p.(Gln419*) dn | c.1214+5G>A dn with in silico predictions in favor of splice disruption | c.419C>T - p.(Thr140Met) dn].

Arg230Trp is however present once in gnomAD. The stopgain variant is located in the last exon and predicted to skip NMD.

There were no variant studies performed.

The Drosophila gish gene encodes a CK1γ homolog with preferential expression in the mushroom body. Heterozygous and homozygous mutants exhibit impairment in memory retention, more severe in homozygous flies. gish was also identified as a seizure modifier in a fly epilepsy model (heterozygous para mt flies).

The authors also speculate that impaired transduction of LRP6 (and WNT signaling) might be implicated.

Finally the authors discuss the phenotype of individuals in Decipher one of whom (327861) harbors a frameshift variant and presenting ID, epilepsy and progressive spasticity. [NB. Inheritance of this variant is not specified, while this individual has a further inherited SCN2A missense SNV]. Two further Decipher cases with microdeletions spanning CSNK1G1 (and additional variants) also discussed.

Overall, this gene can be considered for inclusion with probably amber rating.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.3078 LMNB2 Konstantinos Varvagiannis changed review comment from: Please consider inclusion of LMNB2 in the ID panel with amber/green rating.

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

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

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

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

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

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

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

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

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

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

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

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

[Please also note the additional OMIM phenotypes for LMNB1 / LMNB2 - not here reviewed]
Sources: Literature; to: Please consider inclusion of LMNB2 in the ID panel with amber/green rating.

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

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

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

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

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

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

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

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

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

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

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

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

[Please also note the additional OMIM phenotypes for LMNB1 / LMNB2 - not here reviewed]
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.3078 LMNB2 Konstantinos Varvagiannis gene: LMNB2 was added
gene: LMNB2 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: LMNB2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: LMNB2 were set to 33033404
Phenotypes for gene: LMNB2 were set to Congenital microcephaly; Global developmental delay; Intellectual disability
Penetrance for gene: LMNB2 were set to Complete
Mode of pathogenicity for gene: LMNB2 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: LMNB2 was set to GREEN
Added comment: Please consider inclusion of LMNB2 in the ID panel with amber/green rating.

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

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

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

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

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

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

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

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

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

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

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

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

[Please also note the additional OMIM phenotypes for LMNB1 / LMNB2 - not here reviewed]
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.3078 LMNB1 Konstantinos Varvagiannis commented on gene: LMNB1: There is an additional report on LMBN1/2-associated phenotypes supporting green rating of the gene in the current panel.

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

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

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

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

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

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

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

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

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

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

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

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

[Please also note the additional OMIM phenotypes for LMNB1 / LMNB2 - not here reviewed]

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Intellectual disability syndromic and non-syndromic v0.3078 MICU1 Zornitza Stark Marked gene: MICU1 as ready
Intellectual disability syndromic and non-syndromic v0.3078 MICU1 Zornitza Stark Gene: micu1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3078 MICU1 Zornitza Stark Phenotypes for gene: MICU1 were changed from to Myopathy with extrapyramidal signs, MIM# 615673
Intellectual disability syndromic and non-syndromic v0.3077 MICU1 Zornitza Stark Publications for gene: MICU1 were set to
Intellectual disability syndromic and non-syndromic v0.3076 MICU1 Zornitza Stark Mode of inheritance for gene: MICU1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3075 MICU1 Zornitza Stark Tag founder tag was added to gene: MICU1.
Intellectual disability syndromic and non-syndromic v0.3075 MICU1 Zornitza Stark reviewed gene: MICU1: Rating: GREEN; Mode of pathogenicity: None; Publications: 24336167, 29721912, 32395406; Phenotypes: Myopathy with extrapyramidal signs, MIM# 615673; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3075 PIBF1 Zornitza Stark Phenotypes for gene: PIBF1 were changed from Joubert syndrome 33; OMIM #617767 to Joubert syndrome 33, OMIM #617767
Intellectual disability syndromic and non-syndromic v0.3074 PIBF1 Zornitza Stark Publications for gene: PIBF1 were set to PubMed: 26167768; 30858804; 29695797
Intellectual disability syndromic and non-syndromic v0.3073 PIBF1 Zornitza Stark reviewed gene: PIBF1: Rating: GREEN; Mode of pathogenicity: None; Publications: 33004012; Phenotypes: Joubert syndrome 33, OMIM #617767; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3073 WDPCP Zornitza Stark Publications for gene: WDPCP were set to
Intellectual disability syndromic and non-syndromic v0.3072 WDPCP Zornitza Stark Classified gene: WDPCP as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.3072 WDPCP Zornitza Stark Gene: wdpcp has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3071 WDPCP Zornitza Stark edited their review of gene: WDPCP: Changed rating: GREEN
Intellectual disability syndromic and non-syndromic v0.3071 WDPCP Zornitza Stark changed review comment from: Two families reported; the first one with a BBS phenotype, and in the second one affected individual had polysyndactyly and tongue hamartomas, so phenotype consistent with OFD rather than BBS.; to: At least four families reported with ciliopathy phenotypes (BBS, OFD, syndromic retinopathy).
Intellectual disability syndromic and non-syndromic v0.3071 WDPCP Zornitza Stark edited their review of gene: WDPCP: Changed publications: 20671153, 25427950, 32055034, 29588463, 28289185
Intellectual disability syndromic and non-syndromic v0.3071 WDPCP Zornitza Stark Mode of inheritance for gene: WDPCP was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3070 WDPCP Zornitza Stark Classified gene: WDPCP as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.3070 WDPCP Zornitza Stark Gene: wdpcp has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.3069 WDPCP Zornitza Stark reviewed gene: WDPCP: Rating: AMBER; Mode of pathogenicity: None; Publications: 20671153, 25427950; Phenotypes: Bardet-Biedl syndrome 15, MIM# 615992, OFD, Congenital heart defects, hamartomas of tongue, and polysyndactyly, 217085; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3069 TRAPPC9 Zornitza Stark Tag SV/CNV tag was added to gene: TRAPPC9.
Intellectual disability syndromic and non-syndromic v0.3069 TRAPPC9 Zornitza Stark Publications for gene: TRAPPC9 were set to 30853973
Intellectual disability syndromic and non-syndromic v0.3068 TRAPPC9 Zornitza Stark reviewed gene: TRAPPC9: Rating: GREEN; Mode of pathogenicity: None; Publications: 22549410, 20004765, 20004763, 30853973, 29187737; Phenotypes: Mental retardation, autosomal recessive 13, MIM# 613192; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3068 EPG5 Zornitza Stark Phenotypes for gene: EPG5 were changed from Vici syndrome, MIM# 242840 to Vici syndrome, MIM# 242840
Intellectual disability syndromic and non-syndromic v0.3068 EPG5 Zornitza Stark Marked gene: EPG5 as ready
Intellectual disability syndromic and non-syndromic v0.3068 EPG5 Zornitza Stark Gene: epg5 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3068 EPG5 Zornitza Stark Phenotypes for gene: EPG5 were changed from to Vici syndrome, MIM# 242840
Intellectual disability syndromic and non-syndromic v0.3067 EPG5 Zornitza Stark Publications for gene: EPG5 were set to
Intellectual disability syndromic and non-syndromic v0.3066 EPG5 Zornitza Stark Mode of inheritance for gene: EPG5 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3065 EPG5 Zornitza Stark reviewed gene: EPG5: Rating: GREEN; Mode of pathogenicity: None; Publications: 23222957, 26917586; Phenotypes: Vici syndrome, MIM# 242840; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3065 KIRREL3 Zornitza Stark Tag refuted tag was added to gene: KIRREL3.
Intellectual disability syndromic and non-syndromic v0.3065 HK1 Zornitza Stark Phenotypes for gene: HK1 were changed from to Neurodevelopmental disorder with visual defects and brain anomalies, MIM# 618547
Intellectual disability syndromic and non-syndromic v0.3064 HK1 Zornitza Stark reviewed gene: HK1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with visual defects and brain anomalies, MIM# 618547; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3064 ITFG2 Zornitza Stark Marked gene: ITFG2 as ready
Intellectual disability syndromic and non-syndromic v0.3064 ITFG2 Zornitza Stark Added comment: Comment when marking as ready: Agree with Amber rating, considering reported as part of heterogenous cohort reporting diagnostic outcomes and multiple candidate genes.
Intellectual disability syndromic and non-syndromic v0.3064 ITFG2 Zornitza Stark Gene: itfg2 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.3064 ITFG2 Zornitza Stark Classified gene: ITFG2 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.3064 ITFG2 Zornitza Stark Gene: itfg2 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.3063 SHMT2 Zornitza Stark Marked gene: SHMT2 as ready
Intellectual disability syndromic and non-syndromic v0.3063 SHMT2 Zornitza Stark Gene: shmt2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3063 SHMT2 Zornitza Stark Classified gene: SHMT2 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.3063 SHMT2 Zornitza Stark Gene: shmt2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3062 ITFG2 Konstantinos Varvagiannis gene: ITFG2 was added
gene: ITFG2 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: ITFG2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ITFG2 were set to 28397838; https://doi.org/10.1038/s41525-020-00150-z
Phenotypes for gene: ITFG2 were set to Neurodevelopmental abnormality; Intellectual disability; Developmental regression; Ataxia
Penetrance for gene: ITFG2 were set to Complete
Review for gene: ITFG2 was set to AMBER
Added comment: ITFG2 was suggested to be a candidate gene for autosomal recessive ID in the study by Harripaul et al (2018 - PMID: 28397838). The authors performed microarray and exome sequencing in 192 consanguineous families and identified a homozygous ITGF2 stopgain variant (NM_018463.3:c.472G>T / p.Glu158*) along with 3 additional variants segregating with ID within an investigated family (PK51).

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

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

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

Please consider inclusion in the ID panel with amber rating, pending further details.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.3062 SHMT2 Konstantinos Varvagiannis gene: SHMT2 was added
gene: SHMT2 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: SHMT2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SHMT2 were set to 33015733
Phenotypes for gene: SHMT2 were set to Congenital microcephaly; Infantile axial hypotonia; Spastic paraparesis; Global developmental delay; Intellectual disability; Abnormality of the corpus callosum; Abnormal cortical gyration; Hypertrophic cardiomyopathy; Abnormality of the face; Proximal placement of thumb; 2-3 toe syndactyly
Penetrance for gene: SHMT2 were set to Complete
Review for gene: SHMT2 was set to GREEN
Added comment: García‑Cazorla et al. (2020 - PMID: 33015733) report 5 individuals (from 4 families) with a novel brain and heart developmental syndrome caused by biallelic SHMT2 pathogenic variants.

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

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

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

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

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

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

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

Overall this gene can be considered for inclusion with (probably) green rating in gene panels for ID, metabolic / mitochondrial disorders, cardiomyopathy, congenital microcephaly, corpus callosum anomalies, etc.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.3062 VPS41 Zornitza Stark Marked gene: VPS41 as ready
Intellectual disability syndromic and non-syndromic v0.3062 VPS41 Zornitza Stark Gene: vps41 has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v0.3062 VPS41 Zornitza Stark gene: VPS41 was added
gene: VPS41 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: VPS41 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: VPS41 were set to 32808683
Phenotypes for gene: VPS41 were set to Dystonia; intellectual disability
Review for gene: VPS41 was set to RED
Added comment: Single individual reported with homozygous canonical splice site variant resulting in exon 7 skipping, and global developmental delay and generalized dystonia. He attained a few words and voluntary limb movements but never sat unsupported. He had pale optic discs and an axonal neuropathy. From 6 years of age, his condition began to deteriorate, with reduced motor abilities and alertness. An MRI of the brain showed atrophy of the superior cerebellar vermis and slimming of the posterior limb of the corpus callosum. VPS41 is component of the HOPS complex and other genes in the complex have been implicated in movement disorders.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.3061 ALG14 Zornitza Stark Phenotypes for gene: ALG14 were changed from Intellectual developmental disorder with epilepsy, behavioral abnormalities, and coarse facies (IDDEBF), MIM#619031 to Intellectual developmental disorder with epilepsy, behavioral abnormalities, and coarse facies (IDDEBF), MIM#619031; Myopathy, epilepsy, and progressive cerebral atrophy, MIM# 619036
Intellectual disability syndromic and non-syndromic v0.3060 ALG14 Zornitza Stark edited their review of gene: ALG14: Changed phenotypes: intellectual developmental disorder with epilepsy, behavioral abnormalities, and coarse facies (IDDEBF), MIM#619031, Myopathy, epilepsy, and progressive cerebral atrophy, MIM# 619036
Intellectual disability syndromic and non-syndromic v0.3060 QRICH1 Zornitza Stark Marked gene: QRICH1 as ready
Intellectual disability syndromic and non-syndromic v0.3060 QRICH1 Zornitza Stark Gene: qrich1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3060 QRICH1 Zornitza Stark Phenotypes for gene: QRICH1 were changed from to Ververi-Brady syndrome, MIM#617982
Intellectual disability syndromic and non-syndromic v0.3059 QRICH1 Zornitza Stark Publications for gene: QRICH1 were set to
Intellectual disability syndromic and non-syndromic v0.3058 QRICH1 Zornitza Stark Mode of inheritance for gene: QRICH1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3057 QRICH1 Zornitza Stark reviewed gene: QRICH1: Rating: GREEN; Mode of pathogenicity: None; Publications: 28692176, 30281152, 33009816; Phenotypes: Ververi-Brady syndrome, MIM#617982; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3057 SON Zornitza Stark Marked gene: SON as ready
Intellectual disability syndromic and non-syndromic v0.3057 SON Zornitza Stark Gene: son has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3057 SON Zornitza Stark Phenotypes for gene: SON were changed from to ZTTK syndrome, MIM# 617140
Intellectual disability syndromic and non-syndromic v0.3056 SON Zornitza Stark Publications for gene: SON were set to
Intellectual disability syndromic and non-syndromic v0.3055 SON Zornitza Stark Mode of inheritance for gene: SON was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3054 SON Zornitza Stark reviewed gene: SON: Rating: GREEN; Mode of pathogenicity: None; Publications: 27545680, 27545676, 31005274; Phenotypes: ZTTK syndrome, MIM# 617140; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3054 NEMF Zornitza Stark Mode of inheritance for gene: NEMF was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3053 NEMF Zornitza Stark edited their review of gene: NEMF: Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3053 NEMF Konstantinos Varvagiannis changed review comment from: Biallelic (and possibly monoallelic) pathogenic variants in this gene are associated with DD/ID.

Martin et al (2020 - PMID:32934225) report on 8 individuals from 6 families with a juvenile neuromuscular disease due to biallelic NEMF variants. (In one of these 8 cases it could not be ruled out that a de novo and maternally inherited variant were on the same allele, as phase was not determined). A ninth individual with similar presentation was found to harbor a single NEMF missense SNV as de novo event (due to a speculated dominant-negative effect). This individual had a similar presentation.

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

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

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

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

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

Overall NEMF is thought to play a role in neuronal translational homeostasis and the disorder to be mediated by dysfunction of the RQC pathway (normally protecting neurons against degeneration).; to: Biallelic (and possibly monoallelic) pathogenic variants in this gene are associated with DD/ID.

Martin et al (2020 - PMID:32934225) report on 8 individuals from 6 families with a juvenile neuromuscular disease due to biallelic NEMF variants. (In one of these 8 cases it could not be ruled out that a de novo and maternally inherited variant were on the same allele, as phase was not determined). A ninth individual with similar presentation was found to harbor a single NEMF missense SNV as de novo event (due to a speculated dominant-negative effect). This individual had a similar presentation.

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

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

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

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

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

Overall NEMF is thought to play a role in neuronal translational homeostasis and the disorder to be mediated by dysfunction of the RQC pathway (normally protecting neurons against degeneration).
Intellectual disability syndromic and non-syndromic v0.3053 NEMF Konstantinos Varvagiannis changed review comment from: Biallelic (and possibly monoallelic) pathogenic variants in this gene are associated with DD/ID.

Martin et al (2020 - PMID:32934225) report on 8 individuals from 6 families with a juvenile neuromuscular disease due to biallelic NEMF variants. (In one of these 8 cases it could not be ruled out that a de novo and maternally inherited variants were on the same allele, as phase was not been determined). A ninth individual with similar presentation was found to harbor a single NEMF missense SNV as de novo event (due to a speculated dominant-negative effect). This individual had a similar presentation.

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

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

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

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

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

Overall NEMF is thought to play a role in neuronal translational homeostasis and the disorder to be mediated by dysfunction of the RQC pathway (normally protecting neurons against degeneration).; to: Biallelic (and possibly monoallelic) pathogenic variants in this gene are associated with DD/ID.

Martin et al (2020 - PMID:32934225) report on 8 individuals from 6 families with a juvenile neuromuscular disease due to biallelic NEMF variants. (In one of these 8 cases it could not be ruled out that a de novo and maternally inherited variant were on the same allele, as phase was not determined). A ninth individual with similar presentation was found to harbor a single NEMF missense SNV as de novo event (due to a speculated dominant-negative effect). This individual had a similar presentation.

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

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

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

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

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

Overall NEMF is thought to play a role in neuronal translational homeostasis and the disorder to be mediated by dysfunction of the RQC pathway (normally protecting neurons against degeneration).
Intellectual disability syndromic and non-syndromic v0.3053 NEMF Konstantinos Varvagiannis changed review comment from: Biallelic (and possibly monoallelic) pathogenic variants in this gene are associated with DD/ID.

Martin et al (2020 - PMID:32934225) report on 8 individuals from 6 families with a juvenile neuromuscular disease due to biallelic NEMF variants. (In one of these 8 cases it could be ruled out that the de novo and maternally inherited variants were on the same allele, as phase was not been determined). A ninth individual with similar presentation was found to harbor a single NEMF missense SNV as de novo event (due to a speculated dominant-negative effect). This individual had a similar presentation.

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

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

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

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

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

Overall NEMF is thought to play a role in neuronal translational homeostasis and the disorder to be mediated by dysfunction of the RQC pathway (normally protecting neurons against degeneration).; to: Biallelic (and possibly monoallelic) pathogenic variants in this gene are associated with DD/ID.

Martin et al (2020 - PMID:32934225) report on 8 individuals from 6 families with a juvenile neuromuscular disease due to biallelic NEMF variants. (In one of these 8 cases it could not be ruled out that a de novo and maternally inherited variants were on the same allele, as phase was not been determined). A ninth individual with similar presentation was found to harbor a single NEMF missense SNV as de novo event (due to a speculated dominant-negative effect). This individual had a similar presentation.

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

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

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

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

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

Overall NEMF is thought to play a role in neuronal translational homeostasis and the disorder to be mediated by dysfunction of the RQC pathway (normally protecting neurons against degeneration).
Intellectual disability syndromic and non-syndromic v0.3053 NEMF Konstantinos Varvagiannis reviewed gene: NEMF: Rating: GREEN; Mode of pathogenicity: None; Publications: 32934225; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3053 NUP188 Zornitza Stark Phenotypes for gene: NUP188 were changed from microcephaly; ID; cataract; structural brain abnormalities; hypoventilation to Sandestig-Stefanova syndrome, 618804; microcephaly; ID; cataract; structural brain abnormalities; hypoventilation
Intellectual disability syndromic and non-syndromic v0.3052 NUP188 Zornitza Stark edited their review of gene: NUP188: Changed phenotypes: Sandestig-Stefanova syndrome, 618804, microcephaly, ID, cataract, structural brain abnormalities, hypoventilation
Intellectual disability syndromic and non-syndromic v0.3052 SETD1A Zornitza Stark Marked gene: SETD1A as ready
Intellectual disability syndromic and non-syndromic v0.3052 SETD1A Zornitza Stark Gene: setd1a has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3052 SETD1A Zornitza Stark Classified gene: SETD1A as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.3052 SETD1A Zornitza Stark Gene: setd1a has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3051 SETD1A Zornitza Stark gene: SETD1A was added
gene: SETD1A was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: SETD1A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SETD1A were set to 31197650; 32346159
Phenotypes for gene: SETD1A were set to Epilepsy, early-onset, with or without developmental delay, MIM# 618832
Review for gene: SETD1A was set to GREEN
Added comment: 19 unrelated individuals reported with de novo variants in this gene and a neurodevelopmental phenotype, primarily manifesting and ID and seizures. LOF mechanism supported by functional data. Three mouse models.

SNPs in this gene have also been associated with risk of developing schizophrenia.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.3050 HPDL Zornitza Stark changed review comment from: Intellectual impairment is variable, ranging from poor visual contact with inability to walk or speak to milder intellectual disability with the ability to say some words.; to: 17 individuals from 13 families, with a spectrum of neurologic impairment ranging from a severe congenital form without any neurological development (n = 2/17, 12%) to infantile-onset presentations (n = 10/17, 59%) with moderate to severe neurodevelopmental issues, partly with a pathology reminiscent of mitochondrial disease (Leigh-like syndrome), to juvenile-onset spastic paraplegia (n = 5/17, 29%).

Intellectual impairment is variable, ranging from poor visual contact with inability to walk or speak to milder intellectual disability with the ability to say some words.

Frequently observed additional clinical findings included chronic progression of neurological signs (n = 16/17, 94%), microcephaly (n = 9/16, 56%), and seizures/epilepsy (n = 9/17, 53%). Other relevant clinical findings were visual disturbances/strabismus (n = 9/17, 53%) and loss of developmental milestones (n = 6/17, 35%).

Acute central respiratory failure leading to life-threatening events requiring partly mechanically assisted ventilation occurred in half of individuals with infantile presentation (n = 5/10, 50%), respectively one third of all individuals (n = 5/17, 29%).

Demyelinating neuropathy was present in three individuals (n = 3/11, 27%), with reduced sensory nerve conduction velocity (NCV) in all and severely reduced motor NCV in one.
Intellectual disability syndromic and non-syndromic v0.3050 HPDL Zornitza Stark Phenotypes for gene: HPDL were changed from Progressive neurological disorder; Leigh-like syndrome to Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities (NEDSWMA), MIM#619026; Progressive neurological disorder; Leigh-like syndrome
Intellectual disability syndromic and non-syndromic v0.3049 HPDL Zornitza Stark reviewed gene: HPDL: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities (NEDSWMA), MIM#619026; Mode of inheritance: None
Intellectual disability syndromic and non-syndromic v0.3049 PRKD1 Zornitza Stark Marked gene: PRKD1 as ready
Intellectual disability syndromic and non-syndromic v0.3049 PRKD1 Zornitza Stark Added comment: Comment when marking as ready: Literature reviewed again: ID/DD reported in 2/5 but unclear at present if this is part of the phenotype given low number of affected individuals.
Intellectual disability syndromic and non-syndromic v0.3049 PRKD1 Zornitza Stark Gene: prkd1 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.3049 PRKD1 Zornitza Stark Publications for gene: PRKD1 were set to 27479907
Intellectual disability syndromic and non-syndromic v0.3048 PRKD1 Zornitza Stark Classified gene: PRKD1 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.3048 PRKD1 Zornitza Stark Gene: prkd1 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.3047 PRKD1 Arina Puzriakova reviewed gene: PRKD1: Rating: AMBER; Mode of pathogenicity: None; Publications: 27479907, 32817298; Phenotypes: Congenital heart defects and ectodermal dysplasia, 617364; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability syndromic and non-syndromic v0.3047 KPTN Zornitza Stark Marked gene: KPTN as ready
Intellectual disability syndromic and non-syndromic v0.3047 KPTN Zornitza Stark Gene: kptn has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3047 KPTN Zornitza Stark Phenotypes for gene: KPTN were changed from to Mental retardation, autosomal recessive 41 (MIM#615637)
Intellectual disability syndromic and non-syndromic v0.3046 KPTN Zornitza Stark Publications for gene: KPTN were set to
Intellectual disability syndromic and non-syndromic v0.3045 KPTN Zornitza Stark Mode of inheritance for gene: KPTN was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3044 KPTN Zornitza Stark reviewed gene: KPTN: Rating: GREEN; Mode of pathogenicity: None; Publications: 24239382, 32358097, 32808430; Phenotypes: Mental retardation, autosomal recessive 41 (MIM#615637); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3044 TTI2 Zornitza Stark Marked gene: TTI2 as ready
Intellectual disability syndromic and non-syndromic v0.3044 TTI2 Zornitza Stark Gene: tti2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3044 TTI2 Zornitza Stark Phenotypes for gene: TTI2 were changed from to Mental retardation, autosomal recessive 39 (MIM#615541) AR
Intellectual disability syndromic and non-syndromic v0.3043 TTI2 Zornitza Stark Publications for gene: TTI2 were set to
Intellectual disability syndromic and non-syndromic v0.3042 TTI2 Zornitza Stark Mode of inheritance for gene: TTI2 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3041 TTI2 Michelle Torres reviewed gene: TTI2: Rating: GREEN; Mode of pathogenicity: None; Publications: 32061250, 23956177, 31737043; Phenotypes: Mental retardation, autosomal recessive 39 (MIM#615541) AR; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3041 ARID2 Zornitza Stark reviewed gene: ARID2: Rating: GREEN; Mode of pathogenicity: None; Publications: 26238514, 30838730, 29698805, 28884947, 28124119; Phenotypes: Coffin-Siris syndrome 6, MIM# 617808; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3041 ARID2 Zornitza Stark Marked gene: ARID2 as ready
Intellectual disability syndromic and non-syndromic v0.3041 ARID2 Zornitza Stark Gene: arid2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3041 ARID2 Zornitza Stark Phenotypes for gene: ARID2 were changed from to Coffin-Siris syndrome 6, MIM# 617808
Intellectual disability syndromic and non-syndromic v0.3040 ARID2 Zornitza Stark Publications for gene: ARID2 were set to
Intellectual disability syndromic and non-syndromic v0.3039 ARID2 Zornitza Stark Mode of inheritance for gene: ARID2 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3038 ARID2 Ee Ming Wong reviewed gene: ARID2: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 26238514; Phenotypes: neurodevelopmental delay, global developmental delay, gross motor delay; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Intellectual disability syndromic and non-syndromic v0.3038 PIGT Zornitza Stark Marked gene: PIGT as ready
Intellectual disability syndromic and non-syndromic v0.3038 PIGT Zornitza Stark Gene: pigt has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3038 PIGT Zornitza Stark Phenotypes for gene: PIGT were changed from to Multiple congenital anomalies-hypotonia-seizures syndrome 3, MIM# 615398
Intellectual disability syndromic and non-syndromic v0.3037 PIGT Zornitza Stark Publications for gene: PIGT were set to
Intellectual disability syndromic and non-syndromic v0.3036 PIGT Zornitza Stark Mode of inheritance for gene: PIGT was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3035 PIGT Zornitza Stark reviewed gene: PIGT: Rating: GREEN; Mode of pathogenicity: None; Publications: 30976099, 25943031, 24906948, 24906948, 24906948, 28728837, 28728837, 28728837; Phenotypes: Multiple congenital anomalies-hypotonia-seizures syndrome 3, MIM# 615398; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3035 ALG13 Zornitza Stark Marked gene: ALG13 as ready
Intellectual disability syndromic and non-syndromic v0.3035 ALG13 Zornitza Stark Gene: alg13 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3035 ALG13 Zornitza Stark Phenotypes for gene: ALG13 were changed from to Congenital disorder of glycosylation, type Is (MIM# 300884)
Intellectual disability syndromic and non-syndromic v0.3034 ALG13 Zornitza Stark Publications for gene: ALG13 were set to
Intellectual disability syndromic and non-syndromic v0.3033 ALG13 Zornitza Stark Mode of inheritance for gene: ALG13 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 v0.3032 ALG13 Zornitza Stark reviewed gene: ALG13: Rating: GREEN; Mode of pathogenicity: None; Publications: 23033978, 23934111, 24781210, 24896178, 25732998, 26138355, 26482601, 28940310, 32238909; Phenotypes: Congenital disorder of glycosylation, type Is (MIM# 300884); 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 v0.3032 GPSM2 Zornitza Stark edited their review of gene: GPSM2: Changed publications: 20602914, 22578326, 28387217, 27180139, 27064331
Intellectual disability syndromic and non-syndromic v0.3032 GPSM2 Zornitza Stark Publications for gene: GPSM2 were set to
Intellectual disability syndromic and non-syndromic v0.3031 GPSM2 Zornitza Stark Mode of inheritance for gene: GPSM2 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3030 CNOT1 Zornitza Stark Phenotypes for gene: CNOT1 were changed from Holoprosencephaly 12, with or without pancreatic agenesis 618500 to Vissers-Bodmer syndrome, MIM#619033; Holoprosencephaly 12, with or without pancreatic agenesis 618500
Intellectual disability syndromic and non-syndromic v0.3029 CNOT1 Zornitza Stark Publications for gene: CNOT1 were set to 31006510; 21679367; 31006513
Intellectual disability syndromic and non-syndromic v0.3028 CNOT1 Zornitza Stark reviewed gene: CNOT1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Vissers-Bodmer syndrome, MIM#619033; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3028 COQ5 Zornitza Stark Phenotypes for gene: COQ5 were changed from Cerebellar ataxia; encephalopathy; generalized tonic-clonic seizures; intellectual disability to Coenzyme Q10 deficiency, primary 9, MIM#619028; Cerebellar ataxia; encephalopathy; generalized tonic-clonic seizures; intellectual disability
Intellectual disability syndromic and non-syndromic v0.3027 COQ5 Zornitza Stark edited their review of gene: COQ5: Changed phenotypes: Coenzyme Q10 deficiency, primary 9, MIM#619028, Cerebellar ataxia, encephalopathy, generalized tonic-clonic seizures, intellectual disability
Intellectual disability syndromic and non-syndromic v0.3027 SECISBP2 Zornitza Stark Marked gene: SECISBP2 as ready
Intellectual disability syndromic and non-syndromic v0.3027 SECISBP2 Zornitza Stark Gene: secisbp2 has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v0.3027 SECISBP2 Zornitza Stark Classified gene: SECISBP2 as Red List (low evidence)
Intellectual disability syndromic and non-syndromic v0.3027 SECISBP2 Zornitza Stark Gene: secisbp2 has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v0.3026 SECISBP2 Anna Le Fevre gene: SECISBP2 was added
gene: SECISBP2 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: SECISBP2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SECISBP2 were set to 16228000; 19602558; 21084748; 22247018
Phenotypes for gene: SECISBP2 were set to #609698 THYROID HORMONE METABOLISM, ABNORMAL
Penetrance for gene: SECISBP2 were set to unknown
Review for gene: SECISBP2 was set to RED
Added comment: Multiple families with biallelic loss of function variants have been reported with a disorder of thyroid hormone metabolism involving synthesis of selenoproteins. Features include short stature with delayed bone age, muscle weakness with fatty infiltration of skeletal muscle, azoospermia, and mild developmental delay. Photosensitivity and high frequency SNHL have been reported. Thyroid function tests show elevated FT4 and rT3, low FT3 and normal or mildly elevated TSH. Incomplete loss of SECISBP2 function has been hypothesized to cause a milder phenotype.

At least two reports of children with delayed milestones.
One report of an affected adult with mild ID.
Further reports may clarify if this phenotype typically includes ID.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.3026 LAS1L Zornitza Stark Mode of inheritance for gene: LAS1L was changed from Unknown to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability syndromic and non-syndromic v0.3025 LAS1L Zornitza Stark edited their review of gene: LAS1L: Changed rating: GREEN; Changed mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability syndromic and non-syndromic v0.3025 UPF3B Zornitza Stark Marked gene: UPF3B as ready
Intellectual disability syndromic and non-syndromic v0.3025 UPF3B Zornitza Stark Gene: upf3b has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3025 UPF3B Zornitza Stark Phenotypes for gene: UPF3B were changed from to Mental retardation, X-linked, syndromic 14, MIM# 300676
Intellectual disability syndromic and non-syndromic v0.3024 UPF3B Zornitza Stark Publications for gene: UPF3B were set to
Intellectual disability syndromic and non-syndromic v0.3023 UPF3B Zornitza Stark Mode of inheritance for gene: UPF3B was changed from Unknown to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability syndromic and non-syndromic v0.3022 UPF3B Zornitza Stark reviewed gene: UPF3B: Rating: GREEN; Mode of pathogenicity: None; Publications: 19377476, 17704778, 31737052, 28948974; Phenotypes: Mental retardation, X-linked, syndromic 14, MIM# 300676; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability syndromic and non-syndromic v0.3022 UPF3B Arina Puzriakova reviewed gene: UPF3B: Rating: GREEN; Mode of pathogenicity: None; Publications: 32667670; Phenotypes: Mental retardation, X-linked, syndromic 14, 300676; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability syndromic and non-syndromic v0.3022 ALG14 Zornitza Stark Phenotypes for gene: ALG14 were changed from Myasthenic syndrome, congenital, 15, without tubular aggregates, MIM#616227; Intellectual disability to Intellectual developmental disorder with epilepsy, behavioral abnormalities, and coarse facies (IDDEBF), MIM#619031
Intellectual disability syndromic and non-syndromic v0.3021 ALG14 Zornitza Stark edited their review of gene: ALG14: Changed phenotypes: intellectual developmental disorder with epilepsy, behavioral abnormalities, and coarse facies (IDDEBF), MIM#619031
Intellectual disability syndromic and non-syndromic v0.3021 MADD Zornitza Stark Phenotypes for gene: MADD were changed from intellectual disability to DEEAH syndrome, MIM#619004 (Developmental Delay With Endocrine, Exocrine, Autonomic, and Hematologic Abnormalities); Neurodevelopmental disorder with dysmorphic facies, impaired speech and hypotonia (NEDDISH), MIM# 619005
Intellectual disability syndromic and non-syndromic v0.3020 MADD Zornitza Stark Publications for gene: MADD were set to 28940097
Intellectual disability syndromic and non-syndromic v0.3019 MADD Zornitza Stark reviewed gene: MADD: Rating: GREEN; Mode of pathogenicity: None; Publications: 28940097, 29302074, 32761064; Phenotypes: DEEAH syndrome, MIM#619004 (Developmental Delay With Endocrine, Exocrine, Autonomic, and Hematologic Abnormalities), Neurodevelopmental disorder with dysmorphic facies, impaired speech and hypotonia (NEDDISH), MIM# 619005; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3019 SLC12A2 Zornitza Stark Publications for gene: SLC12A2 were set to 30740830
Intellectual disability syndromic and non-syndromic v0.3018 SLC12A2 Zornitza Stark Mode of inheritance for gene: SLC12A2 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3017 SLC12A2 Konstantinos Varvagiannis reviewed gene: SLC12A2: Rating: GREEN; Mode of pathogenicity: None; Publications: 28135719, 32658972, 27900370, 32294086, 29288388, 30740830, 32754646; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3017 TECPR2 Zornitza Stark Marked gene: TECPR2 as ready
Intellectual disability syndromic and non-syndromic v0.3017 TECPR2 Zornitza Stark Gene: tecpr2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3017 TECPR2 Zornitza Stark Phenotypes for gene: TECPR2 were changed from to Spastic paraplegia 49, autosomal recessive, 615031; Autonomic-sensory neuropathy; Intellectual disability
Intellectual disability syndromic and non-syndromic v0.3016 TECPR2 Zornitza Stark Publications for gene: TECPR2 were set to
Intellectual disability syndromic and non-syndromic v0.3015 TECPR2 Zornitza Stark Mode of inheritance for gene: TECPR2 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3014 TECPR2 Zornitza Stark reviewed gene: TECPR2: Rating: GREEN; Mode of pathogenicity: None; Publications: 23176824, 26542466; Phenotypes: Spastic paraplegia 49, autosomal recessive, 615031, Autonomic-sensory neuropathy, Intellectual disability; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3014 ZMYM2 Zornitza Stark edited their review of gene: ZMYM2: Changed rating: GREEN; Changed publications: 32891193; Changed phenotypes: Congenital anomalies of kidney and urinary tract, Neurodevelopmental disorder; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3014 ZMYM2 Zornitza Stark Marked gene: ZMYM2 as ready
Intellectual disability syndromic and non-syndromic v0.3014 ZMYM2 Zornitza Stark Added comment: Comment when marking as ready: Syndromic CAKUT, variable extra-renal phenotype but sufficient families with ID for Green rating.
Intellectual disability syndromic and non-syndromic v0.3014 ZMYM2 Zornitza Stark Gene: zmym2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3014 ZMYM2 Zornitza Stark Classified gene: ZMYM2 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.3014 ZMYM2 Zornitza Stark Gene: zmym2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3013 ZMYM2 Konstantinos Varvagiannis gene: ZMYM2 was added
gene: ZMYM2 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: ZMYM2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ZMYM2 were set to 32891193
Phenotypes for gene: ZMYM2 were set to Abnormality of the urinary system; Global developmental delay; Intellectual disability; Microcephaly; Abnormality of the cardiovascular system; Autism; Seizures; Abnormality of the head or neck; Abnormality of the nail; Small hand; Short foot; Clinodactyly
Penetrance for gene: ZMYM2 were set to unknown
Review for gene: ZMYM2 was set to AMBER
Added comment: Heterozygous pathogenic (pLoF) ZMYM2 variants have been reported in individuals with syndromic presentation including CAKUT (in several cases) and variable neurological manifestations among extra-renal features. DD and ID were reported in some of the families described to date as summarized below. You might consider inclusion with green/amber rating in the ID panel and green in the panel for CAKUT.

--

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

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

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

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

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

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

The authors provide evidence for loss of interaction of the truncated ZMYM2 with FOXP1 (mutations in the latter having recently been reported in syndromic CAKUT).
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.3013 NEMF Zornitza Stark Marked gene: NEMF as ready
Intellectual disability syndromic and non-syndromic v0.3013 NEMF Zornitza Stark Gene: nemf has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3013 NEMF Zornitza Stark Classified gene: NEMF as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.3013 NEMF Zornitza Stark Gene: nemf has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3012 NEMF Zornitza Stark gene: NEMF was added
gene: NEMF was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: NEMF was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NEMF were set to 32934225
Phenotypes for gene: NEMF were set to Intellectual disability; neuropathy
Review for gene: NEMF was set to GREEN
Added comment: Nine individuals from 7 unrelated families reported with a mixed CNS/PNS phenotype. 7/9 had ID, 4/9 had formal assessments demonstrating axonal neuropathy, 3/9 had ataxia; muscular atrophy, hypotonia, respiratory distress, scoliosis also described in some. Three independently generated mouse models had progressive motor neuron degeneration.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.3011 LMNB1 Zornitza Stark Marked gene: LMNB1 as ready
Intellectual disability syndromic and non-syndromic v0.3011 LMNB1 Zornitza Stark Added comment: Comment when marking as ready: Note different mechanism for LMNB1-related neurodevelopmental phenotype cf Adult-onset leukodystrophy phenotype previously associated with this gene.
Intellectual disability syndromic and non-syndromic v0.3011 LMNB1 Zornitza Stark Gene: lmnb1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3011 LMNB1 Zornitza Stark Phenotypes for gene: LMNB1 were changed from Leukodystrophy, adult-onset, autosomal dominant, MIM#169500 to Global developmental delay, Intellectual disability, Microcephaly, Short stature, Seizures, Abnormality of the corpus callosum, Cortical gyral simplification, Feeding difficulties, Scoliosis; Leukodystrophy, adult-onset, autosomal dominant, MIM#169500
Intellectual disability syndromic and non-syndromic v0.3010 LMNB1 Zornitza Stark Publications for gene: LMNB1 were set to
Intellectual disability syndromic and non-syndromic v0.3009 LMNB1 Zornitza Stark Mode of pathogenicity for gene: LMNB1 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 v0.3008 LMNB1 Zornitza Stark Classified gene: LMNB1 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.3008 LMNB1 Zornitza Stark Gene: lmnb1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3007 LMNB1 Konstantinos Varvagiannis edited their review of gene: LMNB1: Changed mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Intellectual disability syndromic and non-syndromic v0.3007 LMNB1 Konstantinos Varvagiannis edited their review of gene: LMNB1: Changed mode of pathogenicity: Other
Intellectual disability syndromic and non-syndromic v0.3007 LMNB1 Konstantinos Varvagiannis reviewed gene: LMNB1: 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: 32910914; Phenotypes: Global developmental delay, Intellectual disability, Microcephaly, Short stature, Seizures, Abnormality of the corpus callosum, Cortical gyral simplification, Feeding difficulties, Scoliosis; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability syndromic and non-syndromic v0.3007 VPS11 Zornitza Stark Tag founder tag was added to gene: VPS11.
Intellectual disability syndromic and non-syndromic v0.3007 SVBP Zornitza Stark Tag founder tag was added to gene: SVBP.
Intellectual disability syndromic and non-syndromic v0.3007 SVBP Zornitza Stark reviewed gene: SVBP: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with ataxia, hypotonia, and microcephaly, OMIM #618569; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.3007 MAPK8IP3 Zornitza Stark Publications for gene: MAPK8IP3 were set to 30612693
Intellectual disability syndromic and non-syndromic v0.3006 MAPK8IP3 Zornitza Stark reviewed gene: MAPK8IP3: Rating: GREEN; Mode of pathogenicity: None; Publications: 30612693, 30945334; Phenotypes: Neurodevelopmental disorder with or without variable brain abnormalities, MIM# 618443; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3006 KCNA2 Zornitza Stark Marked gene: KCNA2 as ready
Intellectual disability syndromic and non-syndromic v0.3006 KCNA2 Zornitza Stark Gene: kcna2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3006 KCNA2 Zornitza Stark Phenotypes for gene: KCNA2 were changed from to Early infantile encephalopathy 32, MIM#616366
Intellectual disability syndromic and non-syndromic v0.3005 KCNA2 Zornitza Stark Publications for gene: KCNA2 were set to
Intellectual disability syndromic and non-syndromic v0.3004 KCNA2 Zornitza Stark Mode of inheritance for gene: KCNA2 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3003 KCNA2 Zornitza Stark reviewed gene: KCNA2: Rating: GREEN; Mode of pathogenicity: None; Publications: 29050392; Phenotypes: Early infantile encephalopathy 32, MIM#616366; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3003 EBF3 Zornitza Stark Marked gene: EBF3 as ready
Intellectual disability syndromic and non-syndromic v0.3003 EBF3 Zornitza Stark Gene: ebf3 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3003 EBF3 Zornitza Stark Phenotypes for gene: EBF3 were changed from to Hypotonia, ataxia, and delayed development syndrome, MIM# 617330
Intellectual disability syndromic and non-syndromic v0.3002 EBF3 Zornitza Stark Publications for gene: EBF3 were set to
Intellectual disability syndromic and non-syndromic v0.3001 EBF3 Zornitza Stark Mode of inheritance for gene: EBF3 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3000 EBF3 Zornitza Stark reviewed gene: EBF3: Rating: GREEN; Mode of pathogenicity: None; Publications: 28017373, 28017372, 28017370, 32366537; Phenotypes: Hypotonia, ataxia, and delayed development syndrome, MIM# 617330; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3000 DOCK3 Zornitza Stark Marked gene: DOCK3 as ready
Intellectual disability syndromic and non-syndromic v0.3000 DOCK3 Zornitza Stark Gene: dock3 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.3000 DOCK3 Zornitza Stark Phenotypes for gene: DOCK3 were changed from to Neurodevelopmental disorder with impaired intellectual development, hypotonia, and ataxia, MIM#618292
Intellectual disability syndromic and non-syndromic v0.2999 DOCK3 Zornitza Stark Publications for gene: DOCK3 were set to
Intellectual disability syndromic and non-syndromic v0.2998 DOCK3 Zornitza Stark Mode of inheritance for gene: DOCK3 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.2997 DOCK3 Zornitza Stark reviewed gene: DOCK3: Rating: GREEN; Mode of pathogenicity: None; Publications: 28195318, 29130632, 30976111; Phenotypes: Neurodevelopmental disorder with impaired intellectual development, hypotonia, and ataxia, MIM#618292; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.2997 ALDH5A1 Zornitza Stark Marked gene: ALDH5A1 as ready
Intellectual disability syndromic and non-syndromic v0.2997 ALDH5A1 Zornitza Stark Gene: aldh5a1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.2997 ALDH5A1 Zornitza Stark Phenotypes for gene: ALDH5A1 were changed from to Succinic semialdehyde dehydrogenase deficiency, MIM# 271980
Intellectual disability syndromic and non-syndromic v0.2996 ALDH5A1 Zornitza Stark Publications for gene: ALDH5A1 were set to
Intellectual disability syndromic and non-syndromic v0.2995 ALDH5A1 Zornitza Stark Mode of inheritance for gene: ALDH5A1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.2994 ALDH5A1 Zornitza Stark reviewed gene: ALDH5A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 14635103; Phenotypes: Succinic semialdehyde dehydrogenase deficiency, MIM# 271980; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.2994 SPRED1 Zornitza Stark Marked gene: SPRED1 as ready
Intellectual disability syndromic and non-syndromic v0.2994 SPRED1 Zornitza Stark Gene: spred1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.2994 SPRED1 Zornitza Stark Phenotypes for gene: SPRED1 were changed from to Legius syndrome, MIM# 611431
Intellectual disability syndromic and non-syndromic v0.2993 SPRED1 Zornitza Stark Publications for gene: SPRED1 were set to
Intellectual disability syndromic and non-syndromic v0.2992 SPRED1 Zornitza Stark Mode of inheritance for gene: SPRED1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.2991 SPRED1 Zornitza Stark reviewed gene: SPRED1: Rating: GREEN; Mode of pathogenicity: None; Publications: 17704776, 19366998, 21548021; Phenotypes: Legius syndrome, MIM# 611431; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.2991 SOS1 Zornitza Stark Marked gene: SOS1 as ready
Intellectual disability syndromic and non-syndromic v0.2991 SOS1 Zornitza Stark Gene: sos1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.2991 SOS1 Zornitza Stark Phenotypes for gene: SOS1 were changed from to Noonan syndrome 4, MIM# 610733
Intellectual disability syndromic and non-syndromic v0.2990 SOS1 Zornitza Stark Publications for gene: SOS1 were set to
Intellectual disability syndromic and non-syndromic v0.2989 SOS1 Zornitza Stark Mode of pathogenicity for gene: SOS1 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 v0.2988 SOS1 Zornitza Stark Mode of inheritance for gene: SOS1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.2987 SOS1 Zornitza Stark reviewed gene: SOS1: 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: 17143285, 17143282, 28884940, 17586837; Phenotypes: Noonan syndrome 4, MIM# 610733; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.2987 HRAS Zornitza Stark Marked gene: HRAS as ready
Intellectual disability syndromic and non-syndromic v0.2987 HRAS Zornitza Stark Gene: hras has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.2987 HRAS Zornitza Stark Phenotypes for gene: HRAS were changed from to Costello syndrome, MIM# 218040
Intellectual disability syndromic and non-syndromic v0.2986 HRAS Zornitza Stark Publications for gene: HRAS were set to
Intellectual disability syndromic and non-syndromic v0.2985 HRAS Zornitza Stark Mode of pathogenicity for gene: HRAS 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 v0.2984 HRAS Zornitza Stark Mode of inheritance for gene: HRAS was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.2983 HRAS Zornitza Stark reviewed gene: HRAS: 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: 16329078, 16372351, 16443854; Phenotypes: Costello syndrome, MIM# 218040; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.2983 VAMP2 Zornitza Stark Phenotypes for gene: VAMP2 were changed from Intellectual disability; autism; no OMIM number yet to Neurodevelopmental disorder with hypotonia and autistic features with or without hyperkinetic movements 618760; Cortical visual impairment; Seizures; Stereotypic behaviour; Generalized hypotonia; Intellectual disability
Intellectual disability syndromic and non-syndromic v0.2982 VAMP2 Zornitza Stark reviewed gene: VAMP2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with hypotonia and autistic features with or without hyperkinetic movements 618760, Cortical visual impairment, Seizures, Stereotypic behaviour, Generalized hypotonia, Intellectual disability; Mode of inheritance: None
Intellectual disability syndromic and non-syndromic v0.2982 SLC16A2 Zornitza Stark changed review comment from: Allan-Herndon-Dudley syndrome (AHDS) is an X-linked condition characterized by severely impaired intellectual development, dysarthria, athetoid movements, muscle hypoplasia, and spastic paraplegia. There is large phenotypic interfamilial and intrafamilial variability.; to: Allan-Herndon-Dudley syndrome (AHDS) is an X-linked condition characterized by severely impaired intellectual development, dysarthria, athetoid movements, muscle hypoplasia, and spastic paraplegia. There is large phenotypic interfamilial and intrafamilial variability. In a recent review of 24 affected individuals (PMID 31410843), 16 presented with profound developmental delay, three had severe intellectual disability with poor language and walking with an aid, four had moderate intellectual disability with language and walking abilities, and one had mild intellectual disability with hypotonia. Overall, eight had learned to walk, all had hypotonia, 17 had spasticity, 18 had dystonia, 12 had choreoathetosis, 19 had hypomyelination, and 10 had brain atrophy. Kyphoscoliosis (n=12), seizures (n=7), and pneumopathies (n=5) were the most severe complications.
Intellectual disability syndromic and non-syndromic v0.2982 SLC16A2 Zornitza Stark Marked gene: SLC16A2 as ready
Intellectual disability syndromic and non-syndromic v0.2982 SLC16A2 Zornitza Stark Gene: slc16a2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.2982 SLC16A2 Zornitza Stark Phenotypes for gene: SLC16A2 were changed from to Allan-Herndon-Dudley syndrome, MIM# 300523
Intellectual disability syndromic and non-syndromic v0.2981 SLC16A2 Zornitza Stark Publications for gene: SLC16A2 were set to
Intellectual disability syndromic and non-syndromic v0.2980 SLC16A2 Zornitza Stark Mode of inheritance for gene: SLC16A2 was changed from Unknown to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability syndromic and non-syndromic v0.2979 SLC16A2 Zornitza Stark reviewed gene: SLC16A2: Rating: GREEN; Mode of pathogenicity: None; Publications: 15980113, 31410843, 20301789; Phenotypes: Allan-Herndon-Dudley syndrome, MIM# 300523; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability syndromic and non-syndromic v0.2979 HECW2 Zornitza Stark Marked gene: HECW2 as ready
Intellectual disability syndromic and non-syndromic v0.2979 HECW2 Zornitza Stark Gene: hecw2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.2979 HECW2 Zornitza Stark Phenotypes for gene: HECW2 were changed from to Neurodevelopmental disorder with hypotonia, seizures, and absent language (MIM#617268)
Intellectual disability syndromic and non-syndromic v0.2978 HECW2 Zornitza Stark Publications for gene: HECW2 were set to
Intellectual disability syndromic and non-syndromic v0.2977 HECW2 Zornitza Stark Mode of inheritance for gene: HECW2 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.2976 HECW2 Teresa Zhao reviewed gene: HECW2: Rating: GREEN; Mode of pathogenicity: None; Publications: 27389779; Phenotypes: Neurodevelopmental disorder with hypotonia, seizures, and absent language (MIM#617268); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability syndromic and non-syndromic v0.2976 NR2F1 Zornitza Stark Marked gene: NR2F1 as ready
Intellectual disability syndromic and non-syndromic v0.2976 NR2F1 Zornitza Stark Gene: nr2f1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.2976 NR2F1 Zornitza Stark Phenotypes for gene: NR2F1 were changed from to Bosch-Boonstra-Schaaf optic atrophy syndrome, MIM# 615722
Intellectual disability syndromic and non-syndromic v0.2975 NR2F1 Zornitza Stark Publications for gene: NR2F1 were set to
Intellectual disability syndromic and non-syndromic v0.2974 NR2F1 Zornitza Stark Mode of inheritance for gene: NR2F1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.2973 NR2F1 Zornitza Stark reviewed gene: NR2F1: Rating: GREEN; Mode of pathogenicity: None; Publications: 32275123; Phenotypes: Bosch-Boonstra-Schaaf optic atrophy syndrome, MIM# 615722; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.2973 HSPA9 Zornitza Stark Marked gene: HSPA9 as ready
Intellectual disability syndromic and non-syndromic v0.2973 HSPA9 Zornitza Stark Gene: hspa9 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.2973 HSPA9 Zornitza Stark Phenotypes for gene: HSPA9 were changed from OMIM 616854; skeletal anomalies; congenital cardiac and renal anom to Even-plus syndrome, OMIM 616854; skeletal anomalies; congenital cardiac and renal anom
Intellectual disability syndromic and non-syndromic v0.2972 HSPA9 Sue White Classified gene: HSPA9 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.2972 HSPA9 Sue White Gene: hspa9 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.2971 HSPA9 Sue White commented on gene: HSPA9: 2 patients with dev delay in 5 published patients with Even-plus syndrome
Intellectual disability syndromic and non-syndromic v0.2971 HSPA9 Sue White gene: HSPA9 was added
gene: HSPA9 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: HSPA9 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HSPA9 were set to 32869452; 26598328
Phenotypes for gene: HSPA9 were set to OMIM 616854; skeletal anomalies; congenital cardiac and renal anom
Penetrance for gene: HSPA9 were set to Complete
Review for gene: HSPA9 was set to AMBER
Added comment: Sources: Literature
Intellectual disability syndromic and non-syndromic v0.2970 WASHC4 Zornitza Stark reviewed gene: WASHC4: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.2970 WASHC4 Alison Yeung Classified gene: WASHC4 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.2970 WASHC4 Alison Yeung Gene: washc4 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.2969 WASHC4 Alison Yeung Deleted their comment
Intellectual disability syndromic and non-syndromic v0.2969 WASHC4 Alison Yeung reviewed gene: WASHC4: Rating: GREEN; Mode of pathogenicity: None; Publications: 31953988; Phenotypes: Intellectual disability; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.2969 ATP1A3 Seb Lunke Classified gene: ATP1A3 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.2969 ATP1A3 Seb Lunke Gene: atp1a3 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.2968 ATP1A3 Seb Lunke reviewed gene: ATP1A3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability syndromic and non-syndromic v0.2968 MYT1L Zornitza Stark Tag SV/CNV tag was added to gene: MYT1L.
Intellectual disability syndromic and non-syndromic v0.2968 MYT1L Zornitza Stark Publications for gene: MYT1L were set to 28859103
Intellectual disability syndromic and non-syndromic v0.2967 MYT1L Zornitza Stark reviewed gene: MYT1L: Rating: GREEN; Mode of pathogenicity: None; Publications: 32065501; Phenotypes: Mental retardation, autosomal dominant 39, MIM# 616521; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.2967 ARID1A Crystle Lee reviewed gene: ARID1A: Rating: GREEN; Mode of pathogenicity: None; Publications: 23929686, 22426308, 25168959; Phenotypes: Coffin-Siris syndrome 2 (MIM#614607); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability syndromic and non-syndromic v0.2967 GTPBP2 Zornitza Stark Marked gene: GTPBP2 as ready
Intellectual disability syndromic and non-syndromic v0.2967 GTPBP2 Zornitza Stark Gene: gtpbp2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.2967 GTPBP2 Zornitza Stark Phenotypes for gene: GTPBP2 were changed from to Jaberi-Elahi syndrome, MIM#617988
Intellectual disability syndromic and non-syndromic v0.2966 GTPBP2 Zornitza Stark Publications for gene: GTPBP2 were set to
Intellectual disability syndromic and non-syndromic v0.2965 GTPBP2 Zornitza Stark Mode of inheritance for gene: GTPBP2 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.2964 GTPBP2 Zornitza Stark reviewed gene: GTPBP2: Rating: GREEN; Mode of pathogenicity: None; Publications: 26675814, 29449720, 30790272; Phenotypes: Jaberi-Elahi syndrome, MIM#617988; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.2964 GNB1 Zornitza Stark Marked gene: GNB1 as ready
Intellectual disability syndromic and non-syndromic v0.2964 GNB1 Zornitza Stark Gene: gnb1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.2964 GNB1 Zornitza Stark Phenotypes for gene: GNB1 were changed from to Mental retardation, autosomal dominant 42, MIM# 616973
Intellectual disability syndromic and non-syndromic v0.2963 GNB1 Zornitza Stark Publications for gene: GNB1 were set to
Intellectual disability syndromic and non-syndromic v0.2962 GNB1 Zornitza Stark Mode of inheritance for gene: GNB1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.2961 GNB1 Zornitza Stark reviewed gene: GNB1: Rating: GREEN; Mode of pathogenicity: None; Publications: 27108799, 30194818, 27668284, 31034681; Phenotypes: Mental retardation, autosomal dominant 42, MIM# 616973; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.2961 FITM2 Zornitza Stark Marked gene: FITM2 as ready
Intellectual disability syndromic and non-syndromic v0.2961 FITM2 Zornitza Stark Gene: fitm2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.2961 FITM2 Zornitza Stark Classified gene: FITM2 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.2961 FITM2 Zornitza Stark Gene: fitm2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.2960 FITM2 Zornitza Stark gene: FITM2 was added
gene: FITM2 was added to Intellectual disability syndromic and non-syndromic. Sources: Expert list
Mode of inheritance for gene: FITM2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FITM2 were set to 28067622; 30214770; 30288795
Phenotypes for gene: FITM2 were set to Siddiqi syndrome MIM#618635
Review for gene: FITM2 was set to GREEN
Added comment: Autosomal recessive condition characterised by global developmental delay, early-onset progressive sensorineural hearing impairment, regression of motor skills, dystonia, poor overall growth, and low body mass index (BMI). More variable features may include ichthyosis-like skin abnormalities or sensory neuropathy. 7 individuals from three unrelated families reported, supportive Drosophila model.
Sources: Expert list
Intellectual disability syndromic and non-syndromic v0.2959 FDXR Zornitza Stark Publications for gene: FDXR were set to
Intellectual disability syndromic and non-syndromic v0.2958 FDXR Zornitza Stark changed review comment from: ID is not part of the phenotype.; to: Bi-allelic variants in FDXR cause an autosomal recessive neurologic disorder characterised by onset of visual and hearing impairment in the first or second decades. Two individuals described with a more severe phenotype, including one with intellectual disability.
Intellectual disability syndromic and non-syndromic v0.2958 FDXR Zornitza Stark edited their review of gene: FDXR: Changed publications: 30250212
Intellectual disability syndromic and non-syndromic v0.2958 EIF2S3 Zornitza Stark Marked gene: EIF2S3 as ready
Intellectual disability syndromic and non-syndromic v0.2958 EIF2S3 Zornitza Stark Gene: eif2s3 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.2958 EIF2S3 Zornitza Stark Phenotypes for gene: EIF2S3 were changed from to MEHMO syndrome, MIM# 300148
Intellectual disability syndromic and non-syndromic v0.2957 EIF2S3 Zornitza Stark Publications for gene: EIF2S3 were set to
Intellectual disability syndromic and non-syndromic v0.2956 EIF2S3 Zornitza Stark Mode of inheritance for gene: EIF2S3 was changed from Unknown to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability syndromic and non-syndromic v0.2955 EIF2S3 Zornitza Stark reviewed gene: EIF2S3: Rating: GREEN; Mode of pathogenicity: None; Publications: 23063529, 27333055, 28055140, 32799315; Phenotypes: MEHMO syndrome, MIM# 300148; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability syndromic and non-syndromic v0.2955 SETD1B Zornitza Stark Phenotypes for gene: SETD1B were changed from SETD1B-related neurodevelopmental disorder to Intellectual developmental disorder with seizures and language delay (IDDSELD), MIM#619000
Intellectual disability syndromic and non-syndromic v0.2954 TRIP13 Zornitza Stark Tag founder tag was added to gene: TRIP13.
Intellectual disability syndromic and non-syndromic v0.2954 TRIP13 Zornitza Stark changed review comment from: Early-onset Wilms tumor and either aneuploidy or premature chromatid separation in cells. Some individuals described as having additional developmental features, such as microcephaly, growth retardation, or developmental delay but these are highly variable.; to: Early-onset Wilms tumor and either aneuploidy or premature chromatid separation in cells. Some individuals described as having additional developmental features, such as microcephaly, growth retardation, or developmental delay but these are highly variable. Also note 5/6 reported families had the same homozygous variant, p.Arg354X, suggestive of founder effect.
Intellectual disability syndromic and non-syndromic v0.2954 TRAPPC6B Zornitza Stark Marked gene: TRAPPC6B as ready
Intellectual disability syndromic and non-syndromic v0.2954 TRAPPC6B Zornitza Stark Gene: trappc6b has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.2954 TRAPPC6B Zornitza Stark Phenotypes for gene: TRAPPC6B were changed from to Neurodevelopmental disorder with microcephaly, epilepsy, and brain atrophy, MIM# 617862
Intellectual disability syndromic and non-syndromic v0.2953 TRAPPC6B Zornitza Stark Publications for gene: TRAPPC6B were set to
Intellectual disability syndromic and non-syndromic v0.2952 TRAPPC6B Zornitza Stark Mode of inheritance for gene: TRAPPC6B was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.2951 TRAPPC6B Zornitza Stark reviewed gene: TRAPPC6B: Rating: GREEN; Mode of pathogenicity: None; Publications: 28626029, 28397838, 31687267; Phenotypes: Neurodevelopmental disorder with microcephaly, epilepsy, and brain atrophy, MIM# 617862; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.2951 DHX37 Zornitza Stark changed review comment from: Overall, 5 unrelated families with bi-allelic variants, all with ID as part of the phenotype. Green for bi-allelic disease

Much less clear association between mono-allelic variants and ID, two missense variants reported. Note one was mosaic, and for the other, paternal sample was not available, so not confirmed to be de novo. No mechanism for mono-allelic vs bi-allelic disease proposed. Overall, Red for mono-allelic disease causing a neurodevelopmental phenotype at this stage. Note there is a separate association between mono allelic variants and DSD.; to: Overall, 5 unrelated families with bi-allelic variants, all with ID as part of the phenotype. Green for bi-allelic disease

Much less clear association between mono-allelic variants and ID, two missense variants reported. Note one was mosaic, and for the other, paternal sample was not available, so not confirmed to be de novo. No mechanism for mono-allelic vs bi-allelic disease proposed. Overall, Red for mono-allelic variants causing a neurodevelopmental phenotype at this stage. Note there is a separate association between mono allelic variants and DSD.
Intellectual disability syndromic and non-syndromic v0.2951 DHX37 Zornitza Stark changed review comment from: Overall, 5 unrelated families with bi-allelic variants, all with ID as part of the phenotype. Green for bi-allelic disease

Much less clear association between mono-allelic variants and disease, two missense variants reported. Note one was mosaic, and for the other, paternal sample was not available, so not confirmed to be de novo. No mechanism for mono-allelic vs bi-allelic disease proposed. Overall, Red for mono-allelic disease at this stage.; to: Overall, 5 unrelated families with bi-allelic variants, all with ID as part of the phenotype. Green for bi-allelic disease

Much less clear association between mono-allelic variants and ID, two missense variants reported. Note one was mosaic, and for the other, paternal sample was not available, so not confirmed to be de novo. No mechanism for mono-allelic vs bi-allelic disease proposed. Overall, Red for mono-allelic disease causing a neurodevelopmental phenotype at this stage. Note there is a separate association between mono allelic variants and DSD.
Intellectual disability syndromic and non-syndromic v0.2951 DHX37 Zornitza Stark Mode of inheritance for gene: DHX37 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.2950 DHX37 Zornitza Stark changed review comment from: Overall, 5 unrelated families with bi-allelic variants, all with ID as part of the phenotype.

Much less clear association between mono-allelic variants and disease, two missense variants reported. Note one was mosaic, and for the other, paternal sample was not available, so not confirmed to be de novo.; to: Overall, 5 unrelated families with bi-allelic variants, all with ID as part of the phenotype. Green for bi-allelic disease

Much less clear association between mono-allelic variants and disease, two missense variants reported. Note one was mosaic, and for the other, paternal sample was not available, so not confirmed to be de novo. No mechanism for mono-allelic vs bi-allelic disease proposed. Overall, Red for mono-allelic disease at this stage.
Intellectual disability syndromic and non-syndromic v0.2950 DHX37 Zornitza Stark Marked gene: DHX37 as ready
Intellectual disability syndromic and non-syndromic v0.2950 DHX37 Zornitza Stark Gene: dhx37 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.2950 DHX37 Zornitza Stark Classified gene: DHX37 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.2950 DHX37 Zornitza Stark Gene: dhx37 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.2949 DHX37 Zornitza Stark reviewed gene: DHX37: Rating: GREEN; Mode of pathogenicity: None; Publications: 26539891, 31256877; Phenotypes: Neurodevelopmental disorder with brain anomalies and with or without vertebral or cardiac anomalies, MIM#618731; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.2949 DHX37 Naomi Baker gene: DHX37 was added
gene: DHX37 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: DHX37 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: DHX37 were set to PMID: 26539891; 31256877
Phenotypes for gene: DHX37 were set to Neurodevelopmental disorder with brain anomalies and with or without vertebral or cardiac anomalies, MIM#618731
Review for gene: DHX37 was set to GREEN
Added comment: Two unrelated patients from consanguineous families reported with biallelic missense variants. Clinical presentation included severe microcephaly, DD/ID, and cortical atrophy (PMID: 26539891).

Five individuals who share a phenotype of DD and/or ID and CNS dysfunction. Three out of five individuals also have scoliosis, and two have cardiac phenotypes (PMID: 31256877). Three of the patients had bialleleic missense variants, while two patients had a de novo monoallelic missense variant.

Note that OMIM lists inheritance as biallelic, however two monoallelic cases reportes.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.2949 PAK3 Zornitza Stark Marked gene: PAK3 as ready
Intellectual disability syndromic and non-syndromic v0.2949 PAK3 Zornitza Stark Gene: pak3 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.2949 PAK3 Zornitza Stark Phenotypes for gene: PAK3 were changed from to Mental retardation, X-linked 30/47, MIM# 300558; Intellectual disability
Intellectual disability syndromic and non-syndromic v0.2948 PAK3 Zornitza Stark Publications for gene: PAK3 were set to
Intellectual disability syndromic and non-syndromic v0.2947 PAK3 Zornitza Stark Mode of inheritance for gene: PAK3 was changed from Unknown to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability syndromic and non-syndromic v0.2946 PAK3 Zornitza Stark reviewed gene: PAK3: Rating: GREEN; Mode of pathogenicity: None; Publications: 9731525, 10946356, 12884430, 17853471, 18523455, 32050918, 32005903, 31943058, 31843706, 31678216; Phenotypes: Mental retardation, X-linked 30/47, MIM# 300558, Intellectual disability; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability syndromic and non-syndromic v0.2946 CLTC Zornitza Stark Marked gene: CLTC as ready
Intellectual disability syndromic and non-syndromic v0.2946 CLTC Zornitza Stark Gene: cltc has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.2946 CLTC Zornitza Stark Phenotypes for gene: CLTC were changed from to Mental retardation, autosomal dominant 56, MIM# 617854
Intellectual disability syndromic and non-syndromic v0.2945 CLTC Zornitza Stark Publications for gene: CLTC were set to
Intellectual disability syndromic and non-syndromic v0.2944 CLTC Zornitza Stark Mode of inheritance for gene: CLTC was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.2943 CLTC Zornitza Stark reviewed gene: CLTC: Rating: GREEN; Mode of pathogenicity: None; Publications: 29100083, 26822784; Phenotypes: Mental retardation, autosomal dominant 56, MIM# 617854; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.2943 PLK4 Zornitza Stark Marked gene: PLK4 as ready
Intellectual disability syndromic and non-syndromic v0.2943 PLK4 Zornitza Stark Gene: plk4 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.2943 PLK4 Zornitza Stark Phenotypes for gene: PLK4 were changed from to Microcephaly and chorioretinopathy, autosomal recessive, 2, MIM# 616171
Intellectual disability syndromic and non-syndromic v0.2942 PLK4 Zornitza Stark Publications for gene: PLK4 were set to
Intellectual disability syndromic and non-syndromic v0.2941 PLK4 Zornitza Stark Mode of inheritance for gene: PLK4 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.2940 PLK4 Zornitza Stark reviewed gene: PLK4: Rating: GREEN; Mode of pathogenicity: None; Publications: 25344692, 25320347, 27650967; Phenotypes: Microcephaly and chorioretinopathy, autosomal recessive, 2, MIM# 616171; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.2940 TRAPPC2L Zornitza Stark Marked gene: TRAPPC2L as ready
Intellectual disability syndromic and non-syndromic v0.2940 TRAPPC2L Zornitza Stark Gene: trappc2l has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.2940 TRAPPC2L Zornitza Stark Classified gene: TRAPPC2L as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.2940 TRAPPC2L Zornitza Stark Gene: trappc2l has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.2939 TRAPPC2L Zornitza Stark Tag founder tag was added to gene: TRAPPC2L.
Intellectual disability syndromic and non-syndromic v0.2939 TRAPPC2L Zornitza Stark gene: TRAPPC2L was added
gene: TRAPPC2L was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: TRAPPC2L was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TRAPPC2L were set to 30120216; 32843486
Phenotypes for gene: TRAPPC2L were set to Encephalopathy, progressive, early-onset, with episodic rhabdomyolysis, 618331
Review for gene: TRAPPC2L was set to AMBER
Added comment: Total of three families, but two share a founder variant, and there are some disparities between the clinical presentations reported in the two publications. Rating Amber as additional cases required to delineate the genotype-phenotype relationship. PMID: 30120216 (2018) - Two unrelated probands with an identical homozygous missense (c.109G>T, p.Asp37Tyr) variant in TRAPPC2L. Both individuals presented neurodevelopmental delay, febrile illness-induced encephalopathy, and episodic rhabdomyolysis, followed by developmental arrest, seizures and tetraplegia. The variant segregated with the phenotype in each family, and haplotype analysis suggested a founder effect. The mutant protein was expressed in patient fibroblasts, but displayed membrane trafficking delays. Studies in yeast showed that the variant impaired interaction with TRAPPC10, and increased levels of the active RAB11. PMID: 32843486 (2020) - In an Ashkenazi Jewish family with three affected sibs with GDD/ID, WGS revealed a segregating homozygous missense variant (c.5G>C, p.Ala2Gly) in the TRAPPC2L gene. No seizures, brain MRI abnormalities, or illness provoked regression were documented in this family. Comparable to the previous study, the variant resulted in delayed ER-to-Golgi trafficking and elevated levels of active RAB11. Studies using yeast and in vitro binding, showed that the variant disrupted interaction with another core TRAPP protein, TRAPPC6a.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.2938 DPP6 Zornitza Stark Marked gene: DPP6 as ready
Intellectual disability syndromic and non-syndromic v0.2938 DPP6 Zornitza Stark Gene: dpp6 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.2938 DPP6 Zornitza Stark Phenotypes for gene: DPP6 were changed from to Mental retardation, autosomal dominant 33 (MIM#616311)
Intellectual disability syndromic and non-syndromic v0.2937 DPP6 Zornitza Stark Publications for gene: DPP6 were set to
Intellectual disability syndromic and non-syndromic v0.2936 DPP6 Zornitza Stark Mode of inheritance for gene: DPP6 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.2935 DPP6 Zornitza Stark Classified gene: DPP6 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.2935 DPP6 Zornitza Stark Gene: dpp6 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.2934 DPP6 Zornitza Stark reviewed gene: DPP6: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Mental retardation, autosomal dominant 33 (MIM#616311); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.2934 DPP6 Ain Roesley edited their review of gene: DPP6: Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability syndromic and non-syndromic v0.2934 DPP6 Ain Roesley reviewed gene: DPP6: Rating: AMBER; Mode of pathogenicity: None; Publications: 23832105; Phenotypes: Mental retardation, autosomal dominant 33 (MIM#616311); Mode of inheritance: None
Intellectual disability syndromic and non-syndromic v0.2934 PCGF2 Zornitza Stark Marked gene: PCGF2 as ready
Intellectual disability syndromic and non-syndromic v0.2934 PCGF2 Zornitza Stark Gene: pcgf2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.2934 PCGF2 Zornitza Stark Phenotypes for gene: PCGF2 were changed from to Turnpenny-Fry syndrome, MIM# 618371
Intellectual disability syndromic and non-syndromic v0.2933 PCGF2 Zornitza Stark Publications for gene: PCGF2 were set to
Intellectual disability syndromic and non-syndromic v0.2932 PCGF2 Zornitza Stark Mode of inheritance for gene: PCGF2 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.2931 PCGF2 Zornitza Stark reviewed gene: PCGF2: Rating: GREEN; Mode of pathogenicity: None; Publications: 30343942; Phenotypes: Turnpenny-Fry syndrome, MIM# 618371; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.2931 TRIT1 Zornitza Stark Marked gene: TRIT1 as ready
Intellectual disability syndromic and non-syndromic v0.2931 TRIT1 Zornitza Stark Gene: trit1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.2931 TRIT1 Zornitza Stark Phenotypes for gene: TRIT1 were changed from to Combined oxidative phosphorylation deficiency 35, MIM#617873
Intellectual disability syndromic and non-syndromic v0.2930 TRIT1 Zornitza Stark Publications for gene: TRIT1 were set to
Intellectual disability syndromic and non-syndromic v0.2929 TRIT1 Zornitza Stark Mode of inheritance for gene: TRIT1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.2928 TRIT1 Zornitza Stark reviewed gene: TRIT1: Rating: GREEN; Mode of pathogenicity: None; Publications: 32088416, 24901367, 28185376, 30977854; Phenotypes: Combined oxidative phosphorylation deficiency 35, MIM#617873; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.2928 CREBBP Zornitza Stark Marked gene: CREBBP as ready
Intellectual disability syndromic and non-syndromic v0.2928 CREBBP Zornitza Stark Gene: crebbp has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.2928 CREBBP Zornitza Stark Phenotypes for gene: CREBBP were changed from to Rubinstein-Taybi syndrome 1, MIM# 180849; Menke-Hennekam syndrome 1, MIM# 618332
Intellectual disability syndromic and non-syndromic v0.2927 CREBBP Zornitza Stark Publications for gene: CREBBP were set to
Intellectual disability syndromic and non-syndromic v0.2926 CREBBP Zornitza Stark Mode of inheritance for gene: CREBBP was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.2925 CREBBP Zornitza Stark reviewed gene: CREBBP: Rating: GREEN; Mode of pathogenicity: None; Publications: 10699051, 17855048, 27311832, 29460469; Phenotypes: Rubinstein-Taybi syndrome 1, MIM# 180849, Menke-Hennekam syndrome 1, MIM# 618332; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.2925 CDC6 Seb Lunke Marked gene: CDC6 as ready
Intellectual disability syndromic and non-syndromic v0.2925 CDC6 Seb Lunke Gene: cdc6 has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v0.2925 CDC6 Seb Lunke Phenotypes for gene: CDC6 were changed from to Meier-Gorlin syndrome 5 (MIM#613805)
Intellectual disability syndromic and non-syndromic v0.2924 CDC6 Seb Lunke Publications for gene: CDC6 were set to
Intellectual disability syndromic and non-syndromic v0.2923 CDC6 Seb Lunke Mode of inheritance for gene: CDC6 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.2922 CDC6 Seb Lunke Classified gene: CDC6 as Red List (low evidence)
Intellectual disability syndromic and non-syndromic v0.2922 CDC6 Seb Lunke Gene: cdc6 has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v0.2921 CDC6 Ain Roesley reviewed gene: CDC6: Rating: RED; Mode of pathogenicity: None; Publications: 21358632; Phenotypes: Meier-Gorlin syndrome 5 (MIM#613805); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.2921 CTNND1 Zornitza Stark Marked gene: CTNND1 as ready
Intellectual disability syndromic and non-syndromic v0.2921 CTNND1 Zornitza Stark Gene: ctnnd1 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.2921 CTNND1 Zornitza Stark Classified gene: CTNND1 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.2921 CTNND1 Zornitza Stark Gene: ctnnd1 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.2920 CTNND1 Zornitza Stark gene: CTNND1 was added
gene: CTNND1 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: CTNND1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CTNND1 were set to 28301459; 32196547
Phenotypes for gene: CTNND1 were set to Blepharocheilodontic syndrome 2, MIM# 617681
Review for gene: CTNND1 was set to AMBER
Added comment: 4 individuals from 3 unrelated families with blepharocheilodontic syndrome and mutations in the CTNND1 gene reported originally in PMID 28301459. All had eyelid anomalies, including ectropion of the lower lids, euryblepharon, lagophthalmia, and distichiasis. In addition, all 4 showed typical facial dysmorphism with hypertelorism, flat face, and high forehead, and all had conical teeth and tooth agenesis. Three had cleft lip and palate, 3 had hair anomalies, and 1 had hypothyroidism due to hypoplasia or aplasia of the thyroid gland. None of the patients exhibited anal atresia or neural tube defects.

PMID: 32196547 - Alharatani et al 2020 - report an expanded phenotype for CTNND1 patients. They report 13 individuals from nine families with novel protein-truncating variants in CTNND1 identified by WES. The mutations were not previously described in blepharocheilodontic (BCD), orofacial cleft cases nor in gnomAD. 8 patients had de novo variants, 2 inherited from affected parents, 2 participants inherited a variant from a parent with a mild phenotype. 8/13 patients showed cleft palate. Additional phenotypic features seen include mild limb phenotypes (9/13), cardiovascular anomalies (6/13) and Developmental delay and other neurodevelopmental problems (8/13).

This more recent publication suggests a broader phenotype associated with CTNND1 variants including dev delay, ADHD/ASD, behavioural issues. Unclear from description whether significant ID present.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.2919 ADARB1 Zornitza Stark Phenotypes for gene: ADARB1 were changed from Intellectual disability; microcephaly; seizures to Neurodevelopmental disorder with hypotonia, microcephaly, and seizures, 618862; Intellectual disability; microcephaly; seizures
Intellectual disability syndromic and non-syndromic v0.2918 ADARB1 Zornitza Stark Publications for gene: ADARB1 were set to 32220291
Intellectual disability syndromic and non-syndromic v0.2917 ADARB1 Arina Puzriakova reviewed gene: ADARB1: Rating: GREEN; Mode of pathogenicity: None; Publications: 32220291, 32719099; Phenotypes: Neurodevelopmental disorder with hypotonia, microcephaly, and seizures, 618862; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.2917 IARS Zornitza Stark Tag new gene name tag was added to gene: IARS.
Intellectual disability syndromic and non-syndromic v0.2917 KIF14 Zornitza Stark Marked gene: KIF14 as ready
Intellectual disability syndromic and non-syndromic v0.2917 KIF14 Zornitza Stark Gene: kif14 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.2917 KIF14 Zornitza Stark Phenotypes for gene: KIF14 were changed from to Microcephaly 20, primary, autosomal recessive, MIM# 617914; Meckel syndrome 12, MIM# 616258
Intellectual disability syndromic and non-syndromic v0.2916 KIF14 Zornitza Stark Publications for gene: KIF14 were set to
Intellectual disability syndromic and non-syndromic v0.2915 KIF14 Zornitza Stark Mode of inheritance for gene: KIF14 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.2914 KIF14 Zornitza Stark reviewed gene: KIF14: Rating: GREEN; Mode of pathogenicity: None; Publications: 28892560, 29343805; Phenotypes: Microcephaly 20, primary, autosomal recessive, MIM# 617914, Meckel syndrome 12, MIM# 616258; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.2914 MOCS1 Zornitza Stark Marked gene: MOCS1 as ready
Intellectual disability syndromic and non-syndromic v0.2914 MOCS1 Zornitza Stark Gene: mocs1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.2914 MOCS1 Zornitza Stark Phenotypes for gene: MOCS1 were changed from to Molybdenum cofactor deficiency A, MIM# 252150
Intellectual disability syndromic and non-syndromic v0.2913 MOCS1 Zornitza Stark Publications for gene: MOCS1 were set to
Intellectual disability syndromic and non-syndromic v0.2912 MOCS1 Zornitza Stark Mode of inheritance for gene: MOCS1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.2911 MOCS1 Zornitza Stark reviewed gene: MOCS1: Rating: GREEN; Mode of pathogenicity: None; Publications: 9921896, 12754701, 21031595; Phenotypes: Molybdenum cofactor deficiency A, MIM# 252150; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.2911 KDM1A Zornitza Stark Marked gene: KDM1A as ready
Intellectual disability syndromic and non-syndromic v0.2911 KDM1A Zornitza Stark Gene: kdm1a has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.2911 KDM1A Zornitza Stark Phenotypes for gene: KDM1A were changed from to Cleft palate, psychomotor retardation, and distinctive facial features 616728
Intellectual disability syndromic and non-syndromic v0.2910 KDM1A Zornitza Stark Publications for gene: KDM1A were set to
Intellectual disability syndromic and non-syndromic v0.2909 KDM1A Zornitza Stark Mode of inheritance for gene: KDM1A was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.2908 KDM1A Zornitza Stark reviewed gene: KDM1A: Rating: GREEN; Mode of pathogenicity: None; Publications: 26656649, 24838796, 27094131; Phenotypes: Cleft palate, psychomotor retardation, and distinctive facial features 616728; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.2908 NSD2 Zornitza Stark Marked gene: NSD2 as ready
Intellectual disability syndromic and non-syndromic v0.2908 NSD2 Zornitza Stark Gene: nsd2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.2908 NSD2 Zornitza Stark Publications for gene: NSD2 were set to
Intellectual disability syndromic and non-syndromic v0.2907 NSD2 Zornitza Stark Phenotypes for gene: NSD2 were changed from to Microcephaly; intellectual disability
Intellectual disability syndromic and non-syndromic v0.2906 NSD2 Zornitza Stark Mode of inheritance for gene: NSD2 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.2905 NSD2 Zornitza Stark reviewed gene: NSD2: Rating: GREEN; Mode of pathogenicity: None; Publications: 30345613, 31171569; Phenotypes: Microcephaly, intellectual disability; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.2905 AP4E1 Zornitza Stark Marked gene: AP4E1 as ready
Intellectual disability syndromic and non-syndromic v0.2905 AP4E1 Zornitza Stark Gene: ap4e1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.2905 AP4E1 Zornitza Stark Phenotypes for gene: AP4E1 were changed from to Spastic paraplegia 51, autosomal recessive, MIM# 613744
Intellectual disability syndromic and non-syndromic v0.2904 AP4E1 Zornitza Stark Publications for gene: AP4E1 were set to
Intellectual disability syndromic and non-syndromic v0.2903 AP4E1 Zornitza Stark Mode of inheritance for gene: AP4E1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.2902 AP4E1 Zornitza Stark reviewed gene: AP4E1: Rating: GREEN; Mode of pathogenicity: None; Publications: 20972249, 21620353, 21937992; Phenotypes: Spastic paraplegia 51, autosomal recessive, MIM# 613744; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.2902 AASS Zornitza Stark Tag disputed tag was added to gene: AASS.
Intellectual disability syndromic and non-syndromic v0.2902 AASS Zornitza Stark Mode of inheritance for gene: AASS was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.2901 AASS Zornitza Stark Mode of inheritance for gene: AASS was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.2900 AASS Zornitza Stark Phenotypes for gene: AASS were changed from to Hyperlysinemia, MIM# 238700
Intellectual disability syndromic and non-syndromic v0.2899 AASS Zornitza Stark Publications for gene: AASS were set to
Intellectual disability syndromic and non-syndromic v0.2898 AASS Zornitza Stark Classified gene: AASS as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.2898 AASS Zornitza Stark Gene: aass has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.2897 AASS Zornitza Stark reviewed gene: AASS: Rating: AMBER; Mode of pathogenicity: None; Publications: 23570448; Phenotypes: Hyperlysinemia, MIM# 238700; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.2897 AARS Zornitza Stark Marked gene: AARS as ready
Intellectual disability syndromic and non-syndromic v0.2897 AARS Zornitza Stark Gene: aars has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.2897 AARS Zornitza Stark Phenotypes for gene: AARS were changed from to Epileptic encephalopathy, early infantile, 29, MIM# 616339
Intellectual disability syndromic and non-syndromic v0.2896 AARS Zornitza Stark Publications for gene: AARS were set to
Intellectual disability syndromic and non-syndromic v0.2896 AARS Zornitza Stark Mode of inheritance for gene: AARS was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.2895 AARS Zornitza Stark Mode of inheritance for gene: AARS was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.2894 AARS Zornitza Stark reviewed gene: AARS: Rating: GREEN; Mode of pathogenicity: None; Publications: 28493438, 25817015; Phenotypes: Epileptic encephalopathy, early infantile, 29, MIM# 616339; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.2894 PAFAH1B1 Zornitza Stark Marked gene: PAFAH1B1 as ready
Intellectual disability syndromic and non-syndromic v0.2894 PAFAH1B1 Zornitza Stark Gene: pafah1b1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.2894 PAFAH1B1 Zornitza Stark Phenotypes for gene: PAFAH1B1 were changed from to Lissencephaly 1, MIM# 607432; Subcortical laminar heterotopia, MIM# 607432; MONDO:0011830
Intellectual disability syndromic and non-syndromic v0.2893 PAFAH1B1 Zornitza Stark Publications for gene: PAFAH1B1 were set to
Intellectual disability syndromic and non-syndromic v0.2892 PAFAH1B1 Zornitza Stark Mode of inheritance for gene: PAFAH1B1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.2891 PAFAH1B1 Zornitza Stark Tag SV/CNV tag was added to gene: PAFAH1B1.
Intellectual disability syndromic and non-syndromic v0.2891 PAFAH1B1 Zornitza Stark reviewed gene: PAFAH1B1: Rating: GREEN; Mode of pathogenicity: None; Publications: 11754098, 18285425; Phenotypes: Lissencephaly 1, MIM# 607432, Subcortical laminar heterotopia, MIM# 607432, MONDO:0011830; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.2891 KIF5C Zornitza Stark Marked gene: KIF5C as ready
Intellectual disability syndromic and non-syndromic v0.2891 KIF5C Zornitza Stark Gene: kif5c has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.2891 KIF5C Zornitza Stark Phenotypes for gene: KIF5C were changed from to Cortical dysplasia, complex, with other brain malformations 2, MIM# 615282
Intellectual disability syndromic and non-syndromic v0.2890 KIF5C Zornitza Stark Publications for gene: KIF5C were set to
Intellectual disability syndromic and non-syndromic v0.2889 KIF5C Zornitza Stark Mode of inheritance for gene: KIF5C was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.2888 KIF5C Zornitza Stark reviewed gene: KIF5C: Rating: GREEN; Mode of pathogenicity: None; Publications: 23603762, 23033978, 32562872; Phenotypes: Cortical dysplasia, complex, with other brain malformations 2, MIM# 615282; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.2888 DPM3 Zornitza Stark edited their review of gene: DPM3: Changed phenotypes: Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 15 612937, Muscular dystrophy-dystroglycanopathy (congenital with impaired intellectual development), type B, 15 618992
Intellectual disability syndromic and non-syndromic v0.2888 GRIN2B Zornitza Stark Marked gene: GRIN2B as ready
Intellectual disability syndromic and non-syndromic v0.2888 GRIN2B Zornitza Stark Gene: grin2b has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.2888 GRIN2B Zornitza Stark Phenotypes for gene: GRIN2B were changed from Mental retardation, autosomal dominant 6, MIM# 613970; Epileptic encephalopathy, early infantile, 27, MIM# 616139 to Mental retardation, autosomal dominant 6, MIM# 613970; Epileptic encephalopathy, early infantile, 27, MIM# 616139
Intellectual disability syndromic and non-syndromic v0.2888 GRIN2B Zornitza Stark Phenotypes for gene: GRIN2B were changed from to Mental retardation, autosomal dominant 6, MIM# 613970; Epileptic encephalopathy, early infantile, 27, MIM# 616139
Intellectual disability syndromic and non-syndromic v0.2887 GRIN2B Zornitza Stark Publications for gene: GRIN2B were set to
Intellectual disability syndromic and non-syndromic v0.2886 GRIN2B Zornitza Stark Mode of inheritance for gene: GRIN2B was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.2885 GRIN2B Zornitza Stark reviewed gene: GRIN2B: Rating: GREEN; Mode of pathogenicity: None; Publications: 28377535; Phenotypes: Mental retardation, autosomal dominant 6, MIM# 613970, Epileptic encephalopathy, early infantile, 27, MIM# 616139; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.2885 GRIN1 Zornitza Stark Marked gene: GRIN1 as ready
Intellectual disability syndromic and non-syndromic v0.2885 GRIN1 Zornitza Stark Gene: grin1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.2885 GRIN1 Zornitza Stark Phenotypes for gene: GRIN1 were changed from to 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 v0.2884 GRIN1 Zornitza Stark Publications for gene: GRIN1 were set to
Intellectual disability syndromic and non-syndromic v0.2883 GRIN1 Zornitza Stark Mode of inheritance for gene: GRIN1 was changed from Unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.2882 GRIN1 Zornitza Stark reviewed gene: GRIN1: Rating: GREEN; Mode of pathogenicity: None; Publications: 29365063, 27164704, 27164704, 28051072; Phenotypes: 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; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.2882 HARS Zornitza Stark Publications for gene: HARS were set to 32296180
Intellectual disability syndromic and non-syndromic v0.2881 HARS Zornitza Stark commented on gene: HARS: Please note this is the correct PMID for this disease association
Intellectual disability syndromic and non-syndromic v0.2881 HARS Zornitza Stark reviewed gene: HARS: Rating: AMBER; Mode of pathogenicity: None; Publications: 32333447; Phenotypes: multisystem ataxic syndrome, mild-severe intellectual disability; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.2881 ALG12 Zornitza Stark Marked gene: ALG12 as ready
Intellectual disability syndromic and non-syndromic v0.2881 ALG12 Zornitza Stark Gene: alg12 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.2881 ALG12 Zornitza Stark Phenotypes for gene: ALG12 were changed from to Congenital disorder of glycosylation, type Ig, MIM# 607143
Intellectual disability syndromic and non-syndromic v0.2880 ALG12 Zornitza Stark Publications for gene: ALG12 were set to
Intellectual disability syndromic and non-syndromic v0.2879 ALG12 Zornitza Stark Mode of inheritance for gene: ALG12 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.2878 ALG12 Zornitza Stark reviewed gene: ALG12: Rating: GREEN; Mode of pathogenicity: None; Publications: 31481313; Phenotypes: Congenital disorder of glycosylation, type Ig, MIM# 607143; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.2878 ALG11 Zornitza Stark Marked gene: ALG11 as ready
Intellectual disability syndromic and non-syndromic v0.2878 ALG11 Zornitza Stark Gene: alg11 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.2878 ALG11 Zornitza Stark Phenotypes for gene: ALG11 were changed from to Congenital disorder of glycosylation, type Ip, MIM# 613661
Intellectual disability syndromic and non-syndromic v0.2877 ALG11 Zornitza Stark Publications for gene: ALG11 were set to
Intellectual disability syndromic and non-syndromic v0.2876 ALG11 Zornitza Stark Mode of inheritance for gene: ALG11 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.2875 ALG11 Zornitza Stark reviewed gene: ALG11: Rating: GREEN; Mode of pathogenicity: None; Publications: 30676690; Phenotypes: Congenital disorder of glycosylation, type Ip, MIM# 613661; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.2875 PDE2A Zornitza Stark Marked gene: PDE2A as ready
Intellectual disability syndromic and non-syndromic v0.2875 PDE2A Zornitza Stark Gene: pde2a has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.2875 PDE2A Zornitza Stark Classified gene: PDE2A as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.2875 PDE2A Zornitza Stark Gene: pde2a has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.2874 PDE2A Zornitza Stark gene: PDE2A was added
gene: PDE2A was added to Intellectual disability syndromic and non-syndromic. Sources: Expert list
Mode of inheritance for gene: PDE2A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PDE2A were set to 32467598; 32196122; 29392776
Phenotypes for gene: PDE2A were set to Paroxysmal dyskinesia
Review for gene: PDE2A was set to AMBER
Added comment: Four unrelated families reported with childhood-onset refractory paroxysmal dyskinesia with cognitive impairment, sometimes associated with choreodystonia and interictal baseline EEG abnormalities or epilepsy. One of the reports characterises the disorder as 'Rett-like'. Unclear at this time what proportion of affected individuals have ID as part of the phenotype.
Sources: Expert list
Intellectual disability syndromic and non-syndromic v0.2873 CRADD Zornitza Stark Marked gene: CRADD as ready
Intellectual disability syndromic and non-syndromic v0.2873 CRADD Zornitza Stark Gene: cradd has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.2873 CRADD Zornitza Stark Phenotypes for gene: CRADD were changed from to Mental retardation, autosomal recessive 34, with variant lissencephaly, MIM# 614499
Intellectual disability syndromic and non-syndromic v0.2872 CRADD Zornitza Stark Publications for gene: CRADD were set to
Intellectual disability syndromic and non-syndromic v0.2871 CRADD Zornitza Stark Mode of inheritance for gene: CRADD was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.2870 CRADD Zornitza Stark reviewed gene: CRADD: Rating: GREEN; Mode of pathogenicity: None; Publications: 27773430; Phenotypes: Mental retardation, autosomal recessive 34, with variant lissencephaly, MIM# 614499; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.2870 TDGF1 Zornitza Stark Marked gene: TDGF1 as ready
Intellectual disability syndromic and non-syndromic v0.2870 TDGF1 Zornitza Stark Added comment: Comment when marking as ready: Variant reported is present in 46 hets in gnomad.
Intellectual disability syndromic and non-syndromic v0.2870 TDGF1 Zornitza Stark Gene: tdgf1 has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v0.2870 TDGF1 Zornitza Stark Tag disputed tag was added to gene: TDGF1.
Intellectual disability syndromic and non-syndromic v0.2870 TMTC3 Zornitza Stark Marked gene: TMTC3 as ready
Intellectual disability syndromic and non-syndromic v0.2870 TMTC3 Zornitza Stark Gene: tmtc3 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.2870 TMTC3 Zornitza Stark Phenotypes for gene: TMTC3 were changed from to Lissencephaly 8 (MIM#617255)
Intellectual disability syndromic and non-syndromic v0.2869 TMTC3 Zornitza Stark Publications for gene: TMTC3 were set to
Intellectual disability syndromic and non-syndromic v0.2868 TMTC3 Zornitza Stark Mode of inheritance for gene: TMTC3 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.2867 TMTC3 Zornitza Stark reviewed gene: TMTC3: Rating: GREEN; Mode of pathogenicity: None; Publications: 27773428, 28973161; Phenotypes: Lissencephaly 8 (MIM#617255); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.2867 MAOA Zornitza Stark Marked gene: MAOA as ready
Intellectual disability syndromic and non-syndromic v0.2867 MAOA Zornitza Stark Gene: maoa has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.2867 MAOA Zornitza Stark Phenotypes for gene: MAOA were changed from to Brunner syndrome, MIM# 300615
Intellectual disability syndromic and non-syndromic v0.2866 MAOA Zornitza Stark Publications for gene: MAOA were set to
Intellectual disability syndromic and non-syndromic v0.2865 MAOA Zornitza Stark Mode of inheritance for gene: MAOA was changed from Unknown to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability syndromic and non-syndromic v0.2864 MAOA Zornitza Stark reviewed gene: MAOA: Rating: GREEN; Mode of pathogenicity: None; Publications: 25807999, 24169519; Phenotypes: Brunner syndrome, MIM# 300615; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability syndromic and non-syndromic v0.2864 GABRG2 Zornitza Stark Marked gene: GABRG2 as ready
Intellectual disability syndromic and non-syndromic v0.2864 GABRG2 Zornitza Stark Gene: gabrg2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.2864 GABRG2 Zornitza Stark Phenotypes for gene: GABRG2 were changed from to Epileptic encephalopathy, early infantile, 74 618396; Epilepsy, generalized, with febrile seizures plus, type 3 607681
Intellectual disability syndromic and non-syndromic v0.2863 GABRG2 Zornitza Stark Publications for gene: GABRG2 were set to
Intellectual disability syndromic and non-syndromic v0.2862 GABRG2 Zornitza Stark Mode of inheritance for gene: GABRG2 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.2861 GABRG2 Zornitza Stark reviewed gene: GABRG2: Rating: GREEN; Mode of pathogenicity: None; Publications: 11326274, 11326275, 27864268; Phenotypes: Epileptic encephalopathy, early infantile, 74 618396, Epilepsy, generalized, with febrile seizures plus, type 3 607681; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.2861 GABRB3 Zornitza Stark Marked gene: GABRB3 as ready
Intellectual disability syndromic and non-syndromic v0.2861 GABRB3 Zornitza Stark Gene: gabrb3 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.2861 GABRB3 Zornitza Stark Phenotypes for gene: GABRB3 were changed from to Epileptic encephalopathy, early infantile, 43, MIM# 617113
Intellectual disability syndromic and non-syndromic v0.2860 GABRB3 Zornitza Stark Publications for gene: GABRB3 were set to
Intellectual disability syndromic and non-syndromic v0.2859 GABRB3 Zornitza Stark Mode of inheritance for gene: GABRB3 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.2858 GABRB3 Zornitza Stark reviewed gene: GABRB3: Rating: GREEN; Mode of pathogenicity: None; Publications: 23934111, 27476654; Phenotypes: Epileptic encephalopathy, early infantile, 43, MIM# 617113; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.2858 FOLR1 Zornitza Stark Marked gene: FOLR1 as ready
Intellectual disability syndromic and non-syndromic v0.2858 FOLR1 Zornitza Stark Gene: folr1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.2858 FOLR1 Zornitza Stark Phenotypes for gene: FOLR1 were changed from to Neurodegeneration due to cerebral folate transport deficiency, MIM# 613068
Intellectual disability syndromic and non-syndromic v0.2857 FOLR1 Zornitza Stark Publications for gene: FOLR1 were set to
Intellectual disability syndromic and non-syndromic v0.2856 FOLR1 Zornitza Stark Mode of inheritance for gene: FOLR1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.2855 FOLR1 Zornitza Stark reviewed gene: FOLR1: Rating: GREEN; Mode of pathogenicity: None; Publications: 19732866, 30420205, 27743887; Phenotypes: Neurodegeneration due to cerebral folate transport deficiency, MIM# 613068; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.2855 LMBRD2 Zornitza Stark reviewed gene: LMBRD2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Intellectual disability; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.2855 LMBRD2 Zornitza Stark Marked gene: LMBRD2 as ready
Intellectual disability syndromic and non-syndromic v0.2855 LMBRD2 Zornitza Stark Gene: lmbrd2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.2855 LMBRD2 Zornitza Stark Classified gene: LMBRD2 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.2855 LMBRD2 Zornitza Stark Gene: lmbrd2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.2854 KAT5 Zornitza Stark Phenotypes for gene: KAT5 were changed from to Severe global developmental delay; Intellectual disability; Seizures; Microcephaly; Behavioral abnormality; Sleep disturbance; Morphological abnormality of the central nervous system; Short stature; Oral cleft; Abnormality of the face
Intellectual disability syndromic and non-syndromic v0.2853 KAT5 Zornitza Stark Publications for gene: KAT5 were set to
Intellectual disability syndromic and non-syndromic v0.2852 KAT5 Zornitza Stark Mode of pathogenicity for gene: KAT5 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 v0.2851 KAT5 Zornitza Stark Mode of inheritance for gene: KAT5 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.2850 KAT5 Zornitza Stark Classified gene: KAT5 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.2850 KAT5 Zornitza Stark Gene: kat5 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.2849 KAT5 Konstantinos Varvagiannis reviewed gene: KAT5: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: 32822602; Phenotypes: Severe global developmental delay, Intellectual disability, Seizures, Microcephaly, Behavioral abnormality, Sleep disturbance, Morphological abnormality of the central nervous system, Short stature, Oral cleft, Abnormality of the face; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability syndromic and non-syndromic v0.2849 LMBRD2 Konstantinos Varvagiannis gene: LMBRD2 was added
gene: LMBRD2 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: LMBRD2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: LMBRD2 were set to 32820033; https://doi.org/10.1101/797787
Phenotypes for gene: LMBRD2 were set to Global developmental delay; Intellectual disability; Microcephaly; Seizures; Abnormality of nervous system morphology; Abnormality of the eye
Penetrance for gene: LMBRD2 were set to unknown
Mode of pathogenicity for gene: LMBRD2 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: LMBRD2 was set to AMBER
Added comment: You may consider inclusion with green (13 individuals with dn missense SNVs overall, overlapping features for 10 with available phenotype / a recurring variant has been identified in 2 different studies) or amber rating (role of the gene not known, no variant studies, animal model probably not available).

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

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

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

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

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

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

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

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

► Kaplanis et al (2020 - https://doi.org/10.1101/797787) in a dataset of 31058 parent-offspring trios (WES) previously identified 3 individuals with developmental disorder, harboring c.1448G>A - p.Arg483His. These individuals (1 from the DDD study, and 2 GeneDx patients) appear in Decipher. [ https://decipher.sanger.ac.uk/ddd/research-variant/40e17c78cc9655a6721006fc1e0c98db/overview ]. The preprint by Kaplanis et al is cited by Malhotra et al, with Arg483His reported in 6 patients overall in both studies.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.2849 TMEM237 Zornitza Stark Marked gene: TMEM237 as ready
Intellectual disability syndromic and non-syndromic v0.2849 TMEM237 Zornitza Stark Gene: tmem237 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.2849 TMEM237 Zornitza Stark Phenotypes for gene: TMEM237 were changed from to Joubert syndrome 14, MIM# 614424
Intellectual disability syndromic and non-syndromic v0.2848 TMEM237 Zornitza Stark Publications for gene: TMEM237 were set to
Intellectual disability syndromic and non-syndromic v0.2847 TMEM237 Zornitza Stark Mode of inheritance for gene: TMEM237 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.2846 TMEM237 Zornitza Stark reviewed gene: TMEM237: Rating: GREEN; Mode of pathogenicity: None; Publications: 22152675; Phenotypes: Joubert syndrome 14, MIM# 614424; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.2846 KANSL1 Zornitza Stark Marked gene: KANSL1 as ready
Intellectual disability syndromic and non-syndromic v0.2846 KANSL1 Zornitza Stark Gene: kansl1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.2846 KANSL1 Zornitza Stark Phenotypes for gene: KANSL1 were changed from to Koolen-De Vries syndrome (MIM#610443)
Intellectual disability syndromic and non-syndromic v0.2845 KANSL1 Zornitza Stark Publications for gene: KANSL1 were set to
Intellectual disability syndromic and non-syndromic v0.2844 KANSL1 Zornitza Stark Mode of inheritance for gene: KANSL1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.2843 KANSL1 Zornitza Stark reviewed gene: KANSL1: Rating: GREEN; Mode of pathogenicity: None; Publications: 22544363; Phenotypes: Koolen-De Vries syndrome (MIM#610443); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.2843 TAOK1 Zornitza Stark Marked gene: TAOK1 as ready
Intellectual disability syndromic and non-syndromic v0.2843 TAOK1 Zornitza Stark Gene: taok1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.2843 TAOK1 Zornitza Stark Phenotypes for gene: TAOK1 were changed from to Intellectual disability; hypotonia; macrocephaly
Intellectual disability syndromic and non-syndromic v0.2842 TAOK1 Zornitza Stark Publications for gene: TAOK1 were set to
Intellectual disability syndromic and non-syndromic v0.2841 TAOK1 Zornitza Stark Mode of inheritance for gene: TAOK1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.2840 TAOK1 Sue White commented on gene: TAOK1: Monoallelic de novo variants reported in 8 individuals with nonspecific phenotype of intellectual disability and hypotonia. Most were LOF, 2 missense. 3 had macrocephaly.
Intellectual disability syndromic and non-syndromic v0.2840 TAOK1 Sue White reviewed gene: TAOK1: Rating: GREEN; Mode of pathogenicity: None; Publications: 31230721; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.2840 RAI1 Zornitza Stark Marked gene: RAI1 as ready
Intellectual disability syndromic and non-syndromic v0.2840 RAI1 Zornitza Stark Gene: rai1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.2840 RAI1 Zornitza Stark Phenotypes for gene: RAI1 were changed from to Smith-Magenis syndrome (MIM#182290)
Intellectual disability syndromic and non-syndromic v0.2839 RAI1 Zornitza Stark Publications for gene: RAI1 were set to
Intellectual disability syndromic and non-syndromic v0.2838 RAI1 Zornitza Stark Mode of inheritance for gene: RAI1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.2837 RAI1 Zornitza Stark reviewed gene: RAI1: Rating: GREEN; Mode of pathogenicity: None; Publications: 11404004, 12652298, 15788730; Phenotypes: Smith-Magenis syndrome (MIM#182290); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.2837 TAF1C Zornitza Stark Classified gene: TAF1C as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.2837 TAF1C Zornitza Stark Gene: taf1c has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.2836 TAF1C Konstantinos Varvagiannis gene: TAF1C was added
gene: TAF1C was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: TAF1C was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TAF1C were set to 32779182
Phenotypes for gene: TAF1C were set to Global developmental delay; Intellectual disability; Spasticity; Strabismus; Seizures; Abnormality of nervous system morphology
Penetrance for gene: TAF1C were set to Complete
Review for gene: TAF1C was set to AMBER
Added comment: Knuutinen et al (2020 - PMID: 32779182) report on 2 individuals from 2 consanguineous families, homozygous for TAF1C missense variants.

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

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

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

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

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

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

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

As a result, TAF1C may be considered for inclusion in the ID panel with amber rating pending further evidence.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.2836 KAT8 Zornitza Stark Phenotypes for gene: KAT8 were changed from Intellectual disability; seizures; autism; dysmorphic features to Intellectual disability; seizures; autism; dysmorphic features; Li-Ghorbani-Weisz syndrome, MIM#618974
Intellectual disability syndromic and non-syndromic v0.2835 MADD Konstantinos Varvagiannis reviewed gene: MADD: Rating: GREEN; Mode of pathogenicity: None; Publications: 28940097, 29302074, 32761064; Phenotypes: Global developmental delay / Intellectual disability / Seizures, Global developmental delay / Intellectual disability / Seizures / Abnormality of the endocrine system / Exocrine pancreatic insufficiency / Constipation / Diarrhea / Anemia / Thrombocytopenia / Abnormality of the autonomic nervous system; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.2835 SLC5A6 Zornitza Stark Phenotypes for gene: SLC5A6 were changed from Developmental delay; epilepsy; neurodegeneration to Developmental delay; epilepsy; neurodegeneration; Neurodegeneration, infantile-onset, biotin-responsive, MIM# 618973
Intellectual disability syndromic and non-syndromic v0.2834 FAM50A Zornitza Stark Marked gene: FAM50A as ready
Intellectual disability syndromic and non-syndromic v0.2834 FAM50A Zornitza Stark Gene: fam50a has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.2834 FAM50A Zornitza Stark Classified gene: FAM50A as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.2834 FAM50A Zornitza Stark Gene: fam50a has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.2833 FAM50A Konstantinos Varvagiannis gene: FAM50A was added
gene: FAM50A was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: FAM50A was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Publications for gene: FAM50A were set to 32703943
Phenotypes for gene: FAM50A were set to Mental retardation syndrome, X-linked, Armfield type (MIM #300261)
Penetrance for gene: FAM50A were set to unknown
Review for gene: FAM50A was set to GREEN
Added comment: Lee et al (2020 - PMID: 32703943) provide evidence that Armfield X-Linked intellectual disability syndrome is caused by monoallelic FAM50A pathogenic variants. The current review is based only on this reference.

The authors provide clinical details on 6 affected individuals from 5 families.

Features included postnatal growth delay, DD and ID (6/6 - also evident for those without formal IQ assesment), seizures (3/6 from 2 families), prominent forehead with presence of other facial features and variable head circumference (5th to >97th %le), ocular anomalies (5/6 - strabismus/nystagmus/Axenfeld-Rieger), cardiac (3/6 - ASD/Fallot) and genitourinary anomalies (3/6).

In the first of these families (Armfield et al 1999 - PMID: 10398235), linkage analysis followed by additional studies (Sanger, NGS of 718 genes on chrX, X-exome NGS - several refs provided) allowed the identification of a FAM50A variant. Variants in other families were identified by singleton (1 fam) or trio-ES (3 fam).

In affected individuals from 3 families, the variant had occurred de novo. Carrier females in the other families were unaffected (based on pedigrees and/or the original publication). XCI was rather biased in most obligate carrier females from the 1st family (although this ranged from 95:5 to 60:40).

Missense variants were reported in all affected subjects incl. Trp206Gly, Asp255Gly, Asp255Asn (dn), Glu254Gly (dn), Arg273Trp (dn) (NM_004699.3).

Previous studies have demonstrated that FAM50A has ubiquitous expression in human fetal and adult tissues (incl. brain in fetal ones).

Immunostaining suggests a nuclear localization for the protein (NIH/3T3 cells). Comparison of protein levels in LCLs from affected males and controls did not demonstrate significant differences. Protein localization for 3 variants (transfection of COS-7 cells) was shown to be similar to wt.

Complementation studies in zebrafish provided evidence that the identified variants confer partial loss of function (rescue of the morpholino phenotype with co-injection of wt but not mt mRNA). The zebrafish ko model seemed to recapitulate the abnormal development of cephalic structures and was indicative of diminished/defective neurogenesis. Transcriptional dysregulation was demonstrated in zebrafish (altered levels and mis-splicing). Upregulation of spliceosome effectors was demonstrated in ko zebrafish.

Similarly, mRNA expression and splicing defects were demonstrated in LCLs from affected individuals. FAM50A pulldown followed by mass spectrometry in transfected HEK293T cells demonstrated enrichment of binding proteins involved in RNA processing and co-immunoprecipitation assays (transfected U-87 cells) suggested that FAM50A interacts with spliceosome U5 and C-complex proteins.

Overall aberrant spliceosome C-complex function is suggested as the underlying pathogenetic mechanism.

Several other neurodevelopmental syndromes are caused by variants in genes encoding C-complex affiliated proteins (incl. EFTUD2, EIF4A3, THOC2, etc.).

Please consider inclusion in the ID panel with green rating and epilepsy panel with amber (seizures in individuals from 2 families).
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.2833 ADK Zornitza Stark Marked gene: ADK as ready
Intellectual disability syndromic and non-syndromic v0.2833 ADK Zornitza Stark Gene: adk has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.2833 ADK Zornitza Stark Phenotypes for gene: ADK were changed from to Hypermethioninemia due to adenosine kinase deficiency, MIM# 614300
Intellectual disability syndromic and non-syndromic v0.2832 ADK Zornitza Stark Publications for gene: ADK were set to
Intellectual disability syndromic and non-syndromic v0.2831 ADK Zornitza Stark Mode of inheritance for gene: ADK was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.2830 ADK Zornitza Stark reviewed gene: ADK: Rating: GREEN; Mode of pathogenicity: None; Publications: 21963049, 17120046; Phenotypes: Hypermethioninemia due to adenosine kinase deficiency, MIM# 614300; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.2830 SOX6 Zornitza Stark Phenotypes for gene: SOX6 were changed from ADHD; Craniosynostosis; Osteochondromas to ADHD; Craniosynostosis; Osteochondromas; Tolchin-Le Caignec syndrome, MIM#618971
Intellectual disability syndromic and non-syndromic v0.2829 SOX6 Zornitza Stark edited their review of gene: SOX6: Changed rating: GREEN; Changed phenotypes: Tolchin-Le Caignec syndrome, MIM#618971; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.2829 HYLS1 Zornitza Stark Tag founder tag was added to gene: HYLS1.
Intellectual disability syndromic and non-syndromic v0.2829 HYLS1 Zornitza Stark Classified gene: HYLS1 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.2829 HYLS1 Zornitza Stark Gene: hyls1 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.2828 HYLS1 Zornitza Stark changed review comment from: Given that generally most affected individuals die in utero or shortly after birth, this is probably not the right panel for this gene.; to: Single family reported with Joubert phenotype, generally most affected individuals with hydrolethalus die in utero or shortly after birth so would not present with ID. Note founder variant in Finnish population associated with the hydrolethalus phenotype.
Intellectual disability syndromic and non-syndromic v0.2828 HYLS1 Zornitza Stark edited their review of gene: HYLS1: Changed rating: AMBER; Changed publications: 15843405, 18648327, 19400947, 19656802, 32509774, 26830932
Intellectual disability syndromic and non-syndromic v0.2828 RAC1 Zornitza Stark Marked gene: RAC1 as ready
Intellectual disability syndromic and non-syndromic v0.2828 RAC1 Zornitza Stark Gene: rac1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.2828 RAC1 Zornitza Stark Phenotypes for gene: RAC1 were changed from Mental retardation, autosomal dominant 48, MIM# 617751 to Mental retardation, autosomal dominant 48, MIM# 617751
Intellectual disability syndromic and non-syndromic v0.2827 RAC1 Zornitza Stark Phenotypes for gene: RAC1 were changed from Mental retardation, autosomal dominant 48 617751 to Mental retardation, autosomal dominant 48, MIM# 617751
Intellectual disability syndromic and non-syndromic v0.2827 RAC1 Zornitza Stark Phenotypes for gene: RAC1 were changed from to Mental retardation, autosomal dominant 48 617751
Intellectual disability syndromic and non-syndromic v0.2826 RAC1 Zornitza Stark Publications for gene: RAC1 were set to
Intellectual disability syndromic and non-syndromic v0.2825 RAC1 Zornitza Stark Mode of pathogenicity for gene: RAC1 was changed from to Other
Intellectual disability syndromic and non-syndromic v0.2824 RAC1 Zornitza Stark Mode of inheritance for gene: RAC1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.2823 RAC1 Zornitza Stark edited their review of gene: RAC1: Changed phenotypes: Mental retardation, autosomal dominant 48 617751
Intellectual disability syndromic and non-syndromic v0.2823 RAC1 Zornitza Stark reviewed gene: RAC1: Rating: GREEN; Mode of pathogenicity: Other; Publications: 30042656, 29276006, 30293988; Phenotypes: Neurodevelopmental disorder with structural brain anomalies and dysmorphic facies (MIM#618577), AD; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.2823 BCOR Zornitza Stark Marked gene: BCOR as ready
Intellectual disability syndromic and non-syndromic v0.2823 BCOR Zornitza Stark Gene: bcor has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.2823 BCOR Zornitza Stark Phenotypes for gene: BCOR were changed from to Microphthalmia, syndromic 2, MIM# 300166; Oculofaciocardiodental syndrome; Lenz microphthalmia
Intellectual disability syndromic and non-syndromic v0.2822 BCOR Zornitza Stark Publications for gene: BCOR were set to
Intellectual disability syndromic and non-syndromic v0.2821 BCOR Zornitza Stark Mode of inheritance for gene: BCOR 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 v0.2820 BCOR Zornitza Stark reviewed gene: BCOR: Rating: GREEN; Mode of pathogenicity: None; Publications: 29974297; Phenotypes: Microphthalmia, syndromic 2, MIM# 300166, Oculofaciocardiodental syndrome, Lenz microphthalmia; 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 v0.2820 ARSE Zornitza Stark Marked gene: ARSE as ready
Intellectual disability syndromic and non-syndromic v0.2820 ARSE Zornitza Stark Added comment: Comment when marking as ready: Note HGNC approved name is ARSL.
Intellectual disability syndromic and non-syndromic v0.2820 ARSE Zornitza Stark Gene: arse has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.2820 ARSE Zornitza Stark Phenotypes for gene: ARSE were changed from to Chondrodysplasia punctata, X-linked recessive, MIM# 302950
Intellectual disability syndromic and non-syndromic v0.2819 ARSE Zornitza Stark Publications for gene: ARSE were set to
Intellectual disability syndromic and non-syndromic v0.2818 ARSE Zornitza Stark Mode of inheritance for gene: ARSE was changed from Unknown to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability syndromic and non-syndromic v0.2817 ARSE Zornitza Stark Tag new gene name tag was added to gene: ARSE.
Intellectual disability syndromic and non-syndromic v0.2817 ARSE Zornitza Stark reviewed gene: ARSE: Rating: GREEN; Mode of pathogenicity: None; Publications: 20301713; Phenotypes: Chondrodysplasia punctata, X-linked recessive, MIM# 302950; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability syndromic and non-syndromic v0.2817 FBXO11 Zornitza Stark Marked gene: FBXO11 as ready
Intellectual disability syndromic and non-syndromic v0.2817 FBXO11 Zornitza Stark Gene: fbxo11 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.2817 FBXO11 Zornitza Stark Phenotypes for gene: FBXO11 were changed from to Intellectual Developmental Disorder with Dysmorphic Facies and Behavioural Abnormalities, MIM#618089
Intellectual disability syndromic and non-syndromic v0.2816 FBXO11 Zornitza Stark Mode of inheritance for gene: FBXO11 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.2815 FBXO11 Zornitza Stark Publications for gene: FBXO11 were set to
Intellectual disability syndromic and non-syndromic v0.2815 FBXO11 Zornitza Stark Mode of inheritance for gene: FBXO11 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.2814 FBXO11 Vivian WEI reviewed gene: FBXO11: Rating: GREEN; Mode of pathogenicity: None; Publications: 30679813, 30057029, 29796876; Phenotypes: Intellectual Developmental Disorder with Dysmorphic Facies and Behavioural Abnormalities; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Intellectual disability syndromic and non-syndromic v0.2814 PIGQ Zornitza Stark Marked gene: PIGQ as ready
Intellectual disability syndromic and non-syndromic v0.2814 PIGQ Zornitza Stark Gene: pigq has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.2814 PIGQ Zornitza Stark Classified gene: PIGQ as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.2814 PIGQ Zornitza Stark Gene: pigq has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.2813 PIGQ Konstantinos Varvagiannis gene: PIGQ was added
gene: PIGQ was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: PIGQ was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PIGQ were set to 32588908; 24463883; 25558065; 31148362
Phenotypes for gene: PIGQ were set to Epileptic encephalopathy, early infantile, 77 (MIM #618548)
Penetrance for gene: PIGQ were set to Complete
Review for gene: PIGQ was set to GREEN
Added comment: Homozygous or compound heterozygous mutations in PIGQ cause Epileptic encephalopathy, early infantile, 77 (MIM #618548).

Johnstone et al (2020 - PMID: 32588908) describe the phenotype of 7 children (from 6 families) with biallelic PIGQ pathogenic variants. The authors also review the phenotype of 3 subjects previously reported in the literature (by Martin et al, Alazami et al, Starr et al - respective PMIDs: 24463883, 25558065, 31148362).

Affected individuals displayed severe to profound global DD/ID and seizures with onset in the first year of life. There were variable other features incl. - among others - genitourinary, cardiac, skeletal, ophthalmological anomalies, gastrointestinal issues. Within the cohort there was significant morbidity/mortality.

PIGQ encodes phosphatidylinositol glycan anchor biosynthesis class Q protein, playing a role (early) in the biosynthesis of the GPI-anchor. Several genes in the GPI biosynthesis pathway cause multi-system disease with DD/ID and seizures. Flow cytometry has been used in individuals with PIGQ-related disorder. Serum ALP was elevated in some (4) although - as the authors comment - elevations are more typical in disorders affecting later steps of GPI biosynthesis.

More than 10 variants have been reported to date (missense / pLoF).

Overall PIGQ can be considered for green rating in both ID and epilepsy gene panels.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.2813 HPDL Zornitza Stark Marked gene: HPDL as ready
Intellectual disability syndromic and non-syndromic v0.2813 HPDL Zornitza Stark Gene: hpdl has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.2813 HPDL Zornitza Stark Phenotypes for gene: HPDL were changed from Progressive neurological disorder to Progressive neurological disorder; Leigh-like syndrome
Intellectual disability syndromic and non-syndromic v0.2812 HPDL Zornitza Stark Classified gene: HPDL as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.2812 HPDL Zornitza Stark Gene: hpdl has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.2811 HPDL Crystle Lee gene: HPDL was added
gene: HPDL was added to Intellectual disability syndromic and non-syndromic. Sources: Expert Review
Mode of inheritance for gene: HPDL was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HPDL were set to 32707086
Phenotypes for gene: HPDL were set to Progressive neurological disorder
Review for gene: HPDL was set to GREEN
Added comment: Biallelic variants reported in 13 families with a neurodegenerative disease ranging from neonatal encephalopathy to adolescent-onset spastic paraplegia
Sources: Expert Review
Intellectual disability syndromic and non-syndromic v0.2811 PIGP Seb Lunke Publications for gene: PIGP were set to 28334793; 31139695
Intellectual disability syndromic and non-syndromic v0.2810 PIGP Seb Lunke Classified gene: PIGP as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.2810 PIGP Seb Lunke Gene: pigp has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.2809 PIGP Seb Lunke reviewed gene: PIGP: Rating: GREEN; Mode of pathogenicity: None; Publications: 32042915; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.2809 SCAF4 Zornitza Stark Marked gene: SCAF4 as ready
Intellectual disability syndromic and non-syndromic v0.2809 SCAF4 Zornitza Stark Gene: scaf4 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.2809 SCAF4 Zornitza Stark Classified gene: SCAF4 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.2809 SCAF4 Zornitza Stark Gene: scaf4 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.2808 PJA1 Zornitza Stark Tag founder tag was added to gene: PJA1.
Intellectual disability syndromic and non-syndromic v0.2808 PJA1 Zornitza Stark Marked gene: PJA1 as ready
Intellectual disability syndromic and non-syndromic v0.2808 PJA1 Zornitza Stark Gene: pja1 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.2808 PJA1 Zornitza Stark Classified gene: PJA1 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.2808 PJA1 Zornitza Stark Gene: pja1 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.2807 PJA1 Zornitza Stark gene: PJA1 was added
gene: PJA1 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: PJA1 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: PJA1 were set to 32530565
Phenotypes for gene: PJA1 were set to Intellectual disability; trigonocephaly
Review for gene: PJA1 was set to AMBER
Added comment: Recurrent variant, p.Arg376Cys, reported in 7 Japanese individuals, supportive mouse model. Individuals shared a common haplotype, suggestive of founder effect.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.2806 SCAF4 Crystle Lee gene: SCAF4 was added
gene: SCAF4 was added to Intellectual disability syndromic and non-syndromic. Sources: Expert Review
Mode of inheritance for gene: SCAF4 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SCAF4 were set to 32730804
Phenotypes for gene: SCAF4 were set to Mild intellectual disability; seizures; behavioral abnormalities
Review for gene: SCAF4 was set to GREEN
Added comment: > 5 variants reported in individuals with variable neurodevelopmental disorder characterized by mild intellectual disability, seizures, behavioral abnormalities, and various skeletal and structural anomalies.
Sources: Expert Review
Intellectual disability syndromic and non-syndromic v0.2806 NARS Zornitza Stark Marked gene: NARS as ready
Intellectual disability syndromic and non-syndromic v0.2806 NARS Zornitza Stark Gene: nars has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.2806 NARS Zornitza Stark Classified gene: NARS as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.2806 NARS Zornitza Stark Gene: nars has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.2805 NARS Zornitza Stark Tag new gene name tag was added to gene: NARS.
Intellectual disability syndromic and non-syndromic v0.2805 NARS Konstantinos Varvagiannis changed review comment from: [Please note that HGNC Approved Gene Symbol for this gene is NARS1]

Manole et al (2020 - PMID: 32738225) provide evidence that both biallelic and monoallelic (de novo) pathogenic NARS1 variants cause a neurodevelopmental disorder. In total 32 individuals from 21 families are reported, with biallelic variants identified in individuals from 13 families and de novo in 8 families.

Similar features were reported for AR/AD occurrences of the disorder and included of microcephaly (90% - most often primary), epilepsy (23/32 or 74% - variable semiology incl. partial/myoclonic/generalized tonic-clonic seizures), DD and ID (as a universal feature), abnormal tone in several (hypotonia/spasticity), ataxia, demyelinating peripheral neuropathy (in 3 or more for each inheritance mode - or a total of 25%). Some individuals had dysmorphic features.

NARS1 encodes an aminoacyl-tRNA synthetase (ARS) [asparaginyl-tRNA synthetase 1]. Aminoacyl-tRNA synthetases constitute a family of enzymes catalyzing attachment of amino-acids to their cognate tRNAs. As the authors comment, mutations in genes encoding several other ARSs result in neurological disorders ranging from peripheral neuropathy to severe multi-systemic NDD. Dominant, recessive or both modes for inheritance for mutations in the same gene (e.g. AARS1, YARS1, MARS1, etc) have been reported.

Some variants were recurrent, e.g. the c.1600C>T / p.Arg534* which occurred in 6 families as a de novo event or c.1633C>T p.Arg545Cys (homozygous in 6 families). 3 different variants were reported to have occured de novo (c.965G>T - p.Arg322Leu, c.1525G>A - p.Gly509Ser, p.Arg534*) with several other variants identified in hmz/compound htz individuals. A single SNV (c.1067A>C - p.Asp356Ala) was suggested to be acting as modifier and pathogenic only when in trans with a severe variant. [NM_004539.4 used as RefSeq for all].

The authors provide several lines of evidence for a partial loss-of-function effect (e.g. reduction in mRNA expression, enzyme levels and activity in fibroblasts or iNPCs) underlying pathogenicity of the variants identified in individuals with biallelic variants. A gain-of-function (dominant-negative) effect is proposed for de novo variants (such effect also demonstrated for the p.Arg534* in a zebrafish model).

As also Manole et al suggest, NARS1 can be considered for inclusion in gene panels for DD/ID, epilepsy and/or demyelinating neuropathy.
Sources: Literature; to: [Please note that HGNC Approved Gene Symbol for this gene is NARS1]

Manole et al (2020 - PMID: 32738225) provide evidence that both biallelic and monoallelic (de novo) pathogenic NARS1 variants cause a neurodevelopmental disorder. In total 32 individuals from 21 families are reported, with biallelic variants identified in individuals from 13 families and de novo in 8 families.

Similar features were reported for AR/AD occurrences of the disorder and included microcephaly (90% - most often primary), epilepsy (23/32 or 74% - variable semiology incl. partial/myoclonic/generalized tonic-clonic seizures), DD and ID (as a universal feature), abnormal tone in several (hypotonia/spasticity), ataxia, demyelinating peripheral neuropathy (in 3 or more for each inheritance mode - or a total of 25%). Some individuals had dysmorphic features.

NARS1 encodes an aminoacyl-tRNA synthetase (ARS) [asparaginyl-tRNA synthetase 1]. Aminoacyl-tRNA synthetases constitute a family of enzymes catalyzing attachment of amino-acids to their cognate tRNAs. As the authors comment, mutations in genes encoding several other ARSs result in neurological disorders ranging from peripheral neuropathy to severe multi-systemic NDD. Dominant, recessive or both modes for inheritance for mutations in the same gene (e.g. AARS1, YARS1, MARS1, etc) have been reported.

Some variants were recurrent, e.g. the c.1600C>T / p.Arg534* which occurred in 6 families as a de novo event or c.1633C>T p.Arg545Cys (homozygous in 6 families). 3 different variants were reported to have occured de novo (c.965G>T - p.Arg322Leu, c.1525G>A - p.Gly509Ser, p.Arg534*) with several other variants identified in hmz/compound htz individuals. A single SNV (c.1067A>C - p.Asp356Ala) was suggested to be acting as modifier and pathogenic only when in trans with a severe variant. [NM_004539.4 used as RefSeq for all].

The authors provide several lines of evidence for a partial loss-of-function effect (e.g. reduction in mRNA expression, enzyme levels and activity in fibroblasts or iNPCs) underlying pathogenicity of the variants identified in individuals with biallelic variants. A gain-of-function (dominant-negative) effect is proposed for de novo variants (such effect also demonstrated for the p.Arg534* in a zebrafish model).

As also Manole et al suggest, NARS1 can be considered for inclusion in gene panels for DD/ID, epilepsy and/or demyelinating neuropathy.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.2805 NARS Konstantinos Varvagiannis gene: NARS was added
gene: NARS was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: NARS was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: NARS were set to 32738225
Phenotypes for gene: NARS were set to Abnormal muscle tone; Microcephaly; Global developmental delay; Intellectual disability; Seizures; Ataxia; Abnormality of the face; Demyelinating peripheral neuropathy
Penetrance for gene: NARS were set to Complete
Review for gene: NARS was set to GREEN
Added comment: [Please note that HGNC Approved Gene Symbol for this gene is NARS1]

Manole et al (2020 - PMID: 32738225) provide evidence that both biallelic and monoallelic (de novo) pathogenic NARS1 variants cause a neurodevelopmental disorder. In total 32 individuals from 21 families are reported, with biallelic variants identified in individuals from 13 families and de novo in 8 families.

Similar features were reported for AR/AD occurrences of the disorder and included of microcephaly (90% - most often primary), epilepsy (23/32 or 74% - variable semiology incl. partial/myoclonic/generalized tonic-clonic seizures), DD and ID (as a universal feature), abnormal tone in several (hypotonia/spasticity), ataxia, demyelinating peripheral neuropathy (in 3 or more for each inheritance mode - or a total of 25%). Some individuals had dysmorphic features.

NARS1 encodes an aminoacyl-tRNA synthetase (ARS) [asparaginyl-tRNA synthetase 1]. Aminoacyl-tRNA synthetases constitute a family of enzymes catalyzing attachment of amino-acids to their cognate tRNAs. As the authors comment, mutations in genes encoding several other ARSs result in neurological disorders ranging from peripheral neuropathy to severe multi-systemic NDD. Dominant, recessive or both modes for inheritance for mutations in the same gene (e.g. AARS1, YARS1, MARS1, etc) have been reported.

Some variants were recurrent, e.g. the c.1600C>T / p.Arg534* which occurred in 6 families as a de novo event or c.1633C>T p.Arg545Cys (homozygous in 6 families). 3 different variants were reported to have occured de novo (c.965G>T - p.Arg322Leu, c.1525G>A - p.Gly509Ser, p.Arg534*) with several other variants identified in hmz/compound htz individuals. A single SNV (c.1067A>C - p.Asp356Ala) was suggested to be acting as modifier and pathogenic only when in trans with a severe variant. [NM_004539.4 used as RefSeq for all].

The authors provide several lines of evidence for a partial loss-of-function effect (e.g. reduction in mRNA expression, enzyme levels and activity in fibroblasts or iNPCs) underlying pathogenicity of the variants identified in individuals with biallelic variants. A gain-of-function (dominant-negative) effect is proposed for de novo variants (such effect also demonstrated for the p.Arg534* in a zebrafish model).

As also Manole et al suggest, NARS1 can be considered for inclusion in gene panels for DD/ID, epilepsy and/or demyelinating neuropathy.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.2805 ZNF407 Zornitza Stark Marked gene: ZNF407 as ready
Intellectual disability syndromic and non-syndromic v0.2805 ZNF407 Zornitza Stark Added comment: Comment when marking as ready: Evidence both for mono allelic and bi-allelic disease, though neither sufficient for Green rating at present.
Intellectual disability syndromic and non-syndromic v0.2805 ZNF407 Zornitza Stark Gene: znf407 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.2805 ZNF407 Zornitza Stark Classified gene: ZNF407 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.2805 ZNF407 Zornitza Stark Gene: znf407 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.2804 ZNF407 Konstantinos Varvagiannis gene: ZNF407 was added
gene: ZNF407 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: ZNF407 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: ZNF407 were set to 24907849; 32737394; 23195952
Phenotypes for gene: ZNF407 were set to Global developmental delay; Intellectual disability
Penetrance for gene: ZNF407 were set to unknown
Review for gene: ZNF407 was set to AMBER
Added comment: You may consider inclusion of this gene probably with amber rating (or green if the evidence for biallelic variants is considered sufficient).

Biallelic variants:

- Kambouris et al. (2014 - PMID: 24907849) described 2 brothers with severe DD and ID, born to first cousin parents. Homozygosity mapping, following other non-diagnostic investigations (incl. aCGH), revealed 4 major homozygosity intervals. Exome sequencing in one identified 5 variants within these intervals, ZNF407 (c.5054C>G, p.Ser1685Trp) being the best candidate, supported also by segregation studies. The authors commented that zinc finger proteins act as transcriptional regulators, with mutations in genes encoding for other zinc finger proteins interfering with normal brain development.

- Zahra et al. (2020 - PMID: 32737394) report on 7 affected individuals (from 3 families) homozygous or compound heterozygous for ZNF407 variants. Features included hypotonia, DD and ID (in all) and variable occurrence of short stature (6/6), microcephaly (in at least 5), behavioural, visual problems and deafness. Linkage analysis in the first family revealed a 4.4 Mb shared homozygosity region and exome (30x) revealed a 3-bp duplication, confirmed by Sanger sequencing and segregating with the disease (NM_001146189:c.2814_2816dup, p.Val939dup). Affected subjects from the 2 other families were each found to be homozygous (c.2405G>T) or compound heterozygous (c.2884C>G, c.3642G>C) for other variants. Segregation was compatible in all families. Other studies were not performed. The authors comment than only the 3-bp duplication fullfilled ACMG criteria for classification as LP, the other variants being all formally classified as VUS (also due to in silico predictions predicting a LB effect). In addition, while several features such as DD/ID and short stature appeared to be frequent among all patients reported, Zahra et all comment that there was partial clinical overlap with the sibs described by Kambouris et al (additional variants?).


Monoallelic disruption of ZNF407:

- Ren et al (2013 - PMID: 23195952) described an 8 y.o. boy with ID and ASD. The boy was found to harbor a de novo translocation between chromosomes 3 and 18 [46,XY,t(3;18)(p13;q22.3)]. Array CGH did not reveal any P/LP CNV. Delineation of the breakpoints (FISH, long-range PCR) revealed that the chr18 breakpoint disrupted intron 3 of ZNF407 (isoform 1) with the other breakpoint within a gene-free region of exon 3. There was a loss of 4-8 nt in chr18 and 2-6 in chr3. Sequencing of ZNF407 did not reveal additional variants. RNA isolation in blood followed by RT-PCR studied expression of all 3 ZNF407 isoforms (the intronic region being shared by isoforms 1 and 2). Expression of isoform 1 was shown to be significantly reduced compared to controls. Isoform 2 was undetectable (in blood) while isoform 3 expression was similar to controls. Sequencing of 105 additional patients with similar clinical presentation (ID & ASD) revealed 2 further individuals with de novo missense variants.

- Based on the discussion by Kambouris et al (PMID: 24907849 - cited literature not here reviewed) ZNF407 may be deleted in patients with congenital aural atresia due to deletion of a critical region of 18q22.3 (though TSHZ1 is responsible for this phenotype) or 18q- although such deletions span several other genes (cited PMID: 16639285). In one case the breakpoint was shown to be disrupting ZNF407 (cited PMID: 24092497).

- The denovo db and Decipher (research variant tab) list few individuals with de novo ZNF407 SNVs although these do not seem to allow conclusions.

https://denovo-db.gs.washington.edu/denovo-db/QueryVariantServlet?searchBy=Gene&target=ZNF407
https://decipher.sanger.ac.uk/search/ddd-research-variants/results?q=znf407
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.2804 MAPK1 Zornitza Stark Marked gene: MAPK1 as ready
Intellectual disability syndromic and non-syndromic v0.2804 MAPK1 Zornitza Stark Gene: mapk1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.2804 MAPK1 Zornitza Stark Classified gene: MAPK1 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.2804 MAPK1 Zornitza Stark Gene: mapk1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.2803 MAPK1 Konstantinos Varvagiannis gene: MAPK1 was added
gene: MAPK1 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: MAPK1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: MAPK1 were set to 32721402
Phenotypes for gene: MAPK1 were set to Global developmental delay; Intellectual disability; Behavioral abnormality; Growth delay; Abnormality of the face; Abnormality of the neck; Abnormality of the cardiovascular system; Abnormality of the skin
Penetrance for gene: MAPK1 were set to unknown
Mode of pathogenicity for gene: MAPK1 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: MAPK1 was set to GREEN
Added comment: Motta et al (2020 - PMID: 32721402) report on 7 unrelated individuals harboring de novo missense MAPK1 pathogenic variants.

The phenotype corresponded to a neurodevelopmental disorder and - as the authors comment - consistently included DD, ID , behavioral problems. Postnatal growth delay was observed in approximately half. Hypertelorism, ptosis, downslant of palpebral fissures, wide nasal bridge as low-set/posteriorly rotated ears were among the facial features observed (each in 3 or more subjects within this cohort). Together with short/webbed neck and abnormalities of skin (lentigines / CAL spots) and growth delay these led to clinical suspicion of Noonan s. or disorder of the same pathway in some. Congenital heart defects (ASD, mitral valve insufficiency, though not cardiomyopathy) occurred in 4/7. Bleeding diathesis and lymphedema were reported only once.

MAPK1 encodes the mitogen-activated protein kinase 1 (also known as ERK2) a serine/threonine kinase of the RAS-RAF-MEK-(MAPK/)ERK pathway.

MAPK1 de novo variants were identified in all individuals following trio exome sequencing (and extensive previous genetic investigations which were non-diagnostic).

The distribution of variants, as well as in silico/vitro/vivo studies suggest a GoF effect (boosted signal through the MAPK cascade. MAPK signaling also upregulated in Noonan syndrome).

The authors comment that screening of 267 additional individuals with suspected RASopathy (without mutations in previously implicated genes) did not reveal other MAPK1 variants.

Overall this gene can be considered for inclusion in the ID panel with green rating.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.2803 ASPM Zornitza Stark Marked gene: ASPM as ready
Intellectual disability syndromic and non-syndromic v0.2803 ASPM Zornitza Stark Gene: aspm has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.2803 ASPM Zornitza Stark Phenotypes for gene: ASPM were changed from to Microcephaly 5, primary, autosomal recessive, MIM#608716
Intellectual disability syndromic and non-syndromic v0.2802 ASPM Zornitza Stark Publications for gene: ASPM were set to
Intellectual disability syndromic and non-syndromic v0.2801 ASPM Zornitza Stark Mode of inheritance for gene: ASPM was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.2800 ASPM Zornitza Stark reviewed gene: ASPM: Rating: GREEN; Mode of pathogenicity: None; Publications: 29243349, 19028728; Phenotypes: Microcephaly 5, primary, autosomal recessive, MIM#608716; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.2800 TUBB2A Zornitza Stark Marked gene: TUBB2A as ready
Intellectual disability syndromic and non-syndromic v0.2800 TUBB2A Zornitza Stark Gene: tubb2a has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.2800 TUBB2A Zornitza Stark Phenotypes for gene: TUBB2A were changed from to Cortical dysplasia, complex, with other brain malformations 5, MIM# 615763
Intellectual disability syndromic and non-syndromic v0.2799 TUBB2A Zornitza Stark Publications for gene: TUBB2A were set to
Intellectual disability syndromic and non-syndromic v0.2798 TUBB2A Zornitza Stark Mode of inheritance for gene: TUBB2A was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.2797 TUBB2A Zornitza Stark reviewed gene: TUBB2A: Rating: GREEN; Mode of pathogenicity: None; Publications: 32571897; Phenotypes: Cortical dysplasia, complex, with other brain malformations 5, MIM# 615763; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.2797 EEF1A2 Zornitza Stark Marked gene: EEF1A2 as ready
Intellectual disability syndromic and non-syndromic v0.2797 EEF1A2 Zornitza Stark Gene: eef1a2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.2797 EEF1A2 Zornitza Stark Phenotypes for gene: EEF1A2 were changed from to Epileptic encephalopathy, early infantile, 33, MIM# 616409; Mental retardation, autosomal dominant 38, MIM# 616393
Intellectual disability syndromic and non-syndromic v0.2796 EEF1A2 Zornitza Stark Publications for gene: EEF1A2 were set to
Intellectual disability syndromic and non-syndromic v0.2795 EEF1A2 Zornitza Stark Mode of pathogenicity for gene: EEF1A2 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 v0.2794 EEF1A2 Zornitza Stark Mode of inheritance for gene: EEF1A2 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.2793 EEF1A2 Zornitza Stark reviewed gene: EEF1A2: 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: 32160274; Phenotypes: Epileptic encephalopathy, early infantile, 33, MIM# 616409, Mental retardation, autosomal dominant 38, MIM# 616393; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.2793 TASP1 Zornitza Stark Phenotypes for gene: TASP1 were changed from Developmental delay; microcephaly; dysmorphic features; congenital abnormalities to Developmental delay; microcephaly; dysmorphic features; congenital abnormalities; Suleiman-El-Hattab syndrome, MIM#618950
Intellectual disability syndromic and non-syndromic v0.2792 TASP1 Zornitza Stark edited their review of gene: TASP1: Changed phenotypes: Developmental delay, microcephaly, dysmorphic features, congenital abnormalities, Suleiman-El-Hattab syndrome, MIM#618950
Intellectual disability syndromic and non-syndromic v0.2792 LARS Zornitza Stark Tag new gene name tag was added to gene: LARS.
Intellectual disability syndromic and non-syndromic v0.2792 LARS Zornitza Stark Marked gene: LARS as ready
Intellectual disability syndromic and non-syndromic v0.2792 LARS Zornitza Stark Added comment: Comment when marking as ready: HGNC approved name LARS1
Intellectual disability syndromic and non-syndromic v0.2792 LARS Zornitza Stark Gene: lars has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.2792 LARS Zornitza Stark Phenotypes for gene: LARS were changed from Infantile liver failure syndrome 1, MIM# 615438 to Infantile liver failure syndrome 1, MIM# 615438; Seizures; Intellectual disability; Encephalopathy
Intellectual disability syndromic and non-syndromic v0.2791 LARS Zornitza Stark Classified gene: LARS as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.2791 LARS Zornitza Stark Gene: lars has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.2790 LARS Konstantinos Varvagiannis gene: LARS was added
gene: LARS was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: LARS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LARS were set to 32699352
Phenotypes for gene: LARS were set to Infantile liver failure syndrome 1, MIM# 615438
Penetrance for gene: LARS were set to Complete
Review for gene: LARS was set to GREEN
Added comment: Please consider inclusion with amber/green rating in the current panel.

Biallelic pathogenic LARS1 variants cause Infantile liver failure syndrome 1, MIM# 615438.

Lenz et al (2020 - PMID: 32699352) review the phenotype of 25 affected individuals from 15 families.

Seizures occurred in 19/24 and were commonly associated with infections. Encephalopathic episodes (in 13 patients) accompanied by seizures up to status epilepticus occurred independently of hepatic decompensation.

In addition 22/24 presented with neurodevelopmental delay. The authors comment that cognitive impairment was present in 13/17 individuals (mild-severe) whereas most presented with learning disabilities.

These patients will most likely investigated for their liver disease (although presentation was highly variable and/or very mild in few).

The gene encodes a cytoplasmic amino-acyl tRNA synthetase (ARS) with neurologic manifestations observed in almost all patients (and seizures / DD and ID common to other disorders due to mutations in other genes encoding for ARSs).

Please note that the HGNC approved symbol for this gene is LARS1.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.2790 SMARCA2 Zornitza Stark Marked gene: SMARCA2 as ready
Intellectual disability syndromic and non-syndromic v0.2790 SMARCA2 Zornitza Stark Gene: smarca2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.2790 SMARCA2 Zornitza Stark Phenotypes for gene: SMARCA2 were changed from to Nicolaides-Baraitser syndrome, MIM #601358; Blepharophimosis-intellectual disability syndrome
Intellectual disability syndromic and non-syndromic v0.2789 SMARCA2 Zornitza Stark Publications for gene: SMARCA2 were set to
Intellectual disability syndromic and non-syndromic v0.2788 SMARCA2 Zornitza Stark Mode of pathogenicity for gene: SMARCA2 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 v0.2787 SMARCA2 Zornitza Stark Mode of inheritance for gene: SMARCA2 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.2786 MORC2 Zornitza Stark reviewed gene: MORC2: Rating: GREEN; Mode of pathogenicity: None; Publications: 32693025; Phenotypes: Intellectual disability; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.2786 MORC2 Zornitza Stark Marked gene: MORC2 as ready
Intellectual disability syndromic and non-syndromic v0.2786 MORC2 Zornitza Stark Gene: morc2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.2786 MORC2 Zornitza Stark Phenotypes for gene: MORC2 were changed from Charcot-Marie-Tooth disease, axonal, type 2Z, MIM #616688 to Charcot-Marie-Tooth disease, axonal, type 2Z, MIM #616688; Intellectual disability
Intellectual disability syndromic and non-syndromic v0.2785 MORC2 Zornitza Stark Publications for gene: MORC2 were set to https://doi.org/10.1016/j.ajhg.2020.06.013
Intellectual disability syndromic and non-syndromic v0.2784 MORC2 Zornitza Stark Classified gene: MORC2 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.2784 MORC2 Zornitza Stark Gene: morc2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.2783 SMARCA2 Konstantinos Varvagiannis reviewed gene: SMARCA2: 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: 26468571, 32694869; Phenotypes: Nicolaides-Baraitser syndrome, MIM #601358, Blepharophimosis-intellectual disability syndrome; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Intellectual disability syndromic and non-syndromic v0.2783 MORC2 Konstantinos Varvagiannis gene: MORC2 was added
gene: MORC2 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: MORC2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: MORC2 were set to https://doi.org/10.1016/j.ajhg.2020.06.013
Phenotypes for gene: MORC2 were set to Charcot-Marie-Tooth disease, axonal, type 2Z, MIM #616688
Penetrance for gene: MORC2 were set to unknown
Mode of pathogenicity for gene: MORC2 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: MORC2 was set to GREEN
Added comment: The current review is based on a recent report by Sacoto et al (2020 - https://doi.org/10.1016/j.ajhg.2020.06.013).

While several previous studies focused on the phenotype of axonal motor and senory neuropathy in individuals with heterozygous MORC2 pathogenic variants (Charcot-Marie-Tooth disease, axonal, type 2Z, MIM #616688) some of them presented among others with hypotonia, muscle weakness, intellectual disability, microcephaly or hearing loss [refs provided by Sacoto et al - learning disabilities (in some patients) also listed in OMIM's clinical synopsis].

Sacoto et al present a cohort of 20 individuals having genetic testing for developmental delay or growth failure (with a single one for a diagnosis of sensorimotor neuropathy).

Overlapping features included DD, ID (18/20 - mild to severe), short stature (18/20), microcephaly (15/20) and variable craniofacial dysmorphisms. The authors comment that features suggestive of neuropathy (weakness, hyporeflexia, abnormal EMG/NCS) were frequent but not the predominant complaint. EMG/NCS abnormalities were abnormal in 6 out of 10 subjects investigated in this cohort. Other findings included brain MRI abnormalities (12/18 - in 5/18 Leigh-like lesions), hearing loss (11/19) and pigmentary retinopathy in few (5).

Affected subjects were found to harbor in all cases missense variants in the ATPase module of MORC2 [residues 1 to 494 - NM_001303256.1 - the module consists of an ATPase domain (aa 1-265), a transducer S5-like domain (266-494) and a coiled-coiled domain (CC1 - aa 282-361)].

Variants had occured mostly as de novo events although inheritance from a similarly affected parent was also reported.

Some of them were recurring within this cohort and/or the literature eg. c.79G>A/p.Glu27Lys (x5), c.260C>T/p.Ser87Leu (x2), c.394C>T/p.Arg132Cys (4x), c.1164C>G/p.Ser388Arg (x2), c.1181A>G/p.Tyr394Cys (x3).

MORC2 encodes an ATPase involved in chromatin remodeling, DNA repair and transcriptional regulation. Chromatin remodeling and epigenetic silencing by MORC2 is mediated by the HUSH (Human Silencing Hub) complex. Functional studies (MORC2-knockout HeLa cells harboring a HUSH-sensitive GFP reporter were transduced with wt or mt MORC2 followed by measurement of reporter repression) supported the deleterious effect of most variants known at the time (hyperactivation of HUSH-mediating silencing, in line with previous observations).

Overall this gene can be considered for inclusion in the ID panel with green rating. Also other gene panels (e.g. for short stature, microcephaly, hearing loss, pigmentary retinopathy, etc) if it meets the respective criteria for inclusion.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.2783 HDAC8 Zornitza Stark Marked gene: HDAC8 as ready
Intellectual disability syndromic and non-syndromic v0.2783 HDAC8 Zornitza Stark Gene: hdac8 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.2783 HDAC8 Zornitza Stark Phenotypes for gene: HDAC8 were changed from to Cornelia de Lange syndrome 5, MIM# 300882
Intellectual disability syndromic and non-syndromic v0.2782 HDAC8 Zornitza Stark Publications for gene: HDAC8 were set to
Intellectual disability syndromic and non-syndromic v0.2781 HDAC8 Zornitza Stark Mode of inheritance for gene: HDAC8 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 v0.2780 HDAC8 Zornitza Stark reviewed gene: HDAC8: Rating: GREEN; Mode of pathogenicity: None; Publications: 30614194, 24403048; Phenotypes: Cornelia de Lange syndrome 5, MIM# 300882; 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 v0.2779 NSDHL Zornitza Stark Marked gene: NSDHL as ready
Intellectual disability syndromic and non-syndromic v0.2779 NSDHL Zornitza Stark Gene: nsdhl has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.2779 NSDHL Zornitza Stark Phenotypes for gene: NSDHL were changed from to CK syndrome (MIM#300831)
Intellectual disability syndromic and non-syndromic v0.2778 NSDHL Zornitza Stark Publications for gene: NSDHL were set to
Intellectual disability syndromic and non-syndromic v0.2777 NSDHL Zornitza Stark Mode of inheritance for gene: NSDHL was changed from Unknown to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability syndromic and non-syndromic v0.2776 NSDHL Crystle Lee reviewed gene: NSDHL: Rating: GREEN; Mode of pathogenicity: None; Publications: 21129721, 15689440, 25900314; Phenotypes: CK syndrome (MIM#300831); Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability syndromic and non-syndromic v0.2776 ZNF462 Zornitza Stark Phenotypes for gene: ZNF462 were changed from Weiss-Kruszka syndrome; OMIM# 618619 to Weiss-Kruszka syndrome, OMIM# 618619
Intellectual disability syndromic and non-syndromic v0.2775 ZNF462 Zornitza Stark Publications for gene: ZNF462 were set to PubMed: 31361404; 28513610
Intellectual disability syndromic and non-syndromic v0.2774 DEAF1 Zornitza Stark Marked gene: DEAF1 as ready
Intellectual disability syndromic and non-syndromic v0.2774 DEAF1 Zornitza Stark Gene: deaf1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.2774 DEAF1 Zornitza Stark Phenotypes for gene: DEAF1 were changed from to Neurodevelopmental disorder with hypotonia, impaired expressive language, and with or without seizures 617171; Vulto-van Silfout-de Vries syndrome 615828
Intellectual disability syndromic and non-syndromic v0.2773 DEAF1 Zornitza Stark Publications for gene: DEAF1 were set to
Intellectual disability syndromic and non-syndromic v0.2772 DEAF1 Zornitza Stark Mode of inheritance for gene: DEAF1 was changed from Unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.2771 DEAF1 Zornitza Stark reviewed gene: DEAF1: Rating: GREEN; Mode of pathogenicity: None; Publications: 30923367, 24726472, 26048982, 28940898, 26834045; Phenotypes: Neurodevelopmental disorder with hypotonia, impaired expressive language, and with or without seizures 617171, Vulto-van Silfout-de Vries syndrome 615828; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.2771 GRM7 Zornitza Stark Phenotypes for gene: GRM7 were changed from Epilepsy, microcephaly, developmental delay to Epilepsy, microcephaly, developmental delay; neurodevelopmental disorder with seizures, hypotonia, and brain imaging abnormalities (NEDSHBA), MIM#618922
Intellectual disability syndromic and non-syndromic v0.2770 GRM7 Zornitza Stark edited their review of gene: GRM7: Changed phenotypes: Epilepsy, microcephaly, developmental delay, neurodevelopmental disorder with seizures, hypotonia, and brain imaging abnormalities (NEDSHBA), MIM#618922
Intellectual disability syndromic and non-syndromic v0.2770 LHX3 Zornitza Stark Marked gene: LHX3 as ready