Activity

Filter

Cancel
Date Panel Item Activity
3000 actions
Intellectual disability v3.226 EIF2AK2 Arina Puzriakova Classified gene: EIF2AK2 as Amber List (moderate evidence)
Intellectual disability v3.226 EIF2AK2 Arina Puzriakova Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Intellectual disability v3.226 EIF2AK2 Arina Puzriakova Gene: eif2ak2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.225 EIF2AK2 Arina Puzriakova Tag for-review tag was added to gene: EIF2AK2.
Intellectual disability v3.225 EIF2AK2 Arina Puzriakova reviewed gene: EIF2AK2: Rating: GREEN; Mode of pathogenicity: None; Publications: 32197074; Phenotypes: Leukoencephalopathy, developmental delay, and episodic neurologic regression syndrome, 618877; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.225 FARSB Arina Puzriakova Classified gene: FARSB as Amber List (moderate evidence)
Intellectual disability v3.225 FARSB Arina Puzriakova Added comment: Comment on list classification: Rating Amber following consultation with the clinical team in view of the inconsistent phenotype. Patients are more likely to be recognised on the basis of other phenotypic features, for which FARSB has been rated Green
Intellectual disability v3.225 FARSB Arina Puzriakova Gene: farsb has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.224 FARSB Arina Puzriakova reviewed gene: FARSB: Rating: AMBER; Mode of pathogenicity: None; Publications: 29573043, 29979980, 30014610; Phenotypes: Rajab interstitial lung disease with brain calcifications, 613658; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.224 IREB2 Arina Puzriakova Tag watchlist tag was added to gene: IREB2.
Intellectual disability v3.224 IREB2 Arina Puzriakova Classified gene: IREB2 as Amber List (moderate evidence)
Intellectual disability v3.224 IREB2 Arina Puzriakova Added comment: Comment on list classification: Phenotype is appropriate for this panel, but additional cases necessary to support causation. Therefore rated Amber, awaiting further publications/clinical evidence (added to watchlist).
Intellectual disability v3.224 IREB2 Arina Puzriakova Gene: ireb2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.223 IREB2 Arina Puzriakova reviewed gene: IREB2: Rating: ; Mode of pathogenicity: None; Publications: 30915432, 31243445; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.223 CHD1 Arina Puzriakova changed review comment from: Gene is associated with Pilarowski-Bjornsson syndrome in OMIM, but not in G2P.

Pilarowski et al (2018) (PMID: 28866611) reported heterozygous missense variants in five individuals (two sibs and three singletons) as the cause of developmental delay, speech apraxia, hypotonia, and facial dysmorphic features. Two variants were confirmed de novo, while segregation for others could not be determined (including the two sibs who were conceived by egg donor). Developmental delay was noted for all participants; however, ID was only reported in the two sibs.; to: Gene is associated with Pilarowski-Bjornsson syndrome in OMIM, but not in G2P.

Pilarowski et al (2018) (PMID: 28866611) reported heterozygous missense variants in five individuals (two sibs and three singletons) as the cause of developmental delay, speech apraxia, hypotonia, and facial dysmorphic features. Two variants were confirmed de novo, while segregation for others could not be determined (including the two sibs who were conceived by egg donor). Developmental delay was noted for all participants; however, ID was only reported in the two sibs. Further insight may be gained from re-evaluation of the two patients in the present study who were too young for a formal neurocognitive evaluation at the time of publication.
Intellectual disability v3.223 CHD1 Arina Puzriakova Classified gene: CHD1 as Amber List (moderate evidence)
Intellectual disability v3.223 CHD1 Arina Puzriakova Added comment: Comment on list classification: Phenotype is appropriate for the panel, but insufficient cases to support causation (ID only reported in two sibs). Therefore rated Amber, awaiting further publications/clinical evidence.
Intellectual disability v3.223 CHD1 Arina Puzriakova Gene: chd1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.222 CHD1 Arina Puzriakova reviewed gene: CHD1: Rating: ; Mode of pathogenicity: None; Publications: 28866611; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.222 PAM16 Arina Puzriakova Tag founder-effect tag was added to gene: PAM16.
Intellectual disability v3.222 PAM16 Arina Puzriakova Classified gene: PAM16 as Amber List (moderate evidence)
Intellectual disability v3.222 PAM16 Arina Puzriakova Added comment: Comment on list classification: Three unrelated cases, but two share the same founder mutation - Rating Amber until further cases are reported (added to watchlist).
Intellectual disability v3.222 PAM16 Arina Puzriakova Gene: pam16 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.221 PAM16 Arina Puzriakova Tag watchlist tag was added to gene: PAM16.
Intellectual disability v3.221 PAM16 Arina Puzriakova reviewed gene: PAM16: Rating: ; Mode of pathogenicity: None; Publications: 24786642, 27354339; Phenotypes: Spondylometaphyseal dysplasia, Megarbane-Dagher-Melike type, 613320; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.221 NDUFA2 Arina Puzriakova Classified gene: NDUFA2 as Amber List (moderate evidence)
Intellectual disability v3.221 NDUFA2 Arina Puzriakova Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review - at least four unrelated cases reported with DD/ID, mostly following a period of regression.
Intellectual disability v3.221 NDUFA2 Arina Puzriakova Gene: ndufa2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.220 NDUFA2 Arina Puzriakova Tag watchlist was removed from gene: NDUFA2.
Tag for-review tag was added to gene: NDUFA2.
Intellectual disability v3.220 NDUFA2 Arina Puzriakova Tag watchlist tag was added to gene: NDUFA2.
Intellectual disability v3.220 NDUFA2 Arina Puzriakova reviewed gene: NDUFA2: Rating: GREEN; Mode of pathogenicity: None; Publications: 18513682, 28857146, 32154054; Phenotypes: Mitochondrial complex I deficiency, nuclear type 13, 618235; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.220 NDUFAF1 Arina Puzriakova Classified gene: NDUFAF1 as Amber List (moderate evidence)
Intellectual disability v3.220 NDUFAF1 Arina Puzriakova Added comment: Comment on list classification: Additional case of ID required before inclusion of NDUFAF1 on a diagnostic panel (added to watchlist).
Intellectual disability v3.220 NDUFAF1 Arina Puzriakova Gene: ndufaf1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.219 NDUFAF1 Arina Puzriakova Tag watchlist tag was added to gene: NDUFAF1.
Intellectual disability v3.219 NDUFAF1 Arina Puzriakova reviewed gene: NDUFAF1: Rating: ; Mode of pathogenicity: None; Publications: 17557076, 21931170, 24963768; Phenotypes: Mitochondrial complex I deficiency, nuclear type 11, 618234; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.219 NARS Konstantinos Varvagiannis changed review comment from: [Please note that HGNC Approved Gene Symbol for this gene is NARS1]

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

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

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

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

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

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

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

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

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

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

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

As also Manole et al suggest, NARS1 can be considered for inclusion in gene panels for DD/ID, epilepsy and/or demyelinating neuropathy.
Sources: Literature
Intellectual disability v3.219 NARS Konstantinos Varvagiannis gene: NARS was added
gene: NARS was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: NARS was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: NARS were set to 32738225
Phenotypes for gene: NARS were set to Abnormal muscle tone; Microcephaly; Global developmental delay; Intellectual disability; Seizures; Ataxia; Abnormality of the face; Demyelinating peripheral neuropathy
Penetrance for gene: NARS were set to Complete
Review for gene: NARS was set to GREEN
Added comment: [Please note that HGNC Approved Gene Symbol for this gene is NARS1]

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

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

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

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

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

As also Manole et al suggest, NARS1 can be considered for inclusion in gene panels for DD/ID, epilepsy and/or demyelinating neuropathy.
Sources: Literature
Intellectual disability v3.219 ZNF407 Konstantinos Varvagiannis gene: ZNF407 was added
gene: ZNF407 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: ZNF407 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: ZNF407 were set to 24907849; 32737394; 23195952
Phenotypes for gene: ZNF407 were set to Global developmental delay; Intellectual disability
Penetrance for gene: ZNF407 were set to unknown
Review for gene: ZNF407 was set to AMBER
Added comment: You may consider inclusion of this gene probably with amber rating (or green if the evidence for biallelic variants is considered sufficient).

Biallelic variants:

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

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


Monoallelic disruption of ZNF407:

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

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

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

https://denovo-db.gs.washington.edu/denovo-db/QueryVariantServlet?searchBy=Gene&target=ZNF407
https://decipher.sanger.ac.uk/search/ddd-research-variants/results?q=znf407
Sources: Literature
Intellectual disability v3.219 MAPK1 Konstantinos Varvagiannis gene: MAPK1 was added
gene: MAPK1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: MAPK1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: MAPK1 were set to 32721402
Phenotypes for gene: MAPK1 were set to Global developmental delay; Intellectual disability; Behavioral abnormality; Growth delay; Abnormality of the face; Abnormality of the neck; Abnormality of the cardiovascular system; Abnormality of the skin
Penetrance for gene: MAPK1 were set to unknown
Mode of pathogenicity for gene: MAPK1 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: MAPK1 was set to GREEN
Added comment: Motta et al (2020 - PMID: 32721402) report on 7 unrelated individuals harboring de novo missense MAPK1 pathogenic variants.

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

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

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

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

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

Overall this gene can be considered for inclusion in the ID panel with green rating.
Sources: Literature
Intellectual disability v3.219 NCAPH Arina Puzriakova Classified gene: NCAPH as Red List (low evidence)
Intellectual disability v3.219 NCAPH Arina Puzriakova Added comment: Comment on list classification: Additional cases are required to substantiate causation but added to watchlist.
Intellectual disability v3.219 NCAPH Arina Puzriakova Gene: ncaph has been classified as Red List (Low Evidence).
Intellectual disability v3.218 NCAPH Arina Puzriakova gene: NCAPH was added
gene: NCAPH was added to Intellectual disability. Sources: Literature
watchlist tags were added to gene: NCAPH.
Mode of inheritance for gene: NCAPH was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NCAPH were set to 27737959
Phenotypes for gene: NCAPH were set to Microcephaly 23, primary, autosomal recessive, 617985
Added comment: Associated with Microcephaly 23 in OMIM and a possible gene for microcephaly in G2P.

PMID: 27737959 (2016) - A homozygous missense variant in NCAPH (c.728C>T, p.Pro243Leu) was detected in a 42-year-old male with microcephaly (OFC -4.2 SD) and moderate ID. Functional studies indicated that although the variant did not affect cellular protein levels, it disrupted condensin-dependent mitotic chromosome integrity, providing supporting evidence for pathogenicity. Biallelic variants in other genes encoding subunits of the two condensin complexes result in a similar phenotype.
Sources: Literature
Intellectual disability v3.217 NCAPG2 Arina Puzriakova Classified gene: NCAPG2 as Amber List (moderate evidence)
Intellectual disability v3.217 NCAPG2 Arina Puzriakova Added comment: Comment on list classification: Additional cases required to ascertain the contribution of NCAPG2 variants to an ID phenotype.
Intellectual disability v3.217 NCAPG2 Arina Puzriakova Gene: ncapg2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.216 NCAPG2 Arina Puzriakova reviewed gene: NCAPG2: Rating: AMBER; Mode of pathogenicity: None; Publications: 30609410; Phenotypes: Khan-Khan-Katsanis syndrome, 618460; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.216 NCAPD2 Arina Puzriakova Tag watchlist tag was added to gene: NCAPD2.
Intellectual disability v3.216 NCAPD2 Arina Puzriakova Classified gene: NCAPD2 as Amber List (moderate evidence)
Intellectual disability v3.216 NCAPD2 Arina Puzriakova Added comment: Comment on list classification: Amber rating as only one patient has been described with severe ID. However, added to watchlist in case of new reports of more significant cases of ID. Gene has also been added with a Green rating on the Severe Microcephaly panel.
Intellectual disability v3.216 NCAPD2 Arina Puzriakova Gene: ncapd2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.215 NCAPD2 Arina Puzriakova reviewed gene: NCAPD2: Rating: AMBER; Mode of pathogenicity: None; Publications: 27737959, 28097321, 31056748; Phenotypes: Microcephaly 21, primary, autosomal recessive, 617983; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.215 HADHB Arina Puzriakova Classified gene: HADHB as Amber List (moderate evidence)
Intellectual disability v3.215 HADHB Arina Puzriakova Added comment: Comment on list classification: Rating Amber following consultation with the clinical team, in view of the borderline ID phenotype. Cases are more likely to be recognised on the basis of the metabolic phenotype, for which this gene is Green already.
Intellectual disability v3.215 HADHB Arina Puzriakova Gene: hadhb has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.214 HADHB Arina Puzriakova reviewed gene: HADHB: Rating: AMBER; Mode of pathogenicity: None; Publications: 12754706, 19699128; Phenotypes: Trifunctional protein deficiency, 609015; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.214 MN1 Arina Puzriakova Tag for-review tag was added to gene: MN1.
Intellectual disability v3.214 MN1 Arina Puzriakova Classified gene: MN1 as Amber List (moderate evidence)
Intellectual disability v3.214 MN1 Arina Puzriakova Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Intellectual disability v3.214 MN1 Arina Puzriakova Gene: mn1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.213 VPS51 Arina Puzriakova Classified gene: VPS51 as Amber List (moderate evidence)
Intellectual disability v3.213 VPS51 Arina Puzriakova Added comment: Comment on list classification: Additional cases are required before inclusion of VPS51 on a diagnostic panel; however, gene added to watchlist.
Intellectual disability v3.213 VPS51 Arina Puzriakova Gene: vps51 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.212 VPS51 Arina Puzriakova reviewed gene: VPS51: Rating: AMBER; Mode of pathogenicity: None; Publications: 30624672, 31207318; Phenotypes: Pontocerebellar hypoplasia, type 13, 618606; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.212 LRRC32 Arina Puzriakova changed review comment from: Not associated with phenotype in OMIM or G2P.

PMID: 30976112 (2019) - homozygous stop-gain variant in LRRC32 (c.1630C>T; p.Arg544Ter) in three affected individuals from two families with global developmental delay, cleft palate, and proliferative retinopathy. In one family developmental quotient (DQ) varied from borderline low in the female (DQ = 72 at 3 years-2 months) to severely delayed in the male (DQ = 57 at 2 years-11 months). The male in the second family was even more severely delayed (DQ = 23 at 3 years-3 months).

Haplotype analysis indicates a founder effect, and therefore further cases are required to substantiate causation.; to: Not associated with phenotype in OMIM or G2P.

PMID: 30976112 (2019) - homozygous stop-gain variant in LRRC32 (c.1630C>T; p.Arg544Ter) in three affected individuals from two families with global developmental delay, cleft palate, and proliferative retinopathy. In one family developmental quotient (DQ) varied from borderline low in the female (DQ = 72 at 3 years-2 months) to severely delayed in the male (DQ = 57 at 2 years-11 months). The male in the second family was even more severely delayed (DQ = 23 at 3 years-3 months).

Haplotype analysis indicates a founder effect, and therefore further cases are required to substantiate causation (added founder-effect tag).
Intellectual disability v3.212 LRRC32 Arina Puzriakova Tag founder-effect tag was added to gene: LRRC32.
Intellectual disability v3.212 LRRC32 Arina Puzriakova Classified gene: LRRC32 as Red List (low evidence)
Intellectual disability v3.212 LRRC32 Arina Puzriakova Added comment: Comment on list classification: Rated Red as there is not currently enough evidence that other variants in the LRRC32 gene are disease causing.
Intellectual disability v3.212 LRRC32 Arina Puzriakova Gene: lrrc32 has been classified as Red List (Low Evidence).
Intellectual disability v3.211 LRRC32 Arina Puzriakova reviewed gene: LRRC32: Rating: RED; Mode of pathogenicity: None; Publications: 30976112; Phenotypes: Global developmental delay, Speech delay, Hypotonia, Cleft palate, Proliferative retinopathy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.211 LMAN2L Arina Puzriakova Classified gene: LMAN2L as Amber List (moderate evidence)
Intellectual disability v3.211 LMAN2L Arina Puzriakova Added comment: Comment on list classification: Two families with ID phenotype (one mild, one severe). Amber rating as additional cases and functional data are required to validate the causal association with the phenotype.
Intellectual disability v3.211 LMAN2L Arina Puzriakova Gene: lman2l has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.210 LMAN2L Arina Puzriakova Tag watchlist tag was added to gene: LMAN2L.
Intellectual disability v3.210 LAMB2 Arina Puzriakova Classified gene: LAMB2 as Amber List (moderate evidence)
Intellectual disability v3.210 LAMB2 Arina Puzriakova Added comment: Comment on list classification: Given the incomplete penetrance of the ID phenotype, these patients are more likely to be recognised on the basis of the renal phenotype and ocular abnormalilites - LAMB2 has a Green rating on these panels, while an Amber classification might be most appropriate for the ID panel.
Intellectual disability v3.210 LAMB2 Arina Puzriakova Gene: lamb2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.209 LAMB2 Arina Puzriakova reviewed gene: LAMB2: Rating: AMBER; Mode of pathogenicity: None; Publications: 15367484, 17256789; Phenotypes: Pierson syndrome, 609049; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.209 TUBB2A Arina Puzriakova reviewed gene: TUBB2A: Rating: GREEN; Mode of pathogenicity: None; Publications: 32571897; Phenotypes: Cortical dysplasia, complex, with other brain malformations 5, 615763; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.209 NGLY1 Eleanor Williams reviewed gene: NGLY1: Rating: ; Mode of pathogenicity: None; Publications: 32259258; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.209 SETD1B Arina Puzriakova reviewed gene: SETD1B: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.209 EEF1A2 Eleanor Williams changed review comment from: PMID: 32160274 - Davies et al 2020 - several reports of de novo missense mutations in EEF1A2 associated with neurodevelopmental disorders but no clear loss of function mutations. They created mice with a missense mutation in EEF1A2 (D252H) in both heterozygous and homozygous state and EEF1AS null mutant mice and analysed using behavioural and motor phenotyping alongside molecular modelling and analysis of binding partners. They found the D252H homozygous mice were more severely affected than null homozygotes on the same genetic background. The results suggest that the D252H mutation results in a gain of function.; to: PMID: 32160274 - Davies et al 2020 - several reports of de novo missense mutations in EEF1A2 associated with neurodevelopmental disorders but no clear loss of function mutations. They created mice with a missense mutation in EEF1A2 (D252H) in both heterozygous and homozygous state and EEF1A2 null mutant mice and analysed using behavioural and motor phenotyping alongside molecular modelling and analysis of binding partners. They found the D252H homozygous mice were more severely affected than null homozygotes on the same genetic background. The results suggest that the D252H mutation results in a gain of function.
Intellectual disability v3.209 EEF1A2 Eleanor Williams Tag for-review tag was added to gene: EEF1A2.
Intellectual disability v3.209 EEF1A2 Eleanor Williams reviewed gene: EEF1A2: Rating: ; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: 32160274; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.209 HERC2 Arina Puzriakova Tag for-review tag was added to gene: HERC2.
Intellectual disability v3.209 HERC2 Arina Puzriakova Classified gene: HERC2 as Amber List (moderate evidence)
Intellectual disability v3.209 HERC2 Arina Puzriakova Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review - more than 3 distinct variants in unrelated cases presenting the relevant phenotype.
Intellectual disability v3.209 HERC2 Arina Puzriakova Gene: herc2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.208 IFT27 Arina Puzriakova Classified gene: IFT27 as Amber List (moderate evidence)
Intellectual disability v3.208 IFT27 Arina Puzriakova Added comment: Comment on list classification: Given the mild ID phenotype, IFT27 is classified Amber on this panel. Patients are more likely to be recognised in view of other features (e.g. Limb disorders panel), for which this gene is Green.
Intellectual disability v3.208 IFT27 Arina Puzriakova Gene: ift27 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.207 IFT27 Arina Puzriakova reviewed gene: IFT27: Rating: AMBER; Mode of pathogenicity: None; Publications: 24488770, 30761183, 29588463; Phenotypes: Bardet-Biedl syndrome 19, 615996; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.207 HNMT Arina Puzriakova Classified gene: HNMT as Amber List (moderate evidence)
Intellectual disability v3.207 HNMT Arina Puzriakova Added comment: Comment on list classification: Amber rating as additional unrelated pedigrees are required before inclusion of HNMT on a diagnostic panel (added to watchlist).
Intellectual disability v3.207 HNMT Arina Puzriakova Gene: hnmt has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.206 HNMT Arina Puzriakova Tag watchlist tag was added to gene: HNMT.
Intellectual disability v3.206 HNMT Arina Puzriakova reviewed gene: HNMT: Rating: AMBER; Mode of pathogenicity: None; Publications: 26206890; Phenotypes: Intellectual disability, Mental retardation, 616739; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.206 GNE Arina Puzriakova Classified gene: GNE as Amber List (moderate evidence)
Intellectual disability v3.206 GNE Arina Puzriakova Added comment: Comment on list classification: Rating Amber in view of the mild ID phenotype.
Intellectual disability v3.206 GNE Arina Puzriakova Gene: gne has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.205 GNE Arina Puzriakova reviewed gene: GNE: Rating: AMBER; Mode of pathogenicity: None; Publications: 32053088, 29923088, 10356312, 11326336, 11486897, 27142465; Phenotypes: Sialuria, 269921; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.205 EXOSC8 Arina Puzriakova Classified gene: EXOSC8 as Amber List (moderate evidence)
Intellectual disability v3.205 EXOSC8 Arina Puzriakova Added comment: Comment on list classification: Three unrelated cases, but two share the same founder mutation - Rating Amber until further cases are reported (added to watchlist).
Intellectual disability v3.205 EXOSC8 Arina Puzriakova Gene: exosc8 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.204 EXOSC8 Arina Puzriakova Tag watchlist tag was added to gene: EXOSC8.
Tag founder-effect tag was added to gene: EXOSC8.
Intellectual disability v3.204 EXOSC8 Arina Puzriakova reviewed gene: EXOSC8: Rating: AMBER; Mode of pathogenicity: None; Publications: 24989451; Phenotypes: Pontocerebellar hypoplasia type 1C, 616081; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.204 DSCR3 Arina Puzriakova commented on gene: DSCR3: Added new-gene-name tag, new approved HGNC gene symbol is VPS26C.
Intellectual disability v3.204 DSCR3 Arina Puzriakova Tag new-gene-name tag was added to gene: DSCR3.
Intellectual disability v3.204 DSCR3 Arina Puzriakova Classified gene: DSCR3 as Red List (low evidence)
Intellectual disability v3.204 DSCR3 Arina Puzriakova Added comment: Comment on list classification: Currently not associated with any phenotype in OMIM or G2P. Variants only found in one family - additional cases required to validate pathogenicity.
Intellectual disability v3.204 DSCR3 Arina Puzriakova Gene: dscr3 has been classified as Red List (Low Evidence).
Intellectual disability v3.203 ATP6AP1 Arina Puzriakova Classified gene: ATP6AP1 as Amber List (moderate evidence)
Intellectual disability v3.203 ATP6AP1 Arina Puzriakova Added comment: Comment on list classification: Unclear whether other ATP6AP1 variants are associated with a neurological phenotype. Amber rating in view of the mild ID phenotype, as a more significant, or consistent pattern, of DD/ID is required (added to watchlist).
Intellectual disability v3.203 ATP6AP1 Arina Puzriakova Gene: atp6ap1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.202 ATP6AP1 Arina Puzriakova Tag watchlist tag was added to gene: ATP6AP1.
Intellectual disability v3.202 ATP6AP1 Arina Puzriakova reviewed gene: ATP6AP1: Rating: AMBER; Mode of pathogenicity: None; Publications: 27231034; Phenotypes: Immunodeficiency, 300972, Hepatopathy, Intellectual disability, Cutis laxa, Epilepsy; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability v3.202 PDE10A Arina Puzriakova Classified gene: PDE10A as Amber List (moderate evidence)
Intellectual disability v3.202 PDE10A Arina Puzriakova Added comment: Comment on list classification: Only mild cognitive delay reported in one family. Additional cases with a more significant, or consistent pattern, of DD/ID required to ascertain the contribution of PDE10A variants to an ID phenotype.
Intellectual disability v3.202 PDE10A Arina Puzriakova Gene: pde10a has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.201 PDE10A Arina Puzriakova reviewed gene: PDE10A: Rating: AMBER; Mode of pathogenicity: None; Publications: 27058446; Phenotypes: Dyskinesia, limb and orofacial, infantile-onset, 616921; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.201 LARS Konstantinos Varvagiannis gene: LARS was added
gene: LARS was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: LARS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LARS were set to 32699352
Phenotypes for gene: LARS were set to Infantile liver failure syndrome 1, MIM# 615438
Penetrance for gene: LARS were set to Complete
Review for gene: LARS was set to GREEN
Added comment: Please consider inclusion with amber/green rating in the current panel.

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

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

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

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

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

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

Please note that the HGNC approved symbol for this gene is LARS1.
Sources: Literature
Intellectual disability v3.201 SMARCA2 Konstantinos Varvagiannis reviewed gene: SMARCA2: Rating: GREEN; Mode of pathogenicity: None; Publications: 32694869; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.201 MORC2 Konstantinos Varvagiannis gene: MORC2 was added
gene: MORC2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: MORC2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: MORC2 were set to https://doi.org/10.1016/j.ajhg.2020.06.013
Phenotypes for gene: MORC2 were set to Charcot-Marie-Tooth disease, axonal, type 2Z, MIM #616688
Penetrance for gene: MORC2 were set to unknown
Mode of pathogenicity for gene: MORC2 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: MORC2 was set to GREEN
Added comment: The current review is based on a recent report by Sacoto et al (2020 - https://doi.org/10.1016/j.ajhg.2020.06.013).

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

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

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

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

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

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

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

Overall this gene can be considered for inclusion in the ID panel with green rating. Also other gene panels (e.g. for short stature, microcephaly, hearing loss, pigmentary retinopathy, etc) if it meets the respective criteria for inclusion.
Sources: Literature
Intellectual disability v3.201 HIST1H4J Arina Puzriakova changed review comment from: This is a possible gene for intellectual disability with facial dysmorphism in G2P.

Tessadori et al. (2020) (PMID: 31804630) reported a 14-year old Hispanic male with profound intellectual disability, who was heterozygous for a de novo (c.274 A>G, p.K91E) variant in HIST1H4J. Clinical features were said to resemble those reported in patients with HIST1H4C variants, which encodes an identical H4 protein to that of HIST1H4J. Functional data obtained in zebrafish showed the missense variant caused developmental defects, specifically resulting in defective head structures and reduced body axis length.; to: Added new-gene-name tag, new approved HGNC gene symbol is H4C11.

This is a possible gene for intellectual disability with facial dysmorphism in G2P.

Tessadori et al. (2020) (PMID: 31804630) reported a 14-year old Hispanic male with profound intellectual disability, who was heterozygous for a de novo (c.274 A>G, p.K91E) variant in HIST1H4J. Clinical features were said to resemble those reported in patients with HIST1H4C variants, which encodes an identical H4 protein to that of HIST1H4J. Functional data obtained in zebrafish showed the missense variant caused developmental defects, specifically resulting in defective head structures and reduced body axis length.
Intellectual disability v3.201 HIST1H4J Arina Puzriakova Classified gene: HIST1H4J as Amber List (moderate evidence)
Intellectual disability v3.201 HIST1H4J Arina Puzriakova Added comment: Comment on list classification: Amber rating as additional cases are required to validate pathogenicity, but added to watchlist.
Intellectual disability v3.201 HIST1H4J Arina Puzriakova Gene: hist1h4j has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.200 HIST1H4J Arina Puzriakova reviewed gene: HIST1H4J: Rating: AMBER; Mode of pathogenicity: None; Publications: 31804630; Phenotypes: Microcephaly, Intellectual disability, Dysmorphic facial features, Growth delay; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.200 ADAMTS10 Arina Puzriakova edited their review of gene: ADAMTS10: Changed publications: 15368195, 18567016, 19836009, 25469541
Intellectual disability v3.200 ADAMTS10 Arina Puzriakova Classified gene: ADAMTS10 as Amber List (moderate evidence)
Intellectual disability v3.200 ADAMTS10 Arina Puzriakova Added comment: Comment on list classification: While mild ID is reportedly a phenotypic feature associated with Weill–Marchesani syndrome, this is not evident in the literature cases. Therefore, a more consistent and/or significant pattern of ID is necessary for inclusion of ADAMTS10 on a diagnostic ID panel.
Intellectual disability v3.200 ADAMTS10 Arina Puzriakova Gene: adamts10 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.199 ADAMTS10 Arina Puzriakova reviewed gene: ADAMTS10: Rating: AMBER; Mode of pathogenicity: None; Publications: 15368195, 18567016, 19836009; Phenotypes: Weill-Marchesani syndrome, 277600; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.199 TOMM70 Eleanor Williams Classified gene: TOMM70 as Amber List (moderate evidence)
Intellectual disability v3.199 TOMM70 Eleanor Williams Added comment: Comment on list classification: After consultation with the Genomics England clinical team it was decided to rate this gene as Amber for now, until a clearer phenotype is established and the predominant mode of inheritance is determined.
Intellectual disability v3.199 TOMM70 Eleanor Williams Gene: tomm70 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.198 LZTFL1 Arina Puzriakova Classified gene: LZTFL1 as Amber List (moderate evidence)
Intellectual disability v3.198 LZTFL1 Arina Puzriakova Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Intellectual disability v3.198 LZTFL1 Arina Puzriakova Gene: lztfl1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.197 LZTFL1 Arina Puzriakova changed review comment from: Associated with phenotype in OMIM and probable in G2P. Biallelic variants in the LZTFL1 gene are an established cause of BBS17, with supporting functional data. Cognitive impairment is a feature of the BBS17 associated phenotype in all cases reported to date. Two families have been reported in literature - PMID: 22510444 (2012) - cognitive impairment reported in a 10-year-old BBS17 patient, harbouring a homozygous 5 bp deletion leading to a premature stop codon (c.402-406del, p.Pro136ThrfsX5) in LZTFL1.; to: Associated with phenotype in OMIM and probable in G2P.

Biallelic variants in the LZTFL1 gene are an established cause of BBS17, with supporting functional data. Cognitive impairment is a feature of the BBS17 associated phenotype in all cases reported in literature to date:

PMID: 22510444 (2012) - cognitive impairment reported in a 10-year-old BBS17 patient, harbouring a homozygous 5 bp deletion leading to a premature stop codon (c.402-406del, p.Pro136ThrfsX5) in LZTFL1.

PMID: 23692385 (2014) - cognitive impairment reported in a pair of dizygotic twins with two compound heterozygous LZTFL1 variants ([c.260T>C, p.Leu87Pro];[c.778G>T, p.Glu260*]). One twin was said to have learning difficulties since childhood. She attended a specialised school, and at the age of 36, her educational level was equivalent to the elementary school level. The second twin was also reported to have scholastic difficulties and slowness with an educational level equivalent to primary school.
Intellectual disability v3.197 LYRM7 Arina Puzriakova Classified gene: LYRM7 as Amber List (moderate evidence)
Intellectual disability v3.197 LYRM7 Arina Puzriakova Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Intellectual disability v3.197 LYRM7 Arina Puzriakova Gene: lyrm7 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.196 LYRM7 Arina Puzriakova Tag for-review tag was added to gene: LYRM7.
Intellectual disability v3.196 LYRM7 Arina Puzriakova changed review comment from: PMID: 24014394 (2013) - Homozygous variant (c.73G>A) in LYRM7 identified in a patient with normal initial development until the first 20 months of life, when she presented rapid deterioration which included severe psychomotor regression. Functional studies performed in yeast indicate functional impairment. PMID: 26912632 (2016) - Six distinct homozygous variants in the LYRM7 gene were identified in seven affected individuals (including 2 sibs). Initial cognitive development was delayed in three patients and borderline in one.; to: PMID: 24014394 (2013) - Homozygous variant (c.73G>A) in LYRM7 identified in a patient with normal initial development until the first 20 months of life, when she presented rapid deterioration which included severe psychomotor regression. Functional studies performed in yeast indicate functional impairment.

PMID: 26912632 (2016) - Six distinct homozygous variants in the LYRM7 gene were identified in seven affected individuals (including 2 sibs). Initial cognitive development was delayed in three patients and borderline in one. Continued development was delayed to variable degrees in five individuals, and all were said to have impaired intelligence at the time of the most recent assessment (aged 2.5-16 yrs).

PMID: 28694194 (2017) - Three affected family members with homozygosity for a splice site deletion (c.243_244+2delGAGT) in LYRM7. Development was normal for the first few months of life, however all experienced a rapidly progressive clinical course which included profound impairment of psychomotor and mental functions.
Intellectual disability v3.196 LIPT1 Arina Puzriakova Classified gene: LIPT1 as Amber List (moderate evidence)
Intellectual disability v3.196 LIPT1 Arina Puzriakova Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review - cognitive impairment has been reported in more than 3 unrelated surviving patients.
Intellectual disability v3.196 LIPT1 Arina Puzriakova Gene: lipt1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.195 LIPT1 Arina Puzriakova Tag for-review tag was added to gene: LIPT1.
Intellectual disability v3.195 LIPT1 Arina Puzriakova changed review comment from: Associated with phenotype in OMIM and probable for Leigh syndrome with secondary deficiency for pyruvate and alpha-ketoglutarate dehydrogenase in G2P. LIPT1 deficiency, resulting from bi-allelic variants, is associated with developmental delay, epilepsy, and broad metabolic abnormalities. To date, five unrelated families have been reported with at least one affected child. PMID: 24341803 (2013) - In a boy with LIPT1 deficiency, exome sequencing revealed two heterozygous mutations (c.875C>G and c.535A>G). Psychomotor development was delayed from birth, but sudden further regression occurred at 18 months.; to: Associated with phenotype in OMIM and probable for Leigh syndrome with secondary deficiency for pyruvate and alpha-ketoglutarate dehydrogenase in G2P.

LIPT1 deficiency, resulting from biallelic variants, is associated with developmental delay, epilepsy, and broad metabolic abnormalities. To date, five unrelated families have been reported with at least one affected child.

PMID: 24341803 (2013) - In a boy with LIPT1 deficiency, exome sequencing revealed two compound heterozygous variants (c.875C>G and c.535A>G). Psychomotor development was delayed from birth, but sudden further regression occurred at 18 months. He could not speak but understood simple orders. He was otherwise fully conscious, alert, and he could smile, laugh and follow with eyes. Supporting functional data, including a yeast model.

PMID: 29681092 (2018) – Compound heterozygous variants (c.212C>T and c.539T>C) identified in a male with seizures, severe lactic acidosis, and failure to thrive. Initially he was reportedly developmentally normal; however, due to subsequent neurodevelopmental regression, he had global developmental delays by 21-months-of-age.

PMID 31042466 (2019) – In an 8-year-old female with developmental delay, seizures, and lactic acidosis, WES revealed two compound heterozygous variants (c.875C>G, c.131A>G). Two older sibs died of a similar condition at 7 months and 3 years. Sequencing was not possible in these individuals; however, a healthy sibling did not carry either variant. Functional analysis in patient-derived fibroblasts and mice confirmed LIPT1 deficiency.

In two unrelated families, the phenotype resulted in early infant death, and therefore ID could not be assessed:
PMID: 24256811 (2014) – compound heterozygous missense variants (c.212C>T and c.292C>G) were identified in a female that died on the ninth day of life.
PMID: 27247813 (2016) – compound heterozygous nonsense variants (c.806G>A and c.980T>G) detected in two sibs who both died on the first day of life. A third sibling, who did not harbour these variants, was healthy and thriving at 12 months of life.
Intellectual disability v3.195 KLF7 Arina Puzriakova Classified gene: KLF7 as Amber List (moderate evidence)
Intellectual disability v3.195 KLF7 Arina Puzriakova Gene: klf7 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.194 KLF7 Arina Puzriakova Classified gene: KLF7 as Green List (high evidence)
Intellectual disability v3.194 KLF7 Arina Puzriakova Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review - more than 3 unrelated cases presenting the relevant phenotype.
Intellectual disability v3.194 KLF7 Arina Puzriakova Gene: klf7 has been classified as Green List (High Evidence).
Intellectual disability v3.193 KLF7 Arina Puzriakova Tag for-review tag was added to gene: KLF7.
Intellectual disability v3.193 KLF7 Arina Puzriakova changed review comment from: Not associated with phenotype in OMIM or G2P. Powis et al. (2018) PMID: 29251763 - Heterozygous de novo missense variants were reported in four unrelated individuals. The two females (aged 15 and 16) were both said to have ID; while the two males (aged 2 and 4) had cognitive delay - though ID had not been formally assessed, presumably due to age. Additional features also included motor and speech delay, hypotonia, and neuromuscular symptoms.; to: Not associated with phenotype in OMIM or G2P.

Powis et al. (2018) PMID: 29251763 - Heterozygous de novo missense variants were reported in four unrelated individuals. The two females (aged 15 and 16) were both said to have ID; while the two males (aged 2 and 4) had cognitive delay - though ID had not been formally assessed, presumably due to age. Additional features also included motor and speech delay, hypotonia, and neuromuscular symptoms.
Intellectual disability v3.193 KCNN3 Arina Puzriakova Added comment: Comment on mode of pathogenicity: Gain-of-function variants identified in all patients, reported to date.
Intellectual disability v3.193 KCNN3 Arina Puzriakova Mode of pathogenicity for gene: KCNN3 was changed from None to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Intellectual disability v3.192 KCNN3 Arina Puzriakova Classified gene: KCNN3 as Amber List (moderate evidence)
Intellectual disability v3.192 KCNN3 Arina Puzriakova Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review - three unrelated cases with relevant phenotype, although future re-evaluation of the two younger patients may be useful.
Intellectual disability v3.192 KCNN3 Arina Puzriakova Gene: kcnn3 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.191 KCNN3 Arina Puzriakova Tag for-review tag was added to gene: KCNN3.
Intellectual disability v3.191 KCNN3 Arina Puzriakova changed review comment from: Associated with phenotype in OMIM, and probable gene-disease association in G2P. Bauer et al. (2019) PMID: 31155282 - De novo heterozygous gain-of-function variants identified in three unrelated individuals with ZimmermannLaband syndrome. Mild-moderate ID was reported in a 46-year-old man, while developmental delay was noted for the other two patients: a 4.5-year-old (first words at 2.5 y; attends nursery) and 5.5-year-old girl (limited spoken language; attends school with a personal aide). Additional features include coarse face, gingival hyperplasia, and/or nail hypo- or aplasia. ; to: Associated with phenotype in OMIM, and probable gene-disease association in G2P.

Bauer et al. (2019) PMID: 31155282 - De novo heterozygous gain-of-function variants identified in three unrelated individuals with ZimmermannLaband syndrome. Mild-moderate ID was reported in a 46-year-old man, while developmental delay was noted for the other two patients: a 4.5-year-old (first words at 2.5 y; attends nursery) and 5.5-year-old girl (limited spoken language; attends school with a personal aide). Additional features include coarse face, gingival hyperplasia, and/or nail hypo- or aplasia.
Intellectual disability v3.191 GPC4 Arina Puzriakova Mode of inheritance for gene: GPC4 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 v3.190 GPC4 Arina Puzriakova Classified gene: GPC4 as Amber List (moderate evidence)
Intellectual disability v3.190 GPC4 Arina Puzriakova Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review - more than 3 unrelated cases presenting the relevant phenotype.
Intellectual disability v3.190 GPC4 Arina Puzriakova Gene: gpc4 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.189 GPC4 Arina Puzriakova Tag for-review tag was added to gene: GPC4.
Tag Skewed X-inactivation tag was added to gene: GPC4.
Intellectual disability v3.189 GPC4 Arina Puzriakova changed review comment from: Associated with phenotype in OMIM and a confirmed gene in G2P. Amor et al. (2019) (PMID: 30982611) reported ten affected males from six familes, each harbouring distinct GPC4 variants. All identified variants were truncating or resulted in a frameshift, suggesting loss of function as the likely disease mechanism. Variable degrees of ID (mild-moderate) were reported in 8/10 participants. Some supporting functional data. ; to: Associated with phenotype in OMIM and a confirmed gene for Keipert syndrome in G2P.

Amor et al. (2019) (PMID: 30982611) reported ten affected males from six familes, each harbouring distinct GPC4 variants. All identified variants were truncating or resulted in a frameshift, suggesting loss of function as the likely disease mechanism. Variable degrees of ID (mild-moderate) were reported in 8/10 participants. Some supporting functional data.
Intellectual disability v3.189 IQSEC3 Arina Puzriakova Classified gene: IQSEC3 as Red List (low evidence)
Intellectual disability v3.189 IQSEC3 Arina Puzriakova Gene: iqsec3 has been classified as Red List (Low Evidence).
Intellectual disability v3.188 EIF2AK1 Arina Puzriakova Classified gene: EIF2AK1 as Red List (low evidence)
Intellectual disability v3.188 EIF2AK1 Arina Puzriakova Added comment: Comment on list classification: Phenotype not relevant to this panel.
Intellectual disability v3.188 EIF2AK1 Arina Puzriakova Gene: eif2ak1 has been classified as Red List (Low Evidence).
Intellectual disability v3.187 EIF2A Arina Puzriakova Classified gene: EIF2A as Red List (low evidence)
Intellectual disability v3.187 EIF2A Arina Puzriakova Gene: eif2a has been classified as Red List (Low Evidence).
Intellectual disability v3.186 DNM1L Arina Puzriakova Classified gene: DNM1L as Amber List (moderate evidence)
Intellectual disability v3.186 DNM1L Arina Puzriakova Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review - more than 3 unrelated cases with distinct variants, presenting with a relevant phenotype.
Intellectual disability v3.186 DNM1L Arina Puzriakova Gene: dnm1l has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.185 DNM1L Arina Puzriakova Tag for-review tag was added to gene: DNM1L.
Intellectual disability v3.185 DNM1L Arina Puzriakova changed review comment from: Associated with related phenotype in OMIM and 'probable' gene in G2P. Variants in DNM1L cause a chronic neurological disorder, which is commonly associated with neonatal lethality. Global developmental delay or cognitive impairment (mild-profound) is reported in several surviving patients: PMID: 26931468 - Two unrelated cases: A male with global developmental delay, hypotonia and status epilepticus. WES revealed a c.1048G>A, p.G350R variant, for which low-level (68%) mosaicism was detected in the maternal sample.; to: Associated with related phenotype in OMIM and 'probable' gene in G2P.

Variants in DNM1L cause a chronic neurological disorder, which is commonly associated with neonatal lethality. Global developmental delay or cognitive impairment (mild-profound) is reported in several surviving patients:

PMID: 26931468 - Two unrelated cases: A male with global developmental delay, hypotonia and status epilepticus. WES revealed a c.1048G>A, p.G350R variant, for which low-level (6–8%) mosaicism was detected in the maternal sample. The second patient, with diffuse hypotonia, global developmental delay, poor growth, and persistent elevation of lactate, was found to harbour a de novo DNM1L variant (c.1135G>A, p.E379K). However, another de novo change in the PDHA1 gene (c.448G>A, p.G150R) was also found, and the definitive contribution of each variant to the patients phenotype could not be ascertained.

PMID: 27328748 - Compound heterozygous DNM1L variants (c.106A>G, p.Ser36Gly; c.346_347delGA, p.Glu116Lysfs*6) identified in two brothers (3 and 16-years-old) with psychomotor delay, ocular and cerebellar involvement, including mild cognitive impairment in the older brother. Some supporting functional evidence using patient fibroblasts and a yeast model.

PMID: 27301544 - De novo missense variant (c.1217T>C, p.Leu406Ser) identified in a child who presented severe hypotonia, infantile spasms with suppression‐burst and a high level of lactate in CSF. Development was profoundly delayed, and he attained no developmental milestones before his death at 18 months of age.

PMID: 26604000 - De novo missense substitution, (c.1085G>A; p.Gly362Asp) identified in a child with refractory epilepsy. Profound global developmental delay was reported, and at the last clinical assessment (age 7 years), he remained nonambulatory with the use of <10 monosyllabic words.

PMID: 26992161 - De novo heterozygous c.1084G>A (p.Gly362Ser) variant. Developmental delay was reported from 6-months of age, and at 2-years-old he was said to not be able to utter any intelligible words.

There are also reports of an identical de novo heterozygous missense variant (p.R403C) in four unrelated individuals who all experienced normal development until a sudden-onset episode of status epilepticus at the age of 4, 5, 10, and 11-years-old, respectively. Subsequently, all presented with rapid neurological regression, diffuse cerebral atrophy and substantial cognitive decline. Functional studies showed the variant confers a dominant negative effect (PMID: 27145208; 30767894; 30711678).
Intellectual disability v3.185 ATAD1 Arina Puzriakova Tag treatable tag was added to gene: ATAD1.
Tag for-review tag was added to gene: ATAD1.
Intellectual disability v3.185 ATAD1 Arina Puzriakova Classified gene: ATAD1 as Amber List (moderate evidence)
Intellectual disability v3.185 ATAD1 Arina Puzriakova Added comment: Comment on list classification: Multiple affected individuals from 3 unrelated families. There is enough evidence for this gene to be rated GREEN at the next major review.
Intellectual disability v3.185 ATAD1 Arina Puzriakova Gene: atad1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.184 ATAD1 Arina Puzriakova changed review comment from: Not associated with any phenotype in G2P. Pathogenic variants have been described in seven affected individuals (three distinct consanguineous families) including a homozygous nonsense (c.826G>T; p.Glu276*), frameshift (c.1070_1071delAT; p.His357Argfs*15), and missense (c.162G>C; p.Gln54His) variant in the ATAD1 gene. Patients present with severe neurological features of essentially total absence of psychomotor development, encephalopathy, extreme hypertonia, non-responsiveness to stimuli, and death within the first few months of life. ; to: Not associated with any phenotype in G2P.

Pathogenic variants have been described in seven affected individuals (three distinct consanguineous families) including a homozygous nonsense (c.826G>T; p.Glu276*), frameshift (c.1070_1071delAT; p.His357Argfs*15), and missense (c.162G>C; p.Gln54His) variant in the ATAD1 gene. Patients present with severe neurological features of essentially total absence of psychomotor development, encephalopathy, extreme hypertonia, non-responsiveness to stimuli, and death within the first few months of life.

Knockout mouse model recapitulates phenotype. ATAD1 encodes Thorase, a mediator of AMPA receptor recycling; and therefore it was postulated that pathogenesis is a result of excessive AMPA receptor activity. Targeted therapy using perampanel, an AMPA receptor antagonist, ameliorated disease in both mice and humans, thus further supporting the role of ATAD1.
Intellectual disability v3.184 ADD3 Arina Puzriakova Classified gene: ADD3 as Amber List (moderate evidence)
Intellectual disability v3.184 ADD3 Arina Puzriakova Added comment: Comment on list classification: More than 3 unrelated individuals with ID. There is enough evidence for this gene to be rated GREEN at the next major review.
Intellectual disability v3.184 ADD3 Arina Puzriakova Gene: add3 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.183 ADD3 Arina Puzriakova Tag for-review tag was added to gene: ADD3.
Intellectual disability v3.183 ADD3 Arina Puzriakova changed review comment from: Biallelic missense variants identified in four families (ten affected patients). Not associated with any phenotype in G2P. OMIM entry currently based on PMID:23836506. PMID: 23836506 (2013) - Homozygous missense variant c.1100G>A (p.G367D). ADD3 first identified in a consanguineous Jordanian family affecting four members. ID severe in two individuals and moderate/borderline in the others, some functional work from fibroblasts. The paper focused on the main phenotype of inheritable cerebral palsy. ; to: Biallelic missense variants identified in four families (ten affected patients). Not associated with any phenotype in G2P. OMIM entry currently based on PMID: 23836506.

PMID: 23836506 (2013) - Homozygous missense variant c.1100G>A (p.G367D). ADD3 first identified in a consanguineous Jordanian family affecting four members. ID severe in two individuals and moderate/borderline in the others, some functional work from fibroblasts. The paper focused on the main phenotype of inheritable cerebral palsy.

PMID: 29768408 (2018) - Two families with ADD3 biallelic variants and one family with ADD3 and KAT2B missense variants. Individuals with ADD3 variants have similar phenotypes and individuals with KAT2B variants have an extension to phenotype with impaired kidney and heart function, also demonstrated with functional evidence in flies. ID was reported in 5/6 participants.
Intellectual disability v3.183 LZTFL1 Arina Puzriakova reviewed gene: LZTFL1: Rating: GREEN; Mode of pathogenicity: ; Publications: 22510444, 23692385; Phenotypes: Bardet-Biedl syndrome 17, 615994; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.183 LYRM7 Arina Puzriakova reviewed gene: LYRM7: Rating: GREEN; Mode of pathogenicity: ; Publications: 24014394, 26912632, 28694194; Phenotypes: Mitochondrial complex III deficiency, nuclear type 8, 615838; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.183 LIPT1 Arina Puzriakova reviewed gene: LIPT1: Rating: GREEN; Mode of pathogenicity: ; Publications: 24341803, 29681092, 31042466, 24256811, 27247813; Phenotypes: Lipoyltransferase 1 deficiency, 616299; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.183 KLF7 Arina Puzriakova reviewed gene: KLF7: Rating: GREEN; Mode of pathogenicity: ; Publications: 29251763; Phenotypes: Intellectual disability; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.183 KCNN3 Arina Puzriakova reviewed gene: KCNN3: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype -please provide details in the comments; Publications: 31155282; Phenotypes: Zimmermann-Laband syndrome 3, 618658; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.183 GPC4 Arina Puzriakova reviewed gene: GPC4: Rating: GREEN; Mode of pathogenicity: ; Publications: 30982611; Phenotypes: Keipert syndrome, 301026; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability v3.183 IQSEC3 Arina Puzriakova reviewed gene: IQSEC3: Rating: RED; Mode of pathogenicity: ; Publications: 31130284; Phenotypes: Intellectual disability; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.183 EIF2AK1 Arina Puzriakova reviewed gene: EIF2AK1: Rating: RED; Mode of pathogenicity: ; Publications: 32197074; Phenotypes: Leukoencephalopathy, motor delay, spasticity, and dysarthria syndrome, 618878, ADHD; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.183 EIF2A Arina Puzriakova reviewed gene: EIF2A: Rating: RED; Mode of pathogenicity: ; Publications: 31130284; Phenotypes: Intellectual disability, Seizures, ASD; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.183 DNM1L Arina Puzriakova reviewed gene: DNM1L: Rating: GREEN; Mode of pathogenicity: ; Publications: 27145208, 30767894, 30711678, 26931468, 27328748, 27301544, 26604000, 26992161; Phenotypes: Epileptic encephalopathy, 614388, Global developmental delay, Cerebral atrophy, Microcephaly; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.183 ATAD1 Arina Puzriakova reviewed gene: ATAD1: Rating: GREEN; Mode of pathogenicity: ; Publications: 28180185, 29390050, 29659736; Phenotypes: Encephalopathy, Progressive hypertonia, Seizures; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.183 ADD3 Arina Puzriakova reviewed gene: ADD3: Rating: GREEN; Mode of pathogenicity: ; Publications: 23836506, 29768408; Phenotypes: Cerebral palsy, spastic quadriplegic, 617008, Intellectual disability, Microcephaly; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.182 ASTN1 Arina Puzriakova Tag watchlist tag was added to gene: ASTN1.
Intellectual disability v3.182 ASTN1 Arina Puzriakova Classified gene: ASTN1 as Amber List (moderate evidence)
Intellectual disability v3.182 ASTN1 Arina Puzriakova Added comment: Comment on list classification: As limited segregation and case-specific details for the individual identified in the second study (PMID:27431290), rating Amber until further cases reported.
Intellectual disability v3.182 ASTN1 Arina Puzriakova Gene: astn1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.181 ASTN1 Arina Puzriakova reviewed gene: ASTN1: Rating: AMBER; Mode of pathogenicity: None; Publications: 26539891, 27431290, 29706646; Phenotypes: Intellectual disability; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.181 GNAI2 Arina Puzriakova Classified gene: GNAI2 as Amber List (moderate evidence)
Intellectual disability v3.181 GNAI2 Arina Puzriakova Gene: gnai2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.180 FEM1B Arina Puzriakova Mode of inheritance for gene: FEM1B was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.179 FEM1B Arina Puzriakova edited their review of gene: FEM1B: Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.179 FEM1B Arina Puzriakova Deleted their comment
Intellectual disability v3.179 FEM1B Arina Puzriakova Deleted their comment
Intellectual disability v3.179 FEM1B Arina Puzriakova Deleted their comment
Intellectual disability v3.179 FEM1B Arina Puzriakova Deleted their comment
Intellectual disability v3.179 FEM1B Arina Puzriakova Deleted their comment
Intellectual disability v3.179 FEM1B Arina Puzriakova Deleted their comment
Intellectual disability v3.179 FEM1B Arina Puzriakova Deleted their comment
Intellectual disability v3.179 FEM1B Arina Puzriakova Classified gene: FEM1B as Red List (low evidence)
Intellectual disability v3.179 FEM1B Arina Puzriakova Added comment: Comment on list classification: Although phenotypic overlap is noted, it is not possible to ascertain whether the additional cases refer to different individuals. Also possible founder effect as all cases harbour the same variant. Additional cases/functional data are required to ascertain the contribution of FEM1B variants to an ID phenotype.
Intellectual disability v3.179 FEM1B Arina Puzriakova Gene: fem1b has been classified as Red List (Low Evidence).
Intellectual disability v3.179 FEM1B Arina Puzriakova Classified gene: FEM1B as Red List (low evidence)
Intellectual disability v3.179 FEM1B Arina Puzriakova Added comment: Comment on list classification: Although phenotypic overlap is noted, it is not possible to ascertain whether the additional cases refer to different individuals. Also possible founder effect as all cases harbour the same variant. Additional cases/functional data are required to ascertain the contribution of FEM1B variants to an ID phenotype.
Intellectual disability v3.179 FEM1B Arina Puzriakova Gene: fem1b has been classified as Red List (Low Evidence).
Intellectual disability v3.178 FEM1B Arina Puzriakova Classified gene: FEM1B as Red List (low evidence)
Intellectual disability v3.178 FEM1B Arina Puzriakova Added comment: Comment on list classification: Although phenotypic overlap is noted, it is not possible to ascertain whether the additional cases refer to different individuals. Also possible founder effect as all cases harbour the same variant. Additional cases/functional data are required to ascertain the contribution of FEM1B variants to an ID phenotype.
Intellectual disability v3.178 FEM1B Arina Puzriakova Gene: fem1b has been classified as Red List (Low Evidence).
Intellectual disability v3.178 FEM1B Arina Puzriakova Classified gene: FEM1B as Red List (low evidence)
Intellectual disability v3.178 FEM1B Arina Puzriakova Added comment: Comment on list classification: Although phenotypic overlap is noted, it is not possible to ascertain whether the additional cases refer to different individuals. Also possible founder effect as all cases harbour the same variant. Additional cases/functional data are required to ascertain the contribution of FEM1B variants to an ID phenotype.
Intellectual disability v3.178 FEM1B Arina Puzriakova Gene: fem1b has been classified as Red List (Low Evidence).
Intellectual disability v3.178 FEM1B Arina Puzriakova Classified gene: FEM1B as Red List (low evidence)
Intellectual disability v3.178 FEM1B Arina Puzriakova Added comment: Comment on list classification: Although phenotypic overlap is noted, it is not possible to ascertain whether the additional cases refer to different individuals. Also possible founder effect as all cases harbour the same variant. Additional cases/functional data are required to ascertain the contribution of FEM1B variants to an ID phenotype.
Intellectual disability v3.178 FEM1B Arina Puzriakova Gene: fem1b has been classified as Red List (Low Evidence).
Intellectual disability v3.178 FEM1B Arina Puzriakova Classified gene: FEM1B as Red List (low evidence)
Intellectual disability v3.178 FEM1B Arina Puzriakova Added comment: Comment on list classification: Although phenotypic overlap is noted, it is not possible to ascertain whether the additional cases refer to different individuals. Also possible founder effect as all cases harbour the same variant. Additional cases/functional data are required to ascertain the contribution of FEM1B variants to an ID phenotype.
Intellectual disability v3.178 FEM1B Arina Puzriakova Gene: fem1b has been classified as Red List (Low Evidence).
Intellectual disability v3.178 FEM1B Arina Puzriakova Classified gene: FEM1B as Red List (low evidence)
Intellectual disability v3.178 FEM1B Arina Puzriakova Added comment: Comment on list classification: Although phenotypic overlap is noted, it is not possible to ascertain whether the additional cases refer to different individuals. Also possible founder effect as all cases harbour the same variant. Additional cases/functional data are required to ascertain the contribution of FEM1B variants to an ID phenotype.
Intellectual disability v3.178 FEM1B Arina Puzriakova Gene: fem1b has been classified as Red List (Low Evidence).
Intellectual disability v3.178 FEM1B Arina Puzriakova Classified gene: FEM1B as Red List (low evidence)
Intellectual disability v3.178 FEM1B Arina Puzriakova Added comment: Comment on list classification: Although phenotypic overlap is noted, it is not possible to ascertain whether the additional cases refer to different individuals. Also possible founder effect as all cases harbour the same variant. Additional cases/functional data are required to ascertain the contribution of FEM1B variants to an ID phenotype.
Intellectual disability v3.178 FEM1B Arina Puzriakova Gene: fem1b has been classified as Red List (Low Evidence).
Intellectual disability v3.177 FEM1B Arina Puzriakova changed review comment from: Gene not associated with any phenotype on OMIM or G2P.

Lecoquierre et al. (2019) (PMID: 31036916) conducted a large candidate gene discovery study and identified a de novo missense variant (p.Arg126Gln) in a patient with syndromic global developmental delay. Recurrence of the same variant was highlighted in an individual from the DDD study, and the another from GeneMatcher. It is said that the three patients share a similar phenotype; however, any further details are limited and it is not possible to ascertain whether the additional cases refer to different individuals. No function analysis was undertaken to validate the implication of FEM1B.; to: Gene not associated with any phenotype on OMIM or G2P.

Lecoquierre et al. (2019) (PMID: 31036916) conducted a large candidate gene discovery study and identified a de novo missense variant (p.Arg126Gln) in a patient with syndromic global developmental delay. Recurrence of the same variant was highlighted in an individual from the DDD study, and the another from GeneMatcher, who were said to share a similar phenotype. No function analysis was undertaken to validate the implication of FEM1B.
Intellectual disability v3.177 CCDC32 Eleanor Williams Tag watchlist tag was added to gene: CCDC32.
Intellectual disability v3.177 CCDC32 Eleanor Williams Classified gene: CCDC32 as Amber List (moderate evidence)
Intellectual disability v3.177 CCDC32 Eleanor Williams Added comment: Comment on list classification: Rating amber as 2 cases plus some limited functional evidence. Rating agreed with Genomics England clinical team.
Intellectual disability v3.177 CCDC32 Eleanor Williams Gene: ccdc32 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.176 CCDC32 Eleanor Williams gene: CCDC32 was added
gene: CCDC32 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: CCDC32 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CCDC32 were set to 32307552
Phenotypes for gene: CCDC32 were set to global developmental delay
Review for gene: CCDC32 was set to AMBER
Added comment: PMID: 32307552 - Harel et al 2020 - report 2 unrelated consanguineous families with probands with homozygous frameshift variants in CCDC32.  Parents are heterozygous. Phenotype is a congenital syndrome characterized by craniofacial, cardiac and neurodevelopmental anomalies.  In one family the child had global developmental delay, in the other the child had moderately delayed motor and language development and hyperactivity.

Functional studies in zebrafish show that ccdc32 depletion impairs cilia formation and demonstrate a contribution of ccdc32 in craniofacial, brain and left/right axis development.
Sources: Literature
Intellectual disability v3.175 ATL1 Zornitza Stark edited their review of gene: ATL1: Changed rating: RED
Intellectual disability v3.175 ATL1 Zornitza Stark edited their review of gene: ATL1: Changed publications: 21336785, 28736820, 29180453, 29691679, 31236401; Changed phenotypes: Neuropathy, hereditary sensory, type ID, MIM# 613708, Spastic paraplegia 3A, autosomal dominant, MIM# 182600
Intellectual disability v3.175 ATL1 Zornitza Stark changed review comment from: Please note additional recent publications. Principal association is with HSP phenotype, often of later onset. Few reports of intellectual disability as part of this condition.; to: Please note additional recent publications. Principal association is with HSP/neuropathy phenotype, often of later onset. Few reports of intellectual disability as part of this condition (two families).
Intellectual disability v3.175 ATL1 Zornitza Stark changed review comment from: Please note additional recent publications; to: Please note additional recent publications. Principal association is with HSP phenotype, often of later onset. Few reports of intellectual disability as part of this condition.
Intellectual disability v3.175 ATL1 Zornitza Stark edited their review of gene: ATL1: Changed rating: AMBER
Intellectual disability v3.175 ATL1 Sarah Leigh commented on gene: ATL1: The "for-review" tag has been added to this gene as there is enough evidence for this gene to be rated RED at the next major review.
Intellectual disability v3.175 ATL1 Sarah Leigh changed review comment from: Associated with phenotype in OMIM, not in G2P. Mild late onset mental retardation in 10 members of a three generation family with Spastic paraplegia 3A, autosomal dominant 182600; to: Associated with phenotype in OMIM, not in G2P. Mild to severe late onset mental retardation in 10 members of a three generation family with Spastic paraplegia 3A, autosomal dominant 182600
Intellectual disability v3.175 ATL1 Sarah Leigh Tag for-review tag was added to gene: ATL1.
Intellectual disability v3.175 ATL1 Sarah Leigh commented on gene: ATL1: Associated with phenotype in OMIM, not in G2P. Mental retardation has been reported in a second family (PMID 31236401). In this publication, the 9 year old proband and his maternal grandfather had hereditary spastic paraplegia and intellectual disability, however, proband's mother had hereditary spastic paraplegia, but no intelectual disability.
Intellectual disability v3.175 ATL1 Sarah Leigh Publications for gene: ATL1 were set to 21336785; 28736820; 29180453; 29691679
Intellectual disability v3.174 FEM1B Arina Puzriakova changed review comment from: Lecoquierre et al. (2019) (PMID: 31036916) conducted a large candidate gene discovery studying and identified a de novo missense variant (p.Arg126Gln) in a patient with syndromic global developmental delay. Recurrence of the same variant was highlighted in an individual from the DDD study, and the another from GeneMatcher. It is said that the three patients share a similar phenotype; however, any further details are limited and it is not possible to ascertain whether the additional patients refer to different individuals. No function analysis was undertaken to validate the implication of FEM1B.

Gene not associated with any phenotype on OMIM or G2P.; to: Gene not associated with any phenotype on OMIM or G2P.

Lecoquierre et al. (2019) (PMID: 31036916) conducted a large candidate gene discovery study and identified a de novo missense variant (p.Arg126Gln) in a patient with syndromic global developmental delay. Recurrence of the same variant was highlighted in an individual from the DDD study, and the another from GeneMatcher. It is said that the three patients share a similar phenotype; however, any further details are limited and it is not possible to ascertain whether the additional cases refer to different individuals. No function analysis was undertaken to validate the implication of FEM1B.
Intellectual disability v3.174 PTPN23 Eleanor Williams Added comment: Comment on phenotypes: Added disease association from OMIM.
Intellectual disability v3.174 PTPN23 Eleanor Williams Phenotypes for gene: PTPN23 were changed from Developmental epileptic encephalopathy with hypomyelination and brain atrophy; Intellectual disability; Severe developmental delay, to Developmental epileptic encephalopathy with hypomyelination and brain; Neurodevelopmental disorder and structural brain anomalies with or without seizures and spasticity MIM#618890 atrophy; Intellectual disability; Severe developmental delay,
Intellectual disability v3.173 GRIA2 Eleanor Williams Added comment: Comment on phenotypes: Added disease association which has been added to OMIM.
Intellectual disability v3.173 GRIA2 Eleanor Williams Phenotypes for gene: GRIA2 were changed from Epileptic encephalopathy intellectual disability stereotypic hand movements to Epileptic encephalopathy intellectual disability stereotypic hand movements; Neurodevelopmental disorder with language impairment and behavioral abnormalities MIM#618917
Intellectual disability v3.172 FBXW11 Eleanor Williams Added comment: Comment on phenotypes: Added disease association which has been added in OMIM.
Intellectual disability v3.172 FBXW11 Eleanor Williams Phenotypes for gene: FBXW11 were changed from Global developmental delay; Intellectual disability; Abnormality of the eye; Abnormality of the head; Abnormality of digit to Global developmental delay; Intellectual disability; Abnormality of the eye; Abnormality of the head; Abnormality of digit; Neurodevelopmental, jaw, eye, and digital syndrome MIM#618914
Intellectual disability v3.171 CARS Eleanor Williams Added comment: Comment on phenotypes: Added disease term which has now been added to OMIM.
Intellectual disability v3.171 CARS Eleanor Williams Phenotypes for gene: CARS were changed from Brittle hair; Fragile nails; Microcephaly; Neurodevelopmental delay to Brittle hair; Fragile nails; Microcephaly; Neurodevelopmental delay; Microcephaly, developmental delay, and brittle hair syndrome MIM#618891
Intellectual disability v3.170 ADARB1 Arina Puzriakova changed review comment from: Variants reported in four unrelated individuals with severe/profound intellectual disability, microcephaly, and seizures. Functional studies demonstrate variants result in reduction of ADARB1 product activity or changes in splicing (PMID: 32220291). Homozygous knockout mice presented with seizures and early death, supporting the role of ADARB1 in brain function (PMID: 10894545)

Gene is associated with phenotype in OMIM and G2P.; to: Gene is associated with phenotype in OMIM and G2P.

PMID: 32220291 - Bi-allelic variants reported in four unrelated individuals with severe/profound intellectual disability, microcephaly, and seizures. Functional studies demonstrate variants result in reduction in ADARB1 product activity or changes in splicing.
PMID: 10894545 - Homozygous knockout mice presented with siezures and early death, supporting the role of ADARB1 in brain function.

This gene has also been added to the Genetic Epilepsy and Severe Microcephaly panels with a suggested Green classification at the next major review.
Intellectual disability v3.170 CNPY3 Konstantinos Varvagiannis gene: CNPY3 was added
gene: CNPY3 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: CNPY3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CNPY3 were set to 29394991; 30237576
Phenotypes for gene: CNPY3 were set to Epileptic encephalopathy, early infantile, 60 (MIM 617929)
Penetrance for gene: CNPY3 were set to Complete
Review for gene: CNPY3 was set to GREEN
Added comment: Biallelic CNPY3 mutations cause Epileptic encephalopathy, early infantile, 60 (MIM 617929).

The phenotype including among others hypotonia, intractable seizures, DD and ID has been first reported by Mutoh et al (2018 - PMID: 29394991) in 3 subjects from 2 families. Evidence was provided for the role of the gene (incl. mouse model) and pathogenicity of the identified variants (resulting in LoF).

Another subject with similar features of hypotonia, DD, intractable epilepsy, feeding problems has been described briefly by Maddirevula et al (2019 - PMID: 30237576).
Sources: Literature
Intellectual disability v3.170 KIF21B Konstantinos Varvagiannis gene: KIF21B was added
gene: KIF21B was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: KIF21B was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: KIF21B were set to 32415109
Phenotypes for gene: KIF21B were set to Global developmental delay; Intellectual disability; Abnormality of brain morphology; Microcephaly
Penetrance for gene: KIF21B were set to unknown
Mode of pathogenicity for gene: KIF21B was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: KIF21B was set to GREEN
Added comment: Asselin et al (2020 - PMID: 32415109) report on 4 individuals with KIF21B pathogenic variants. DD/ID (borderline intellectual functioning to severe ID) was a feature in all. Variable other findings included brain malformations (CCA) and microcephaly. 3 missense variants and a 4-bp insertion were identified, in 3 cases as de novo events while in a single subject the variant was inherited from the father who was also affected. The authors provide evidence for a role of KIF21B in the regulation of processes involved in cortical development and deleterious effect of the missense variants impeding neuronal migration and kinesin autoinhibition. Phenotypes specific to variants (e.g. CCA or microcephaly) were recapitulated in animal models. Missense variants are thought to exert a gain-of-function effect. As commented on, the 4-bp duplication (/frameshift) variant might not be pathogenic. In blood sample from the respective individual, RT-qPCR analysis suggested that haploinsufficiency (NMD) applies. Although Kif21b haploinsufficiency in mice was shown to lead to impaired neuronal positioning, the gene might partially tolerate LoF variants as also suggested by 28 such variants in gnomAD. Homozygous Kif21b ko mice display severe morphological abnormalities, partial loss of commissural fibers, cognitive deficits and altered synaptic transmission (several refs to previous studies provided by the authors).
Sources: Literature
Intellectual disability v3.170 PAX1 Konstantinos Varvagiannis gene: PAX1 was added
gene: PAX1 was added to Intellectual disability. Sources: Literature,Radboud University Medical Center, Nijmegen
Mode of inheritance for gene: PAX1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PAX1 were set to 29681087; 23851939; 28657137
Phenotypes for gene: PAX1 were set to Otofaciocervical syndrome 2, 615560
Penetrance for gene: PAX1 were set to Complete
Review for gene: PAX1 was set to AMBER
Added comment: Biallelic PAX1 pathogenic variants cause Otofaciocervical syndrome 2 (OMIM 615560).

Brief review of the literature suggests 3 relevant publications to date (04-07-2020).

2 individuals with DD and ID have been reported (Patil et al, 2018 - PMID: 29681087 and Pohl et al, 2013 - PMID: 23851939). Other subjects reported were only evaluated as newborns(mostly)/infants [Paganini et al, 2017 - PMID: 28657137, Patil et al, 2018 - PMID: 29681087].

While the first report by Pohl et al identified a homozygous missense variant supported by functional studies [NM_006192.5:c.497G>T - p.(Gly166Val)] subsequent ones identified homozygosity for pLoF mutations [Patil et al: NM_006192.4:c.1173_1174insGCCCG / Paganini et al: NM_006192:c.1104C>A - p.(Cys368*)].

As discussed by Pohl et al:

PAX1 encodes a transcription factor with critical role in pattern formation during embryogenesis. Study of the mouse Gly157Val (equivalent to human Gly166Val) Pax1 variant suggested reduced binding affinity (reduced transactivation of a regulatory sequence of the Nkx3-2 promoter) and hypofunctional nature of this variant.

Mouse models seem to recapitulate features of the disorder (skeletal, immunodeficiency) while the role of Pax1 in hearing process was thought to be supported by early expression (P6) in mouse cochlea.

Overall this gene can be considered for inclusion in the ID panel with amber/green rating.
Sources: Literature, Radboud University Medical Center, Nijmegen
Intellectual disability v3.170 TMEM106B Konstantinos Varvagiannis gene: TMEM106B was added
gene: TMEM106B was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: TMEM106B was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: TMEM106B were set to 29186371; 29444210; 32595021
Phenotypes for gene: TMEM106B were set to Leukodystrophy, hypomyelinating, 16 (MIM #617964)
Penetrance for gene: TMEM106B were set to Complete
Mode of pathogenicity for gene: TMEM106B was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: TMEM106B was set to GREEN
Added comment: 6 unrelated individuals with Leukodystrophy, hypomyelinating, 16 (MIM #617964) due to a recurrent TMEM106B variant have been reported to date in the literature (Simons et al 2017 - PMID: 29186371, Yan et al 2018 - PMID: 29444210, Ikemoto et al 2020 - PMID: 32595021).

While a 3 y.o. female described by Yan et al had DD (eg sitting at 9m, walking at 25m) with normal cognitive functioning, and a 38 y.o. female had borderline intellectual functioning (IQ 76), 4 affected individuals had ID. Among them, a 19 y.o. male with severe ID was also found to harbor a second de novo possibly damaging USP7 variant. Seizures have been reported in 2 unrelated subjects. [Clinical features are also summarized in table 1 - Ikemoto et al].

All harbored NM_001134232.2(TMEM106B):c.754G>A (p.Asp252Asn) which in almost all cases occurred as a de novo event. In a single case this variant was inherited from a mosaic parent with mild DD in infancy but normal cognition (reported by Simons et al).

As discussed by Ito et al (2018 - PMID: 30643851) the encoded protein is a structural component of the lysosomal membrane, playing a role on lysosome acidification. Acidity of the lysosome mediates multiple aspects of lysosomal function. Ito et al, using patient-derived fibroblasts assessed mRNA and protein levels. These were unaltered compared with controls. While TMEM106B had been previously shown to affect lysosome number, morphology and acidification, Ito et al demonstrated increased number of lysosomes in patient cells as well as impaired acidification compared to controls. As commented lysosomes are required for generation of myelin.

Recurrence of this missense variant, the presence of pLoF TMEM106B variants in gnomAD as well as the phenotypically normal Tmem106b null mice suggest that this variant may have a gain-of-function or dominant negative effect.

Genes for other forms of hypomyelinating lipodystrophy (incl. PLP1) have green rating in the ID panel.

Overall TMEM106B can be considered for the ID panel with green rating and the epilepsy panel with amber rating.
Sources: Literature
Intellectual disability v3.170 TBC1D2B Konstantinos Varvagiannis gene: TBC1D2B was added
gene: TBC1D2B was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: TBC1D2B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TBC1D2B were set to 32623794
Phenotypes for gene: TBC1D2B were set to Global developmental delay; Intellectual disability; Seizures; Gingival overgrowth; Behavioral abnormality; Abnormality of the mandible; Abnormality of brain morphology; Abnormality of the eye; Hearing abnormality
Penetrance for gene: TBC1D2B were set to Complete
Review for gene: TBC1D2B was set to AMBER
Added comment: Harms et al (2020 - PMID: 32623794) report on 3 unrelated individuals with biallelic pLoF TBC1D2B variants.

Features included cognitive impairment (mild ID in one case, regression at the age of 12y in another, hypotonia and delayed milestones in a third aged 8m), seizures (3/3 - variable age of onset) and/or gingival overgrowth (2/3 - prior to initiation of AEDs). Other findings included behavioral abnormalities, mandibular anomalies, abnormal brain imaging and ophthalmologic or (rarely) audiometric evaluations.

All were born to non-consanguineous couples and additional investigations were performed in some.

Variants were identified by WES or trio WGS, with Sanger confirmation/compatible segregation analyses.

In line with the pLoF variants, mRNA studies in fibroblasts from 2 unrelated affected individuals demonstrated significantly reduced (~80-90%) TBC1C2D mRNA levels compared to controls, restored following cycloheximide treatment. Protein was absent in patient fibroblasts.

TBC-domain containing GTPase activating proteins are known as key regulators of RAB GTPase activity. TBC1D2B was shown to colocalize with RAB5-positive endocytic vesicles. CRISPR/Cas9-mediated ko of TBC1D2B in HeLa cells suggested a role in EGF receptor endocytosis and decreased cell viability of TBC1D2B-deficient HeLa cells upon serum deprivation.

Genes encoding other TBC domain-containg GTPase-activating proteins, e.g. TBC1D7 and TBC1D20, TBC1D24 are associated with recessive neurodevelopmental disorders (with ID and/or seizures) and the pathophysiological defect in TBC1D2B-related disorder (deficit in vesicle trafficking and/or cell survival) is proposed to be similar to that of TBC1D24.

Overall this gene can be considered for inclusion with amber/green rating in the ID panel and green in epilepsy panel.
Sources: Literature
Intellectual disability v3.170 EXOC2 Konstantinos Varvagiannis gene: EXOC2 was added
gene: EXOC2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: EXOC2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EXOC2 were set to 32639540
Phenotypes for gene: EXOC2 were set to Global developmental delay; Intellectual disability; Abnormality of the face; Abnormality of brain morphology
Penetrance for gene: EXOC2 were set to Complete
Review for gene: EXOC2 was set to AMBER
Added comment: Van Bergen et al (2020 - PMID: 32639540) report on 3 individuals from 2 families, harboring biallelic EXOC2 mutations.

Clinical presentation included DD, ID (severe in 2 subjects from fam1, borderline intellectual functioning in fam2), dysmorphic features and brain abnormalities. Cerebellar anomalies were common to all with a molar tooth sign observed in one (1/3). Other findings limited to subjects from one family included acquired microcephaly, congenital contractures, spastic quadriplegia (each observed 2/3).

Previous investigations were in all cases non-diagnostic. WES identified biallelic EXOC2 mutations in all affected individuals.

EXOC2 encodes an exocyst subunit. The latter is an octameric complex, component of the membrane transport machinery, required for tethering and fusion of vesicles at the plasma membrane. As discussed ,vesicle transport is important for the development of brain and the function of neurons and glia. Exocyst function is also important for delivery of Arl13b to the primary cilium (biallelic ARL13B mutations cause Joubert syndrome 8) and ciliogenesis.

Affected subjects from a broader consanguineous family (fam1) were homozygous for a truncating variant. Fibroblast studies revealed mRNA levels compatible with NMD (further restored in presence of CHX) as well as reduced protein levels. The female belonging to the second non-consanguineous family was found to harbor 2 missense variants in trans configuration.

An exocytosis defect was demonstrated in fibroblasts from individuals belonging to both families. Ciliogenesis appeared to be normal, however Arl13b localization/recruitment to the cilia was reduced compared with control cells with the defect rescued upon exogenous expression of wt EXOC2.

Mutations in other genes encoding components of the exocyst complex have been previously reported in individuals with relevant phenotypes (e.g. EXOC8 in a boy with features of Joubert s. or EXOC4 in nephrotic syndrome).

The authors discuss on the essential role of EXOC2 based on model organism studies (e.g. impaired neuronal membrane traffic, failure of neuronal polarization and neuromuscular junction expansion seen in Drosophila Sec5 (EXOC2) null mutants).
Sources: Literature
Intellectual disability v3.170 CEP120 Konstantinos Varvagiannis gene: CEP120 was added
gene: CEP120 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: CEP120 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CEP120 were set to 27208211
Phenotypes for gene: CEP120 were set to Joubert syndrome 31 (MIM 617761); Short-rib thoracic dysplasia 13 with or without polydactyly (MIM 616300)
Penetrance for gene: CEP120 were set to Complete
Review for gene: CEP120 was set to GREEN
Added comment: Pathogenic CEP120 variants have been reported in recessive ciliopathies, namely Short-rib thoracic dysplasia 13 with or without polydactyly (MIM 616300) and Joubert syndrome 31 (MIM 617761).

The former is associated with a severe/lethal outcome (4 unrelated infants described by Shaheen et al 2015 - PMID: 25361962, 2 fetuses reported by Roosing et al 2016 - PMID: 27208211).

Roosing et al however, also provided details on 4 unrelated subjects with Joubert syndrome diagnosis. All presented with a neurologic phenotype of hypotonia, DD, cognitive impairment and exhibited a molar tooth sign.

As a result, this gene can be considered for inclusion in the ID panel with green rating (>3 individuals/variants, consistent ciliopathy phenotype).
Sources: Literature
Intellectual disability v3.170 CCDC174 Konstantinos Varvagiannis gene: CCDC174 was added
gene: CCDC174 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: CCDC174 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CCDC174 were set to 26358778
Phenotypes for gene: CCDC174 were set to Hypotonia, infantile, with psychomotor retardation - IHPMR, 616816
Penetrance for gene: CCDC174 were set to Complete
Mode of pathogenicity for gene: CCDC174 was set to Other
Review for gene: CCDC174 was set to AMBER
Added comment: Biallelic pathogenic CCDC174 variants cause Hypotonia, infantile, with psychomotor retardation - IHPMR (MIM 616816).

Volodarsky et al [2015 - PMID: 26358778] describe 6 children from 2 unrelated families with - among others - severe hypotonia, psychomotor delay and abducens nerve palsy. All affected subjects were homozygous for a stoploss variant. Evidence from functional studies/animal model is provided supporting the role of the gene in this phenotype.

Overall this gene can be considered for inclusion in the ID panel with amber rating (2 families, single founder variant, consistent phenotype, supportive studies) pending further reports.
Sources: Literature
Intellectual disability v3.170 ACOX2 Konstantinos Varvagiannis gene: ACOX2 was added
gene: ACOX2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: ACOX2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ACOX2 were set to 27647924; 27884763; 29287774
Phenotypes for gene: ACOX2 were set to Bile acid synthesis defect, congenital, 6 - 617308
Penetrance for gene: ACOX2 were set to unknown
Review for gene: ACOX2 was set to RED
Added comment: Biallelic pathogenic ACOX2 variants cause Bile acid synthesis defect, congenital, 6 (MIM 617308). Overall the phenotype corresponds to an IEM/peroxisomal disorder.

As per 01-07-2020 there are 3 reports, briefly reviewed :

- Vilarinho et al [2016 - PMID: 27647924] provided details on an 8-year-old boy with ID.
- Monte et al [2017 - PMID: 27884763] described a 16 year old male with sustained elevation of transaminases *without* accompanying neurologic symptomatology (as they comment).
- Ferdinandusse et al [2018 - PMID: 29287774] reported on a girl deceased at the age of few months.

Please consider inclusion in the ID panel with amber/red rating pending further reports.
Sources: Literature
Intellectual disability v3.170 ABCA2 Konstantinos Varvagiannis gene: ABCA2 was added
gene: ABCA2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: ABCA2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ABCA2 were set to 30237576; 29302074; 31047799
Phenotypes for gene: ABCA2 were set to Intellectual developmental disorder with poor growth and with or without seizures or ataxia, 618808
Penetrance for gene: ABCA2 were set to Complete
Review for gene: ABCA2 was set to GREEN
Added comment: Biallelic pathogenic ABCA2 variants cause Intellectual developmental disorder with poor growth and with or without seizures or ataxia (MIM 618808).

There are 3 relevant publications (01-07-2020) :
- Maddirevula et al [2019 - PMID: 30237576] described briefly 2 unrelated subjects (16-2987, 16DG0071) both DD and seizures among other manifestations.
- Hu et al [2019 - PMID: 29302074] reported 3 sibs (M8600615 - III:1-3) born to consanguineous parents (M8600615 - III:1-3) with DD/ID (formal confirmation of moderate ID, in those (2) evaluated). One also presented with seizures.
- Aslam and Naz [2019 - PMID: 31047799] provided clinical details on 2 siblings born to consanguineous parents. ID was reported for the older sib but was absent in the younger one. Seizures were not part of the phenotype.

All subjects harbored biallelic pLoF variants.

N.B. : Steinberg et al [2015 - PMID: 25773295], within a cohort of patients with ALS, identified one with biallelic ABCA2 variants. As however Aslam and Naz comment, this person harbored a single pathogenic variant, with a second one rather unlikely to be pathogenic due to high allele frequency.

Overall this gene can be considered for inclusion with green rating in both ID and epilepsy panels (each in >=3 unrelated individuals).
Sources: Literature
Intellectual disability v3.170 HERC2 Konstantinos Varvagiannis edited their review of gene: HERC2: Added comment: Please consider upgrading this gene to green in the current panel based on the following updated review (13-07-2020):

Biallelic pathogenic HERC2 variants cause Mental retardation, autosomal recessive 38 (MIM 615516).

The current review is based mostly on the information provided by Elpidorou et al (2020 - PMID: 32571899) summarizing the findings in several affected individuals as published in the literature. ID was a universal feature among them (27/27) and seizures were reported in some (9/27):
- 22 subjects from Amish/Mennonite families were homozygous for p.Pro594Leu [NM_004667.5(HERC2):c.1781C>T] (Puffenberger et al 2012 - PMID: 23065719, Harlalka et al 2013 - PMID: 23243086, Abraham et al - PMID: 30902390)
- 2 additional patients were homozygous for another missense SNV [NM_004667.5(HERC2):c.4625G>A - p.Arg1542His] (Abraham et al 2019 - PMID: 30902390)
- 3 sibs born to consanguineous parents, homozygous for NM_004667.5:c.13767_13770delTGAA - p.(Asn4589LysTer4598)] as described by Elpidorou et al.
- 1 male homozygous 286 kb deletion spanning several 5' exons of HERC2 as well as the first exons of OCA2 was described by Morice-Picard et al (2016 - PMID: 27759030). Despite a neurological presentation (axial hypotonia, peripheral hypertonia, extrapyramidal symptoms and uncoordinated movements) further information was not available.

Apart from the cases summarized by Elpidorou et al, there have been few additional ones e.g. :
- Trujillano et al (2017 - PMID: 27848944) reported briefly on a patient, homozygous for NM_004667.5:c.4676-1G>A displaying seizures, hypotonia, global DD, "Encephalopathy" and abnormality of the liver.
- Yavarna et al (2015 - PMID: 26077850) provided few details with on an individual with primarily 'neurocognitive' phenotype but rather atypical presentation (MRI abnormalities, TGA, VSD, renal anomaly, growth retardation, hearing loss) due to p.Q3164X variant (recessive inheritance was specified).

Several lines of evidence support an important role for the protein encoded (an E3 ubiquitin protein ligase, interacting also with UBE3A, involved in several cellular processes incl. cell cycle regulation, spindle formation during mitosis, mitochondrial functions, DNA damage responses by targeting proteins such as XPA) as well as the effect of the reported variants (mRNA studies, Western blot, detection of a fusion transcript in the case of the deletion, etc).

Individuals from the Amish families displayed Angelman-like features (in line with HERC2-UBE3A interaction) with - among others - gait instability. Mouse models recapitulate some of these features (e.g. the movement disorder) as extensively discussed by Abraham et al.

Overall this gene can be included in the ID and epilepsy panels with green rating.

-----; Changed rating: GREEN; Changed publications: 23065719, 23243086, 30902390, 32571899, 27848944, 26077850, 27759030
Intellectual disability v3.170 SEC31A Sarah Leigh Classified gene: SEC31A as Amber List (moderate evidence)
Intellectual disability v3.170 SEC31A Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. One homozygous terminating variant reported in sibs of consanguineous Bedouin parents, together with a Drosophila model in which loss of sec31a was embryonically lethal and associated with defects in eye and brain development, consistent with abnormal neurodevelopment.
Intellectual disability v3.170 SEC31A Sarah Leigh Gene: sec31a has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.169 SEC31A Sarah Leigh Phenotypes for gene: SEC31A were changed from Neurodevelopmental disorder with spastic quadriplegia, optic atrophy, seizures, and structural brain anomalies, OMIM #618651 to Neurodevelopmental disorder with spastic quadriplegia, optic atrophy, seizures, and structural brain anomalies 618651
Intellectual disability v3.168 SBF1 Sarah Leigh changed review comment from: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 7 variants reported in at least 5 unrelated cases.; to: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 7 variants reported in at least 5 unrelated cases. The phenotypes vary, but early‐onset microcephaly and moderate‐severe developmental delay were reported in 3 cases (PMID 30039846, 21210780, 20658556).
Intellectual disability v3.168 SBF1 Sarah Leigh Classified gene: SBF1 as Amber List (moderate evidence)
Intellectual disability v3.168 SBF1 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 7 variants reported in at least 5 unrelated cases.
Intellectual disability v3.168 SBF1 Sarah Leigh Gene: sbf1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.167 SBF1 Sarah Leigh reviewed gene: SBF1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.167 SBF1 Sarah Leigh Tag for-review tag was added to gene: SBF1.
Intellectual disability v3.167 SBF1 Sarah Leigh Phenotypes for gene: SBF1 were changed from Charcot-Marie-Tooth disease, type 4B3, MIM# 615284 to Charcot-Marie-Tooth disease, type 4B3 615284
Intellectual disability v3.166 SARS2 Sarah Leigh edited their review of gene: SARS2: Added comment: There is enough evidence for this gene to be rated GREEN at the next major review.; Changed rating: GREEN
Intellectual disability v3.166 SARS2 Sarah Leigh Tag for-review tag was added to gene: SARS2.
Intellectual disability v3.166 SARS2 Sarah Leigh Classified gene: SARS2 as Amber List (moderate evidence)
Intellectual disability v3.166 SARS2 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 3 variants reported in at least 3 unrelated cases. Segregates with the disease.
Intellectual disability v3.166 SARS2 Sarah Leigh Gene: sars2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.165 SARS2 Sarah Leigh Publications for gene: SARS2 were set to 21255763; 24034276
Intellectual disability v3.164 SARS2 Sarah Leigh Phenotypes for gene: SARS2 were changed from Hyperuricemia, pulmonary hypertension, renal failure, and alkalosis, MIM#613845 to Hyperuricemia, pulmonary hypertension, renal failure, and alkalosis 613845
Intellectual disability v3.163 RUSC2 Sarah Leigh Classified gene: RUSC2 as Amber List (moderate evidence)
Intellectual disability v3.163 RUSC2 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 2 variants reported in at least 2 unrelated cases. No functional studies have been reported, although authors of PMID 27612186 suggest that p.R866* results in total loss of function as the sibs biallelic with this variant have a more severe phenotype than the case who is biallelic for p.R1318*, which they conclude results in partial loss of function.
Intellectual disability v3.163 RUSC2 Sarah Leigh Gene: rusc2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.162 RUSC2 Sarah Leigh Phenotypes for gene: RUSC2 were changed from Mental retardation, autosomal recessive 61, MIM# 617773 to Mental retardation, autosomal recessive 61 617773
Intellectual disability v3.161 SLC12A6 Sarah Leigh commented on gene: SLC12A6: For-review tag has been added as it maybe appropriate to change the MOI to BOTH monoallelic and biallelic, autosomal or pseudoautosomal at the next major review, to ensure that de novo heterozgous variants are identified.
Intellectual disability v3.161 SLC12A6 Sarah Leigh commented on gene: SLC12A6
Intellectual disability v3.161 SLC12A6 Sarah Leigh Publications for gene: SLC12A6 were set to
Intellectual disability v3.160 SLC12A6 Sarah Leigh Tag for-review tag was added to gene: SLC12A6.
Intellectual disability v3.160 RIC1 Sarah Leigh Tag founder-effect tag was added to gene: RIC1.
Intellectual disability v3.160 GALNT2 Sarah Leigh Classified gene: GALNT2 as Amber List (moderate evidence)
Intellectual disability v3.160 GALNT2 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Intellectual disability v3.160 GALNT2 Sarah Leigh Gene: galnt2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.159 GALNT2 Sarah Leigh gene: GALNT2 was added
gene: GALNT2 was added to Intellectual disability. Sources: Literature
for-review tags were added to gene: GALNT2.
Mode of inheritance for gene: GALNT2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GALNT2 were set to 27508872; 32293671
Phenotypes for gene: GALNT2 were set to Congenital disorder of glycosylation, type IIt 618885
Review for gene: GALNT2 was set to GREEN
Added comment: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 5 variants reported in at least 5 unrelated cases, together with mouse and rat models (PMID 27508872;32293671).
Sources: Literature
Intellectual disability v3.158 ADARB1 Sarah Leigh Classified gene: ADARB1 as Amber List (moderate evidence)
Intellectual disability v3.158 ADARB1 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Intellectual disability v3.158 ADARB1 Sarah Leigh Gene: adarb1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.157 ADARB1 Sarah Leigh Tag for-review tag was added to gene: ADARB1.
Intellectual disability v3.157 ALG14 Sarah Leigh changed review comment from: Have added the "for review" tag, to address the phenotypic variability of published carriers of ALG14 variants.; to: Have added the "for review" tag, to address the phenotypic variability of published carriers of ALG14 variants. This will be reviewed as more cases are reported.
Intellectual disability v3.157 ADARB1 Arina Puzriakova reviewed gene: ADARB1: Rating: GREEN; Mode of pathogenicity: None; Publications: 32220291; Phenotypes: Neurodevelopmental disorder with hypotonia, microcephaly, and seizures, 618862; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.157 SETD1A Sarah Leigh reviewed gene: SETD1A: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.157 FEM1B Arina Puzriakova edited their review of gene: FEM1B: Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.157 FEM1B Arina Puzriakova changed review comment from: Lecoquierre et al. (2019) (PMID: 31036916) conducted a large candidate gene discovery studying and identified a de novo missense variant (p.Arg126Gln) in a patient with syndromic global developmental delay. Recurrence of the same variant was highlighted in an individual from the DDD study, and the another from GeneMatcher. It is said that the three patients share a similar phenotype; however, any further details are limited and it is not possible to ascertain whether the additional patients refer to different individuals.

No function analysis was undertaken to validate the implication of FEM1B.

Gene not associated with any phenotype on OMIM or G2P.; to: Lecoquierre et al. (2019) (PMID: 31036916) conducted a large candidate gene discovery studying and identified a de novo missense variant (p.Arg126Gln) in a patient with syndromic global developmental delay. Recurrence of the same variant was highlighted in an individual from the DDD study, and the another from GeneMatcher. It is said that the three patients share a similar phenotype; however, any further details are limited and it is not possible to ascertain whether the additional patients refer to different individuals. No function analysis was undertaken to validate the implication of FEM1B.

Gene not associated with any phenotype on OMIM or G2P.
Intellectual disability v3.157 SETD1A Sarah Leigh Publications for gene: SETD1A were set to 28135719; 26974950
Intellectual disability v3.156 GNAI2 Arina Puzriakova reviewed gene: GNAI2: Rating: AMBER; Mode of pathogenicity: None; Publications: 31036916, 27787898; Phenotypes: Syndromic developmental disorder; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.156 NRROS Sarah Leigh Phenotypes for gene: NRROS were changed from neurodegeneration; intracranial calcification; epilepsy to Seizures, early-onset, with neurodegeneration and brain calcification 618875
Intellectual disability v3.155 NRROS Sarah Leigh Deleted their comment
Intellectual disability v3.155 NRROS Sarah Leigh Classified gene: NRROS as Amber List (moderate evidence)
Intellectual disability v3.155 NRROS Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene for NRROS-related Infantile-Onset Neurodegeneration with Intracranial Calcification. At least 6 variants reported in at least 5 unrelated cases (PMIDs 32100099;32197075), together with supportive mouse model (PMID 28459434).
Intellectual disability v3.155 NRROS Sarah Leigh Gene: nrros has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.154 NRROS Sarah Leigh Classified gene: NRROS as Amber List (moderate evidence)
Intellectual disability v3.154 NRROS Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene for NRROS-related Infantile-Onset Neurodegeneration with Intracranial Calcification. At least 6 variants reported in at least 5 unrelated cases (PMIDs 32100099;32197075), together with supportive mouse model (PMID 28459434).
Intellectual disability v3.154 NRROS Sarah Leigh Gene: nrros has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.154 NRROS Sarah Leigh Publications for gene: NRROS were set to 32100099; 32197075
Intellectual disability v3.153 NRROS Sarah Leigh reviewed gene: NRROS: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.153 FEM1B Arina Puzriakova reviewed gene: FEM1B: Rating: RED; Mode of pathogenicity: None; Publications: 31036916; Phenotypes: Global developmental delay; Mode of inheritance: None
Intellectual disability v3.153 NOVA2 Sarah Leigh Tag for-review tag was added to gene: NOVA2.
Intellectual disability v3.153 NOVA2 Sarah Leigh Deleted their comment
Intellectual disability v3.153 NOVA2 Sarah Leigh edited their review of gene: NOVA2: Added comment: There is enough evidence for this gene to be rated GREEN at the next major review.; Changed rating: GREEN
Intellectual disability v3.153 NOVA2 Sarah Leigh Classified gene: NOVA2 as Amber List (moderate evidence)
Intellectual disability v3.153 NOVA2 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least 6 terminating variants reported in unrelated cases, together supportive functional studies in a zebrafish knockdown of the NOVA2 ortholog (nova1a) (PMID 32197073).
Intellectual disability v3.153 NOVA2 Sarah Leigh Gene: nova2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.152 NOVA2 Sarah Leigh Classified gene: NOVA2 as Amber List (moderate evidence)
Intellectual disability v3.152 NOVA2 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least 6 terminating variants reported in unrelated cases, together supportive functional studies in a zebrafish knockdown of the NOVA2 ortholog (nova1a) (PMID 32197073).
Intellectual disability v3.152 NOVA2 Sarah Leigh Gene: nova2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.151 NOVA2 Sarah Leigh Phenotypes for gene: NOVA2 were changed from Intellectual disability; autism; hypotonia; spasticity; ataxia to Neurodevelopmental disorder with or without autistic features and/or structural brain abnormalities 618859
Intellectual disability v3.150 CDK19 Sarah Leigh Tag for-review tag was added to gene: CDK19.
Intellectual disability v3.150 CDK19 Sarah Leigh Classified gene: CDK19 as Amber List (moderate evidence)
Intellectual disability v3.150 CDK19 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least 2 variants reported in 3 unrelated cases, together with supportive Drosophila, demonstating the effects of the variants (PMID 32330417).
Intellectual disability v3.150 CDK19 Sarah Leigh Gene: cdk19 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.149 CDK19 Sarah Leigh Phenotypes for gene: CDK19 were changed from microcephaly, congenital bilateral falciform retinal folds, nystagmus, and mental retardation to Epileptic encephalopathy, early infantile, 87 618916
Intellectual disability v3.148 CDK19 Sarah Leigh Publications for gene: CDK19 were set to 20563892
Intellectual disability v3.148 CDK19 Sarah Leigh Mode of inheritance for gene: CDK19 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.147 WIPI2 Sarah Leigh Classified gene: WIPI2 as Red List (low evidence)
Intellectual disability v3.147 WIPI2 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 1 homozygous variant was reported in 4 members of a consanguineous family.
Intellectual disability v3.147 WIPI2 Sarah Leigh Gene: wipi2 has been classified as Red List (Low Evidence).
Intellectual disability v3.146 WIPI2 Sarah Leigh Phenotypes for gene: WIPI2 were changed from Intellectual developmental disorder with short stature and variable skeletal anomalies 618453 to ?Intellectual developmental disorder with short stature and variable skeletal anomalies 618453
Intellectual disability v3.145 GSX2 Sarah Leigh changed review comment from: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 2 variants reported in at least 2 unrealated cases.; to: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 2 variants reported in at least 2 unrealated cases, together with supportive functional studies (PMID 31412107).
Intellectual disability v3.145 GSX2 Sarah Leigh Classified gene: GSX2 as Amber List (moderate evidence)
Intellectual disability v3.145 GSX2 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 2 variants reported in at least 2 unrealated cases.
Intellectual disability v3.145 GSX2 Sarah Leigh Gene: gsx2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.144 YARS Sarah Leigh changed review comment from: Comment on list classification: Biallelic variants in three families with complex clinical conditions including developmental delay.; to: Comment on list classification: Biallelic variants in three families with complex clinical conditions including developmental delay. PMID 30304524 reports an extended family with microcephaly, expressive language delay, hearing loss, amongst other features. PMID 29232904 reports a proband whose phenotype included hearing loss, retnititis pigmentosa and hypotonia, but did not include intellectual disability. PMID 27633801 reports two sibblings with hypotionia, the older brother at 15 years of age has mild delays, he attends school on an individualized educational program and functions at a grade 3 level. He speaks and understands English and Polish.
Intellectual disability v3.144 YARS Sarah Leigh Classified gene: YARS as Amber List (moderate evidence)
Intellectual disability v3.144 YARS Sarah Leigh Added comment: Comment on list classification: Biallelic variants in three families with complex clinical conditions including developmental delay.
Intellectual disability v3.144 YARS Sarah Leigh Gene: yars has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.143 YARS Sarah Leigh Tag for-review was removed from gene: YARS.
Intellectual disability v3.143 YARS Sarah Leigh commented on gene: YARS
Intellectual disability v3.143 YARS Sarah Leigh Tag new-gene-name tag was added to gene: YARS.
Intellectual disability v3.143 YARS Sarah Leigh Tag for-review tag was added to gene: YARS.
Intellectual disability v3.143 CACNB4 Sarah Leigh Deleted their comment
Intellectual disability v3.143 CACNB4 Sarah Leigh Classified gene: CACNB4 as Amber List (moderate evidence)
Intellectual disability v3.143 CACNB4 Sarah Leigh Added comment: Comment on list classification: PMID 32176688 reports intellectual disability in homozygous sibs.
Intellectual disability v3.143 CACNB4 Sarah Leigh Gene: cacnb4 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.142 CACNB4 Sarah Leigh Classified gene: CACNB4 as Amber List (moderate evidence)
Intellectual disability v3.142 CACNB4 Sarah Leigh Added comment: Comment on list classification: PMID 32176688 reports intellectual disability in homozygous sibs.
Intellectual disability v3.142 CACNB4 Sarah Leigh Gene: cacnb4 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.141 CACNB4 Sarah Leigh Mode of inheritance for gene: CACNB4 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.140 CACNB4 Sarah Leigh Publications for gene: CACNB4 were set to 0
Intellectual disability v3.139 RSRC1 Sarah Leigh commented on gene: RSRC1: There is enough evidence for this gene to be rated GREEN at the next major review.
Intellectual disability v3.139 RSRC1 Sarah Leigh Classified gene: RSRC1 as Amber List (moderate evidence)
Intellectual disability v3.139 RSRC1 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least 9 variants reported in unrelated families.
Intellectual disability v3.139 RSRC1 Sarah Leigh Gene: rsrc1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.138 RSRC1 Sarah Leigh Tag for-review tag was added to gene: RSRC1.
Intellectual disability v3.138 RSRC1 Sarah Leigh Publications for gene: RSRC1 were set to 28640246; 29522154; 32227164
Intellectual disability v3.137 RSRC1 Sarah Leigh Phenotypes for gene: RSRC1 were changed from Intellectual developmental disorder, autosomal recessive 70 618402 to Intellectual developmental disorder, autosomal recessive 70 618402
Intellectual disability v3.137 RSRC1 Sarah Leigh Publications for gene: RSRC1 were set to 28640246; 29522154; 32227164
Intellectual disability v3.136 RSRC1 Sarah Leigh Phenotypes for gene: RSRC1 were changed from Intellectual developmental disorder, autosomal recessive 70, MIM# 618402 to Intellectual developmental disorder, autosomal recessive 70 618402
Intellectual disability v3.136 RSRC1 Sarah Leigh Publications for gene: RSRC1 were set to 28640246; 29522154
Intellectual disability v3.135 SLC12A2 Zornitza Stark gene: SLC12A2 was added
gene: SLC12A2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: SLC12A2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC12A2 were set to 30740830
Phenotypes for gene: SLC12A2 were set to Kilquist syndrome; deafness; intellectual disability; dysmorphic features; absent salivation; ectodermal dysplasia; constipation; intestinal malrotation; multiple congenital anomalies
Review for gene: SLC12A2 was set to GREEN
gene: SLC12A2 was marked as current diagnostic
Added comment: Two families reported and a mouse model. New report is not on PubMed yet: (https://doi.org/10.1212/NXG.0000000000000478)
Sources: Literature
Intellectual disability v3.135 RAP1GDS1 Zornitza Stark gene: RAP1GDS1 was added
gene: RAP1GDS1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: RAP1GDS1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RAP1GDS1 were set to 32431071
Phenotypes for gene: RAP1GDS1 were set to Intellectual disability; dysmorphic features
Review for gene: RAP1GDS1 was set to AMBER
Added comment: Four individuals from two consanguineous families, same homozygous splice site variant detected, borderline Red/Amber.
Sources: Literature
Intellectual disability v3.135 RIC1 Sarah Leigh Deleted their comment
Intellectual disability v3.135 RIC1 Sarah Leigh Publications for gene: RIC1 were set to 31932796
Intellectual disability v3.134 RIC1 Sarah Leigh Classified gene: RIC1 as Amber List (moderate evidence)
Intellectual disability v3.134 RIC1 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as possible Gen2Phen gene. At least one variant reported in numerous members of two families, who shared an autozygous interval, confirming Founder effect (PMID 27878435). Segregation was demonstrated, together with supportive functional and zebra fish model (PMID 31932796).
Intellectual disability v3.134 RIC1 Sarah Leigh Gene: ric1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.134 RIC1 Sarah Leigh Classified gene: RIC1 as Amber List (moderate evidence)
Intellectual disability v3.134 RIC1 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as possible Gen2Phen gene. At least one variant reported in numerous members of two families, who shared an autozygous interval, confirming Founder effect (PMID 27878435). Segregation was demonstrated, together with supportive functional and zebra fish model (PMID 31932796).
Intellectual disability v3.134 RIC1 Sarah Leigh Gene: ric1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.133 RIC1 Sarah Leigh Tag watchlist tag was added to gene: RIC1.
Intellectual disability v3.133 RIC1 Sarah Leigh Phenotypes for gene: RIC1 were changed from Cleft lip; cataract; tooth abnormality; intellectual disability; facial dysmorphism; ADHD to CATIFA syndrome 618761; Cleft lip; cataract; tooth abnormality; intellectual disability; facial dysmorphism; ADHD
Intellectual disability v3.132 OTUD7A Sarah Leigh Classified gene: OTUD7A as Red List (low evidence)
Intellectual disability v3.132 OTUD7A Sarah Leigh Added comment: Comment on list classification: Not associated with phenotype in OMIM or in Gen2Phen, Although the region ISCA-46295-Loss, which encompasses the OTUD7A locus, is associated with seizures 20236110, mental retardation 22775350, dysmorphic features, developmental delay and severe epileptic encephalopathy. PMID 31997314 report a homozygous variant in a case of severe global developmental delay, language impairment and epileptic encephalopathy; segregation and functional studies support this gene disease association.
Intellectual disability v3.132 OTUD7A Sarah Leigh Gene: otud7a has been classified as Red List (Low Evidence).
Intellectual disability v3.131 ISCA-46295-Loss Sarah Leigh Publications for Region: ISCA-46295-Loss were set to 19898479; 20236110; 22775350
Intellectual disability v3.130 TOMM70 Eleanor Williams changed review comment from: Not associated with a disease phenotype in OMIM or Gene2Phenotype

PMID: 31907385 - Wei et al 2020 - report a patient with severe anemia, lactic acidosis, and developmental delay in which two compound heterozygous variants in TOMM70 [c.794C>T (p.T265M) and c.1745C>T (p.A582V)] were identified. Functional studies showed that patient-derived cells exhibited multi-oxidative phosphorylation system (OXPHOS) complex defects. Abstract only accessed.

PMID: 32356556 - Dutta et al 2020 - report 2 patients with de novo heterozygous missense variants in the C-terminal region of TOMM70. Both patients had shared symptoms including hypotonia, hyper-reflexia, ataxia, dystonia and significant white matter abnormalities. However, for patient 1 a neurodevelopmental disorder was noted in infancy, but patient 2 developed as normal until age 4 when neurological regression occurred. Some functional data from Drosophila show that the variants cause partial loss of function.

3 cases but different mode of inheritance and phenotypic presentation.
Sources: Literature; to: Not associated with a disease phenotype in OMIM or Gene2Phenotype

PMID: 31907385 - Wei et al 2020 - report a patient with severe anemia, lactic acidosis, and developmental delay in which two compound heterozygous variants in TOMM70 [c.794C>T (p.T265M) and c.1745C>T (p.A582V)] were identified. Functional studies showed that patient-derived cells exhibited multi-oxidative phosphorylation system (OXPHOS) complex defects. Abstract only accessed.

PMID: 32356556 - Dutta et al 2020 - report 2 patients with de novo heterozygous missense variants in the C-terminal region of TOMM70. Both patients had shared symptoms including hypotonia, hyper-reflexia, ataxia, dystonia and significant white matter abnormalities. Patient 1 showed severe global developmental delay. However, for patient 1 a neurodevelopmental disorder was noted in infancy, but patient 2 developed as normal until age 4 when neurological regression occurred. Some functional data from Drosophila show that the variants cause partial loss of function.

3 cases but different mode of inheritance and phenotypic presentation.
Sources: Literature
Intellectual disability v3.130 TOMM70 Eleanor Williams gene: TOMM70 was added
gene: TOMM70 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: TOMM70 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: TOMM70 were set to 31907385; 32356556
Phenotypes for gene: TOMM70 were set to Severe anaemia, lactic acidosis; developmental delay; white matter abnormalities
Review for gene: TOMM70 was set to AMBER
Added comment: Not associated with a disease phenotype in OMIM or Gene2Phenotype

PMID: 31907385 - Wei et al 2020 - report a patient with severe anemia, lactic acidosis, and developmental delay in which two compound heterozygous variants in TOMM70 [c.794C>T (p.T265M) and c.1745C>T (p.A582V)] were identified. Functional studies showed that patient-derived cells exhibited multi-oxidative phosphorylation system (OXPHOS) complex defects. Abstract only accessed.

PMID: 32356556 - Dutta et al 2020 - report 2 patients with de novo heterozygous missense variants in the C-terminal region of TOMM70. Both patients had shared symptoms including hypotonia, hyper-reflexia, ataxia, dystonia and significant white matter abnormalities. However, for patient 1 a neurodevelopmental disorder was noted in infancy, but patient 2 developed as normal until age 4 when neurological regression occurred. Some functional data from Drosophila show that the variants cause partial loss of function.

3 cases but different mode of inheritance and phenotypic presentation.
Sources: Literature
Intellectual disability v3.129 CAPZA2 Eleanor Williams Phenotypes for gene: CAPZA2 were changed from to intellectual disability
Intellectual disability v3.128 CAPZA2 Eleanor Williams Classified gene: CAPZA2 as Amber List (moderate evidence)
Intellectual disability v3.128 CAPZA2 Eleanor Williams Added comment: Comment on list classification: 2 cases reported. Some functional evidence but not enough to promote to green.
Intellectual disability v3.128 CAPZA2 Eleanor Williams Gene: capza2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.127 CAPZA2 Eleanor Williams gene: CAPZA2 was added
gene: CAPZA2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: CAPZA2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CAPZA2 were set to 32338762
Review for gene: CAPZA2 was set to AMBER
Added comment: Not associated with a disease phenotype in OMIM.

PMID: 32338762 - Huang et al 2020 - report 2 unrelated families (Chinese and European) in which a de novo heterozygous variant has been identified in CAPZA2 in paediatric probands that present with global motor development delay, speech delay, intellectual disability, hypotonia. One proband had seizures at 7 months but these were controlled with medication and did not repeat. The other proband at age one had an atypical febrile seizure that was controlled without medication. Functional studies in Drosophila suggest that these variants are mild loss of function mutations but that they can act as dominant negative variants in actin polymerization in bristles.
Sources: Literature
Intellectual disability v3.126 HARS Zornitza Stark changed review comment from: 3 cases from 2 unrelated families with biallelic variants and mild to severe intellectual disability as a feature of the condition.

Please note association with Usher syndrome (deafness/retinal phenotypes) has been assessed as 'refuted' by ClinGen, and this gene has a well-established association between heterozygous variants and CMT.
Sources: Literature; to: 3 cases from 2 unrelated families with biallelic variants and mild to severe intellectual disability as a feature of the condition. We have also added to paediatric ataxia panel as Amber.

Please note association with Usher syndrome (deafness/retinal phenotypes) has been assessed as 'refuted' by ClinGen, and this gene has a well-established association between heterozygous variants and CMT.
Sources: Literature
Intellectual disability v3.126 HARS Zornitza Stark gene: HARS was added
gene: HARS was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: HARS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HARS were set to 32296180
Phenotypes for gene: HARS were set to multisystem ataxic syndrome; mild-severe intellectual disability
Review for gene: HARS was set to AMBER
Added comment: 3 cases from 2 unrelated families with biallelic variants and mild to severe intellectual disability as a feature of the condition.

Please note association with Usher syndrome (deafness/retinal phenotypes) has been assessed as 'refuted' by ClinGen, and this gene has a well-established association between heterozygous variants and CMT.
Sources: Literature
Intellectual disability v3.126 EXOC7 Zornitza Stark gene: EXOC7 was added
gene: EXOC7 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: EXOC7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EXOC7 were set to 32103185
Phenotypes for gene: EXOC7 were set to brain atrophy; seizures; developmental delay; microcephaly
Review for gene: EXOC7 was set to GREEN
gene: EXOC7 was marked as current diagnostic
Added comment: 4 families with 8 affected individuals with brain atrophy, seizures, and developmental delay, and in more severe cases microcephaly and infantile death. Four novel homozygous or comp.heterozygous variants found in EXOC7, which segregated with disease in the families. They showed that EXOC7, a member of the mammalian exocyst complex, is highly expressed in developing human cortex. In addition, a zebrafish model of Exoc7 deficiency recapitulates the human disorder with increased apoptosis and decreased progenitor cells during telencephalon development, suggesting that the brain atrophy in human cases reflects neuronal degeneration. We have added to the Microcephaly and Genetic Epilepsies panels as well.
Sources: Literature
Intellectual disability v3.126 HNRNPH1 Zornitza Stark gene: HNRNPH1 was added
gene: HNRNPH1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: HNRNPH1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: HNRNPH1 were set to 32335897; 29938792
Phenotypes for gene: HNRNPH1 were set to HNRNPH1‐related syndromic intellectual disability
Review for gene: HNRNPH1 was set to GREEN
Added comment: 1st patient reported in 2018 with intellectual disability and dysmorphic features and HNRNPH1 heterozygous missense variant. 2020 paper reports additional 7 cases with ID, short stature, microcephaly, distinctive dysmorphic facial features, and congenital anomalies (cranial, brain, genitourinary, palate, ophthalmologic). They all had HNRNPH1 heterozygous pathogenic variants (missense, frameshift, in‐frame deletion, entire gene duplication) and were identified using clinical networks and GeneMatcher.
Sources: Literature
Intellectual disability v3.126 PDCD6IP Zornitza Stark gene: PDCD6IP was added
gene: PDCD6IP was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: PDCD6IP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PDCD6IP were set to 32286682
Phenotypes for gene: PDCD6IP were set to microcephaly; Intellectual disability
Review for gene: PDCD6IP was set to AMBER
Added comment: One consanguineous family with 2 affected sibs with primary microcephaly (-4SD), intellectual disability and short stature (-5/6SD), and homozygous frameshift variant in PDCD6IP. The homozygous variant was confirmed in both affected sibs, while the four healthy siblings and parents were heterozygous. The clinical features observed in the patients were similar to the phenotypes observed in mouse and zebrafish models of PDCD6IP mutations in previous studies.
Sources: Literature
Intellectual disability v3.126 MCM3AP Eleanor Williams Publications for gene: MCM3AP were set to 24123876; 28633435; 28969388; 29982295; 32202298
Intellectual disability v3.125 RBL2 Sarah Leigh Deleted their comment
Intellectual disability v3.125 RBL2 Sarah Leigh Deleted their comment
Intellectual disability v3.125 MCM3AP Eleanor Williams Publications for gene: MCM3AP were set to 24123876; 28633435; 28969388; 29982295; 32202298
Intellectual disability v3.124 COG4 Sarah Leigh reviewed gene: COG4: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.124 MCM3AP Eleanor Williams Publications for gene: MCM3AP were set to 24123876; 28633435; 28969388; 29982295; 32202298
Intellectual disability v3.124 COG4 Sarah Leigh Tag for-review tag was added to gene: COG4.
Intellectual disability v3.124 MCM3AP Eleanor Williams Publications for gene: MCM3AP were set to 24123876; 28633435; 28969388; 29982295
Intellectual disability v3.123 MCM3AP Eleanor Williams reviewed gene: MCM3AP: Rating: GREEN; Mode of pathogenicity: None; Publications: 32202298; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.123 RBL2 Sarah Leigh Classified gene: RBL2 as Red List (low evidence)
Intellectual disability v3.123 RBL2 Sarah Leigh Added comment: Comment on list classification: Not associated with phenotype in OMIM or in Gen2Phen. Identified as a candidate gene in PMIDs 32105419; 9806916, with two variants in sibblings.
Intellectual disability v3.123 RBL2 Sarah Leigh Gene: rbl2 has been classified as Red List (Low Evidence).
Intellectual disability v3.122 SOX6 Sarah Leigh Tag for-review tag was added to gene: SOX6.
Intellectual disability v3.122 SOX6 Sarah Leigh edited their review of gene: SOX6: Added comment: There is enough evidence for this gene to be rated GREEN at the next major review.; Changed rating: GREEN
Intellectual disability v3.122 SOX6 Sarah Leigh Classified gene: SOX6 as Amber List (moderate evidence)
Intellectual disability v3.122 SOX6 Sarah Leigh Added comment: Comment on list classification: Not associated with relevant phenotype in OMIM and as probable Gen2Phen gene for SOX6-related neurodevelopmental syndrome. At least 17 unrelated cases, with 14 de novo heterozygous variants, a further 2 families where the variant appeared to inherited from the affected father and a single case where the variant was found to be mosaic in the unaffected father.
Intellectual disability v3.122 SOX6 Sarah Leigh Gene: sox6 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.121 RBL2 Sarah Leigh Classified gene: RBL2 as Red List (low evidence)
Intellectual disability v3.121 RBL2 Sarah Leigh Added comment: Comment on list classification: Not associated with phenotype in OMIM or in Gen2Phen. Identified as a candidate gene in PMIDs 32105419; 9806916, with two variants in sibblings.
Intellectual disability v3.121 RBL2 Sarah Leigh Gene: rbl2 has been classified as Red List (Low Evidence).
Intellectual disability v3.120 TTC5 Sarah Leigh edited their review of gene: TTC5: Added comment: There is enough evidence for this gene to be rated GREEN at the next major review.; Changed rating: GREEN
Intellectual disability v3.120 TTC5 Sarah Leigh Classified gene: TTC5 as Amber List (moderate evidence)
Intellectual disability v3.120 TTC5 Sarah Leigh Added comment: Comment on list classification: Not associated with a relevant phenotype in OMIM and as probable Gen2Phen gene for TTC5-associated neurodevelopmental disorder. At least 7 cases with biallelic variants.
Intellectual disability v3.120 TTC5 Sarah Leigh Gene: ttc5 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.119 TTC5 Sarah Leigh Tag for-review tag was added to gene: TTC5.
Intellectual disability v3.119 RBL2 Sarah Leigh Classified gene: RBL2 as Red List (low evidence)
Intellectual disability v3.119 RBL2 Sarah Leigh Added comment: Comment on list classification: Not associated with phenotype in OMIM or in Gen2Phen. Identified as a candidate gene in PMIDs 32105419; 9806916, with two variants in sibblings.
Intellectual disability v3.119 RBL2 Sarah Leigh Gene: rbl2 has been classified as Red List (Low Evidence).
Intellectual disability v3.118 SIX5 Sarah Leigh Deleted their comment
Intellectual disability v3.118 SIX5 Sarah Leigh Classified gene: SIX5 as Red List (low evidence)
Intellectual disability v3.118 SIX5 Sarah Leigh Added comment: Comment on list classification: Based on expert review and lack evidence for association with intellectual disability in publications.
Intellectual disability v3.118 SIX5 Sarah Leigh Gene: six5 has been classified as Red List (Low Evidence).
Intellectual disability v3.117 SKIV2L Sarah Leigh Classified gene: SKIV2L as Red List (low evidence)
Intellectual disability v3.117 SKIV2L Sarah Leigh Added comment: Comment on list classification: Based on expert review and lack evidence for association with intellectual disability in publications.
Intellectual disability v3.117 SKIV2L Sarah Leigh Gene: skiv2l has been classified as Red List (Low Evidence).
Intellectual disability v3.116 SKIV2L Sarah Leigh Publications for gene: SKIV2L were set to
Intellectual disability v3.115 SIX5 Sarah Leigh Publications for gene: SIX5 were set to
Intellectual disability v3.115 SIX5 Sarah Leigh Classified gene: SIX5 as Red List (low evidence)
Intellectual disability v3.115 SIX5 Sarah Leigh Added comment: Comment on list classification: Based on expert review and lack evidence for association with intellectual disability in publications.
Intellectual disability v3.115 SIX5 Sarah Leigh Gene: six5 has been classified as Red List (Low Evidence).
Intellectual disability v3.114 SIX1 Sarah Leigh Publications for gene: SIX1 were set to 25529582; Version 12 ukgtn.nhs.uk
Intellectual disability v3.113 SIX1 Sarah Leigh Classified gene: SIX1 as Red List (low evidence)
Intellectual disability v3.113 SIX1 Sarah Leigh Added comment: Comment on list classification: Based on expert review and lack evidence for association with intellectual disability in publications.
Intellectual disability v3.113 SIX1 Sarah Leigh Gene: six1 has been classified as Red List (Low Evidence).
Intellectual disability v3.112 SIX1 Sarah Leigh Publications for gene: SIX1 were set to
Intellectual disability v3.112 SIX1 Sarah Leigh Classified gene: SIX1 as Red List (low evidence)
Intellectual disability v3.112 SIX1 Sarah Leigh Added comment: Comment on list classification: Based on expert review and lack evidence for association with intellectual disability.
Intellectual disability v3.112 SIX1 Sarah Leigh Gene: six1 has been classified as Red List (Low Evidence).
Intellectual disability v3.111 SLC1A1 Sarah Leigh Publications for gene: SLC1A1 were set to 21123949; 16311588; 16311588
Intellectual disability v3.110 SLC1A1 Sarah Leigh Classified gene: SLC1A1 as Amber List (moderate evidence)
Intellectual disability v3.110 SLC1A1 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 2 variants reported in 2 unrelated cases (PMID 21123949), a SLC1A1 null mouse model with age-dependent chronic neurodegeneration (PMID 16311588), together with historic reports of intellectual disability associated with the phenotype (PMID 894411).
Intellectual disability v3.110 SLC1A1 Sarah Leigh Gene: slc1a1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.109 SLC1A1 Sarah Leigh reviewed gene: SLC1A1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.109 SLC1A1 Sarah Leigh Phenotypes for gene: SLC1A1 were changed from Dicarboxylic aminoaciduria 222730 to Dicarboxylic aminoaciduria 222730
Intellectual disability v3.108 SLC1A1 Sarah Leigh Tag for-review tag was added to gene: SLC1A1.
Intellectual disability v3.108 SLC1A1 Sarah Leigh Phenotypes for gene: SLC1A1 were changed from Dicarboxylic aminoaciduria 222730 to Dicarboxylic aminoaciduria 222730
Intellectual disability v3.107 SLC1A1 Sarah Leigh Publications for gene: SLC1A1 were set to 21123949; 21123949
Intellectual disability v3.106 SLC1A1 Sarah Leigh Publications for gene: SLC1A1 were set to Dicarboxylic aminoaciduria, MIM#222730
Intellectual disability v3.105 SLC1A1 Sarah Leigh Phenotypes for gene: SLC1A1 were changed from to Dicarboxylic aminoaciduria 222730
Intellectual disability v3.104 DMD Sarah Leigh commented on gene: DMD
Intellectual disability v3.104 PIGS Sarah Leigh edited their review of gene: PIGS: Added comment: There is enough evidence for this gene to be rated GREEN at the next major review.; Changed rating: GREEN
Intellectual disability v3.104 PIGS Sarah Leigh Deleted their comment
Intellectual disability v3.104 PIGS Sarah Leigh Deleted their comment
Intellectual disability v3.104 PIGS Sarah Leigh Classified gene: PIGS as Amber List (moderate evidence)
Intellectual disability v3.104 PIGS Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least 5 variants reported in at least 3 unrelated cases.
Intellectual disability v3.104 PIGS Sarah Leigh Gene: pigs has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.103 PIGS Sarah Leigh Classified gene: PIGS as Amber List (moderate evidence)
Intellectual disability v3.103 PIGS Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least 5 variants reported in at least 3 unrelated cases.
Intellectual disability v3.103 PIGS Sarah Leigh Gene: pigs has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.103 PIGS Sarah Leigh Classified gene: PIGS as Amber List (moderate evidence)
Intellectual disability v3.103 PIGS Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least 5 variants reported in at least 3 unrelated cases.
THIS GENE COULD BE RATED GREEN AT THE NEXT MAJOR REVIEW
Intellectual disability v3.103 PIGS Sarah Leigh Gene: pigs has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.102 PIGS Sarah Leigh Tag for-review tag was added to gene: PIGS.
Intellectual disability v3.102 PIGS Sarah Leigh Phenotypes for gene: PIGS were changed from Glycosylphosphatidylinositol biosynthesis defect 18, MIM# 618143 to Glycosylphosphatidylinositol biosynthesis defect 18 618143
Intellectual disability v3.101 ALG14 Sarah Leigh commented on gene: ALG14: Have added the "for review" tag, to address the phenotypic variability of published carriers of ALG14 variants.
Intellectual disability v3.101 ALG14 Sarah Leigh Classified gene: ALG14 as Green List (high evidence)
Intellectual disability v3.101 ALG14 Sarah Leigh Added comment: Comment on list classification: Associated with Myasthenic syndrome, congenital, 15, without tubular aggregates 616227 in OMIM, but not associated with phenotype in Gen2Phen. At least 6 variants reported in at least 5 cases with varying phenotypes. PMID 23404334 reports compound heterozygous (p.P65L, P.R104*) sibs, who manifested with myasthenic syndromes, but did not have intellectural disability nor seizures and were 62 and 51 years old when reported. PMID 28733338 reports two compound heterozygous (p.D74N, pV141G), (p.D74N, p.R109Q) cases and a homozygous ((p.D74N), with early and lethal neurodegeneration with myasthenic and myopathic features, but the cases died before intellectual disability was manifiest. However, seizures were evident in two compound heterozygous families. PMID 30221345 reports a homozygous splicing variant in a case with intellectual disability and seizures. Functional studies were presented showing that this variant resulting in exon skipping, however, this was not completely prenetrant as wild type protein was detected at a low level in the patient.
Intellectual disability v3.101 ALG14 Sarah Leigh Gene: alg14 has been classified as Green List (High Evidence).
Intellectual disability v3.100 ALG14 Sarah Leigh Tag for-review tag was added to gene: ALG14.
Intellectual disability v3.100 CNOT3 Sarah Leigh commented on gene: CNOT3
Intellectual disability v3.100 ALG14 Sarah Leigh Phenotypes for gene: ALG14 were changed from Myasthenic syndrome, congenital, 15, without tubular aggregates, MIM#616227; Intellectual disability to Myasthenic syndrome, congenital, 15, without tubular aggregates 616227; Intellectual disability
Intellectual disability v3.99 PIGK Sarah Leigh Phenotypes for gene: PIGK were changed from Neurodevelopmental disorder with hypotonia and cerebellar atrophy, with or without seizures 618879 to Neurodevelopmental disorder with hypotonia and cerebellar atrophy, with or without seizures 618879
Intellectual disability v3.99 PIGK Sarah Leigh Phenotypes for gene: PIGK were changed from Neurodevelopmental disorder with hypotonia and cerebellar atrophy, with or without seizures 618879 to Neurodevelopmental disorder with hypotonia and cerebellar atrophy, with or without seizures 618879
Intellectual disability v3.98 PIGK Sarah Leigh Deleted their comment
Intellectual disability v3.98 PIGK Sarah Leigh Phenotypes for gene: PIGK were changed from Neurodevelopmental disorder with hypotonia and cerebellar atrophy, with or without seizures 618879 to Neurodevelopmental disorder with hypotonia and cerebellar atrophy, with or without seizures 618879
Intellectual disability v3.97 PIGK Sarah Leigh Phenotypes for gene: PIGK were changed from Neurodevelopmental disorder with hypotonia and cerebellar atrophy, with or without seizures 618879 to Neurodevelopmental disorder with hypotonia and cerebellar atrophy, with or without seizures 618879
Intellectual disability v3.96 PIGK Sarah Leigh Classified gene: PIGK as Green List (high evidence)
Intellectual disability v3.96 PIGK Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene for PIGK-associated Neurodevelopmental Syndrome. At least 10 variants reported in at least 9 unrelated cases.
Intellectual disability v3.96 PIGK Sarah Leigh Gene: pigk has been classified as Green List (High Evidence).
Intellectual disability v3.95 PIGK Sarah Leigh Phenotypes for gene: PIGK were changed from Neurodevelopmental disorder with hypotonia and cerebellar atrophy, with or without seizures 618879 to Neurodevelopmental disorder with hypotonia and cerebellar atrophy, with or without seizures 618879
Intellectual disability v3.95 PIGK Sarah Leigh Classified gene: PIGK as Green List (high evidence)
Intellectual disability v3.95 PIGK Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene for PIGK-associated Neurodevelopmental Syndrome. At least 10 variants reported in at least 9 unrelated cases.
Intellectual disability v3.95 PIGK Sarah Leigh Gene: pigk has been classified as Green List (High Evidence).
Intellectual disability v3.94 PIGK Sarah Leigh Phenotypes for gene: PIGK were changed from Neurodevelopmental disorder with hypotonia and cerebellar atrophy, with or without seizures 618879 to Neurodevelopmental disorder with hypotonia and cerebellar atrophy, with or without seizures 618879
Intellectual disability v3.93 PIGK Sarah Leigh Phenotypes for gene: PIGK were changed from Neurodevelopmental disorder with hypotonia and cerebellar atrophy, with or without seizures 618879 to Neurodevelopmental disorder with hypotonia and cerebellar atrophy, with or without seizures 618879
Intellectual disability v3.92 PIGK Sarah Leigh Phenotypes for gene: PIGK were changed from Intellectual disability; seizures; cerebellar atrophy to Neurodevelopmental disorder with hypotonia and cerebellar atrophy, with or without seizures 618879
Intellectual disability v3.91 SCAF4 Eleanor Williams Tag watchlist tag was added to gene: SCAF4.
Intellectual disability v3.91 SATB1 Eleanor Williams Tag watchlist tag was added to gene: SATB1.
Intellectual disability v3.91 WNT1 Catherine Snow Classified gene: WNT1 as Green List (high evidence)
Intellectual disability v3.91 WNT1 Catherine Snow Added comment: Comment on list classification: Identified by expert review from Zornitza Stark, sufficient number of unrelated patients for WNT1 to be classified as Green
Intellectual disability v3.91 WNT1 Catherine Snow Gene: wnt1 has been classified as Green List (High Evidence).
Intellectual disability v3.90 SCAF4 Eleanor Williams changed review comment from: ESHG2020 - C02.1 - SCAF4 loss of function in humans and Drosophila implicates mRNA transcriptional termination in neurodevelopmental disorders - Fliedner et al - report 9 unrelated patients with likely pathogenic variants in SCAF4 and mild developmental delay and intellectual disability. 8 de novo. 1 inherited. Seizures, skeletal, renal and cardiac anomalies were also seen.
Sources: Literature; to: Conference talk/abstract from ESHG2020 - C02.1 - SCAF4 loss of function in humans and Drosophila implicates mRNA transcriptional termination in neurodevelopmental disorders - Fliedner et al - report 9 unrelated patients with likely pathogenic variants in SCAF4 and mild developmental delay and intellectual disability. 8 de novo. 1 inherited. Seizures, skeletal, renal and cardiac anomalies were also seen.
Sources: Literature
Intellectual disability v3.90 SCAF4 Eleanor Williams gene: SCAF4 was added
gene: SCAF4 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: SCAF4 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Added comment: ESHG2020 - C02.1 - SCAF4 loss of function in humans and Drosophila implicates mRNA transcriptional termination in neurodevelopmental disorders - Fliedner et al - report 9 unrelated patients with likely pathogenic variants in SCAF4 and mild developmental delay and intellectual disability. 8 de novo. 1 inherited. Seizures, skeletal, renal and cardiac anomalies were also seen.
Sources: Literature
Intellectual disability v3.89 CDC42BPB Sarah Leigh Classified gene: CDC42BPB as Amber List (moderate evidence)
Intellectual disability v3.89 CDC42BPB Sarah Leigh Gene: cdc42bpb has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.88 CDC42BPB Sarah Leigh changed review comment from: Comment on list classification: Not associated with phenotype in OMIM and as possible Gen2Phen gene. At least 12 variants reported in 14 unrelated cases of CDC42BPB-related Neurodevelopmental Disorder. intellectual disability was apparent in 7/12 cases and at least 5 of these cases were de novo.; to: Comment on list classification: Not associated with phenotype in OMIM and as possible Gen2Phen gene. At least 12 variants reported in 14 unrelated cases of CDC42BPB-related Neurodevelopmental Disorder. Intellectual disability was apparent in 7/12 cases and at least 5 of these cases were de novo. However, only two of these cases did not have additional genetic changes reported.
Intellectual disability v3.88 CDC42BPB Sarah Leigh Classified gene: CDC42BPB as Green List (high evidence)
Intellectual disability v3.88 CDC42BPB Sarah Leigh Added comment: Comment on list classification: Not associated with phenotype in OMIM and as possible Gen2Phen gene. At least 12 variants reported in 14 unrelated cases of CDC42BPB-related Neurodevelopmental Disorder. intellectual disability was apparent in 7/12 cases and at least 5 of these cases were de novo.
Intellectual disability v3.88 CDC42BPB Sarah Leigh Gene: cdc42bpb has been classified as Green List (High Evidence).
Intellectual disability v3.87 DSCR3 Zornitza Stark gene: DSCR3 was added
gene: DSCR3 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: DSCR3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DSCR3 were set to 31845315
Phenotypes for gene: DSCR3 were set to Intellectual disability, no OMIM # yet
Review for gene: DSCR3 was set to RED
Added comment: 1 family/2 cousins with cognitive impairment, growth failure, skeletal abnormalities, and distinctive facial features. Both shared the homozygous nonsense variant c.178G>T (p.Glu60*) in the VPS26C gene. This gene encodes VPS26C, a member of the retriever integral membrane protein recycling pathway. The nature of the variant which is predicted to result in loss‐of‐function, expression studies revealing significant reduction in the mutant transcript, and the co‐segregation of the homozygous variant with the phenotype in two affected individuals.
Sources: Literature
Intellectual disability v3.87 CDC42BPB Sarah Leigh Added comment: Comment on phenotypes: CDC42BPB-related Neurodevelopmental Disorder is assigned by Gen2Phen.
Intellectual disability v3.87 CDC42BPB Sarah Leigh Phenotypes for gene: CDC42BPB were changed from Central hypotonia; Global developmental delay; Intellectual disability; Seizures; Autistic behavior; Behavioral abnormality to CDC42BPB-related Neurodevelopmental Disorder; Central hypotonia; Global developmental delay; Intellectual disability; Seizures; Autistic behavior; Behavioral abnormality
Intellectual disability v3.86 NFASC Sarah Leigh Publications for gene: NFASC were set to 28940097; 30124836; 30850329
Intellectual disability v3.85 TMX2 Sarah Leigh Publications for gene: TMX2 were set to 31586943; 31270415
Intellectual disability v3.84 C16orf62 Sarah Leigh changed review comment from: Comment on list classification: Not associated with phenotype in OMIM or in Gen2Phen. Two variants have been reported as compound heterozygotes in two sibs with features of 3C/Ritscher-Schinzel syndrome. Functional studies show that loss of VPS35L function results in impared autophagy and VPS35L knockout mouse resulted in early embrionic lethality (PMID 25434475).; to: Comment on list classification: Not associated with phenotype in OMIM or in Gen2Phen. Two variants have been reported as compound heterozygotes in two sibs with features of 3C/Ritscher-Schinzel syndrome. Functional studies show that loss of VPS35L function results in impared autophagy and VPS35L knockout mouse resulted in early embrionic lethality (PMID 31712251).
Intellectual disability v3.84 C16orf62 Sarah Leigh Publications for gene: C16orf62 were set to 25434475
Intellectual disability v3.83 SRCAP Eleanor Williams commented on gene: SRCAP
Intellectual disability v3.83 SATB1 Eleanor Williams changed review comment from: Conference talk/abstract from ESHG 2020 - Mutation-specific pathophysiological mechanisms in a new SATB1-associated neurodevelopmental disorder - Den Hoed et al - report f26 individuals with SATB1 variants, 17 of which have missense variants and 9 have truncating variants. 21 of 26 variants (80%) were confirmed to be de novo in origin. Patients showed a broad phenotypic spectrum, including ID and/or neurodevelopmental delay, epilepsy, dental abnormalities and aspecific brain MRI findings. Additionally, patients with missense variants are more severely affected than those with truncating variants.
No peer reviewed publication was found in PubMed relating to these results so recommend Amber rating for now.
Sources: Other; to: Conference talk/abstract from ESHG 2020 - Mutation-specific pathophysiological mechanisms in a new SATB1-associated neurodevelopmental disorder - Den Hoed et al - report 26 individuals with SATB1 variants, 17 of which have missense variants and 9 have truncating variants. 21 of 26 variants (80%) were confirmed to be de novo in origin. Patients showed a broad phenotypic spectrum, including ID and/or neurodevelopmental delay, epilepsy, dental abnormalities and aspecific brain MRI findings. Additionally, patients with missense variants are more severely affected than those with truncating variants.
No peer reviewed publication was found in PubMed relating to these results so recommend Amber rating for now.
Sources: Other
Intellectual disability v3.83 SATB1 Eleanor Williams gene: SATB1 was added
gene: SATB1 was added to Intellectual disability. Sources: Other
Mode of inheritance for gene: SATB1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: SATB1 were set to intellectual disability
Review for gene: SATB1 was set to AMBER
Added comment: Conference talk/abstract from ESHG 2020 - Mutation-specific pathophysiological mechanisms in a new SATB1-associated neurodevelopmental disorder - Den Hoed et al - report f26 individuals with SATB1 variants, 17 of which have missense variants and 9 have truncating variants. 21 of 26 variants (80%) were confirmed to be de novo in origin. Patients showed a broad phenotypic spectrum, including ID and/or neurodevelopmental delay, epilepsy, dental abnormalities and aspecific brain MRI findings. Additionally, patients with missense variants are more severely affected than those with truncating variants.
No peer reviewed publication was found in PubMed relating to these results so recommend Amber rating for now.
Sources: Other
Intellectual disability v3.82 C16orf62 Sarah Leigh Classified gene: C16orf62 as Amber List (moderate evidence)
Intellectual disability v3.82 C16orf62 Sarah Leigh Added comment: Comment on list classification: Not associated with phenotype in OMIM or in Gen2Phen. Two variants have been reported as compound heterozygotes in two sibs with features of 3C/Ritscher-Schinzel syndrome. Functional studies show that loss of VPS35L function results in impared autophagy and VPS35L knockout mouse resulted in early embrionic lethality (PMID 25434475).
Intellectual disability v3.82 C16orf62 Sarah Leigh Gene: c16orf62 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.81 C16orf62 Sarah Leigh commented on gene: C16orf62: The HGNC approved name for this gene is: VPS35 endosomal protein sorting factor like (VPS35L)
Intellectual disability v3.81 C16orf62 Sarah Leigh Tag new-gene-name tag was added to gene: C16orf62.
Intellectual disability v3.81 C16orf62 Sarah Leigh gene: C16orf62 was added
gene: C16orf62 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: C16orf62 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: C16orf62 were set to 25434475
Phenotypes for gene: C16orf62 were set to 3C/Ritscher-Schinzel-like syndrome
Review for gene: C16orf62 was set to AMBER
Added comment: Sources: Literature
Intellectual disability v3.80 RBL2 Zornitza Stark gene: RBL2 was added
gene: RBL2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: RBL2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RBL2 were set to 32105419; 9806916
Phenotypes for gene: RBL2 were set to intellectual diability
Review for gene: RBL2 was set to RED
Added comment: Single family reported with pair of affected siblings. Supportive mouse model.
Sources: Literature
Intellectual disability v3.80 OTUD7A Zornitza Stark gene: OTUD7A was added
gene: OTUD7A was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: OTUD7A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: OTUD7A were set to 31997314; 29395075; 29395074
Phenotypes for gene: OTUD7A were set to Epileptic encephalopathy, intellectual disability, no OMIM# yet
Review for gene: OTUD7A was set to RED
Added comment: One patient with severe global developmental delay, language impairment and epileptic encephalopathy reported. Homozygous OTUD7A missense variant (c.697C>T, p.Leu233Phe), predicted to alter an ultraconserved amino acid, lying within the OTU catalytic domain. Its subsequent segregation analysis revealed that the parents, presenting with learning disability, and brother were heterozygous carriers. Biochemical assays demonstrated that proteasome complex formation and function were significantly reduced in patient‐derived fibroblasts and in OTUD7A knockout HAP1 cell line. Gene lies in the chromosome 15q13.3 region. Heterozygous microdeletions of chromosome 15q13.3 show incomplete penetrance and are associated with a highly variable phenotype that may include intellectual disability, epilepsy, facial dysmorphism and digit anomalies. Mouse model and other data support the role of this gene in neurodevelopmental phenotypes but nevertheless, single family to date.
Sources: Literature
Intellectual disability v3.80 COG4 Zornitza Stark edited their review of gene: COG4: Set current diagnostic: yes
Intellectual disability v3.80 COG4 Zornitza Stark reviewed gene: COG4: Rating: GREEN; Mode of pathogenicity: None; Publications: 31949312, 30290151, 19494034, 21185756; Phenotypes: Saul-Wilson syndrome, OMIM #618150, Congenital disorder of glycosylation, type IIj, OMIM #613489; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.80 TTC5 Zornitza Stark reviewed gene: TTC5: Rating: GREEN; Mode of pathogenicity: None; Publications: 29302074, 32439809; Phenotypes: Central hypotonia, Global developmental delay, Intellectual disability, Abnormality of nervous system morphology, Microcephaly, Abnormality of the face, Behavioral abnormality, Abnormality of the genitourinary system; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability v3.80 HIST1H4J Zornitza Stark gene: HIST1H4J was added
gene: HIST1H4J was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: HIST1H4J was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: HIST1H4J were set to 31804630
Phenotypes for gene: HIST1H4J were set to microcephaly; intellectual disability; dysmorphic features
Review for gene: HIST1H4J was set to AMBER
Added comment: Single case report but with functional evidence in zebrafish and phenotypic similarity to HIST1H4C phenotype
Sources: Literature
Intellectual disability v3.80 SNX27 Sarah Leigh Classified gene: SNX27 as Green List (high evidence)
Intellectual disability v3.80 SNX27 Sarah Leigh Added comment: Comment on list classification: Not associated with phenotype in OMIM (lasted edited on 05/23/2012) or in Gen2Phen. However, five variants in three unrelated cases, together with supportive functional studies and mouse model.
Intellectual disability v3.80 SNX27 Sarah Leigh Gene: snx27 has been classified as Green List (High Evidence).
Intellectual disability v3.79 SOX6 Zornitza Stark gene: SOX6 was added
gene: SOX6 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: SOX6 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SOX6 were set to 32442410
Phenotypes for gene: SOX6 were set to intellectual diability; ADHD; Craniosynostosis; Osteochondromas
Review for gene: SOX6 was set to GREEN
gene: SOX6 was marked as current diagnostic
Added comment: 19 individuals from 17 families with a neurodevelopmental syndrome reported. 6 LoF, 4 missense, and 6 intragenic deletion variants identified. ID ranged from mild to severe.
Sources: Literature
Intellectual disability v3.79 SLC5A6 Sarah Leigh Classified gene: SLC5A6 as Green List (high evidence)
Intellectual disability v3.79 SLC5A6 Sarah Leigh Added comment: Comment on list classification: Not associated with phenotype in OMIM and as possible Gen2Phen gene for SLC5A6-related Neurodevelopmental Disorder. At least 5 variants published in three unrelated famililies (4 cases total) with SLC5A6-related Neurodevelopmental Disorder, together with supportive functional studies (PMID 29669219; 23104561). One of the cases had mixed semiology seizures including focal dyscognitive, absence, tonic spasms and generalised convulsive seizures with electrographic features of encephalopathy with generalised and independent multifocal spike-wave discharges (PMID 31754459), another case had brain, immune, bone and intestinal dysfunction (PMID 27904971) and the third had metabolic dysfunction mimicking biotinidase deficiency (PMID 31392107). This condition could be treated with biotin supplementation and introduction of pantothenic acid supplementation (PMID 31392107).
Intellectual disability v3.79 SLC5A6 Sarah Leigh Gene: slc5a6 has been classified as Green List (High Evidence).
Intellectual disability v3.78 CXorf56 Sarah Leigh Tag Skewed X-inactivation tag was added to gene: CXorf56.
Intellectual disability v3.78 RNF113A Sarah Leigh Tag Skewed X-inactivation tag was added to gene: RNF113A.
Intellectual disability v3.78 PIGA Sarah Leigh Tag Skewed X-inactivation tag was added to gene: PIGA.
Intellectual disability v3.78 DMD Sarah Leigh Tag Skewed X-inactivation tag was added to gene: DMD.
Intellectual disability v3.78 TTC5 Konstantinos Varvagiannis gene: TTC5 was added
gene: TTC5 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: TTC5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TTC5 were set to 29302074; 32439809
Phenotypes for gene: TTC5 were set to Central hypotonia; Global developmental delay; Intellectual disability; Abnormality of nervous system morphology; Microcephaly; Abnormality of the face; Behavioral abnormality; Abnormality of the genitourinary system
Penetrance for gene: TTC5 were set to Complete
Review for gene: TTC5 was set to GREEN
Added comment: Hu et al (2019 - PMID: 29302074) reported briefly on 3 individuals from 2 consanguineous families (from Turkey and Iran) with biallelic TTC5 variants. Features included DD (3/3), ID (severe in 2/2 with relevant age), microcephaly (3/3), brain abnormalities, etc. A nonsense and a variant affecting splice site were identified by WES/WGS.

---

In a recent report, Rasheed et al (2020 - PMID: 32439809) report on the phenotype of 8 individuals - belonging to 5 consanguineous families - all 8 harboring homozygous TTC5 mutations.

Frequent features included hypotonia (6/8), motor and speech delay, moderate to severe ID (10/10 of relevant age - inclusion of less severely affected subjects was not considered by study design), brain MRI abnormalities (8/8). Other findings included microcephaly in some (6/11), behavioral abnormalities in few (autistic behavior in 2/8, aggression in 2/8), genitourinary anomalies (2/8), seizures (1/11). Facial phenotype incl. thin V-shaped upper lip, low-set ears (in most) and/or additional features.

TTC5 encodes a 440 aa protein, functioning as a scaffold to stabilise p300-JMY interactions. Apart from this role in nucleus, it has functions in the cytoplasm (inhibiting actin nucleataion, autophagosome formation, etc).

The gene has ubiquitous expression, highest in brain.

All variants were identified following WES - as the best candidates - in affected individuals with compatible Sanger studies in all affected family members and carrier parents.

2 missense and 2 nonsense variants were identified with the 2 missense SNVs localizing within TPR domains. qRT-PCR studies for a nonsense variant localizing 19 nt before the last exon, revealed fourfold decreased expression in affected individuals compared to carriers.

Families from Egypt shared a homozygous ~6.3 Mb haplotype block spanning TTC5, suggesting that p.(Arg263Ter) is likely a founder mutation.

The authors underscore some phenotypic (though not facial) similarities with Rubinstein-Taybi syndrome 2 due to EP300 mutations (in line with the role of TTC5).

Biallelic variants in genes encoding other members of the TTC family (containing a TPR motif), e.g. TTC8 or TTC15 cause disorders with neurologic manifestations (and DD/ID).
Sources: Literature
Intellectual disability v3.78 AGMO Rebecca Foulger changed review comment from: Comment on list classification: Gene was added to the panel and rated Green by Zornitza Stark. One family presented in PMID:27000257, and 2 compound het cases in PMID:31555905 (though there is one individual in gnomAD who is homozygous for the p.Gly144Arg variant). Functional data shows decreased enzyme activity of the variants. Although there are 3 cases, the phenotype is variable between patients (ID/DD vs regression). Therefore, rated as Amber awaiting further cases and clinical opinion.; to: Comment on list classification: Gene was added to the panel and rated Green by Zornitza Stark. One family presented in PMID:27000257, and 2 compound het cases in PMID:31555905 (though there is one individual in gnomAD who is homozygous for the p.Gly144Arg variant). Functional data shows decreased enzyme activity of the variants. Although there are 3 cases, the phenotype is variable between patients (ID/DD vs regression) and therefore this is borderline. Therefore, rated as Amber awaiting further cases and clinical opinion.
Intellectual disability v3.78 AGMO Rebecca Foulger changed review comment from: Comment on list classification: Gene was added to the panel and rated Green by Zornitza Stark. One homozygous case presented in PMID:27000257, and 2 compound het cases in PMID:31555905 (though there is one individual in gnomAD who is homozygous for the p.Gly144Arg variant). Functional data shows decreased enzyme activity of the variants. Although there are 3 cases, the phenotype is variable between patients (ID/DD vs regression). Therefore, rated as Amber awaiting further cases and clinical opinion.; to: Comment on list classification: Gene was added to the panel and rated Green by Zornitza Stark. One family presented in PMID:27000257, and 2 compound het cases in PMID:31555905 (though there is one individual in gnomAD who is homozygous for the p.Gly144Arg variant). Functional data shows decreased enzyme activity of the variants. Although there are 3 cases, the phenotype is variable between patients (ID/DD vs regression). Therefore, rated as Amber awaiting further cases and clinical opinion.
Intellectual disability v3.78 AGMO Rebecca Foulger Classified gene: AGMO as Amber List (moderate evidence)
Intellectual disability v3.78 AGMO Rebecca Foulger Added comment: Comment on list classification: Gene was added to the panel and rated Green by Zornitza Stark. One homozygous case presented in PMID:27000257, and 2 compound het cases in PMID:31555905 (though there is one individual in gnomAD who is homozygous for the p.Gly144Arg variant). Functional data shows decreased enzyme activity of the variants. Although there are 3 cases, the phenotype is variable between patients (ID/DD vs regression). Therefore, rated as Amber awaiting further cases and clinical opinion.
Intellectual disability v3.78 AGMO Rebecca Foulger Gene: agmo has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.77 AGMO Rebecca Foulger changed review comment from: PMID:27000257 (2016) Alrayes et al., 2016 enrolled a consanguineous family from Saudi Arabia presenting with primary microcephaly, developmental delay, short stature and intellectual disability. They identified a novel homozygous deletion mutation (c.967delA; p.Glu324Lysfs12*) in exon 10 of the alkylglycerol monooxygenase (AGMO) gene in 2 brothers. Population screening of 178 ethnically matched control chromosomes and consultation of the ExAC database confirmed that this variant was not present outside the family. Epilepsy is not mentioned amongst their phenotypes.; to: PMID:27000257 (2016) Alrayes et al., 2016 enrolled a consanguineous family from Saudi Arabia presenting with primary microcephaly, developmental delay, short stature and intellectual disability. They identified a novel homozygous deletion mutation (c.967delA; p.Glu324Lysfs12*) in exon 10 of the alkylglycerol monooxygenase (AGMO) gene in 2 brothers. Population screening of 178 ethnically matched control chromosomes and consultation of the ExAC database confirmed that this variant was not present outside the family.
Intellectual disability v3.77 AGMO Rebecca Foulger changed review comment from: PMID:31555905. Okur et al., report rare nonsense in-frame deletion and missense compound heterozygous variants in AGMO in 2 unrelated individuals (8 year old European girl, and 4-year old Ashkenazi Jewish boy). They demonstrated significantly diminished enzyme activity for all disease-associated variants. The girl harboured variants p.Trp130Ter & p.Gly238Cys. The boy harboured variants p.Gly144Arg and p.Tyr236del. Note that there is one individual in gnomAD who is homozygous for the p.Gly144Arg variant. Table 1 also mentions MTHFR C677T homozygous for the boy, but this is not referred to within the text. ID/DD (and seizures) was reported in the girl. The boy showed normal development to begin, but began to regress age 3.5 years.; to: PMID:31555905. Okur et al., report rare nonsense in-frame deletion and missense compound heterozygous variants in AGMO in 2 unrelated individuals (8 year old European girl, and 4-year old Ashkenazi Jewish boy). They demonstrated significantly diminished enzyme activity for all disease-associated variants. The girl harboured variants p.Trp130Ter & p.Gly238Cys. The boy harboured variants p.Gly144Arg and p.Tyr236del. Note that there is one individual in gnomAD who is homozygous for the p.Gly144Arg variant. Table 1 also mentions MTHFR C677T homozygous for the boy, but this is not referred to within the text. ID/DD (and seizures) were reported in the girl. The boy showed normal development to begin, but began to regress age 3.5 years.
Intellectual disability v3.77 AGMO Rebecca Foulger Phenotypes for gene: AGMO were changed from microcephaly; intellectual disability; epilepsy to microcephaly; intellectual disability; epilepsy; developmental delay
Intellectual disability v3.77 AGMO Rebecca Foulger Publications for gene: AGMO were set to 31555905
Intellectual disability v3.76 AGMO Rebecca Foulger commented on gene: AGMO: PMID:31555905. Okur et al., report rare nonsense in-frame deletion and missense compound heterozygous variants in AGMO in 2 unrelated individuals (8 year old European girl, and 4-year old Ashkenazi Jewish boy). They demonstrated significantly diminished enzyme activity for all disease-associated variants. The girl harboured variants p.Trp130Ter & p.Gly238Cys. The boy harboured variants p.Gly144Arg and p.Tyr236del. Note that there is one individual in gnomAD who is homozygous for the p.Gly144Arg variant. Table 1 also mentions MTHFR C677T homozygous for the boy, but this is not referred to within the text. ID/DD (and seizures) was reported in the girl. The boy showed normal development to begin, but began to regress age 3.5 years.
Intellectual disability v3.76 AGMO Rebecca Foulger commented on gene: AGMO
Intellectual disability v3.76 KAT8 Rebecca Foulger Tag missense tag was added to gene: KAT8.
Intellectual disability v3.76 KAT8 Rebecca Foulger commented on gene: KAT8: Added 'missense' tag because all de novo variants in PMID:31794431 are missense. Note that for the biallelic case in the same paper, one of the variants is nonsense.
Intellectual disability v3.76 KAT8 Rebecca Foulger Mode of pathogenicity for gene: KAT8 was changed from None to Other
Intellectual disability v3.75 KAT8 Rebecca Foulger Added comment: Comment on mode of inheritance: Individual T9 inherited biallelc variants from her asymptomatic parents. Her sister carried 1 variant and showed no obvious symptoms. This may be due to incomplete genetic penetrance, or the two variants act differently from the de novo heterozygous variants identified. This is the only example of biallelic inheritance, so have set MOI to 'monoallelic' until more cases are identified.
Intellectual disability v3.75 KAT8 Rebecca Foulger Mode of inheritance for gene: KAT8 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.74 KAT8 Rebecca Foulger Classified gene: KAT8 as Green List (high evidence)
Intellectual disability v3.74 KAT8 Rebecca Foulger Added comment: Comment on list classification: Gene was added to the panel and rated Green by Konstantinos Varvagiannis, and subsequently reviewed Green by Zornitza Stark. Not yet associated with a disorder in OMIM or G2P. All cases come from PMID:31794431 (Li et al.2019) who report 8 unrelated individuals with heterozygous de novo pathogenic KAT8 variants (T1,T2,T3 had the same variant), plus one individual compound het for a nonsense and a missense variant (p.Lys175* and p.Arg325Cys). All individuals had DD and/or ID (Supplementary materials). Knockout mice failed to thrive, and showed early lethality and cerebral hypoplasia.
Intellectual disability v3.74 KAT8 Rebecca Foulger Gene: kat8 has been classified as Green List (High Evidence).
Intellectual disability v3.73 CXorf56 Rebecca Foulger changed review comment from: Comment on mode of inheritance: OMIM records XL inheritance for MIM:301013 with X-linked inactivation. In PMID:29374277 carrier females had skewed X-inactivation whereas the affected female did not. In PMID:31822863 X-linked skewing was seen in both affected females and the unaffected carrier.; to: Comment on mode of inheritance: OMIM records XL inheritance for MIM:301013 noting X-linked inactivation in the comments. In PMID:29374277 carrier females had skewed X-inactivation whereas the affected female did not. In PMID:31822863 X-linked skewing was seen in both affected females and the unaffected carrier. Have set MOI to XLD for now, to capture affected females and males.
Intellectual disability v3.73 CXorf56 Rebecca Foulger Classified gene: CXorf56 as Green List (high evidence)
Intellectual disability v3.73 CXorf56 Rebecca Foulger Added comment: Comment on list classification: Updated rating from Grey to Green. Gene was added to panel by Konstantinos Varvagiannis, with a subsequent Green review by Zornitza Stark. Sufficient cases in PMIDs:29374277 and 31822863. The reported pattern of X-inactivation differs between the papers, but sufficient cases and relevant phenotype for inclusion on the panel.
Intellectual disability v3.73 CXorf56 Rebecca Foulger Gene: cxorf56 has been classified as Green List (High Evidence).
Intellectual disability v3.72 CXorf56 Rebecca Foulger Added comment: Comment on mode of inheritance: OMIM records XL inheritance for MIM:301013 with X-linked inactivation. In PMID:29374277 carrier females had skewed X-inactivation whereas the affected female did not. In PMID:31822863 X-linked skewing was seen in both affected females and the unaffected carrier.
Intellectual disability v3.72 CXorf56 Rebecca Foulger Mode of inheritance for gene: CXorf56 was changed from X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Intellectual disability v3.71 CXorf56 Rebecca Foulger commented on gene: CXorf56: PMID:31822863. Rocha et al., 2019 report on 9 affected individuals (3 unrelated families) with mild to severe ID and variants in CXorf56. In comparison to PMID:29374277, X-linked skewing was seen in both affected females and the unaffected carrier had complete inactivation of the carrier X-chromosome.
Intellectual disability v3.71 CXorf56 Rebecca Foulger commented on gene: CXorf56
Intellectual disability v3.71 UGP2 Rebecca Foulger Classified gene: UGP2 as Green List (high evidence)
Intellectual disability v3.71 UGP2 Rebecca Foulger Added comment: Comment on list classification: Gene added to panel and rated Green by Konstantinos Varvagiannis. Subsequently reviewed Green by Zornitza Stark. Sufficient evidence and appropriate phenotype (DD seen in all patients in PMID:31820119) for inclusion on panel: 20 patients from 13 unrelated families all with the same variant identified in PMID:31820119 (2019 publication). Therefore updated rating from Grey to Green.
Intellectual disability v3.71 UGP2 Rebecca Foulger Gene: ugp2 has been classified as Green List (High Evidence).
Intellectual disability v3.70 UGP2 Rebecca Foulger Phenotypes for gene: UGP2 were changed from Seizures; Global developmental delay; Intellectual disability; Feeding difficulties; Abnormality of vision; Abnormality of the face to Epileptic encephalopathy, early infantile, 83, 618744; Global developmental delay; Intellectual disability; Feeding difficulties; Abnormality of vision; Abnormality of the face
Intellectual disability v3.69 TRAPPC4 Rebecca Foulger Classified gene: TRAPPC4 as Green List (high evidence)
Intellectual disability v3.69 TRAPPC4 Rebecca Foulger Added comment: Comment on list classification: Added to panel and rated Green by Konstantinos Varvagiannis. Subsequent Green review by Zornitza Stark. Updated rating from Grey to Green: 7 children from 3 unrelated families with MIM:618741 reported by, Van Bergen et al. (2020) with a recurring homozygous splice site variant in TRAPPC4 resulting in a splice site alteration, the skipping of exon 3, a frameshift, and premature termination (Leu120AspfsTer9). The variant segregated within the disorder within the families and was only found in heterozygous state in gnomAD. Appropriate phenotype and cases just reach threshold for inclusion.
Intellectual disability v3.69 TRAPPC4 Rebecca Foulger Gene: trappc4 has been classified as Green List (High Evidence).
Intellectual disability v3.68 TRAPPC4 Rebecca Foulger Phenotypes for gene: TRAPPC4 were changed from Feeding difficulties; Progressive microcephaly; Intellectual disability; Seizures; Spastic tetraparesis; Abnormality of the face; Scoliosis; Cortical visual impairment; Hearing impairment to Neurodevelopmental disorder with epilepsy, spasticity, and brain atrophy, 618741
Intellectual disability v3.67 WDR45B Rebecca Foulger Phenotypes for gene: WDR45B were changed from AUTOSOMAL RECESSIVE MENTAL RETARDATION to AUTOSOMAL RECESSIVE MENTAL RETARDATION; Neurodevelopmental disorder with spastic quadriplegia and brain abnormalities with or without seizures, 617977
Intellectual disability v3.67 WDR45B Rebecca Foulger Publications for gene: WDR45B were set to 21937992; 28503735
Intellectual disability v3.66 ALKBH8 Rebecca Foulger Classified gene: ALKBH8 as Amber List (moderate evidence)
Intellectual disability v3.66 ALKBH8 Rebecca Foulger Added comment: Comment on list classification: Demoted from Green to Amber based on advice from the Genomics England Clinical Team. In email correspondence, Helen Brittain notes that this is a borderline gene in terms of evidence (two families, 6/7 individuals with seizures and not particularly extensive functional / supportive information). Zornitza's review on the Genetic Epilepsy Syndromes panel focuses on the differing ratings of ALKBH8 on the ID (Green) and Epilepsy (Amber) panels. Based on borderline evidence, I have demoted ALKBH8 to Amber on the ID panel to be consistent with the GLH consensus on the Epilepsy panel (R59 #402).
Intellectual disability v3.66 ALKBH8 Rebecca Foulger Gene: alkbh8 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.65 PTRHD1 Helen Brittain Marked gene: PTRHD1 as ready
Intellectual disability v3.65 PTRHD1 Helen Brittain Added comment: Comment when marking as ready: Further case from personal correspondence. Considered sufficient for a green rating.
Intellectual disability v3.65 PTRHD1 Helen Brittain Gene: ptrhd1 has been classified as Green List (High Evidence).
Intellectual disability v3.65 PTRHD1 Helen Brittain Phenotypes for gene: PTRHD1 were changed from Intellectual disability; Parkinsonism, Intellectual disability; Parkinsonism to Intellectual disability; Parkinsonism
Intellectual disability v3.64 PTRHD1 Helen Brittain Classified gene: PTRHD1 as Green List (high evidence)
Intellectual disability v3.64 PTRHD1 Helen Brittain Gene: ptrhd1 has been classified as Green List (High Evidence).
Intellectual disability v3.63 PTRHD1 Helen Brittain Tag watchlist was removed from gene: PTRHD1.
Intellectual disability v3.63 PTRHD1 Helen Brittain Classified gene: PTRHD1 as Green List (high evidence)
Intellectual disability v3.63 PTRHD1 Helen Brittain Gene: ptrhd1 has been classified as Green List (High Evidence).
Intellectual disability v3.63 PTRHD1 Helen Brittain Classified gene: PTRHD1 as Green List (high evidence)
Intellectual disability v3.63 PTRHD1 Helen Brittain Gene: ptrhd1 has been classified as Green List (High Evidence).
Intellectual disability v3.62 PTRHD1 Helen Brittain reviewed gene: PTRHD1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.62 TMX2 Eleanor Williams Phenotypes for gene: TMX2 were changed from Global developmental delay; Intellectual disability; Seizures; Microcephaly; Abnormal cortical gyration to Global developmental delay; Intellectual disability; Seizures; Microcephaly; Abnormal cortical gyration; Neurodevelopmental disorder with microcephaly, cortical malformations, and spasticity, 618730
Intellectual disability v3.61 SMARCD1 Eleanor Williams Phenotypes for gene: SMARCD1 were changed from Generalized hypotonia; Feeding difficulties; Global developmental delay; Intellectual disability; Abnormality of the hand; Abnormality of the foot to Generalized hypotonia; Feeding difficulties; Global developmental delay; Intellectual disability; Abnormality of the hand; Abnormality of the foot; Coffin-Siris syndrome 11, 618779
Intellectual disability v3.60 NKAP Eleanor Williams Phenotypes for gene: NKAP were changed from Global developmental delay; Intellectual disability to Global developmental delay; Intellectual disability; Intellectual developmental disorder, X-linked, syndromic, Hackman-Di Donato type #301039
Intellectual disability v3.59 DLG4 Eleanor Williams Phenotypes for gene: DLG4 were changed from Intellectual disability; Marfanoid habitus to Intellectual disability; Marfanoid habitus; Intellectual developmental disorder 62 #618793
Intellectual disability v3.58 CDK8 Eleanor Williams Phenotypes for gene: CDK8 were changed from Generalized hypotonia; Feeding difficulties; Global developmental delay; Intellectual disability; Behavioral abnormality; Abnormality of cardiovascular system morphology; Hearing impairment; Abnormality of vision; Anorectal anomaly; Seizures to Generalized hypotonia; Feeding difficulties; Global developmental delay; Intellectual disability; Behavioral abnormality; Abnormality of cardiovascular system morphology; Hearing impairment; Abnormality of vision; Anorectal anomaly; Seizures; Intellectual developmental disorder with hypotonia and behavioral abnormalities #618748
Intellectual disability v3.57 PCYT2 Rebecca Foulger Phenotypes for gene: PCYT2 were changed from Global developmental delay; Developmental regression; Intellectual disability; Spastic paraparesis; Seizures; Spastic tetraparesis; Cerebral atrophy; Cerebellar atrophy to Spastic paraplegia 82, autosomal recessive, 618770; Global developmental delay; Developmental regression; Intellectual disability; Spastic paraparesis; Seizures; Spastic tetraparesis; Cerebral atrophy; Cerebellar atrophy
Intellectual disability v3.56 EXT2 Rebecca Foulger Classified gene: EXT2 as Green List (high evidence)
Intellectual disability v3.56 EXT2 Rebecca Foulger Added comment: Comment on list classification: Updated rating from Amber to Green. Sufficient cases to support causation of MIM:616682, of which ID is a prominent phenotype. Note that I have updated the Mode of Inheritance from AD to AR to match MIM:616682 (and the Genetic epilepsy syndromes panel, #402).
Intellectual disability v3.56 EXT2 Rebecca Foulger Gene: ext2 has been classified as Green List (High Evidence).
Intellectual disability v3.55 EXT2 Rebecca Foulger changed review comment from: PMID:30288735. In 2 siblings with MIM:616682, Gentile et al identified compound het missense variants in EXT2, which segregated with the disorder (D227N and Y608C). The D227N vairant contributes to exostosis (inherited from the mother who had a family history of exostosis).; to: PMID:30288735. In 2 siblings with MIM:616682, Gentile et al identified compound het missense variants in EXT2, which segregated with the disorder (D227N and Y608C). The D227N variant contributes to exostosis (inherited from the mother who had a family history of exostosis).
Intellectual disability v3.55 EXT2 Rebecca Foulger commented on gene: EXT2: PMID:30288735. In 2 siblings with MIM:616682, Gentile et al identified compound het missense variants in EXT2, which segregated with the disorder (D227N and Y608C). The D227N vairant contributes to exostosis (inherited from the mother who had a family history of exostosis).
Intellectual disability v3.55 EXT2 Rebecca Foulger commented on gene: EXT2: PMID:30997052. In a 14 year old girl, Gupta et al. (2019) identified compound het missense variants in the EXT2 gene (V373D and T672M), which segregated with the disorder in the family. The patient also carried a maternal heterozygous variant (R454C) in NDST1. She had developmental delay, autism and epilepsy amongst her phenotypes.
Intellectual disability v3.55 EXT2 Rebecca Foulger commented on gene: EXT2: PMID:30075207. In 2 brothers, born of consanguineous Syrian parents, with MIM:616682 El-Bazzal et al. (2019) identified a homozygous missense mutation in the EXT2 gene (p.Ser4Leu). Psychomotor delay was noted for both at the age of 3 months.
Intellectual disability v3.55 EXT2 Rebecca Foulger commented on gene: EXT2: PMID:26246518: In 4 siblings, born of consanguineous parents in the Old Order Mennonite community, with seizures, scoliosis, and macrocephaly/microcephaly syndrome (MIM:616682), Farhan et al. (2015) identified homozygosity for 2 missense mutations in EXT2 (M87R and R95C). All siblings had moderate ID and a seizure disorder.
Intellectual disability v3.55 EXT2 Rebecca Foulger Phenotypes for gene: EXT2 were changed from Seizures, scoliosis, and macrocephaly syndrome, 616682 to Seizures, scoliosis, and macrocephaly syndrome, 616682; autosomal recessive EXT2-related syndrome
Intellectual disability v3.54 EXT2 Rebecca Foulger Deleted their comment
Intellectual disability v3.54 EXT2 Rebecca Foulger Added comment: Comment on mode of inheritance: Updated MOI from MONOALLELIC to BIALLELIC. EXT2 is associated with 2 different disorders: Seizures, scoliosis, and macrocephaly syndrome, 616682 (AR) and Exostoses, multiple, type 2, 133701 (AD). MIM:616682 is relevant to this panel.
Intellectual disability v3.54 EXT2 Rebecca Foulger Mode of inheritance for gene: EXT2 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.53 EXT2 Rebecca Foulger Publications for gene: EXT2 were set to 25529582; 26246518; 30997052; 30288735
Intellectual disability v3.52 EXT2 Rebecca Foulger Phenotypes for gene: EXT2 were changed from Exostoses, multiple, type 2, 133701 to Seizures, scoliosis, and macrocephaly syndrome, 616682
Intellectual disability v3.51 EXT2 Rebecca Foulger Publications for gene: EXT2 were set to 25529582
Intellectual disability v3.51 EXT2 Rebecca Foulger Added comment: Comment on mode of inheritance: Updated MOI from MONOALLELIC to BIALLELIC. EXT2 is associated with 2 different disorders: Seizures, scoliosis, and macrocephaly syndrome, 616682 (AR) and Exostoses, multiple, type 2, 133701 (AD). MIM:616682 is relevant to this panel.
Intellectual disability v3.51 EXT2 Rebecca Foulger Mode of inheritance for gene: EXT2 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.50 EXT2 Rebecca Foulger Mode of inheritance for gene: EXT2 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.49 EXT2 Rebecca Foulger Publications for gene: EXT2 were set to
Intellectual disability v3.48 WASF1 Rebecca Foulger Phenotypes for gene: WASF1 were changed from ID associated with autistic features, seizures, and developmental delay; intellectual disability to Neurodevelopmental disorder with absent language and variable seizures, 618707; ID associated with autistic features, seizures, and developmental delay; intellectual disability
Intellectual disability v3.47 POU3F3 Rebecca Foulger Phenotypes for gene: POU3F3 were changed from Generalized hypotonia; Delayed speech and language development; Global developmental delay; Intellectual disability; Autistic behavior to Snijders Blok-Fisher syndrome, 618604; Generalized hypotonia; Delayed speech and language development; Global developmental delay; Intellectual disability; Autistic behavior
Intellectual disability v3.46 POLR2A Rebecca Foulger Phenotypes for gene: POLR2A were changed from Global developmental delay; Generalized hypotonia; Feeding difficulties to Neurodevelopmental disorder with hypotonia and variable intellectual and behavioral abnormalities, 618603; Global developmental delay; Generalized hypotonia; Feeding difficulties
Intellectual disability v3.45 PHF21A Rebecca Foulger Added comment: Comment on phenotypes: Potocki-Shaffer syndrome (MIM:601224) is a contiguous gene deletion syndrome involving genes on chromosome 11p11.2.
Intellectual disability v3.45 PHF21A Rebecca Foulger Phenotypes for gene: PHF21A were changed from Potocki-Shaffer syndrome, 601224; PSS; Intellectual disability; Intellectual developmental disorder with behavioral abnormalities and craniofacial dysmorphism with or without seizures, 618725 to Potocki-Shaffer syndrome, 601224; PSS; Intellectual disability; Intellectual developmental disorder with behavioral abnormalities and craniofacial dysmorphism with or without seizures, 618725
Intellectual disability v3.44 PHF21A Rebecca Foulger Phenotypes for gene: PHF21A were changed from Potocki-Shaffer syndrome, 601224; PSS; Intellectual disability to Potocki-Shaffer syndrome, 601224; PSS; Intellectual disability; Intellectual developmental disorder with behavioral abnormalities and craniofacial dysmorphism with or without seizures, 618725
Intellectual disability v3.43 MSL3 Rebecca Foulger Phenotypes for gene: MSL3 were changed from Muscular hypotonia; Feeding difficulties; Neurodevelopmental delay; Intellectual disability; no OMIM number to Muscular hypotonia; Feeding difficulties; Neurodevelopmental delay; Intellectual disability; Basilicata-Akhtar syndrome, 301032
Intellectual disability v3.42 CNOT3 Rebecca Foulger commented on gene: CNOT3
Intellectual disability v3.42 CNOT3 Rebecca Foulger Mode of inheritance for gene: CNOT3 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.41 CNOT3 Rebecca Foulger Publications for gene: CNOT3 were set to 25529582; 28135719
Intellectual disability v3.40 CNOT3 Rebecca Foulger Phenotypes for gene: CNOT3 were changed from CNOT3 syndrome; intellectual disability, global developmental delay to CNOT3 syndrome; intellectual disability, global developmental delay; Intellectual developmental disorder with speech delay, autism, and dysmorphic facies, 618672
Intellectual disability v3.39 NR4A2 Konstantinos Varvagiannis edited their review of gene: NR4A2: Added comment: Singh et al (2020 - https://doi.org/10.1038/s41436-020-0815-4) provide details on the phenotype of 9 unrelated individuals with NR4A2 pathogenic variants (in almost all cases de novo).

Features included hypotonia (in 6/9), DD (9/9), varying levels of ID (mild to severe in 8/8 for whom this information was available), seizures (6/9 - variable epilepsy phenotypes), behavioral problems (5/9 - with autism reported for one). Less frequent features incl. hypermobility (in 3), ataxia/movement disorder (in 3).

8 total pLoF and missense variants were identified as de novo events following trio exome sequencing with Sanger validation (7/8 variants). For 1(/8) individual with a stopgain variant, a single parental sample was available. A 9th individual was found to harbor a ~3.7 Mb 2q deletion spanning also other genes (which might also contribute to his phenotype of epilepsy).

Only the effect of a variant affecting the splice-acceptor site was studied (c.865-1_865delGCinsAAAAAGGAGT - NM_006186.3) with RT-PCR demonstrating an out-of-frame skipping of exon 4. Another variant (NM_006186.3:c.325dup) found in a subject with DD, ID and epilepsy had also previously been reported in another individual with similar phenotype of epilepsy and ID (Ramos et al - PMID: 31428396 - the variant was de novo with other causes for his phenotype excluded).

As discussed by Singh et al, NR4A2 encodes a steroid-thyroid-retinoid receptor which acts as a nuclear receptor transcription factor. The authors summarize previous reports on NR4A2 haploinsufficiency (NR4A2 has a pLI of 1 and HI score of 1.28% - Z-score is 2.24).

The authors comment on mouse models suggesting a role of NR4A2 for dopaminergic neurons, and provide plausible explanations for the phenotype of ID/seizures.; Changed publications: https://doi.org/10.1038/s41436-020-0815-4, 31428396, 29770430, 30504930, 28544326, 27569545, 23554088, 28135719, 27479843, 25363768; Changed phenotypes: Generalized hypotonia, Global developmental delay, Intellectual disability, Seizures, Behavioral abnormality, Abnormality of movement, Joint hypermobility
Intellectual disability v3.39 CUL3 Konstantinos Varvagiannis reviewed gene: CUL3: Rating: GREEN; Mode of pathogenicity: None; Publications: 32341456; Phenotypes: Global developmental delay, Intellectual disability, Seizures, Abnormality of cardiovascular system morphology, Abnormality of the palate, Pseudohypoaldosteronism, type IIE - MIM #614496; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.39 ATP1A2 Rebecca Foulger Phenotypes for gene: ATP1A2 were changed from Migraine, familial hemiplegic, 2 602481 to Migraine, familial hemiplegic, 2 602481; Alternating hemiplegia of childhood 1, 104290
Intellectual disability v3.38 ALG9 Rebecca Foulger Classified gene: ALG9 as Green List (high evidence)
Intellectual disability v3.38 ALG9 Rebecca Foulger Added comment: Comment on list classification: As highlighted by Zornitza Stark, since the last curation review, a number of papers have been published on the ALG9 phenotype, including PMID:26453364 and PMID:28932688 who review the literature and report additional cases. At least 6-7 (of 10/11) patients have developmental delay. Therefore sufficient cases to support causation and have updated rating from Red to Green.
Intellectual disability v3.38 ALG9 Rebecca Foulger Gene: alg9 has been classified as Green List (High Evidence).
Intellectual disability v3.37 ALG9 Rebecca Foulger Phenotypes for gene: ALG9 were changed from Congenital disorder of glycosylation, type Il 608776; Gillessen-Kaesbach-Nishimura syndrome 263210 to Developmental delay; Congenital disorder of glycosylation, type Il 608776; Gillessen-Kaesbach-Nishimura syndrome 263210
Intellectual disability v3.36 ALG9 Rebecca Foulger commented on gene: ALG9: PMID:28932688. Davis et al., 2017 review the literature for ALG9:CDG cases. They summarise 10 patients from 6 different families with one of four ALG9 variants (including the 4 new patients reported by PMID:26453364). They also report an additional patient with ALG9-CDH with a milder phenotype. Prenatally, dysmorphic features, renal cysts and cardiac malformations were detected. She had seizures and developmental delay. She had a homozygous variant in ALG9: p.Tyr287Cys.
Intellectual disability v3.36 ALG9 Rebecca Foulger changed review comment from: PMID:26453364. AlSubhi et al., 2016 summarise 6 patients with ALG9-CDG from the literature and report 4 additional patients from a large consanguineous family. 6/10 patients had developmental disability including the index patient (IV:5), a6 year old girl with global DD, skeletal dysplasia, epilepsy, facial dysmorphisms amongst her phenotypes. The three affected cousins had similar phenotypes.; to: PMID:26453364. AlSubhi et al., 2016 summarise 6 patients with ALG9-CDG from the literature and report 4 additional patients from a large consanguineous family. 6/10 patients had developmental disability including the index patient (IV:5), a 6 year old girl with global DD, skeletal dysplasia, epilepsy, facial dysmorphisms amongst her phenotypes. The three affected cousins had similar phenotypes.
Intellectual disability v3.36 ALG9 Rebecca Foulger Publications for gene: ALG9 were set to 15945070; 15148656
Intellectual disability v3.35 ALG9 Rebecca Foulger commented on gene: ALG9
Intellectual disability v3.35 WDR34 Catherine Snow Tag new-gene-name tag was added to gene: WDR34.
Intellectual disability v3.35 WDR34 Catherine Snow commented on gene: WDR34
Intellectual disability v3.35 WDR60 Catherine Snow Tag new-gene-name tag was added to gene: WDR60.
Intellectual disability v3.35 WDR60 Catherine Snow commented on gene: WDR60
Intellectual disability v3.35 UGDH Konstantinos Varvagiannis gene: UGDH was added
gene: UGDH was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: UGDH was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: UGDH were set to 32001716
Phenotypes for gene: UGDH were set to Epileptic encephalopathy, early infantile, 84 - MIM #618792
Penetrance for gene: UGDH were set to Complete
Review for gene: UGDH was set to GREEN
Added comment: Hengel et al (2020 - PMID: 32001716) report on 36 individuals with biallelic UGDH pathogenic variants.

The phenotype corresponded overall to a developmental epileptic encephalopathy with hypotonia, feeding difficulties, severe global DD, moderate or commonly severe ID in all. Hypotonia and motor disorder (incl. spasticity, dystonia, ataxia, chorea, etc) often occurred prior to the onset of seizures. A single individual did not present seizures and 2 sibs had only seizures in the setting of fever.

Affected subjects were tested by exome sequencing and UGDH variants were the only/best candidates for the phenotype following also segregation studies. Many were compound heterozygous or homozygous (~6 families were consanguineous) for missense variants and few were compound heterozygous for missense and pLoF variants. There were no individuals with biallelic pLoF variants identified. Parental/sib studies were all compatible with AR inheritance mode.

UGDH encodes the enzyme UDP-glucose dehydrogenase which converts UDP-glucose to UDP-glucuronate, the latter being a critical component of the glycosaminoglycans, hyaluronan, chondroitin sulfate, and heparan sulfate [OMIM].

Patient fibroblast and biochemical assays suggested a LoF effect of variants leading to impairment of UGDH stability, oligomerization or enzymatic activity (decreased UGDH-catalyzed reduction of NAD+ to NADH / hyaluronic acid production which requires UDP-glucuronate).

Attempts to model the disorder using an already developped zebrafish model (for a hypomorphic LoF allele) were unsuccessful as fish did not exhibit seizures spontaneously or upon induction with PTZ.

Modelling of the disorder in vitro using patient-derived cerebral organoids demonstrated smaller organoids due to reduced number of proliferating neural progenitors.
Sources: Literature
Intellectual disability v3.35 YIF1B Konstantinos Varvagiannis gene: YIF1B was added
gene: YIF1B was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: YIF1B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: YIF1B were set to 32006098
Phenotypes for gene: YIF1B were set to Central hypotonia; Failure to thrive; Microcephaly; Global developmental delay; Intellectual disability; Seizures; Spasticity; Abnormality of movement
Penetrance for gene: YIF1B were set to Complete
Review for gene: YIF1B was set to GREEN
Added comment: AlMuhaizea et al (2020 - PMID: 32006098) report on the phenotype of 6 individuals (from 5 families) with biallelic YIF1B truncating variants.

Affected subjects presented hypotonia, failure to thrive, microcephaly (5/6), severe global DD and ID (as evident from best motor/language milestones achieved - Table S1) as well as features suggestive of a motor disorder (dystonia/spasticity/dyskinesia). Seizures were reported in 2 unrelated individuals (2/6). MRI abnormalities were observed in some with thin CC being a feature in 3.

Variable initial investigations were performed including SNP CMA, MECP2, microcephaly / neurotransmitter disorders gene panel testing did not reveal P/LP variants.

YIF1B variants were identified in 3 families within ROH. Following exome sequencing, affected individuals were found to be homozygous for truncating variants (4/5 families being consanguineous). The following 3 variants were identified (NM_001039672.2) : c.186dupT or p.Ala64fs / c.360_361insACAT or p.Gly121fs / c.598G>T or p.Glu200*.

YIF1B encodes an intracellular transmembrane protein.

It has been previously demonstrated that - similarly to other proteins of the Yip family being implicated in intracellular traffic between the Golgi - Yif1B is involved in the anterograde traffic pathway. Yif1B KO mice demonstrate a disorganized Golgi architecture in pyramidal hippocampal neurons (Alterio et al 2015 - PMID: 26077767). The rat ortholog interacts with serotonin receptor 1 (5-HT1AR) with colocalization of Yif1BB and 5-HT1AR in intermediate compartment vesicles and involvement of the former in intracellular trafficing/modulation of 5-HT1AR transport to dendrites (PMID cited: 18685031).

Available mRNA and protein expression data (Protein Atlas) suggest that the gene is widely expressed in all tissues incl. neuronal cells. Immunochemistry data from the Human Brain Atlas also suggest that YIF1B is found in vesicles and localized to the Golgi apparatus. Immunohistochemistry in normal human brain tissue (cerebral cortex) demonstrated labeling of neuronal cells (Human Protein Atlas).

Functional/network analysis of genes co-regulated with YIF1B based on available RNAseq data, suggest enrichement in in genes important for nervous system development and function.

Please consider inclusion in other panels that may be relevant (e.g. microcephaly, etc).
Sources: Literature
Intellectual disability v3.35 SPTBN4 Konstantinos Varvagiannis gene: SPTBN4 was added
gene: SPTBN4 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: SPTBN4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SPTBN4 were set to 28540413; 28940097; 29861105; 31230720; 31857255
Phenotypes for gene: SPTBN4 were set to Neurodevelopmental disorder with hypotonia, neuropathy, and deafness MIM#617519
Penetrance for gene: SPTBN4 were set to Complete
Review for gene: SPTBN4 was set to GREEN
Added comment: Biallelic pathogenic SPTBN4 variants cause Neurodevelopmental disorder with hypotonia, neuropathy, and deafness (MIM #617519).

There are several reports on the phenotype of relevant affected individuals with severe/profound DD/ID in at least 9 individuals :

- Knierim et al (2017 - PMID: 28540413) [1 affected individual]
- Anazi et al (2017 - PMID: 28940097) [1]
- Wang et al (2018 - PMID: 29861105) [6]
- Pehlivan et al (2019 - PMID: 31230720) [1]

A recent article by Häusler et al (2019 - PMID: 31857255) describes the phenotype of 2 sibs, both presenting with motor and speech delay, although the older one had reportedly 'normal' cognitive performance allowing attendance of regular school at the age of 6 years.

Features include congenital hypotonia, severe DD and ID (in most as outlined above, ID was the primary indication for testing on several occasions), poor or absent reflexes and weakness secondary to axonal motor neuropathy, feeding and respiratory difficulties, hearing and visual impairment. Seizures have been reported in at least 4 unrelated individuals (3 by Wang et al / 1 by Pehlivan et al).

Variants in most cases were nonsense/frameshift although biallelic missense variants have also been reported. Sibs in the report by Häusler et al harbored a homozygous splicing variant.

SPTBN4 encodes a member of the beta-spectrin protein family that is expressed in the brain, peripheral nervous system, pancreas, and skeletal muscle.

βIV spectrin links ankyrinG and clustered ion channels (at axon initial segments and nodes of Ranvier) to the axonal cytoskeleton. Pathogenic variants are proposed to disrupt the cytoskeletal machinery controlling proper localization of ion channels and function of axonal domains where ion channels are normally clustered in high density. Among the evidence provided : nerve biopsies from an affected individual displayed reduced nodal Na+ channels and no nodal KCNQ2 K+ channels / Loss of AnkyrinG and βIV spectrin in animal model resulted in loss of KCNQ2- and KCNQ3- subunit containing K+ channels.

Apart from the ID / epilepsy panels please consider inclusion in other relevant ones.
Sources: Literature
Intellectual disability v3.35 TNRC6B Konstantinos Varvagiannis reviewed gene: TNRC6B: Rating: GREEN; Mode of pathogenicity: None; Publications: 32152250, 28135719, 25363768, 27479843, 28959963, 25228304; Phenotypes: Global developmental delay, Intellectual disability, Autistic behavior; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.35 CDC42BPB Konstantinos Varvagiannis gene: CDC42BPB was added
gene: CDC42BPB was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: CDC42BPB was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CDC42BPB were set to 32031333
Phenotypes for gene: CDC42BPB were set to Central hypotonia; Global developmental delay; Intellectual disability; Seizures; Autistic behavior; Behavioral abnormality
Penetrance for gene: CDC42BPB were set to unknown
Review for gene: CDC42BPB was set to GREEN
Added comment: Chilton et al (2020 - PMID: 32031333) report on 14 individuals with missense and loss-of-function CDC42BPB variants.

Features included hypotonia (8/11), DD (12/13 - the 14th was a fetus), ID (7/13), ASD (8/12), clinical seizures (in 3 - a 4th had abnormal EEG without seizures), behavioral abnormalities. Variable non-specific dysmorphic features were reported in some (sparse hair being the most frequent - 4/8). Additional features were observed in few (=<4) incl. cryptorchidism, ophthalmological issues, constipation, kidney abnormalities, micropenis, etc.

All individuals had non-diagnostic prior genetic testing (incl. CMA, FMR1, MECP2, Angelman/Prader-Willi methylation studies, autism gene panel - suggesting relevance to the current panel) or metabolic testing.

Variants were identified following clinical exome sequencing with Sanger confirmation. Most occurred as de novo events (11/14) while inheritance was not available for few (3/14). Missense variants did not display (particular) clustering.

Almost all variants were absent from gnomAD and were predicted to be deleterious in silico (among others almost all had CADD scores >25).

As the authors comment, CDC42BPB encodes myotonic dystrophy-related Cdc42-binding kinase β (MRCKβ) a serine/threonine protein kinase playing a role in regulation of cytoskeletal reorganization and cell migration in nonmuscle cells (through phosporylation of MLC2).

Previous studies have demonstrated that it is ubiquitously expressed with prenatal brain expression.

The gene appears to be intolerant to pLoF (pLI of 1) as well as to missense variants (Z-score of 3.66).

CDC42BPB is a downstream effector of CDC42. Mutations of the latter cause Takenouchi-Kosaki syndrome with DD/ID and some further overlapping features (with CDC42BPB-associated phenotypes).

Homozygous Cdc42bpb KO in mouse appears to be nonviable (MGI:2136459). Loss of gek in the eyes of Drosophila results in disrupted growth cone targeting to the lamina (gek is the fly CDC42BPB ortholog).

Please consider inclusion with amber / green rating in the ID panel (>=4 relevant individuals / variants) and other panels (e.g. for epilepsy, ASD).
Sources: Literature
Intellectual disability v3.35 ADAM22 Rebecca Foulger Classified gene: ADAM22 as Amber List (moderate evidence)
Intellectual disability v3.35 ADAM22 Rebecca Foulger Added comment: Comment on list classification: Set rating as Amber: 2 unrelated families with ID as part of the phenotype (PMID:27066583 and 30237576).
Intellectual disability v3.35 ADAM22 Rebecca Foulger Gene: adam22 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.34 ADAM22 Rebecca Foulger commented on gene: ADAM22: PMID:27066583. Muona et al., 2016 report a Finnish proband-parent-trio with intractable seizures and ID. Compound het variants c.1202G>A, p.Cys401Tyr and c.2396delG, p.Ser799IlefsTer96 were found in ADAM22. Functional assays showed that mutant proteins failed to form the LGI1-ADAM22 ligand-receptor complex. The variants are unlikely to be full LOF.
Intellectual disability v3.34 ADAM22 Rebecca Foulger commented on gene: ADAM22: PMID:30237576 (Maddirevula et al., 2019) searched their database of clinical exomes for homozygous variants and report an 18 year old male with Arg860* variant and recurrent seizures (Supplementary Table). His development was normal until 5 months when he had a slower gain of milestones. He has ID with severely delayed speech. Family history revealed ID and epilepsy in his old brother and in wider family.
Intellectual disability v3.34 ADAM22 Rebecca Foulger gene: ADAM22 was added
gene: ADAM22 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: ADAM22 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ADAM22 were set to 27066583; 30237576
Added comment: Added ADAM22 to ID panel based on literature curation for Epilepsy phenotype. Patients in PMID:27066583 (Finnish trio with compound het ADAM22 variants in the proband) and PMID:30237576 (18 year old male with Arg860* variant) both report ID alongside epilepsy.
Sources: Literature
Intellectual disability v3.33 VPS51 Zornitza Stark gene: VPS51 was added
gene: VPS51 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: VPS51 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: VPS51 were set to 30624672; 31207318
Phenotypes for gene: VPS51 were set to Pontocerebellar hypoplasia, type 13, MIM# 618606
Review for gene: VPS51 was set to AMBER
Added comment: Two families reported with bi-allelic variants in this gene and global developmental delay, impaired intellectual development with absent speech, microcephaly, and progressive atrophy of the cerebellar vermis and brainstem. Additional features, including seizures and visual impairment, are variable.
Sources: Literature
Intellectual disability v3.33 LRRC32 Zornitza Stark gene: LRRC32 was added
gene: LRRC32 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: LRRC32 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LRRC32 were set to 30976112
Phenotypes for gene: LRRC32 were set to Intellectual disability; cleft palate; proliferative retinopathy
Review for gene: LRRC32 was set to AMBER
Added comment: Three individuals from two consanguineous families segregated the same homozygous bi-allelic variant, c.1630C>T; p.(Arg544Ter), shared haplotype indicative of founder effect. Mouse model has cleft palate and neonatal death.
Sources: Literature
Intellectual disability v3.33 CTU2 Rebecca Foulger Classified gene: CTU2 as Green List (high evidence)
Intellectual disability v3.33 CTU2 Rebecca Foulger Added comment: Comment on list classification: Gene was added to panel and rated Green by Zornitza Stark. Sufficient cases of global DD in PMID:31301155 in patients that survived infancy to support causation. Therefore updated rating from Grey to Green.
Intellectual disability v3.33 CTU2 Rebecca Foulger Gene: ctu2 has been classified as Green List (High Evidence).
Intellectual disability v3.32 CTU2 Rebecca Foulger commented on gene: CTU2
Intellectual disability v3.32 CTU2 Rebecca Foulger Phenotypes for gene: CTU2 were changed from Microcephaly, facial dysmorphism, renal agenesis, and ambiguous genitalia syndrome, MIM#618142 to DREAM‐PL syndrome; Microcephaly, facial dysmorphism, renal agenesis, and ambiguous genitalia syndrome, 618142
Intellectual disability v3.31 CDK19 Zornitza Stark reviewed gene: CDK19: Rating: GREEN; Mode of pathogenicity: None; Publications: 32330417; Phenotypes: Intellectual disability, epileptic encephalopathy; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.31 GNAI2 Zornitza Stark gene: GNAI2 was added
gene: GNAI2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: GNAI2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: GNAI2 were set to 31036916; 27787898
Phenotypes for gene: GNAI2 were set to Syndromic intellectual disability
Review for gene: GNAI2 was set to AMBER
Added comment: Two individuals reported, some functional data.
Sources: Literature
Intellectual disability v3.31 FEM1B Zornitza Stark gene: FEM1B was added
gene: FEM1B was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: FEM1B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FEM1B were set to 31036916
Phenotypes for gene: FEM1B were set to Syndromic intellectual disability
Review for gene: FEM1B was set to AMBER
Added comment: PMID: 31036916 - a single individual with de novo variant reported in a neurodevelopmental disorder cohort. Authors note another de novo case with the exact same variant (p.Arg126Gln) from the DDD study, and a 3rd patient from GeneMatcher with the same de novo missense again. The variant is in a highly constrained region of the protein. Cannot be certain the DDD and GeneMatcher individuals are unrelated, therefore I have treated as two reports for now.
Sources: Literature
Intellectual disability v3.31 WIPI2 Zornitza Stark gene: WIPI2 was added
gene: WIPI2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: WIPI2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: WIPI2 were set to 30968111
Phenotypes for gene: WIPI2 were set to Intellectual developmental disorder with short stature and variable skeletal anomalies 618453
Review for gene: WIPI2 was set to RED
Added comment: Four homozygous individuals from one consanguineous family with intellectual disability, short stature and variable skeletal anomalies. Functional studies in patient cells showed impaired protein function. One to watch.
Sources: Literature
Intellectual disability v3.31 GSX2 Zornitza Stark gene: GSX2 was added
gene: GSX2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: GSX2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GSX2 were set to 31412107
Phenotypes for gene: GSX2 were set to Diencephalic-mesencephalic junction dysplasia syndrome 2 618646; Intellectual disability; Dystonia; Spastic tetra paresis
Review for gene: GSX2 was set to AMBER
Added comment: Two unrelated families, some functional data.
Sources: Literature
Intellectual disability v3.31 YARS Zornitza Stark gene: YARS was added
gene: YARS was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: YARS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: YARS were set to 30304524; 29232904; 27633801
Phenotypes for gene: YARS were set to Intellectual disability; deafness; nystagmus; liver dysfunction
Review for gene: YARS was set to GREEN
gene: YARS was marked as current diagnostic
Added comment: Mono-allelic variants are associated with CMT. However, 10 individuals from three unrelated families reported with bi-allelic variants and a severe phenotype, comprising ID, nystagmus, deafness, liver dysfunction and a range of other features.
Sources: Literature
Intellectual disability v3.31 CACNB4 Zornitza Stark reviewed gene: CACNB4: Rating: AMBER; Mode of pathogenicity: None; Publications: 32176688; Phenotypes: Intellectual disability, epilepsy, movement disorder; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.31 CEP55 Rebecca Foulger Classified gene: CEP55 as Green List (high evidence)
Intellectual disability v3.31 CEP55 Rebecca Foulger Added comment: Comment on list classification: Rated CEP55 as Green: >3 unrelated cases in PMID:32100459 with DD/ID (2 of which are severe).
Intellectual disability v3.31 CEP55 Rebecca Foulger Gene: cep55 has been classified as Green List (High Evidence).
Intellectual disability v3.30 CEP55 Rebecca Foulger changed review comment from: PMID:32100459 (Barrie et al., 2020) describe 7 living individuals (5 families) with biallelic variants (compound het and homozygous splice site variant) in CEP55. Global/severe DD was seen in patient 2, and the 3 siblings (patients 5,6,7). Mild/delayed motor/speech development was seen in unrelated patients 3 and 4.; to: PMID:32100459 (Barrie et al., 2020) describe 7 living individuals (5 families) with biallelic variants (compound het and homozygous splice site variant) in CEP55. Global/severe DD was seen in patient 2, and the 3 siblings (patients 5,6,7). Mild/delayed motor & speech development was seen in unrelated patients 3 and 4.
Intellectual disability v3.30 CEP55 Rebecca Foulger changed review comment from: PMID:32100459 (Barrie et al., 2020) describe 7 living individuals (5 families) with biallelic variants (compound het and homozygous splice site variant) in CEP55. Global/severe DD wax seen in patient 2, and the 3 siblings (patients 5,6,7). Mild/delayed motor/speech development was seen in unrelated patients 3 and 4.; to: PMID:32100459 (Barrie et al., 2020) describe 7 living individuals (5 families) with biallelic variants (compound het and homozygous splice site variant) in CEP55. Global/severe DD was seen in patient 2, and the 3 siblings (patients 5,6,7). Mild/delayed motor/speech development was seen in unrelated patients 3 and 4.
Intellectual disability v3.30 CEP55 Rebecca Foulger commented on gene: CEP55: PMID:32100459 (Barrie et al., 2020) describe 7 living individuals (5 families) with biallelic variants (compound het and homozygous splice site variant) in CEP55. Global/severe DD wax seen in patient 2, and the 3 siblings (patients 5,6,7). Mild/delayed motor/speech development was seen in unrelated patients 3 and 4.
Intellectual disability v3.30 CEP55 Rebecca Foulger gene: CEP55 was added
gene: CEP55 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: CEP55 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CEP55 were set to 32100459
Phenotypes for gene: CEP55 were set to microcephaly, delayed development, and bilateral toe syndactyly
Added comment: Added to ID panel on advice from Helen Brittain, Genomics England Clinical Team. Phenotype of living individuals in PMID:32100459 (Barrie et al., 2020) includes developmental delay.
Sources: Literature
Intellectual disability v3.29 RSRC1 Zornitza Stark edited their review of gene: RSRC1: Added comment: 17 additional individuals reported.; Changed rating: GREEN; Changed publications: 28640246, 29522154, 32227164; Changed phenotypes: Intellectual developmental disorder, autosomal recessive 70, MIM# 618402; Set current diagnostic: yes
Intellectual disability v3.29 EIF2AK2 Zornitza Stark gene: EIF2AK2 was added
gene: EIF2AK2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: EIF2AK2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: EIF2AK2 were set to 32197074
Phenotypes for gene: EIF2AK2 were set to Intellectual disability; white matter abnormalities; ataxia; regression with febrile illness
Review for gene: EIF2AK2 was set to GREEN
gene: EIF2AK2 was marked as current diagnostic
Added comment: Eight individuals with de novo variants and complex neurodevelopmental phenotype.
Sources: Literature
Intellectual disability v3.29 EIF2AK1 Zornitza Stark gene: EIF2AK1 was added
gene: EIF2AK1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: EIF2AK1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: EIF2AK1 were set to 32197074
Phenotypes for gene: EIF2AK1 were set to Intellectual disability; white matter abnormalities
Review for gene: EIF2AK1 was set to RED
Added comment: Single individual reported with de novo variant in this gene, one to watch.
Sources: Literature
Intellectual disability v3.29 NRROS Zornitza Stark gene: NRROS was added
gene: NRROS was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: NRROS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NRROS were set to 32100099; 32197075
Phenotypes for gene: NRROS were set to neurodegeneration; intracranial calcification; epilepsy
Review for gene: NRROS was set to GREEN
Added comment: Normal development or mild developmental delay until onset of regression around age of 1 concurrent with epilepsy
Biallelic LOF mutations with functional evidence of pathogenicity reported in 6 unrelated families. Suggest also add to Epilepsy panel, possibly others.
Sources: Literature
Intellectual disability v3.29 NOVA2 Zornitza Stark gene: NOVA2 was added
gene: NOVA2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: NOVA2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: NOVA2 were set to 32197073
Phenotypes for gene: NOVA2 were set to Intellectual disability; autism; hypotonia; spasticity; ataxia
Review for gene: NOVA2 was set to GREEN
gene: NOVA2 was marked as current diagnostic
Added comment: Six individuals with de novo frameshift variants resulting in C-terminal extension suggesting partial LoF as mechanism.
Sources: Literature
Intellectual disability v3.29 GAD1 Sarah Leigh Phenotypes for gene: GAD1 were changed from ?Cerebral palsy, spastic quadriplegic, 1; Developmental and epileptic encephalopathies, cleft palate, joint contractures and/or omphalocele to ?Cerebral palsy, spastic quadriplegic, 1 603513; Developmental and epileptic encephalopathies, cleft palate, joint contractures and/or omphalocele
Intellectual disability v3.28 GAD1 Sarah Leigh Publications for gene: GAD1 were set to 26503795; 24896178; 26350204; https://doi-org.ezproxy.library.qmul.ac.uk/10.1093/brain/awaa085
Intellectual disability v3.27 GAD1 Sarah Leigh Added comment: Comment on publications: https://doi-org.ezproxy.library.qmul.ac.uk/10.1093/brain/awaa085 new publication, without a PMID
Intellectual disability v3.27 GAD1 Sarah Leigh Publications for gene: GAD1 were set to 26503795; 24896178; 26350204; https://doi-org.ezproxy.library.qmul.ac.uk/10.1093/brain/awaa085
Intellectual disability v3.27 GAD1 Sarah Leigh Added comment: Comment on publications: https://doi-org.ezproxy.library.qmul.ac.uk/10.1093/brain/awaa085 new publication, without a PMID
Intellectual disability v3.27 GAD1 Sarah Leigh Publications for gene: GAD1 were set to
Intellectual disability v3.26 GAD1 Sarah Leigh Phenotypes for gene: GAD1 were changed from ?Cerebral palsy, spastic quadriplegic, 1 to ?Cerebral palsy, spastic quadriplegic, 1; Developmental and epileptic encephalopathies, cleft palate, joint contractures and/or omphalocele
Intellectual disability v3.25 GAD1 Sarah Leigh Classified gene: GAD1 as Green List (high evidence)
Intellectual disability v3.25 GAD1 Sarah Leigh Added comment: Comment on list classification: Five biallelic loss of function variants reported in 11 cases in 6 unrelated families. All cases had epilepsy syndrome, 10 profound intellectual disabilty (1 case died at day 9 of life) and other nuerological and developement features. Supportive functional studies were also presented
Intellectual disability v3.25 GAD1 Sarah Leigh Gene: gad1 has been classified as Green List (High Evidence).
Intellectual disability v3.24 NUP188 Zornitza Stark reviewed gene: NUP188: Rating: GREEN; Mode of pathogenicity: None; Publications: 32021605, 28726809, 32275884; Phenotypes: microcephaly, ID, cataract, structural brain abnormalities, hypoventilation; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability v3.24 PIGK Zornitza Stark changed review comment from: 12 individuals from 9 unrelated families reported.
Sources: Expert list; to: 12 individuals from 9 unrelated families reported. Suggest adding to Genetic Epilepsy panel as well.
Sources: Expert list
Intellectual disability v3.24 PIGK Zornitza Stark gene: PIGK was added
gene: PIGK was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: PIGK was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PIGK were set to 32220290
Phenotypes for gene: PIGK were set to Intellectual disability; seizures; cerebellar atrophy
Review for gene: PIGK was set to GREEN
gene: PIGK was marked as current diagnostic
Added comment: 12 individuals from 9 unrelated families reported.
Sources: Expert list
Intellectual disability v3.24 ADARB1 Zornitza Stark changed review comment from: Four unrelated individuals with bi-allelic variants in this gene.
Sources: Literature; to: Four unrelated individuals with bi-allelic variants in this gene. Suggest also adding to Genetic Epilepsy and Microcephaly panels.
Sources: Literature
Intellectual disability v3.24 ADARB1 Zornitza Stark gene: ADARB1 was added
gene: ADARB1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: ADARB1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ADARB1 were set to 32220291
Phenotypes for gene: ADARB1 were set to Intellectual disability; microcephaly; seizures
Review for gene: ADARB1 was set to GREEN
gene: ADARB1 was marked as current diagnostic
Added comment: Four unrelated individuals with bi-allelic variants in this gene.
Sources: Literature
Intellectual disability v3.24 RNF13 Sarah Leigh Classified gene: RNF13 as Green List (high evidence)
Intellectual disability v3.24 RNF13 Sarah Leigh Gene: rnf13 has been classified as Green List (High Evidence).
Intellectual disability v3.23 RNF13 Sarah Leigh changed review comment from: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least 2 variants reported in 3 unrelated cases, together with supportive functional studies.; to: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least 2 variants reported in 3 unrelated cases, together with supportive functional studies.

Gain-of-function mechanism has been reported, therefore the mutational spectrum may be limited and is still to be determined through further cases or further functional studies (view of Helen Britain, GeL Clincial Fellow).
Intellectual disability v3.23 SCAMP5 Sarah Leigh Tag watchlist tag was added to gene: SCAMP5.
Intellectual disability v3.23 SCAMP5 Sarah Leigh changed review comment from: Comment on list classification: Not associated with phenotype in OMIM (last edited on 10/06/2014) or in Gen2Phen. Two variants have been identified in three unrelated cases (one monoallelic, one biallelic). Supportive functional studies have been reported.
It would appear that the two variants reported so far in this gene result in differing mode of pathogenicity and phenotypic features. With heterozygous c.538G>T, p.Gly180Trp seeming to have a dominant-negative effect resulting in autistic spectrum disorder, intellectual disability and seizures. While homozygous c.271C>T, p.R91W seems to have a loss of function effect resulting in early onset epilepsy and Parkinson’s disease. This may be due to different functional domains of the mature protein being altered.; to: Comment on list classification: Not associated with phenotype in OMIM (last edited on 10/06/2014) or in Gen2Phen. Two variants have been identified in three unrelated cases (one monoallelic, one biallelic). Supportive functional studies have been reported.
It would appear that the two variants reported so far in this gene result in differing mode of pathogenicity and phenotypic features. With heterozygous c.538G>T, p.Gly180Trp seeming to have a dominant-negative effect resulting in autistic spectrum disorder, intellectual disability and seizures. While homozygous c.271C>T, p.R91W seems to have a loss of function effect resulting in early onset epilepsy and Parkinson’s disease. This may be due to different functional domains of the mature protein being altered.
Based on this evidence, SCAMP5 is rated as Amber, with a Watchlist tag. This status may change if further cases are reported.
Intellectual disability v3.23 SCN8A Sarah Leigh Added comment: Comment on mode of pathogenicity: Based on report in PMID 31625145, reporting biallelic loss of function SCN8A variants in three cases in two families with severe developmental and epileptic encephalopathy. This differs from the previosly reported gain of function monoallelic variants (PMID 24194747;22365152).
Intellectual disability v3.23 SCN8A Sarah Leigh Mode of pathogenicity for gene: SCN8A was changed from to Other
Intellectual disability v3.22 SCN8A Sarah Leigh Added comment: Comment on mode of inheritance: Based on report in PMID 31625145, reporting biallelic loss of function SCN8A variants in three cases in two families with severe developmental and epileptic encephalopathy.
Intellectual disability v3.22 SCN8A Sarah Leigh Mode of inheritance for gene: SCN8A was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.21 SCN8A Sarah Leigh Phenotypes for gene: SCN8A were changed from Cognitive impairment with or without cerebellar ataxia, 614306Epileptic encephalopathy, early infantile, 13, 614558; COGNITIVE IMPAIRMENT WITH OR WITHOUT CEREBELLAR ATAXIA to ?Cognitive impairment with or without cerebellar ataxia,614306; Epileptic encephalopathy, early infantile,614558; Seizures, benign familial infantile,617080
Intellectual disability v3.20 SCN8A Sarah Leigh Publications for gene: SCN8A were set to
Intellectual disability v3.19 SCAMP5 Sarah Leigh Added comment: Comment on mode of pathogenicity: Heterozygous c.538G>T, p.Gly180Trp seeming to have a dominant-negative effect resulting in autistic spectrum disorder, intellectual disability and seizures. While homozygous c.271C>T, p.R91W seems to have a loss of function effect resulting in early onset epilepsy and Parkinson’s disease.
Intellectual disability v3.19 SCAMP5 Sarah Leigh Mode of pathogenicity for gene: SCAMP5 was changed from Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments to Other
Intellectual disability v3.18 SCAMP5 Sarah Leigh Classified gene: SCAMP5 as Amber List (moderate evidence)
Intellectual disability v3.18 SCAMP5 Sarah Leigh Added comment: Comment on list classification: Not associated with phenotype in OMIM (last edited on 10/06/2014) or in Gen2Phen. Two variants have been identified in three unrelated cases (one monoallelic, one biallelic). Supportive functional studies have been reported.
It would appear that the two variants reported so far in this gene result in differing mode of pathogenicity and phenotypic features. With heterozygous c.538G>T, p.Gly180Trp seeming to have a dominant-negative effect resulting in autistic spectrum disorder, intellectual disability and seizures. While homozygous c.271C>T, p.R91W seems to have a loss of function effect resulting in early onset epilepsy and Parkinson’s disease. This may be due to different functional domains of the mature protein being altered.
Intellectual disability v3.18 SCAMP5 Sarah Leigh Gene: scamp5 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.17 SCAMP5 Sarah Leigh Added comment: Comment on mode of inheritance: Based on the reporting of a de novo heterozygous varaiant (NM_001178111.1:c.538G>T) in two unrelated cases (PMID: 31439720) and a homozygous variant (NM_001178111:c.271C>T, rs747966691) in two members of a Chinese consanguienious family (PMID: 32020363).
Intellectual disability v3.17 SCAMP5 Sarah Leigh Mode of inheritance for gene: SCAMP5 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.16 SCAMP5 Sarah Leigh Publications for gene: SCAMP5 were set to 31439720; 20071347
Intellectual disability v3.15 RNF13 Sarah Leigh reviewed gene: RNF13: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.15 RNF113A Sarah Leigh Classified gene: RNF113A as Green List (high evidence)
Intellectual disability v3.15 RNF113A Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as possible Gen2Phen gene for X-linked trichothiodystrophy. At least 3 terminating variants reported in unrelated cases. Supportive functional studies also reported.
Intellectual disability v3.15 RNF113A Sarah Leigh Gene: rnf113a has been classified as Green List (High Evidence).
Intellectual disability v3.14 RNF113A Sarah Leigh Publications for gene: RNF113A were set to 25612912; 29144457
Intellectual disability v3.13 RARS Sarah Leigh Classified gene: RARS as Green List (high evidence)
Intellectual disability v3.13 RARS Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least 19 variants reported in at least 13 cases of Hypomyelinating Leukodystrophy exhibinting intellectual disability to varying degrees. Supportive functional studies were also reported.
Intellectual disability v3.13 RARS Sarah Leigh Gene: rars has been classified as Green List (High Evidence).
Intellectual disability v3.12 RARS Sarah Leigh commented on gene: RARS
Intellectual disability v3.12 RARS Sarah Leigh Tag new-gene-name tag was added to gene: RARS.
Intellectual disability v3.12 RALGAPA1 Sarah Leigh Classified gene: RALGAPA1 as Green List (high evidence)
Intellectual disability v3.12 RALGAPA1 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene for RALGAPA1-related neurodevelopmental disorder. At least 5 variants reported in at least 4 unrelated cases.
Intellectual disability v3.12 RALGAPA1 Sarah Leigh Gene: ralgapa1 has been classified as Green List (High Evidence).
Intellectual disability v3.11 RALGAPA1 Sarah Leigh Added comment: Comment on phenotypes: Intellectual disability;hypotonia;infantile spasms.
Intellectual disability v3.11 RALGAPA1 Sarah Leigh Phenotypes for gene: RALGAPA1 were changed from Intellectual disability; hypotonia; infantile spasms. to Neurodevelopmental disorder with hypotonia, neonatal respiratory insufficiency, and thermodysregulation 618797
Intellectual disability v3.10 PUM1 Sarah Leigh Classified gene: PUM1 as Green List (high evidence)
Intellectual disability v3.10 PUM1 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 3 SNVs in at least 5 unrelated cases and CNVs spanning PUM1 in 9 cases. Supportive functional studies also reported.
Intellectual disability v3.10 PUM1 Sarah Leigh Gene: pum1 has been classified as Green List (High Evidence).
Intellectual disability v3.9 PUM1 Sarah Leigh Added comment: Comment on phenotypes: Global developmental delay;Intellectual disability;Seizures;Abnormality of the face;Ataxia;Cryptorchidism
Intellectual disability v3.9 PUM1 Sarah Leigh Phenotypes for gene: PUM1 were changed from Global developmental delay; Intellectual disability; Seizures; Abnormality of the face; Ataxia; Cryptorchidism to Spinocerebellar ataxia 47 617931
Intellectual disability v3.8 PUM1 Sarah Leigh Publications for gene: PUM1 were set to 29474920; 30903679; 31859446
Intellectual disability v3.7 PIGP Sarah Leigh Classified gene: PIGP as Green List (high evidence)
Intellectual disability v3.7 PIGP Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 2 variants reported (rs768633670, rs778481061). rs768633670 were reported as a compound heterozygotes in one case and was present in at least two geographically separated consanguineous European families; suggesting a founder effect in the European population (PMID 32042915).
Supportive functional studies are also presented.
Intellectual disability v3.7 PIGP Sarah Leigh Gene: pigp has been classified as Green List (High Evidence).
Intellectual disability v3.6 PIGP Sarah Leigh Publications for gene: PIGP were set to 28334793; 31139695; 32042915
Intellectual disability v3.5 PIGP Sarah Leigh Phenotypes for gene: PIGP were changed from ?Epileptic encephalopathy, early infantile, 55, 617599; Generalized hypotonia; Global developmental delay; Seizures; Intellectual disability; Feeding difficulties; Cortical visual impairment to Epileptic encephalopathy, early infantile, 55, 617599; Generalized hypotonia; Global developmental delay; Seizures; Intellectual disability; Feeding difficulties; Cortical visual impairment
Intellectual disability v3.4 PIGP Sarah Leigh Publications for gene: PIGP were set to 28334793; 31139695; 32042915
Intellectual disability v3.4 PIGP Sarah Leigh Publications for gene: PIGP were set to 28334793; 31139695
Intellectual disability v3.3 SLC5A6 Zornitza Stark reviewed gene: SLC5A6: Rating: GREEN; Mode of pathogenicity: None; Publications: 31754459, 27904971, 31392107; Phenotypes: Developmental delay, epilepsy, neurodegeneration; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.3 RARS Zornitza Stark reviewed gene: RARS: Rating: GREEN; Mode of pathogenicity: None; Publications: 31814314; Phenotypes: Leukodystrophy, hypomyelinating, 9 (# 616140); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.3 CXorf56 Zornitza Stark reviewed gene: CXorf56: Rating: GREEN; Mode of pathogenicity: None; Publications: 29374277, 31822863; Phenotypes: Mental retardation, X-linked 107, MIM# 301013; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females; Current diagnostic: yes
Intellectual disability v3.3 TNR Zornitza Stark gene: TNR was added
gene: TNR was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: TNR was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TNR were set to 32099069
Phenotypes for gene: TNR were set to Spastic para- or tetraparesis; Axial muscular hypotonia; Intellectual disability; Transient opisthotonus
Review for gene: TNR was set to GREEN
gene: TNR was marked as current diagnostic
Added comment: 13 individuals from 8 unrelated families reported.
Sources: Expert list
Intellectual disability v3.3 RUSC2 Zornitza Stark gene: RUSC2 was added
gene: RUSC2 was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: RUSC2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RUSC2 were set to 27612186
Phenotypes for gene: RUSC2 were set to Mental retardation, autosomal recessive 61, MIM# 617773
Review for gene: RUSC2 was set to AMBER
Added comment: Two unrelated families reported.
Sources: Expert list
Intellectual disability v3.3 RUNX2 Zornitza Stark reviewed gene: RUNX2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Cleidocranial dysplasia, MIM# 119600; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.3 RSRC1 Zornitza Stark gene: RSRC1 was added
gene: RSRC1 was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: RSRC1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RSRC1 were set to 28640246; 29522154
Phenotypes for gene: RSRC1 were set to Intellectual developmental disorder, autosomal recessive 70, MIM# 618402
Review for gene: RSRC1 was set to AMBER
Added comment: Two unrelated families reported, 8 affected individuals.
Sources: Expert list
Intellectual disability v3.3 RSPO4 Zornitza Stark reviewed gene: RSPO4: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Anonychia congenita, MIM# 206800; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.3 RSPH3 Zornitza Stark reviewed gene: RSPH3: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Ciliary dyskinesia, primary, 32, MIM# 616481; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.3 RSPH1 Zornitza Stark reviewed gene: RSPH1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Ciliary dyskinesia, primary, 24, MIM# 615481; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.3 RPS19 Zornitza Stark reviewed gene: RPS19: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Diamond-Blackfan anemia 1, MIM#105650; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.3 RPGRIP1 Zornitza Stark reviewed gene: RPGRIP1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Cone-rod dystrophy 13, MIM# 608194, Leber congenital amaurosis 6, MIM# 613826; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.3 RPE65 Zornitza Stark reviewed gene: RPE65: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Leber congenital amaurosis 2, MIM# 204100, Retinitis pigmentosa 20, MIM# 613794, Retinitis pigmentosa 87 with choroidal involvement, MIM# 618697; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.3 ROBO3 Zornitza Stark reviewed gene: ROBO3: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Gaze palsy, familial horizontal, with progressive scoliosis, 1 607313; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.3 RNF13 Zornitza Stark reviewed gene: RNF13: Rating: GREEN; Mode of pathogenicity: None; Publications: 30595371; Phenotypes: Epileptic encephalopathy, early infantile, 73, MIM# 618379; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Intellectual disability v3.3 RIC1 Zornitza Stark gene: RIC1 was added
gene: RIC1 was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: RIC1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RIC1 were set to 31932796
Phenotypes for gene: RIC1 were set to Cleft lip; cataract; tooth abnormality; intellectual disability; facial dysmorphism; ADHD
Review for gene: RIC1 was set to AMBER
Added comment: Zebrafish model and consanguineous families but homozygous-by-descent. One to watch.
Sources: Expert list
Intellectual disability v3.3 RHEB Zornitza Stark reviewed gene: RHEB: Rating: GREEN; Mode of pathogenicity: None; Publications: 29051493; Phenotypes: Intellectual disability, Macrocephaly; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Intellectual disability v3.3 RETREG1 Zornitza Stark reviewed gene: RETREG1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Neuropathy, hereditary sensory and autonomic, type IIB, MIM# 613115; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.3 MYO5B Zornitza Stark reviewed gene: MYO5B: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Microvillus inclusion disease, MIM# 251850; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.3 MYH9 Zornitza Stark reviewed gene: MYH9: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss, MIM# 155100; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.3 MYH8 Zornitza Stark reviewed gene: MYH8: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Trismus-pseudocamptodactyly syndrome, MIM# 158300; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.3 MYH6 Zornitza Stark reviewed gene: MYH6: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: {Sick sinus syndrome 3} 614090 3 Atrial septal defect 3, MIM# 614089, Cardiomyopathy, dilated, 1EE, MIM# 613252, Cardiomyopathy, hypertrophic, 14, MIM# 613251; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.3 MTHFS Zornitza Stark reviewed gene: MTHFS: Rating: GREEN; Mode of pathogenicity: None; Publications: 30031689, 31844630, 22303332; Phenotypes: Neurodevelopmental disorder with microcephaly, epilepsy, and hypomyelination, 618367; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability v3.3 MSX2 Zornitza Stark reviewed gene: MSX2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Craniosynostosis 2, MIM# 604757, Parietal foramina 1, MIM# 168500, Parietal foramina with cleidocranial dysplasia, MIM# 168550; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.3 MSX1 Zornitza Stark reviewed gene: MSX1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Ectodermal dysplasia 3, Witkop type 189500, Orofacial cleft 5 608874, Tooth agenesis, selective, 1, with or without orofacial cleft 106600; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.3 MPV17 Zornitza Stark reviewed gene: MPV17: Rating: GREEN; Mode of pathogenicity: None; Publications: 22593919; Phenotypes: Mitochondrial DNA depletion syndrome 6 (hepatocerebral type), OMIM #256810; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability v3.3 MNX1 Zornitza Stark reviewed gene: MNX1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Currarino syndrome, OMIM #176450; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.3 MN1 Zornitza Stark reviewed gene: MN1: Rating: GREEN; Mode of pathogenicity: None; Publications: 31834374, 31839203; Phenotypes: Intellectual disability, dysmophic features, rhombencephalosynapsis; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability v3.3 MMP13 Zornitza Stark reviewed gene: MMP13: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Metaphyseal anadysplasia 1, MIM# 602111, Metaphyseal dysplasia, Spahr type, MIM# 250400, Spondyloepimetaphyseal dysplasia, Missouri type, MIM# 602111; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.3 MGP Zornitza Stark reviewed gene: MGP: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Keutel syndrome, MIM# 245150; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.3 MFSD2A Zornitza Stark reviewed gene: MFSD2A: Rating: GREEN; Mode of pathogenicity: None; Publications: 26005865, 26005868, 24828044; Phenotypes: Microcephaly 15, primary, autosomal recessive, MIM# 616486; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.3 MFRP Zornitza Stark reviewed gene: MFRP: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Microphthalmia, isolated 5, MIM# 611040; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.3 METTL5 Zornitza Stark reviewed gene: METTL5: Rating: GREEN; Mode of pathogenicity: None; Publications: 29302074, 31564433; Phenotypes: Intellectual developmental disorder, autosomal recessive 72, MIM# 618665; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability v3.3 MESP2 Zornitza Stark reviewed gene: MESP2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Spondylocostal dysostosis 2, autosomal recessive, MIM# 608681; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.3 MC2R Zornitza Stark reviewed gene: MC2R: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Glucocorticoid deficiency, due to ACTH unresponsiveness, MIM# 202200; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.3 MATN3 Zornitza Stark reviewed gene: MATN3: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Spondyloepimetaphyseal dysplasia 608728, {Osteoarthritis susceptibility 2} 140600, Epiphyseal dysplasia, multiple, 5 607078; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.3 MAPRE2 Zornitza Stark reviewed gene: MAPRE2: Rating: GREEN; Mode of pathogenicity: None; Publications: 26637975; Phenotypes: Symmetric circumferential skin creases, congenital, 2, MIM# 616734; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Intellectual disability v3.3 MAPK10 Zornitza Stark reviewed gene: MAPK10: Rating: RED; Mode of pathogenicity: None; Publications: 23329067, 16249883; Phenotypes: Intellectual disability, seizures; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.3 MAP3K1 Zornitza Stark reviewed gene: MAP3K1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: 46XY sex reversal 6, MIM# 613762; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.3 MAP1B Zornitza Stark reviewed gene: MAP1B: Rating: GREEN; Mode of pathogenicity: None; Publications: 31317654, 30150678, 30214071; Phenotypes: Intellectual disability, seizures, PVNH, dysmorphic features; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Intellectual disability v3.3 MADD Zornitza Stark reviewed gene: MADD: Rating: GREEN; Mode of pathogenicity: None; Publications: 28940097; Phenotypes: Intellectual disability; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability v3.3 NUP214 Zornitza Stark gene: NUP214 was added
gene: NUP214 was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: NUP214 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NUP214 were set to 31178128
Phenotypes for gene: NUP214 were set to developmental delay; intellectual disability; epileptic encephalopathy; developmental regression; microcephaly
Review for gene: NUP214 was set to GREEN
gene: NUP214 was marked as current diagnostic
Added comment: Three unrelated families reported, regression on background of pre-existing neurodisability.
Sources: Expert list
Intellectual disability v3.3 NUP107 Zornitza Stark reviewed gene: NUP107: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Galloway-Mowat syndrome 7, MIM# 618348, Nephrotic syndrome, type 11, MIM# 616730; Mode of inheritance: None
Intellectual disability v3.3 NRXN2 Zornitza Stark edited their review of gene: NRXN2: Added comment: One individual reported with autism and a paternally inherited variant in this gene, father had a language disorder. Another infant reported with severe EE and a maternally inherited variants in NRXN1 and a paternally inherited variant in NRXN2. Some animal data.; Changed publications: 21424692, 30709877, 25745399; Changed phenotypes: Autism
Intellectual disability v3.3 NR5A1 Zornitza Stark reviewed gene: NR5A1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: 46XY sex reversal 3, 612965, Premature ovarian failure 7, 612964, Adrenocortical insufficiency, Spermatogenic failure 8, 613957; Mode of inheritance: None
Intellectual disability v3.3 NR2F2 Zornitza Stark reviewed gene: NR2F2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Congenital heart defects, multiple types, 4, MIM# 615779; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.3 NPR2 Zornitza Stark reviewed gene: NPR2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Acromesomelic dysplasia, Maroteaux type, MIM# 602875, Epiphyseal chondrodysplasia, Miura type MIM#615923, Short stature with nonspecific skeletal abnormalities 616255; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.3 NPHS1 Zornitza Stark reviewed gene: NPHS1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Nephrotic syndrome, type 1, MIM# 256300; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.3 NPHP4 Zornitza Stark reviewed gene: NPHP4: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Nephronophthisis 4, MIM# 606966, Senior-Loken syndrome 4, MIM# 606996; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.3 NPHP3 Zornitza Stark reviewed gene: NPHP3: Rating: GREEN; Mode of pathogenicity: None; Publications: 18371931; Phenotypes: Meckel syndrome 7, MIM# 267010; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.3 NOTCH2 Zornitza Stark reviewed gene: NOTCH2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Alagille syndrome 2, MIM#610205, Hajdu-Cheney syndrome, MIM#102500; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.3 NOG Zornitza Stark reviewed gene: NOG: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Brachydactyly, type B2, MIM# 611377, Multiple synostoses syndrome 1, MIM# 186500, Stapes ankylosis with broad thumbs and toes, MIM# 184460, Symphalangism, proximal, 1A, MIM# 185800, Tarsal-carpal coalition syndrome, MIM# 186570; Mode of inheritance: None
Intellectual disability v3.3 NODAL Zornitza Stark reviewed gene: NODAL: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Heterotaxy, visceral, 5, MIM# 270100; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.3 NMNAT1 Zornitza Stark reviewed gene: NMNAT1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Leber congenital amaurosis 9, MIM# 608553; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.3 NKX3-2 Zornitza Stark reviewed gene: NKX3-2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Spondylo-megaepiphyseal-metaphyseal dysplasia, MIM# 613330; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.3 NHP2 Zornitza Stark reviewed gene: NHP2: Rating: AMBER; Mode of pathogenicity: None; Publications: 18523010, 31985013; Phenotypes: Dyskeratosis congenita, autosomal recessive 2, MIM# 613987, Høyeraal-Hreidarsson syndrome; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.3 NHEJ1 Zornitza Stark reviewed gene: NHEJ1: Rating: RED; Mode of pathogenicity: None; Publications: 16439204; Phenotypes: Severe combined immunodeficiency with microcephaly, growth retardation, and sensitivity to ionizing radiation; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.3 NGF Zornitza Stark reviewed gene: NGF: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Neuropathy, hereditary sensory and autonomic, type V, MIM# 608654; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.3 NEK1 Zornitza Stark reviewed gene: NEK1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Short-rib thoracic dysplasia 6 with or without polydactyly, MIM# 263520; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.3 NEDD4L Zornitza Stark reviewed gene: NEDD4L: Rating: GREEN; Mode of pathogenicity: None; Publications: 27694961; Phenotypes: Periventricular nodular heterotopia 7, MIM#617201; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Intellectual disability v3.3 NDUFAF1 Zornitza Stark gene: NDUFAF1 was added
gene: NDUFAF1 was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: NDUFAF1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NDUFAF1 were set to 17557076; 21931170; 24963768
Phenotypes for gene: NDUFAF1 were set to Mitochondrial complex I deficiency, nuclear type 11, MIM#618234
Review for gene: NDUFAF1 was set to GREEN
gene: NDUFAF1 was marked as current diagnostic
Added comment: Three unrelated families described, DD/ID part of the phenotype, specifically mentioned in two families, child in third family died in infancy from HOCM.
Sources: Expert list
Intellectual disability v3.3 NDUFA2 Zornitza Stark gene: NDUFA2 was added
gene: NDUFA2 was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: NDUFA2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NDUFA2 were set to 18513682; 28857146
Phenotypes for gene: NDUFA2 were set to Mitochondrial complex I deficiency, nuclear type 13, MIM#618235
Review for gene: NDUFA2 was set to GREEN
gene: NDUFA2 was marked as current diagnostic
Added comment: Three unrelated families reported, DD/IDD in all.
Sources: Expert list
Intellectual disability v3.3 NCAPG2 Zornitza Stark gene: NCAPG2 was added
gene: NCAPG2 was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: NCAPG2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NCAPG2 were set to 30609410
Phenotypes for gene: NCAPG2 were set to Khan-Khan-Katsanis syndrome, MIM# 618460
Review for gene: NCAPG2 was set to GREEN
gene: NCAPG2 was marked as current diagnostic
Added comment: Two unrelated families and an animal model (zebrafish).
Sources: Expert list
Intellectual disability v3.3 NCAPD2 Zornitza Stark gene: NCAPD2 was added
gene: NCAPD2 was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: NCAPD2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NCAPD2 were set to 31056748; 27737959; 28097321
Phenotypes for gene: NCAPD2 were set to Microcephaly 21, primary, autosomal recessive, OMIM #617983
Review for gene: NCAPD2 was set to GREEN
gene: NCAPD2 was marked as current diagnostic
Added comment: 5 individuals from three unrelated families reported, some functional evidence.
Sources: Expert list
Intellectual disability v3.3 ZNF335 Zornitza Stark reviewed gene: ZNF335: Rating: GREEN; Mode of pathogenicity: None; Publications: 23178126, 27540107, 29652087; Phenotypes: Microcephaly 10, primary, autosomal recessive, OMIM #615095; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.3 ZNF148 Zornitza Stark reviewed gene: ZNF148: Rating: GREEN; Mode of pathogenicity: None; Publications: 27964749; Phenotypes: Global developmental delay, absent or hypoplastic corpus callosum, and dysmorphic facies, 617260; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Intellectual disability v3.3 ZMPSTE24 Zornitza Stark reviewed gene: ZMPSTE24: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Mandibuloacral dysplasia with type B lipodystrophy, MIM# 608612, Restrictive dermopathy, lethal, MIM# 275210; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.3 ZIC3 Zornitza Stark reviewed gene: ZIC3: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Heterotaxy, visceral, 1, X-linked 306955, Congenital heart defects, nonsyndromic, 1, X-linked, 306955, VACTERL association, X-linked, 314390; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability v3.3 ZIC1 Zornitza Stark reviewed gene: ZIC1: Rating: GREEN; Mode of pathogenicity: None; Publications: 26340333, 30391508; Phenotypes: Structural brain anomalies with impaired intellectual development and craniosynostosis, OMIM #618736; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Intellectual disability v3.3 XYLT1 Zornitza Stark reviewed gene: XYLT1: Rating: GREEN; Mode of pathogenicity: None; Publications: 24581741, 22711505, 23982343; Phenotypes: Desbuquois dysplasia 2, OMIM# 615777; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.3 XPC Zornitza Stark reviewed gene: XPC: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Xeroderma pigmentosum, group C, MIM# 278720; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.3 WRAP53 Zornitza Stark reviewed gene: WRAP53: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Dyskeratosis congenita, autosomal recessive 3, OMIM# 613988; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.3 WNT7A Zornitza Stark reviewed gene: WNT7A: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Fuhrmann syndrome, MIM# 228930, Ulna and fibula, absence of, with severe limb deficiency, MIM# 276820; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.3 WNT5A Zornitza Stark reviewed gene: WNT5A: Rating: AMBER; Mode of pathogenicity: None; Publications: 17256787; Phenotypes: Robinow syndrome, autosomal dominant 1, OMIM# 180700; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.3 WNT3 Zornitza Stark reviewed gene: WNT3: Rating: RED; Mode of pathogenicity: None; Publications: 14872406; Phenotypes: Tetra-amelia syndrome 1, MIM# 273395; Mode of inheritance: None
Intellectual disability v3.3 WNT10B Zornitza Stark reviewed gene: WNT10B: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Split-hand/foot malformation 6, MIM#225300; Mode of inheritance: None
Intellectual disability v3.3 WNT1 Zornitza Stark reviewed gene: WNT1: Rating: GREEN; Mode of pathogenicity: None; Publications: 26671912; Phenotypes: Osteogenesis imperfecta, type XV, OMIM# 615220; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.3 WFS1 Zornitza Stark reviewed gene: WFS1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Wolfram syndrome 1, MIM# 222300, Wolfram-like syndrome, autosomal dominant, MIM# 614296; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.3 WDR35 Zornitza Stark reviewed gene: WDR35: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.3 WDR34 Zornitza Stark reviewed gene: WDR34: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.3 WDR19 Zornitza Stark reviewed gene: WDR19: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Short-rib thoracic dysplasia 5 with or without polydactyly, OMIM #614376, Nephronophthisis 13, OMIM #614377, Senior-Loken syndrome 8, OMIM#616307; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.3 WDFY3 Zornitza Stark edited their review of gene: WDFY3: Added comment: >10 individuals with heterozygous variants in this gene and mild/moderate intellectual disability now described in the literature. Some evidence for opposing effects on brain size depending on variant location.; Changed rating: GREEN; Changed publications: 31327001, 27008544; Set current diagnostic: yes
Intellectual disability v3.3 VSX2 Zornitza Stark reviewed gene: VSX2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Microphthalmia with coloboma 3, MIM# 610092, Microphthalmia, isolated 2, MIM# 610093; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.3 VARS2 Zornitza Stark gene: VARS2 was added
gene: VARS2 was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: VARS2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: VARS2 were set to 24827421; 25058219; 29137650; 29314548; 31064326
Phenotypes for gene: VARS2 were set to Combined oxidative phosphorylation deficiency 20, OMIM #615917
Review for gene: VARS2 was set to GREEN
gene: VARS2 was marked as current diagnostic
Added comment: ID is part of the phenotype of this metabolic disorder.
Sources: Expert list
Intellectual disability v3.3 VAMP1 Zornitza Stark reviewed gene: VAMP1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Myasthenic syndrome, congenital, 25, MIM# 618323; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.3 UVSSA Zornitza Stark reviewed gene: UVSSA: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: UV-sensitive syndrome 3 614640; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.3 USP7 Zornitza Stark reviewed gene: USP7: Rating: GREEN; Mode of pathogenicity: None; Publications: 30679821; Phenotypes: ID, Autism; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Intellectual disability v3.3 USP18 Zornitza Stark reviewed gene: USP18: Rating: GREEN; Mode of pathogenicity: None; Publications: 31940699, 12833411, 27325888; Phenotypes: Pseudo-TORCH syndrome 2, OMIM #617397; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.3 USB1 Zornitza Stark reviewed gene: USB1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Poikiloderma with neutropenia, MIM# 604173; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.3 UROS Zornitza Stark reviewed gene: UROS: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Porphyria, congenital erythropoietic, MIM# 263700; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.3 UGT1A1 Zornitza Stark reviewed gene: UGT1A1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Crigler-Najjar syndrome, type I, OMIM #218800, Crigler-Najjar syndrome, type II, OMIM #606785; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.3 UGP2 Zornitza Stark reviewed gene: UGP2: Rating: GREEN; Mode of pathogenicity: None; Publications: 31820119; Phenotypes: Epileptic encephalopathy, intellectual disability, microcephaly; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.3 TYRP1 Zornitza Stark reviewed gene: TYRP1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Albinism, oculocutaneous, type III, 203290; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.3 TYR Zornitza Stark reviewed gene: TYR: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Albinism, oculocutaneous, type IA, 203100; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.3 TXNL4A Zornitza Stark reviewed gene: TXNL4A: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Burn-McKeown syndrome, MIM# 608572; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.3 TUBGCP2 Zornitza Stark gene: TUBGCP2 was added
gene: TUBGCP2 was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: TUBGCP2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TUBGCP2 were set to 31630790
Phenotypes for gene: TUBGCP2 were set to Lissencephaly; pachygyria; subcortical band heterotopia; microcephaly; intellectual disability
Review for gene: TUBGCP2 was set to GREEN
gene: TUBGCP2 was marked as current diagnostic
Added comment: Four unrelated families reported.
Sources: Expert list
Intellectual disability v3.3 TUBA8 Zornitza Stark reviewed gene: TUBA8: Rating: RED; Mode of pathogenicity: None; Publications: 19896110, 31481326, 28388629; Phenotypes: Cortical dysplasia, complex, with other brain malformations 8, MIM# 613180; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.3 TSHR Zornitza Stark reviewed gene: TSHR: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Hypothyroidism, congenital, nongoitrous, 1, MIM# 275200; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.3 TRPV4 Zornitza Stark reviewed gene: TRPV4: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.3 TRPS1 Zornitza Stark reviewed gene: TRPS1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Trichorhinophalangeal syndrome, type I (MIM 190350), Trichorhinophalangeal syndrome, type III (MIM 190351); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.3 TRPM3 Zornitza Stark reviewed gene: TRPM3: Rating: GREEN; Mode of pathogenicity: None; Publications: 31278393; Phenotypes: Intellectual disability, epilepsy; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.3 TRPM1 Zornitza Stark reviewed gene: TRPM1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Night blindness, congenital stationary (complete), 1C, autosomal recessive, MIM# 613216; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.3 TRNT1 Zornitza Stark gene: TRNT1 was added
gene: TRNT1 was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: TRNT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TRNT1 were set to 25193871; 23553769; 29170023; 27389523
Phenotypes for gene: TRNT1 were set to Sideroblastic anemia with B-cell immunodeficiency, periodic fevers, and developmental delay, OMIM #616084
Review for gene: TRNT1 was set to GREEN
gene: TRNT1 was marked as current diagnostic
Added comment: > 10 families reported with congenital sideroblastic anemia, B-cell deficiency, periodic fevers, and variable degrees of delayed psychomotor development.
Sources: Expert list
Intellectual disability v3.3 TRIP11 Zornitza Stark reviewed gene: TRIP11: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Achondrogenesis, type IA, MIM# 200600, Osteochondrodysplasia, MIM# 184260; Mode of inheritance: None
Intellectual disability v3.3 TRIM32 Zornitza Stark reviewed gene: TRIM32: Rating: RED; Mode of pathogenicity: None; Publications: 16606853; Phenotypes: Bardet-Biedl syndrome 11, MIM# 615988; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.3 TRAPPC4 Zornitza Stark reviewed gene: TRAPPC4: Rating: GREEN; Mode of pathogenicity: None; Publications: 31794024; Phenotypes: intellectual disability, epilepsy, spasticity, microcephaly; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.3 TRAPPC2 Zornitza Stark reviewed gene: TRAPPC2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Spondyloepiphyseal dysplasia tarda, MIM# 313400; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability v3.3 TRAK1 Zornitza Stark reviewed gene: TRAK1: Rating: GREEN; Mode of pathogenicity: None; Publications: 28940097, 28364549, 29846532; Phenotypes: Epileptic encephalopathy, early infantile, 68, MIM# 618201; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.3 TP73 Zornitza Stark gene: TP73 was added
gene: TP73 was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: TP73 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TP73 were set to 31130284
Phenotypes for gene: TP73 were set to Intellectual disability; lissencephaly
Review for gene: TP73 was set to AMBER
Added comment: Two unrelated families, no functional data.
Sources: Expert list
Intellectual disability v3.3 TP63 Zornitza Stark reviewed gene: TP63: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ADULT syndrome, OMIM #103285, Ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome 3, OMIM #604292, Hay-Wells syndrome, OMIM #106260, Limb-mammary syndrome, OMIM #603543, Orofacial cleft 8, OMIM #618149, Rapp-Hodgkin syndrome, OMIM #129400, Split-hand/foot malformation 4, OMIM #605289; Mode of inheritance: None
Intellectual disability v3.3 SPOP Zornitza Stark gene: SPOP was added
gene: SPOP was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: SPOP was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SPOP were set to 32109420
Phenotypes for gene: SPOP were set to Intellectual disability; dysmorphism; microcephaly; macrocephaly
Mode of pathogenicity for gene: SPOP was set to Other
Review for gene: SPOP was set to GREEN
gene: SPOP was marked as current diagnostic
Added comment: Seven individuals reported with de novo missense variants in this gene. Gain-of-function variants associated with microcephaly whereas dominant-negative variants associated with macrocephaly.
Sources: Literature
Intellectual disability v3.3 TMPRSS6 Zornitza Stark reviewed gene: TMPRSS6: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Iron-refractory iron deficiency anemia 206200; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.3 TMEM126B Zornitza Stark reviewed gene: TMEM126B: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Mitochondrial complex I deficiency, nuclear type 29, MIM# 618250; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.3 TINF2 Zornitza Stark reviewed gene: TINF2: Rating: GREEN; Mode of pathogenicity: None; Publications: 1404302, 18252230, 21477109; Phenotypes: Revesz syndrome, MIM# 268130; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Intellectual disability v3.3 TGFB3 Zornitza Stark reviewed gene: TGFB3: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Arrhythmogenic right ventricular dysplasia 1, MIM# 107970, Loeys-Dietz syndrome 5, MIM# 615582; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.3 TGFB2 Zornitza Stark reviewed gene: TGFB2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Loeys-Dietz syndrome 4, MIM# 614816; Mode of inheritance: None
Intellectual disability v3.3 TGFB1 Zornitza Stark reviewed gene: TGFB1: Rating: AMBER; Mode of pathogenicity: None; Publications: 29483653; Phenotypes: Inflammatory bowel disease, immunodeficiency, and encephalopathy, MIM# 618213; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.3 TET3 Zornitza Stark reviewed gene: TET3: Rating: GREEN; Mode of pathogenicity: None; Publications: 31928709; Phenotypes: Intellectual disability, dysmorphic features, abnormal growth, movement disorders; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.3 TENM3 Zornitza Stark gene: TENM3 was added
gene: TENM3 was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: TENM3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TENM3 were set to 30513139; 22766609; 27103084; 29753094
Phenotypes for gene: TENM3 were set to Microphthalmia, syndromic 15, MIM#615145; coloboma
Review for gene: TENM3 was set to GREEN
gene: TENM3 was marked as current diagnostic
Added comment: At least four unrelated families described with syndromic microphthalmia and bi-allelic variants in this gene, ID is part of the phenotype.
Sources: Expert list
Intellectual disability v3.3 TEK Zornitza Stark reviewed gene: TEK: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Glaucoma 3, primary congenital, E , MIM#617272, Venous malformations, multiple cutaneous and mucosal, MIM# 600195; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.3 TCTN3 Zornitza Stark reviewed gene: TCTN3: Rating: GREEN; Mode of pathogenicity: None; Publications: 22883145, 25118024, 26092869; Phenotypes: Joubert syndrome 18, OMIM #614815, Orofaciodigital syndrome IV, OMIM #258860; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability v3.3 TCF12 Zornitza Stark reviewed gene: TCF12: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Craniosynostosis 3, MIM# 615314; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.3 TBXAS1 Zornitza Stark reviewed gene: TBXAS1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Ghosal hematodiaphyseal syndrome, MIM# 231095; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.3 TBX5 Zornitza Stark reviewed gene: TBX5: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Holt-Oram syndrome, MIM# 142900; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.3 TBX4 Zornitza Stark reviewed gene: TBX4: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Amelia, posterior, with pelvic and pulmonary hypoplasia syndrome, MIM# 601360, Ischiocoxopodopatellar syndrome with or without pulmonary arterial hypertension, MIM# 147891; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.3 TBX3 Zornitza Stark reviewed gene: TBX3: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Ulnar-mammary syndrome, MIM# 181450; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.3 TBX22 Zornitza Stark reviewed gene: TBX22: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Abruzzo-Erickson syndrome, MIM# 302905, Cleft palate with ankyloglossia, MIM# 303400; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability v3.3 TBX20 Zornitza Stark reviewed gene: TBX20: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Atrial septal defect 4, MIM# 611363; Mode of inheritance: None
Intellectual disability v3.3 TBX15 Zornitza Stark reviewed gene: TBX15: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Cousin syndrome, MIM# 260660; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.3 TASP1 Zornitza Stark gene: TASP1 was added
gene: TASP1 was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: TASP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TASP1 were set to 31209944; 31350873
Phenotypes for gene: TASP1 were set to Developmental delay; microcephaly; dysmorphic features; congenital abnormalities
Review for gene: TASP1 was set to GREEN
gene: TASP1 was marked as current diagnostic
Added comment: Four unrelated families reported; two with founder mutation. Protein interacts with KMT2A and KMT2D. Another de novo missense variant reported in a single infant with multiple congenital abnormalities, insufficient evidence for mono allelic disease at present.
Sources: Expert list
Intellectual disability v3.3 TANC2 Zornitza Stark reviewed gene: TANC2: Rating: GREEN; Mode of pathogenicity: None; Publications: 31616000; Phenotypes: Intellectual disability, autism, epilepsy; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Intellectual disability v3.3 TAB2 Zornitza Stark reviewed gene: TAB2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Congenital heart defects, nonsyndromic, 2, MIM# 614980; Mode of inheritance: None
Intellectual disability v3.3 SUZ12 Zornitza Stark edited their review of gene: SUZ12: Changed phenotypes: Imagawa-Matsumoto syndrome, MIM# 618786, Intellectual disability, Overgrowth
Intellectual disability v3.3 SUZ12 Zornitza Stark reviewed gene: SUZ12: Rating: GREEN; Mode of pathogenicity: None; Publications: 31736240, 30019515, 28229514; Phenotypes: Intellectual disability, Overgrowth; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.3 SUCLA2 Zornitza Stark gene: SUCLA2 was added
gene: SUCLA2 was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: SUCLA2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SUCLA2 were set to 27913098; 15877282; 23759946; 17287286; 17301081
Phenotypes for gene: SUCLA2 were set to Mitochondrial DNA depletion syndrome 5 (encephalomyopathic with or without methylmalonic aciduria); OMIM #612073
Review for gene: SUCLA2 was set to GREEN
Added comment: ID is part of the phenotype of this mitochondrial disorder.
Sources: Expert list
Intellectual disability v3.3 STT3A Zornitza Stark reviewed gene: STT3A: Rating: GREEN; Mode of pathogenicity: None; Publications: 23842455, 30701557, 28424003; Phenotypes: Congenital disorder of glycosylation, type Iw, OMIM #615596; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.3 STS Zornitza Stark reviewed gene: STS: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.3 STAT1 Zornitza Stark reviewed gene: STAT1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.3 STAR Zornitza Stark reviewed gene: STAR: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Lipoid adrenal hyperplasia, MIM# 201710; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.3 SRY Zornitza Stark reviewed gene: SRY: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.3 SPEG Zornitza Stark reviewed gene: SPEG: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Centronuclear myopathy 5, OMIM #615959; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.3 SPAG1 Zornitza Stark reviewed gene: SPAG1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Ciliary dyskinesia, primary, 28, MIM# 615505; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.3 SOX17 Zornitza Stark reviewed gene: SOX17: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Vesicoureteral reflux 3, MIM# 613674; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.3 RASA1 Zornitza Stark reviewed gene: RASA1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Capillary malformation-arteriovenous malformation 1, MIM# 608354; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.3 SNX27 Zornitza Stark reviewed gene: SNX27: Rating: GREEN; Mode of pathogenicity: None; Publications: 25894286, 31721175, 21300787, 23524343; Phenotypes: intellectual disability, seizures; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.3 SMG8 Zornitza Stark gene: SMG8 was added
gene: SMG8 was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: SMG8 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SMG8 were set to 31130284
Phenotypes for gene: SMG8 were set to Intellectual disability
Review for gene: SMG8 was set to AMBER
Added comment: Two unrelated families, no functional data.
Sources: Expert list
Intellectual disability v3.3 SMCHD1 Zornitza Stark reviewed gene: SMCHD1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Bosma arhinia microphthalmia syndrome, OMIM #603457, Fascioscapulohumeral muscular dystrophy 2, digenic, OMIM #158901; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.3 DDC Lothar Schlueter reviewed gene: DDC: Rating: GREEN; Mode of pathogenicity: None; Publications: 28100251, 30952622, 30689738, 25597765, 24788355; Phenotypes: Aromatic L-amino acid decarboxylase deficiency 608643, floppy child, dystonia, hypotonia, developmental delay, oculogyric crisis; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.3 SLC9A7 Zornitza Stark gene: SLC9A7 was added
gene: SLC9A7 was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: SLC9A7 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: SLC9A7 were set to 30335141
Phenotypes for gene: SLC9A7 were set to Intellectual developmental disorder, X-linked 108; OMIM #301024
Review for gene: SLC9A7 was set to AMBER
Added comment: 6 males from 2 unrelated families with hemizygous missense mutation in the SLC9A7 gene. The mutation segregated with the disorder in the family. In vitro functional expression studies in CHO cells (AP-1 cells) showed that the mutation caused decreased levels of protein expression and reduced oligosaccharide maturation/glycosylation compared to wildtype, indicating impaired posttranslational processing. Subcellular localization studies indicated that protein trafficking was unaffected by the mutation. However, examination of the trans-Golgi compartment suggested a gain-of-function effect and a perturbation of glycosylation of secretory cargo. Serum transferrin studies in 1 patient suggested a glycosylation defect. One to watch.
Sources: Expert list
Intellectual disability v3.3 SLC1A1 Zornitza Stark gene: SLC1A1 was added
gene: SLC1A1 was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: SLC1A1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC1A1 were set to Dicarboxylic aminoaciduria, MIM#222730
Review for gene: SLC1A1 was set to GREEN
gene: SLC1A1 was marked as current diagnostic
Added comment: ID is part of the phenotype of this metabolic disorder.
Sources: Expert list
Intellectual disability v3.3 SKIV2L Zornitza Stark reviewed gene: SKIV2L: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Trichohepatoenteric syndrome 2, MIM# 614602; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.3 SIX5 Zornitza Stark reviewed gene: SIX5: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Branchiootorenal syndrome 2 610896; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.3 SIX1 Zornitza Stark reviewed gene: SIX1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Branchiootic syndrome 3, MIM# 608389, Deafness, autosomal dominant 23, MIM# 605192; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.3 SH3PXD2B Zornitza Stark reviewed gene: SH3PXD2B: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Frank-ter Haar syndrome, MIM# 249420; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.3 SFXN4 Zornitza Stark gene: SFXN4 was added
gene: SFXN4 was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: SFXN4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SFXN4 were set to 31059822; 24119684
Phenotypes for gene: SFXN4 were set to Combined oxidative phosphorylation deficiency 18, MIM#615578
Review for gene: SFXN4 was set to GREEN
gene: SFXN4 was marked as current diagnostic
Added comment: Three unrelated families reported, mild ID as well as other neurological features are part of the phenotype.
Sources: Expert list
Intellectual disability v3.3 SEC31A Zornitza Stark gene: SEC31A was added
gene: SEC31A was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: SEC31A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SEC31A were set to 30464055
Phenotypes for gene: SEC31A were set to Neurodevelopmental disorder with spastic quadriplegia, optic atrophy, seizures, and structural brain anomalies, OMIM #618651
Review for gene: SEC31A was set to AMBER
Added comment: Single family with two affected sibs with functional data (drosophila), one to watch.
Sources: Expert list
Intellectual disability v3.3 SEC23B Zornitza Stark reviewed gene: SEC23B: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ?Cowden syndrome 7 616858, Dyserythropoietic anemia, congenital, type II 224100; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.3 SCN1B Zornitza Stark reviewed gene: SCN1B: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Epileptic encephalopathy, early infantile, 52, MIM#617350; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability v3.3 SCN11A Zornitza Stark reviewed gene: SCN11A: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Neuropathy, hereditary sensory and autonomic, type VII, MIM#615548; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.3 SCARF2 Zornitza Stark reviewed gene: SCARF2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Van den Ende-Gupta syndrome, MIM# 600920; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.3 SCAMP5 Zornitza Stark reviewed gene: SCAMP5: Rating: GREEN; Mode of pathogenicity: Other; Publications: 31439720; Phenotypes: Intellectual disability, seizures, autism; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Intellectual disability v3.3 SBF1 Zornitza Stark gene: SBF1 was added
gene: SBF1 was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: SBF1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SBF1 were set to 24799518; 23749797; 30039846; 28902413
Phenotypes for gene: SBF1 were set to Charcot-Marie-Tooth disease, type 4B3, MIM# 615284
Review for gene: SBF1 was set to GREEN
Added comment: At least 4 families with multiple affected individuals described. Some have had central features including microcephaly and DD/ID, it is likely this gene causes a mixed picture.
Sources: Expert list
Intellectual disability v3.3 SBDS Zornitza Stark reviewed gene: SBDS: Rating: RED; Mode of pathogenicity: None; Publications: 19906387; Phenotypes: Shwachman-Diamond syndrome, MIM#260400; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.3 SARS2 Zornitza Stark gene: SARS2 was added
gene: SARS2 was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: SARS2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SARS2 were set to 21255763; 24034276
Phenotypes for gene: SARS2 were set to Hyperuricemia, pulmonary hypertension, renal failure, and alkalosis, MIM#613845
Review for gene: SARS2 was set to GREEN
gene: SARS2 was marked as current diagnostic
Added comment: DD/ID is part of the phenotype. Two unrelated families reported, highly specific phenotype.
Sources: Expert list
Intellectual disability v3.3 SALL4 Zornitza Stark reviewed gene: SALL4: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Duane-radial ray syndrome, MIM# 607323; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.3 SOX3 Zornitza Stark reviewed gene: SOX3: Rating: AMBER; Mode of pathogenicity: None; Publications: 29175558, 30125608, 12428212, 15800844; Phenotypes: Mental retardation, X-linked, with isolated growth hormone deficiency, MIM#300123, Panhypopituitarism, X-linked, MIM#312000; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability v3.3 PUM1 Zornitza Stark reviewed gene: PUM1: Rating: GREEN; Mode of pathogenicity: None; Publications: 29474920, 25768905; Phenotypes: Spinocerebellar ataxia 47, MIM#617931; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.3 PSAT1 Zornitza Stark reviewed gene: PSAT1: Rating: AMBER; Mode of pathogenicity: None; Publications: 26960553, 17436247, 25152457; Phenotypes: Phosphoserine aminotransferase deficiency, MIM# 610992, Neu-Laxova syndrome 2, MIM# 616038; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.3 PRSS56 Zornitza Stark reviewed gene: PRSS56: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Microphthalmia, isolated 6, MIM# 613517; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.3 PROP1 Zornitza Stark reviewed gene: PROP1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Pituitary hormone deficiency, combined, 2, MIM# 262600; Mode of inheritance: None
Intellectual disability v3.3 PRKAR1A Zornitza Stark reviewed gene: PRKAR1A: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Acrodysostosis 1, with or without hormone resistance, MIM# 101800; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.3 PRDM12 Zornitza Stark reviewed gene: PRDM12: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Neuropathy, hereditary sensory and autonomic, type VIII, MIM# 616488; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.3 PPP1R12A Zornitza Stark gene: PPP1R12A was added
gene: PPP1R12A was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: PPP1R12A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PPP1R12A were set to 31883643
Phenotypes for gene: PPP1R12A were set to Intellectual disability; holoprosencephaly; disorder of sex development
Review for gene: PPP1R12A was set to GREEN
gene: PPP1R12A was marked as current diagnostic
Added comment: 12 individuals reported.
Sources: Expert list
Intellectual disability v3.3 PPA2 Zornitza Stark reviewed gene: PPA2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Sudden cardiac failure, infantile, MIM# 617222; Mode of inheritance: None
Intellectual disability v3.3 Rebecca Foulger Panel version has been signed off
Intellectual disability v3.1 POMK Zornitza Stark gene: POMK was added
gene: POMK was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: POMK was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: POMK were set to Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 12, MIM# 615249
Review for gene: POMK was set to GREEN
gene: POMK was marked as current diagnostic
Added comment: ID is part of the phenotype.
Sources: Expert list
Intellectual disability v3.1 POLR1D Zornitza Stark reviewed gene: POLR1D: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Treacher Collins syndrome 2, MIM# 613717; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.1 POLR1C Zornitza Stark reviewed gene: POLR1C: Rating: GREEN; Mode of pathogenicity: None; Publications: 26151409; Phenotypes: Leukodystrophy, hypomyelinating, 11, MIM# 616494; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1 POLD1 Zornitza Stark reviewed gene: POLD1: Rating: RED; Mode of pathogenicity: None; Publications: 31449058; Phenotypes: Intellectual disability, immunodeficiency, Mandibular hypoplasia, deafness, progeroid features, and lipodystrophy syndrome, MIM#615381; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.1 POC1B Zornitza Stark reviewed gene: POC1B: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Cone-rod dystrophy 20 615973; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1 PNPT1 Zornitza Stark reviewed gene: PNPT1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Combined oxidative phosphorylation deficiency 13, MIM#614932; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1 PMS2 Zornitza Stark reviewed gene: PMS2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Mismatch repair cancer syndrome, MIM# 276300; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1 PLOD2 Zornitza Stark reviewed gene: PLOD2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Bruck syndrome 2 609220; Mode of inheritance: None
Intellectual disability v3.0 PKHD1 Zornitza Stark reviewed gene: PKHD1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Polycystic kidney disease 4, with or without hepatic disease 263200; Mode of inheritance: None
Intellectual disability v3.0 PKD1L1 Zornitza Stark reviewed gene: PKD1L1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Heterotaxy, visceral, 8, autosomal, MIM# 617205; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.0 PITX3 Zornitza Stark reviewed gene: PITX3: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Anterior segment dysgenesis 1, multiple subtypes, MIM# 107250, cataract; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.0 PITX2 Zornitza Stark reviewed gene: PITX2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Axenfeld-Rieger syndrome, type 1, MIM# 180500; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.0 PISD Zornitza Stark gene: PISD was added
gene: PISD was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: PISD was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PISD were set to 31263216; 30858161
Phenotypes for gene: PISD were set to intellectual disability; cataract; microcephaly; deafness; skeletal dysplasia
Review for gene: PISD was set to GREEN
Added comment: Three unrelated families reported.
Sources: Expert list
Intellectual disability v3.0 PIK3R1 Zornitza Stark reviewed gene: PIK3R1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: SHORT syndrome, MIM#269880; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.0 PIK3C2A Zornitza Stark reviewed gene: PIK3C2A: Rating: GREEN; Mode of pathogenicity: None; Publications: 31034465; Phenotypes: Oculoskeletodental syndrome, 618440; Mode of inheritance: None
Intellectual disability v3.0 PIGS Zornitza Stark gene: PIGS was added
gene: PIGS was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: PIGS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PIGS were set to 30269814
Phenotypes for gene: PIGS were set to Glycosylphosphatidylinositol biosynthesis defect 18, MIM# 618143
Review for gene: PIGS was set to GREEN
gene: PIGS was marked as current diagnostic
Added comment: Three unrelated families reported. Severe neurological phenotype ranging from fetal akinesia to ID/EE.
Sources: Expert list
Intellectual disability v3.0 PIGH Zornitza Stark edited their review of gene: PIGH: Added comment: I note this gene is Green on the epilepsy panel, and I agree this family of genes cause similar phenotypes, there is some functional data to support the gene-disease relationship, so we have rated it Green on both panels.; Changed rating: GREEN; Changed publications: 29573052, 29603516
Intellectual disability v3.0 PIBF1 Zornitza Stark gene: PIBF1 was added
gene: PIBF1 was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: PIBF1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PIBF1 were set to 26167768; 30858804; 29695797
Phenotypes for gene: PIBF1 were set to Joubert syndrome 33; OMIM #617767
Review for gene: PIBF1 was set to GREEN
gene: PIBF1 was marked as current diagnostic
Added comment: 7 families altogether: 3 of these are Hutterite and share the same founder variant.
Sources: Expert list
Intellectual disability v3.0 PGM1 Zornitza Stark reviewed gene: PGM1: Rating: RED; Mode of pathogenicity: None; Publications: 24499211; Phenotypes: Congenital disorder of glycosylation, type It, MIM# 614921; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.0 PET100 Zornitza Stark reviewed gene: PET100: Rating: GREEN; Mode of pathogenicity: None; Publications: 24462369, 25293719, 31406627; Phenotypes: Mitochondrial complex IV deficiency, MIM# 220110; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability v3.0 PDP1 Zornitza Stark gene: PDP1 was added
gene: PDP1 was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: PDP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PDP1 were set to 19184109; 15855260; 31392110
Phenotypes for gene: PDP1 were set to Pyruvate dehydrogenase phosphatase deficiency, MIM#608782
Review for gene: PDP1 was set to GREEN
gene: PDP1 was marked as current diagnostic
Added comment: DD/ID is part of the phenotype of this metabolic condition.
Sources: Expert list
Intellectual disability v3.0 PDHB Zornitza Stark gene: PDHB was added
gene: PDHB was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: PDHB was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PDHB were set to 15138885; 26014431
Phenotypes for gene: PDHB were set to Pyruvate dehydrogenase E1-beta deficiency, MIM#614111
Review for gene: PDHB was set to GREEN
gene: PDHB was marked as current diagnostic
Added comment: DD/ID is a feature of this metabolic disorder.
Sources: Expert list
Intellectual disability v3.0 PDE6G Zornitza Stark reviewed gene: PDE6G: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Retinitis pigmentosa 57 613582; Mode of inheritance: None
Intellectual disability v3.0 PDE10A Zornitza Stark gene: PDE10A was added
gene: PDE10A was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: PDE10A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PDE10A were set to 27058446
Phenotypes for gene: PDE10A were set to Dyskinesia, limb and orofacial, infantile-onset, MIM#616921
Review for gene: PDE10A was set to GREEN
gene: PDE10A was marked as current diagnostic
Added comment: Two unrelated families and functional data (animal model). Note that allelic disorder, Striatal degeneration, autosomal dominant, MIM#616922, is caused by heterozygous variants and ID is not part of the phenotype.
Sources: Expert list
Intellectual disability v3.0 PAX9 Zornitza Stark reviewed gene: PAX9: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Tooth agenesis, selective, 3 604625; Mode of inheritance: None
Intellectual disability v3.0 PAX3 Zornitza Stark reviewed gene: PAX3: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Craniofacial-deafness-hand syndrome, MIM#122880, Waardenburg syndrome, type 1, MIM#193500, Waardenburg syndrome, type 3, MIM#148820; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.0 PAPSS2 Zornitza Stark reviewed gene: PAPSS2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Brachyolmia 4 with mild epiphyseal and metaphyseal changes, MIM# 612847; Mode of inheritance: None
Intellectual disability v3.0 PAM16 Zornitza Stark gene: PAM16 was added
gene: PAM16 was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: PAM16 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PAM16 were set to 24786642; 27354339
Phenotypes for gene: PAM16 were set to Spondylometaphyseal dysplasia, Megarbane-Dagher-Melike type, MIM#613320
Review for gene: PAM16 was set to GREEN
gene: PAM16 was marked as current diagnostic
Added comment: DD/ID is part of the phenotype of this skeletal dysplasia.
Sources: Expert list
Intellectual disability v3.0 OXR1 Zornitza Stark reviewed gene: OXR1: Rating: GREEN; Mode of pathogenicity: None; Publications: 31785787; Phenotypes: Intellectual disability, seizures, cerebellar atrophy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability v3.0 OTULIN Zornitza Stark reviewed gene: OTULIN: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Autoinflammation, panniculitis, and dermatosis syndrome, MIM# 617099; Mode of inheritance: None
Intellectual disability v3.0 OTOGL Zornitza Stark reviewed gene: OTOGL: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Deafness, autosomal recessive 84B, MIM# 614944; Mode of inheritance: None
Intellectual disability v3.0 ORC6 Zornitza Stark edited their review of gene: ORC6: Added comment: Intellect is typically normal.; Changed publications: 26381604; Changed phenotypes: Meier Gorlin syndrome
Intellectual disability v3.0 LZTFL1 Zornitza Stark gene: LZTFL1 was added
gene: LZTFL1 was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: LZTFL1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LZTFL1 were set to 22510444; 23692385; 27312011
Phenotypes for gene: LZTFL1 were set to Bardet-Biedl syndrome 17, MIM#615994
Review for gene: LZTFL1 was set to GREEN
gene: LZTFL1 was marked as current diagnostic
Added comment: Two unrelated families and functional evidence.
Sources: Expert list
Intellectual disability v3.0 LYRM7 Zornitza Stark gene: LYRM7 was added
gene: LYRM7 was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: LYRM7 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: LYRM7 were set to Mitochondrial complex III deficiency, nuclear type 8, MIM#615838
Review for gene: LYRM7 was set to GREEN
gene: LYRM7 was marked as current diagnostic
Added comment: Condition is characterised by progressive deterioration but some individuals described as developmentally delayed from birth.
Sources: Expert list
Intellectual disability v3.0 LTBP3 Zornitza Stark reviewed gene: LTBP3: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Dental anomalies and short stature 601216, Geleophysic dysplasia 3 617809; Mode of inheritance: None
Intellectual disability v3.0 LTBP2 Zornitza Stark reviewed gene: LTBP2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Weill-Marchesani syndrome 3, recessive, MIM# 614819, Glaucoma 3, primary congenital, MIM# 613086, Microspherophakia and/or megalocornea, with ectopia lentis and with or without secondary glaucoma, MIM# 251750; Mode of inheritance: None
Intellectual disability v3.0 LSS Zornitza Stark reviewed gene: LSS: Rating: GREEN; Mode of pathogenicity: None; Publications: 30723320; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.0 LRRC6 Zornitza Stark reviewed gene: LRRC6: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Ciliary dyskinesia, primary, 19, MIM# 614935; Mode of inheritance: None
Intellectual disability v3.0 LRP4 Zornitza Stark reviewed gene: LRP4: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Cenani-Lenz syndactyly syndrome, MIM# 212780, Sclerosteosis 2, MIM# 614305; Mode of inheritance: None
Intellectual disability v3.0 LMX1B Zornitza Stark reviewed gene: LMX1B: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.0 LMNA Zornitza Stark reviewed gene: LMNA: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.0 LMAN2L Zornitza Stark gene: LMAN2L was added
gene: LMAN2L was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: LMAN2L was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: LMAN2L were set to 31020005; 26566883
Phenotypes for gene: LMAN2L were set to Intellectual disability; epilepsy
Review for gene: LMAN2L was set to AMBER
Added comment: 1 consanguineous family with 7 individuals with ID and epilepsy, with homozygous LMAN2L missense mutation. Segregated with disease in family, and unaffected family members were heterozygous variant carriers. No functional studies.

1 non-consanguineous family with 4 affected with heterozygous frameshift LMAN2L mutation. Segregates in family. Mutation eliminates LMAN2L's endoplasmic reticulum retention signal and mislocalizes the protein from that compartment to the plasma membrane.

Amber or Red.
Sources: Expert list
Intellectual disability v3.0 LIPT1 Zornitza Stark gene: LIPT1 was added
gene: LIPT1 was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: LIPT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LIPT1 were set to 24341803; 24256811; 29681092
Phenotypes for gene: LIPT1 were set to Lipoyltransferase 1 deficiency, MIM#616299
Review for gene: LIPT1 was set to GREEN
gene: LIPT1 was marked as current diagnostic
Added comment: Cognitive development is affected in this metabolic condition.
Sources: Expert list
Intellectual disability v3.0 LIAS Zornitza Stark reviewed gene: LIAS: Rating: GREEN; Mode of pathogenicity: None; Publications: 24334290, 22152680; Phenotypes: Hyperglycinemia, lactic acidosis, and seizures, MIM#614462; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability v3.0 LHX4 Zornitza Stark reviewed gene: LHX4: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.0 LHX3 Zornitza Stark reviewed gene: LHX3: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Pituitary hormone deficiency, combined, 3, MIM# 221750; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.0 LGI4 Zornitza Stark reviewed gene: LGI4: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Arthrogryposis multiplex congenita, neurogenic, with myelin defect, MIM#617468; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.0 LFNG Zornitza Stark reviewed gene: LFNG: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.0 LEMD3 Zornitza Stark reviewed gene: LEMD3: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.0 LDB3 Zornitza Stark reviewed gene: LDB3: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.0 LAS1L Zornitza Stark reviewed gene: LAS1L: Rating: GREEN; Mode of pathogenicity: None; Publications: 25644381, 25644381; Phenotypes: Wilson-Turner syndrome, MIM# 309585; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females; Current diagnostic: yes
Intellectual disability v3.0 LAMB2 Zornitza Stark gene: LAMB2 was added
gene: LAMB2 was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: LAMB2 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: LAMB2 were set to Pierson syndrome, MIM#609049
gene: LAMB2 was marked as current diagnostic
Added comment: Cognitive impairment described in survivors.
Sources: Expert list
Intellectual disability v3.0 KLHL40 Zornitza Stark reviewed gene: KLHL40: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Nemaline myopathy 8, autosomal recessive 615348; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.0 KLF7 Zornitza Stark gene: KLF7 was added
gene: KLF7 was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: KLF7 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KLF7 were set to 29251763
Phenotypes for gene: KLF7 were set to Intellectual disability
Review for gene: KLF7 was set to GREEN
gene: KLF7 was marked as current diagnostic
Added comment: Four unrelated individuals with de novo missense variants; animal model data supportive.
Sources: Expert list
Intellectual disability v3.0 KLF1 Zornitza Stark reviewed gene: KLF1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.0 KIT Zornitza Stark reviewed gene: KIT: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.0 KIRREL3 Zornitza Stark reviewed gene: KIRREL3: Rating: RED; Mode of pathogenicity: None; Publications: 19012874; Phenotypes: Intellectual disability; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.0 KIF22 Zornitza Stark reviewed gene: KIF22: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Spondyloepimetaphyseal dysplasia with joint laxity, type 2 603546; Mode of inheritance: None
Intellectual disability v3.0 KDM6B Zornitza Stark reviewed gene: KDM6B: Rating: GREEN; Mode of pathogenicity: None; Publications: 31124279; Phenotypes: Intellectual disability; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Intellectual disability v3.0 KDM3B Zornitza Stark reviewed gene: KDM3B: Rating: GREEN; Mode of pathogenicity: None; Publications: 30929739; Phenotypes: Intellectual disability, short stature; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Intellectual disability v3.0 KCTD1 Zornitza Stark reviewed gene: KCTD1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.0 KCNQ1 Zornitza Stark reviewed gene: KCNQ1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.0 KCNN3 Zornitza Stark gene: KCNN3 was added
gene: KCNN3 was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: KCNN3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KCNN3 were set to 31155282
Phenotypes for gene: KCNN3 were set to Zimmermann-Laband syndrome 3; OMIM# 618658
Review for gene: KCNN3 was set to GREEN
gene: KCNN3 was marked as current diagnostic
Added comment: Three unrelated individuals reported.
Sources: Expert list
Intellectual disability v3.0 KCNMA1 Zornitza Stark reviewed gene: KCNMA1: Rating: GREEN; Mode of pathogenicity: Other; Publications: 27567911, 29545233, 26195193, 31427379; Phenotypes: Cerebellar atrophy, developmental delay, and seizures, MIM# 617643, Paroxysmal nonkinesigenic dyskinesia, 3, with or without generalized epilepsy, MIM#609446; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.0 KCNK4 Zornitza Stark reviewed gene: KCNK4: Rating: GREEN; Mode of pathogenicity: None; Publications: 30290154; Phenotypes: Facial dysmorphism, hypertrichosis, epilepsy, intellectual/developmental delay, and gingival overgrowth syndrome 618381; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Intellectual disability v3.0 KCND3 Zornitza Stark reviewed gene: KCND3: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Spinocerebellar ataxia 19, MIM#607346; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.0 KCNC3 Zornitza Stark reviewed gene: KCNC3: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Spinocerebellar ataxia 13, MIM#605259; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.0 KBTBD13 Zornitza Stark reviewed gene: KBTBD13: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Nemaline myopathy 6, autosomal dominant, MIM# 609273; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.0 KAT8 Zornitza Stark reviewed gene: KAT8: Rating: GREEN; Mode of pathogenicity: None; Publications: 31794431; Phenotypes: Intellectual disability, seizures, autism, dysmorphic features; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.0 JAK3 Zornitza Stark reviewed gene: JAK3: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.0 JAGN1 Zornitza Stark reviewed gene: JAGN1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Neutropenia, severe congenital, 6, autosomal recessive 616022; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.0 JAG1 Zornitza Stark reviewed gene: JAG1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Alagille syndrome; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.0 IRF6 Zornitza Stark reviewed gene: IRF6: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.0 IREB2 Zornitza Stark gene: IREB2 was added
gene: IREB2 was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: IREB2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: IREB2 were set to 30915432; 31243445; 11175792
Phenotypes for gene: IREB2 were set to Neurodegeneration, early-onset, with choreoathetoid movements and microcytic anemia, MIM#618451
Review for gene: IREB2 was set to GREEN
gene: IREB2 was marked as current diagnostic
Added comment: Two affected individuals from unrelated families with functional evidence including highly specific, concordant phenotype in mice.
Sources: Expert list
Intellectual disability v3.0 IQSEC3 Zornitza Stark gene: IQSEC3 was added
gene: IQSEC3 was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: IQSEC3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: IQSEC3 were set to 31130284
Phenotypes for gene: IQSEC3 were set to Intellectual disability
Review for gene: IQSEC3 was set to AMBER
Added comment: Two unrelated families, no functional data.
Sources: Expert list
Intellectual disability v3.0 IQSEC1 Zornitza Stark reviewed gene: IQSEC1: Rating: GREEN; Mode of pathogenicity: None; Publications: 31607425; Phenotypes: Intellectual developmental disorder with short stature and behavioral abnormalities, MIM# 618687; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability v3.0 SCN4A Zornitza Stark reviewed gene: SCN4A: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Hyperkalemic periodic paralysis, type 2, MIM# 170500, Hypokalemic periodic paralysis, type 2, MIM# 613345, Myasthenic syndrome, congenital, 16, MIM# 614198, Myotonia congenita, atypical, acetazolamide-responsive 608390, Paramyotonia congenita 168300; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.0 INPPL1 Zornitza Stark reviewed gene: INPPL1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Opsismodysplasia, MIM# 258480; Mode of inheritance: None
Intellectual disability v3.0 IMPAD1 Zornitza Stark reviewed gene: IMPAD1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Chondrodysplasia with joint dislocations, GPAPP type, MIM# 614078; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.0 IL11RA Zornitza Stark reviewed gene: IL11RA: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Craniosynostosis and dental anomalies, MIM# 614188; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.0 IHH Zornitza Stark reviewed gene: IHH: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Acrocapitofemoral dysplasia, MIM# 607778, Brachydactyly, type A1, MIM# 112500; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.0 IGF2 Zornitza Stark reviewed gene: IGF2: Rating: RED; Mode of pathogenicity: None; Publications: 31544945, 26154720; Phenotypes: Growth restriction, severe, with distinctive facies, MIM#616489; Mode of inheritance: None
Intellectual disability v3.0 IFT80 Zornitza Stark reviewed gene: IFT80: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.0 IFT27 Zornitza Stark gene: IFT27 was added
gene: IFT27 was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: IFT27 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: IFT27 were set to 24488770; 30761183
Phenotypes for gene: IFT27 were set to Bardet-Biedl syndrome 19, MIM#615996
Review for gene: IFT27 was set to AMBER
Added comment: Two families with functional evidence.
Sources: Expert list
Intellectual disability v3.0 IFT122 Zornitza Stark reviewed gene: IFT122: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.0 IFITM5 Zornitza Stark reviewed gene: IFITM5: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.0 HYLS1 Zornitza Stark reviewed gene: HYLS1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Hydrolethalus syndrome, MIM#236680; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.0 HYDIN Zornitza Stark reviewed gene: HYDIN: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.0 HYAL1 Zornitza Stark reviewed gene: HYAL1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.0 HSPG2 Zornitza Stark reviewed gene: HSPG2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Schwartz-Jampel syndrome, type 1, MIM#255800; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.0 HSF4 Zornitza Stark reviewed gene: HSF4: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.0 HSD3B7 Zornitza Stark reviewed gene: HSD3B7: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.0 HR Zornitza Stark reviewed gene: HR: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.0 HPSE2 Zornitza Stark reviewed gene: HPSE2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.0 HPS1 Zornitza Stark reviewed gene: HPS1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.0 HPGD Zornitza Stark reviewed gene: HPGD: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.0 HOXD13 Zornitza Stark reviewed gene: HOXD13: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.0 HOXC13 Zornitza Stark reviewed gene: HOXC13: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.0 HOXA13 Zornitza Stark reviewed gene: HOXA13: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.0 HNMT Zornitza Stark gene: HNMT was added
gene: HNMT was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: HNMT was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HNMT were set to 26206890; 30744146
Phenotypes for gene: HNMT were set to Mental retardation, autosomal recessive 51, MIM#616739
Review for gene: HNMT was set to GREEN
Added comment: 7 individuals from two unrelated families, some functional evidence and other circumstantial evidence linking this gene to brain function. Borderline Amber/Green.
Sources: Expert list
Intellectual disability v3.0 HNF4A Zornitza Stark reviewed gene: HNF4A: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.0 HMGCS2 Zornitza Stark reviewed gene: HMGCS2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: HMG-CoA synthase-2 deficiency, MIM# 605911; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.0 HADHB Zornitza Stark gene: HADHB was added
gene: HADHB was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: HADHB was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: HADHB were set to Trifunctional protein deficiency, MIM#609015
Review for gene: HADHB was set to GREEN
gene: HADHB was marked as current diagnostic
Added comment: ID is part of the phenotype.
Sources: Expert list
Intellectual disability v3.0 HADH Zornitza Stark reviewed gene: HADH: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: 3-hydroxyacyl-CoA dehydrogenase deficiency, MIM#231530, Hyperinsulinemic hypoglycemia, familial, 4, MIM#609975; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.0 GUCY2C Zornitza Stark reviewed gene: GUCY2C: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.0 GRM6 Zornitza Stark reviewed gene: GRM6: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.0 GRIA1 Zornitza Stark reviewed gene: GRIA1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Intellectual disability v3.0 GRHL3 Zornitza Stark reviewed gene: GRHL3: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.0 GPSM2 Zornitza Stark reviewed gene: GPSM2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Chudley-McCullough syndrome, MIM#604213; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.0 GPR179 Zornitza Stark reviewed gene: GPR179: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.0 GPC4 Zornitza Stark gene: GPC4 was added
gene: GPC4 was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: GPC4 was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Publications for gene: GPC4 were set to 30982611
Phenotypes for gene: GPC4 were set to Keipert syndrome OMIM# 301026
Review for gene: GPC4 was set to GREEN
gene: GPC4 was marked as current diagnostic
Added comment: 10 individuals from 6 families reported, functional studies in mice. Mild to moderate ID part of the phenotype.
Sources: Expert list
Intellectual disability v3.0 GOT2 Zornitza Stark reviewed gene: GOT2: Rating: GREEN; Mode of pathogenicity: None; Publications: 31422819; Phenotypes: Epileptic encephalopathy, early infantile, 82, MIM# 618721; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability v3.0 GNE Zornitza Stark gene: GNE was added
gene: GNE was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: GNE was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: GNE were set to Sialuria, MIM#269921
Review for gene: GNE was set to GREEN
gene: GNE was marked as current diagnostic
Added comment: Metabolic disorder with varying degrees of ID being a feature.
Bi-allelic variants cause Nonaka myopathy, MIM#605820
Sources: Expert list
Intellectual disability v3.0 GNAI3 Zornitza Stark reviewed gene: GNAI3: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.0 HDAC4 Zornitza Stark reviewed gene: HDAC4: Rating: AMBER; Mode of pathogenicity: None; Publications: 24715439, 20691407, 31209962; Phenotypes: Brachydactyly mental retardation syndrome, Brachydactyly without intellectual disability; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.0 GLS Zornitza Stark gene: GLS was added
gene: GLS was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: GLS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GLS were set to 30970188
Phenotypes for gene: GLS were set to Global developmental delay, progressive ataxia, and elevated glutamine, MIM# 618412
Review for gene: GLS was set to GREEN
Added comment: Three unrelated individuals described with compound het variants, however, note one of these is a triplet expansion in the 5' UTR.
Sources: Expert list
Intellectual disability v3.0 GLMN Zornitza Stark reviewed gene: GLMN: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.0 GLE1 Zornitza Stark reviewed gene: GLE1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.0 GJB1 Zornitza Stark reviewed gene: GJB1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Charcot-Marie-Tooth neuropathy, X-linked dominant, 1, MIM#302800; Mode of inheritance: None
Intellectual disability v3.0 GJA8 Zornitza Stark reviewed gene: GJA8: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.0 GJA3 Zornitza Stark reviewed gene: GJA3: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.0 GJA1 Zornitza Stark reviewed gene: GJA1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Atrioventricular septal defect 3, MIM#600309, Craniometaphyseal dysplasia, autosomal recessive, MIM#218400, Erythrokeratodermia variabilis et progressiva 3, MIM#617525, Hypoplastic left heart syndrome 1, MIM#241550, Oculodentodigital dysplasia, MIM#164200, Oculodentodigital dysplasia, autosomal recessive, MIM#257850, Palmoplantar keratoderma with congenital alopecia, MIM#104100, Syndactyly, type III, MIM# 186100; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.0 GHR Zornitza Stark reviewed gene: GHR: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Growth hormone insensitivity, partial, MIM#604271, Laron dwarfism, MIM#262500; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.0 GDF6 Zornitza Stark reviewed gene: GDF6: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.0 GDF5 Zornitza Stark reviewed gene: GDF5: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.0 GBA2 Zornitza Stark reviewed gene: GBA2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Spastic paraplegia 46, autosomal recessive, MIM#614409; Mode of inheritance: None
Intellectual disability v3.0 GATA6 Zornitza Stark reviewed gene: GATA6: Rating: GREEN; Mode of pathogenicity: None; Publications: 22158542; Phenotypes: Pancreatic agenesis and congenital heart defects, MIM#600001; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.0 GATA4 Zornitza Stark reviewed gene: GATA4: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.0 GATA2 Zornitza Stark reviewed gene: GATA2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.0 GAS8 Zornitza Stark reviewed gene: GAS8: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.0 GALK1 Zornitza Stark reviewed gene: GALK1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.0 GAA Zornitza Stark reviewed gene: GAA: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.0 FZD6 Zornitza Stark reviewed gene: FZD6: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.0 FYCO1 Zornitza Stark reviewed gene: FYCO1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.0 FXN Zornitza Stark reviewed gene: FXN: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.0 FTL Zornitza Stark reviewed gene: FTL: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodegeneration with brain iron accumulation 3, MIM#606159, Hyperferritinemia-cataract syndrome, MIM#600886, L-ferritin deficiency, dominant and recessive, MIM#615604; Mode of inheritance: None
Intellectual disability v3.0 FRY Zornitza Stark reviewed gene: FRY: Rating: AMBER; Mode of pathogenicity: None; Publications: 31487712, 27457812, 21937992; Phenotypes: Intellectual disability; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.0 FOXN1 Zornitza Stark reviewed gene: FOXN1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.0 FOXF1 Zornitza Stark reviewed gene: FOXF1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.0 FOXE3 Zornitza Stark reviewed gene: FOXE3: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.0 FOXE1 Zornitza Stark reviewed gene: FOXE1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.0 FOXC2 Zornitza Stark reviewed gene: FOXC2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.0 FOXC1 Zornitza Stark reviewed gene: FOXC1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.0 FLVCR1 Zornitza Stark reviewed gene: FLVCR1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Ataxia, posterior column, with retinitis pigmentosa, MIM#609033; Mode of inheritance: None
Intellectual disability v3.0 FLT4 Zornitza Stark reviewed gene: FLT4: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.0 FLNB Zornitza Stark reviewed gene: FLNB: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.0 FKBP14 Zornitza Stark reviewed gene: FKBP14: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.0 FHL1 Zornitza Stark reviewed gene: FHL1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.0 FGFR1 Zornitza Stark edited their review of gene: FGFR1: Added comment: Gene causes several phenotypes but this specific phenotype caused by germline variants is associated with significant ID.; Changed publications: 23812909; Changed phenotypes: Hartsfield syndrome, MIM# 615465
Intellectual disability v3.0 TKFC Zornitza Stark gene: TKFC was added
gene: TKFC was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: TKFC was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TKFC were set to 32004446
Phenotypes for gene: TKFC were set to Developmental delay; cataracts; liver dysfunction
Review for gene: TKFC was set to AMBER
Added comment: Two unrelated individuals reported.
Sources: Expert list
Intellectual disability v3.0 RALGAPA1 Zornitza Stark gene: RALGAPA1 was added
gene: RALGAPA1 was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: RALGAPA1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RALGAPA1 were set to 32004447
Phenotypes for gene: RALGAPA1 were set to Intellectual disability; hypotonia; infantile spasms.
Review for gene: RALGAPA1 was set to GREEN
gene: RALGAPA1 was marked as current diagnostic
Added comment: Four unrelated individuals reported.
Sources: Expert list
Intellectual disability v3.0 FGF3 Zornitza Stark reviewed gene: FGF3: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Deafness, congenital with inner ear agenesis, microtia, and microdontia, MIM#610706; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.0 FGF14 Zornitza Stark reviewed gene: FGF14: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Spinocerebellar ataxia 27, MIM# 609307; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Intellectual disability v3.0 FGF10 Zornitza Stark reviewed gene: FGF10: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.0 FDFT1 Zornitza Stark reviewed gene: FDFT1: Rating: GREEN; Mode of pathogenicity: None; Publications: 29909962; Phenotypes: Squalene synthase deficiency, MIM#618156; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability v3.0 FBXW4 Zornitza Stark reviewed gene: FBXW4: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.0 FBP1 Zornitza Stark reviewed gene: FBP1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.0 FBN1 Zornitza Stark reviewed gene: FBN1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.0 FARSB Zornitza Stark gene: FARSB was added
gene: FARSB was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: FARSB was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FARSB were set to 29573043; 1916114; 29979980; 30014610
Phenotypes for gene: FARSB were set to Rajab syndrome, MIM#613658; interstitial lung disease; brain calcifications; microcephaly; intellectual disability
Review for gene: FARSB was set to GREEN
gene: FARSB was marked as current diagnostic
Added comment: 7 unrelated families reported.
Sources: Expert list
Intellectual disability v3.0 FAR1 Zornitza Stark reviewed gene: FAR1: Rating: AMBER; Mode of pathogenicity: None; Publications: 25439727; Phenotypes: Peroxisomal fatty acyl-CoA reductase 1 disorder, MIM#616154; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.0 FAM20A Zornitza Stark reviewed gene: FAM20A: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.0 FAM161A Zornitza Stark reviewed gene: FAM161A: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.0 FAAH2 Zornitza Stark reviewed gene: FAAH2: Rating: RED; Mode of pathogenicity: None; Publications: 25885783; Phenotypes: Neuropsychiatric disorder; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability v3.0 FA2H Zornitza Stark reviewed gene: FA2H: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.0 EYA1 Zornitza Stark reviewed gene: EYA1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.0 EXT2 Zornitza Stark reviewed gene: EXT2: Rating: GREEN; Mode of pathogenicity: Other; Publications: ; Phenotypes: Seizures, scoliosis, and macrocephaly syndrome, MIM#616682; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability v3.0 EXOSC8 Zornitza Stark gene: EXOSC8 was added
gene: EXOSC8 was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: EXOSC8 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EXOSC8 were set to 24989451; 29656927
Phenotypes for gene: EXOSC8 were set to Pontocerebellar hypoplasia, type 1C, MIM#616081
Review for gene: EXOSC8 was set to GREEN
gene: EXOSC8 was marked as current diagnostic
Added comment: Complex neurological phenotype includes ID.
Sources: Expert list
Intellectual disability v3.0 EVC2 Zornitza Stark reviewed gene: EVC2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Ellis-van Creveld syndrome, MIM#225500; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.0 EVC Zornitza Stark reviewed gene: EVC: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Ellis-van Creveld syndrome, MIM#225500; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.0 ERMARD Zornitza Stark reviewed gene: ERMARD: Rating: RED; Mode of pathogenicity: None; Publications: 24056535, 27087860; Phenotypes: Periventricular nodular heterotopia 6, MIM#615544; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.0 ERF Zornitza Stark reviewed gene: ERF: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Chitayat syndrome, MIM#617180, Craniosynostosis 4, MIM#600775; Mode of inheritance: None
Intellectual disability v3.0 ERCC4 Zornitza Stark reviewed gene: ERCC4: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Xeroderma pigmentosum, group F, MIM#278760, XFE progeroid syndrome, MIM# 610965; Mode of inheritance: None
Intellectual disability v3.0 EOGT Zornitza Stark reviewed gene: EOGT: Rating: RED; Mode of pathogenicity: None; Publications: 31368252; Phenotypes: Adams-Oliver syndrome 4, MIM#615297; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.0 ENPP1 Zornitza Stark reviewed gene: ENPP1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.0 ELN Zornitza Stark reviewed gene: ELN: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Supravalvar aortic stenosis; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.0 EIF2A Zornitza Stark gene: EIF2A was added
gene: EIF2A was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: EIF2A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EIF2A were set to 31130284
Phenotypes for gene: EIF2A were set to Intellectual disability; epilepsy
Review for gene: EIF2A was set to AMBER
Added comment: Two unrelated families reported, no functional data.
Sources: Expert list
Intellectual disability v3.0 ATAD3A Zornitza Stark reviewed gene: ATAD3A: Rating: GREEN; Mode of pathogenicity: None; Publications: 32004445; Phenotypes: Harel-Yoon syndrome 617183; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Intellectual disability v3.0 EDNRA Zornitza Stark reviewed gene: EDNRA: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Mandibulofacial dysostosis with alopecia, MIM# 616367; Mode of inheritance: None
Intellectual disability v3.0 EDA Zornitza Stark reviewed gene: EDA: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.0 ECEL1 Zornitza Stark reviewed gene: ECEL1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.0 EARS2 Zornitza Stark gene: EARS2 was added
gene: EARS2 was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: EARS2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EARS2 were set to 22492562
Phenotypes for gene: EARS2 were set to Combined oxidative phosphorylation deficiency 12, MIM#614924
Review for gene: EARS2 was set to GREEN
gene: EARS2 was marked as current diagnostic
Added comment: ID is part of the phenotype, particularly in those severely affected.
Sources: Expert list
Intellectual disability v3.0 DYNC2H1 Zornitza Stark reviewed gene: DYNC2H1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Short-rib thoracic dysplasia 3 with or without polydactyly, MIM#613091; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.0 DVL1 Zornitza Stark reviewed gene: DVL1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Robinow syndrome, autosomal dominant 2 616331; Mode of inheritance: None
Intellectual disability v3.0 DSTYK Zornitza Stark reviewed gene: DSTYK: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.0 DSPP Zornitza Stark reviewed gene: DSPP: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.0 DPM3 Zornitza Stark reviewed gene: DPM3: Rating: RED; Mode of pathogenicity: None; Publications: 19576565, 28803818, 30931530, 31469168; Phenotypes: Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 15 612937; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.0 DNM1L Zornitza Stark gene: DNM1L was added
gene: DNM1L was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: DNM1L was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Phenotypes for gene: DNM1L were set to Encephalopathy, lethal, due to defective mitochondrial peroxisomal fission 1, MIM#614388
Mode of pathogenicity for gene: DNM1L was set to Other
Review for gene: DNM1L was set to GREEN
gene: DNM1L was marked as current diagnostic
Added comment: Dominant and recessive disease described depending on domain affected; dominant negative effect of heterozygous missense variants. LoF/LoF or LoF/missense for AR variants.
Sources: Expert list
Intellectual disability v3.0 DNAAF4 Zornitza Stark reviewed gene: DNAAF4: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.0 DNAAF3 Zornitza Stark reviewed gene: DNAAF3: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.0 DMP1 Zornitza Stark reviewed gene: DMP1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.0 DLL4 Zornitza Stark reviewed gene: DLL4: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.0 DLL3 Zornitza Stark reviewed gene: DLL3: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.0 DLL1 Zornitza Stark reviewed gene: DLL1: Rating: GREEN; Mode of pathogenicity: None; Publications: 31353024; Phenotypes: Intellectual disability, autism, seizures, variable brain abnormalities, scoliosis; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Intellectual disability v3.0 DENND5A Zornitza Stark reviewed gene: DENND5A: Rating: GREEN; Mode of pathogenicity: None; Publications: 27431290, 27866705; Phenotypes: Epileptic encephalopathy, early infantile, 49 617281; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.0 DDOST Zornitza Stark changed review comment from: Single family reported with supportive functional data, Amber at best.; to: Single family reported with supportive functional data, gene is RED on CDG panel.
Intellectual disability v3.0 DDOST Zornitza Stark reviewed gene: DDOST: Rating: RED; Mode of pathogenicity: None; Publications: 22305527; Phenotypes: Congenital disorder of glycosylation, type Ir, MIM# 614507; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.0 DDB2 Zornitza Stark reviewed gene: DDB2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.0 DCC Zornitza Stark reviewed gene: DCC: Rating: RED; Mode of pathogenicity: None; Publications: 31697046; Phenotypes: Agenesis of the corpus callosum; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.0 CYP7B1 Zornitza Stark reviewed gene: CYP7B1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Spastic paraplegia 5A, autosomal recessive, MIM# 270800; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.0 CYP2U1 Zornitza Stark reviewed gene: CYP2U1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Spastic paraplegia 56, autosomal recessive, MIM#615030; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.0 CYP1B1 Zornitza Stark reviewed gene: CYP1B1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.0 CTU2 Zornitza Stark gene: CTU2 was added
gene: CTU2 was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: CTU2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CTU2 were set to 27480277; 26633546
Phenotypes for gene: CTU2 were set to Microcephaly, facial dysmorphism, renal agenesis, and ambiguous genitalia syndrome, MIM#618142
Review for gene: CTU2 was set to GREEN
Added comment: Multiple Saudi families reported with same homozygous variant; founder effect. Severe disorder of infancy.
Sources: Expert list
Intellectual disability v3.0 CTSK Zornitza Stark reviewed gene: CTSK: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.0 CTSF Zornitza Stark reviewed gene: CTSF: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Ceroid lipofuscinosis, neuronal, 13, Kufs type, MIM#615362; Mode of inheritance: None
Intellectual disability v3.0 CTNS Zornitza Stark reviewed gene: CTNS: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.0 CRYGD Zornitza Stark Deleted their comment
Intellectual disability v3.0 CRYGD Zornitza Stark commented on gene: CRYGD: ID is not part of the phenotype.
Intellectual disability v3.0 CRYGD Zornitza Stark reviewed gene: CRYGD: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.0 CRYBB3 Zornitza Stark reviewed gene: CRYBB3: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.0 CRYBB2 Zornitza Stark reviewed gene: CRYBB2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.0 CRYBB1 Zornitza Stark reviewed gene: CRYBB1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.0 CRYBA1 Zornitza Stark reviewed gene: CRYBA1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.0 CRYAA Zornitza Stark reviewed gene: CRYAA: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.0 CRX Zornitza Stark reviewed gene: CRX: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.0 CRB1 Zornitza Stark commented on gene: CRB1
Intellectual disability v3.0 COMP Zornitza Stark reviewed gene: COMP: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.0 COL9A3 Zornitza Stark reviewed gene: COL9A3: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.0 COL9A2 Zornitza Stark reviewed gene: COL9A2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.0 COL9A1 Zornitza Stark reviewed gene: COL9A1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.0 COL6A1 Zornitza Stark reviewed gene: COL6A1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.0 COL4A4 Zornitza Stark reviewed gene: COL4A4: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.0 COL4A3 Zornitza Stark reviewed gene: COL4A3: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.0 COL2A1 Zornitza Stark reviewed gene: COL2A1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.0 COL1A1 Zornitza Stark reviewed gene: COL1A1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.0 COL18A1 Zornitza Stark reviewed gene: COL18A1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Knobloch syndrome, type 1, MIM#267750; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.0 COL11A1 Zornitza Stark reviewed gene: COL11A1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Stickler syndrome, type II, MIM# 604841; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.0 COL10A1 Zornitza Stark reviewed gene: COL10A1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Metaphyseal chondrodysplasia, Schmid type, MIM# 156500; Mode of inheritance: None
Intellectual disability v3.0 CNTNAP1 Zornitza Stark gene: CNTNAP1 was added
gene: CNTNAP1 was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: CNTNAP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CNTNAP1 were set to 28374019; 29511323; 27668699
Phenotypes for gene: CNTNAP1 were set to Hypomyelinating neuropathy, congenital, 3, MIM#618186; Lethal congenital contracture syndrome 7, MIM# 616286
Review for gene: CNTNAP1 was set to GREEN
gene: CNTNAP1 was marked as current diagnostic
Added comment: Multiple affected individuals reported; ID is part of the phenotype.
Sources: Expert list
Intellectual disability v3.0 CLDN19 Zornitza Stark reviewed gene: CLDN19: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Hypomagnesemia 5, renal, with ocular involvement, MIM# 248190; Mode of inheritance: None
Intellectual disability v3.0 CLCN7 Zornitza Stark reviewed gene: CLCN7: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Osteopetrosis; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.0 CIB2 Zornitza Stark reviewed gene: CIB2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Deafness, autosomal recessive 48, MIM# 609439, Usher syndrome; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.0 CHUK Zornitza Stark reviewed gene: CHUK: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Cocoon syndrome, MIM# 613630; Mode of inheritance: None
Intellectual disability v3.0 CHSY1 Zornitza Stark reviewed gene: CHSY1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Temtamy preaxial brachydactyly syndrome 605282; Mode of inheritance: None
Intellectual disability v3.0 CHST3 Zornitza Stark reviewed gene: CHST3: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Spondyloepiphyseal dysplasia with congenital joint dislocations, MIM# 143095; Mode of inheritance: None
Intellectual disability v3.0 CHRNG Zornitza Stark reviewed gene: CHRNG: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Escobar syndrome, MIM# 265000, Multiple pterygium syndrome, lethal type, MIM# 253290; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.0 CHRDL1 Zornitza Stark reviewed gene: CHRDL1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Megalocornea 1, X-linked, MIM# 309300; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability v3.0 CHM Zornitza Stark reviewed gene: CHM: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Choroideremia, MIM# 303100; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Intellectual disability v3.0 CHD1 Zornitza Stark gene: CHD1 was added
gene: CHD1 was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: CHD1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CHD1 were set to 28866611
Phenotypes for gene: CHD1 were set to Pilarowski-Bjornsson syndrome, MIM#617682
Mode of pathogenicity for gene: CHD1 was set to Other
Review for gene: CHD1 was set to GREEN
gene: CHD1 was marked as current diagnostic
Added comment: Six unrelated individuals with heterozygous variants reported. Possible dominant negative mechanism: reported variants are missense, and an individual with a deletion did not have a neurological phenotype.
Sources: Expert list
Intellectual disability v3.0 CEP104 Zornitza Stark reviewed gene: CEP104: Rating: GREEN; Mode of pathogenicity: None; Publications: 26477546; Phenotypes: Joubert syndrome 25, MIM# 616781; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.0 CDH3 Zornitza Stark reviewed gene: CDH3: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Ectodermal dysplasia, ectrodactyly, and macular dystrophy 225280, Hypotrichosis, congenital, with juvenile macular dystrophy 601553; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.0 CDH23 Zornitza Stark reviewed gene: CDH23: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Deafness, Usher syndrome; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.0 CDH2 Zornitza Stark reviewed gene: CDH2: Rating: GREEN; Mode of pathogenicity: None; Publications: 31585109; Phenotypes: Intellectual disability, corpus callosum abnormalities, congenital abnormalities; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Intellectual disability v3.0 CCT5 Zornitza Stark reviewed gene: CCT5: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Neuropathy, hereditary sensory, with spastic paraplegia, MIM# 256840; Mode of inheritance: None
Intellectual disability v3.0 CCNO Zornitza Stark reviewed gene: CCNO: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Ciliary dyskinesia, primary, 29, MIM# 615872; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.0 CCDC88A Zornitza Stark edited their review of gene: CCDC88A: Added comment: Two unrelated families now plus mouse model.; Changed publications: 26917597, 30392057; Set current diagnostic: yes
Intellectual disability v3.0 CCDC65 Zornitza Stark reviewed gene: CCDC65: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Ciliary dyskinesia, primary, 27, MIM# 615504; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.0 CCDC40 Zornitza Stark reviewed gene: CCDC40: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Ciliary dyskinesia, primary, 15, MIM# 613808; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.0 CCDC114 Zornitza Stark reviewed gene: CCDC114: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Ciliary dyskinesia, primary, 20, MIM# 615067; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.0 CCDC103 Zornitza Stark reviewed gene: CCDC103: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Ciliary dyskinesia, primary, 17, MIM# 614679; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.0 CARS2 Zornitza Stark reviewed gene: CARS2: Rating: GREEN; Mode of pathogenicity: None; Publications: 30139652; Phenotypes: Combined oxidative phosphorylation deficiency 27, MIM#616672; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.0 EBP Zornitza Stark reviewed gene: EBP: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Chondrodysplasia punctata, X-linked dominant MIM#302960, Conradi-Hunermann syndrome, MEND syndrome, MIM#300960; 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 v3.0 SCN4A Andrea Haworth commented on gene: SCN4A
Intellectual disability v3.0 CACNA2D2 Zornitza Stark reviewed gene: CACNA2D2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Cerebellar atrophy with seizures and variable developmental delay, MIM#618501; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability v3.0 CA5A Zornitza Stark reviewed gene: CA5A: Rating: RED; Mode of pathogenicity: None; Publications: 26913920; Phenotypes: Hyperammonemia due to carbonic anhydrase VA deficiency, MIM# 615751; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.0 C8orf37 Zornitza Stark changed review comment from: Two unrelated individuals reported with BBS; note gene has an association with retinal ciliopathies.; to: Two unrelated individuals reported with BBS; note gene has an association with retinal ciliopathies. Suggested rating Amber.
Intellectual disability v3.0 C8orf37 Zornitza Stark reviewed gene: C8orf37: Rating: ; Mode of pathogenicity: None; Publications: 26854863, 27008867; Phenotypes: Bardet-Biedl syndrome 21, MIM#617406; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.0 C4orf26 Zornitza Stark reviewed gene: C4orf26: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Amelogenesis imperfecta, type IIA4, MIM# 614832; Mode of inheritance: None
Intellectual disability v3.0 C2orf71 Zornitza Stark reviewed gene: C2orf71: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Retinitis pigmentosa 54 613428; Mode of inheritance: None
Intellectual disability v3.0 C2CD3 Zornitza Stark reviewed gene: C2CD3: Rating: GREEN; Mode of pathogenicity: None; Publications: 30097616, 27094867, 26477546, 24997988,; Phenotypes: Orofaciodigital syndrome XIV, MIM# 615948; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability v3.0 C19orf12 Zornitza Stark reviewed gene: C19orf12: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodegeneration with brain iron accumulation 4, MIM#614298; Mode of inheritance: None
Intellectual disability v3.0 BMPR1B Zornitza Stark reviewed gene: BMPR1B: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Acromesomelic dysplasia, Demirhan type MIM#609441, Brachydactyly, type A1, D, MIM#616849, Brachydactyly, type A2, MIM# 112600; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.0 BMPER Zornitza Stark reviewed gene: BMPER: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Diaphanospondylodysostosis, MIM# 608022; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.0 BICD2 Zornitza Stark reviewed gene: BICD2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Spinal muscular atrophy, lower extremity-predominant, 2A, autosomal dominant, MIM#615290; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.0 BHLHA9 Zornitza Stark reviewed gene: BHLHA9: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Syndactyly, mesoaxial synostotic, with phalangeal reduction, MIM# 609432; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.0 BGN Zornitza Stark reviewed gene: BGN: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Meester-Loeys syndrome, MIM# 300989, Spondyloepimetaphyseal dysplasia, X-linked, MIM#300106; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability v3.0 BFSP2 Zornitza Stark reviewed gene: BFSP2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Cataract 12, multiple types, MIM# 611597; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.0 BCORL1 Zornitza Stark reviewed gene: BCORL1: Rating: GREEN; Mode of pathogenicity: None; Publications: 24123876, 30941876; Phenotypes: Shukla-Vernon syndrome, MIM# 301029; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females; Current diagnostic: yes
Intellectual disability v3.0 B9D2 Zornitza Stark gene: B9D2 was added
gene: B9D2 was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: B9D2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: B9D2 were set to 26092869; 21763481
Phenotypes for gene: B9D2 were set to Joubert syndrome 34, MIM#614175; Meckel syndrome 10, MIM#614175
Review for gene: B9D2 was set to GREEN
gene: B9D2 was marked as current diagnostic
Added comment: Two unrelated individuals with Joubert syndrome and bi-allelic variants reported; single family with two affected individuals also reported with homozygous variant in this gene and more severe Meckel phenotype, overall supporting gene-disease association for a ciliopathy with CNS involvement. ID is part of the phenotype of these conditions.
Sources: Expert list
Intellectual disability v3.0 B9D1 Zornitza Stark reviewed gene: B9D1: Rating: GREEN; Mode of pathogenicity: None; Publications: 24886560, 21493627; Phenotypes: Joubert syndrome 27, MIM#617120, Meckel syndrome 9, MIM#614209; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability v3.0 ATP8B1 Zornitza Stark reviewed gene: ATP8B1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Cholestasis, benign recurrent intrahepatic, MIM# 243300, Cholestasis, intrahepatic, of pregnancy, 1, MIM#147480, Cholestasis, progressive familial intrahepatic 1, MIM# 211600; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.0 ATP6V1B1 Zornitza Stark reviewed gene: ATP6V1B1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Renal tubular acidosis with deafness 267300; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.0 ATP6AP1 Zornitza Stark gene: ATP6AP1 was added
gene: ATP6AP1 was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: ATP6AP1 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: ATP6AP1 were set to 27231034
Phenotypes for gene: ATP6AP1 were set to Immunodeficiency 47, MIM#300972
Review for gene: ATP6AP1 was set to GREEN
gene: ATP6AP1 was marked as current diagnostic
Added comment: 11 males from 6 unrelated families with primarily an immunodeficiency disorder; six patients from 3 families who carried the same variant (E346K) had neurologic features, including seizures, mild intellectual disability, and behavioral abnormalities
Sources: Expert list
Intellectual disability v3.0 ATP1A2 Zornitza Stark reviewed gene: ATP1A2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Alternating hemiplegia of childhood 1, MIM# 104290; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Intellectual disability v3.0 ATAD1 Zornitza Stark gene: ATAD1 was added
gene: ATAD1 was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: ATAD1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ATAD1 were set to 28180185
Phenotypes for gene: ATAD1 were set to Hyperekplexia 4, MIM#618011
Review for gene: ATAD1 was set to GREEN
Added comment: Severe progressive neurological disorder, severe/profound intellectual disability is a feature
Sources: Expert list
Intellectual disability v3.0 ASTN1 Zornitza Stark gene: ASTN1 was added
gene: ASTN1 was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: ASTN1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ASTN1 were set to 29706646; 27431290; 26539891
Phenotypes for gene: ASTN1 were set to Intellectual disability
Review for gene: ASTN1 was set to GREEN
gene: ASTN1 was marked as current diagnostic
Added comment: Three families reported as part of large cohorts albeit proposing multiple novel candidate genes with minimal detail and no functional validation.
Sources: Expert list
Intellectual disability v3.0 ARHGEF6 Zornitza Stark reviewed gene: ARHGEF6: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: MENTAL RETARDATION X-LINKED TYPE 46; Mode of inheritance: None
Intellectual disability v3.0 ANKH Zornitza Stark reviewed gene: ANKH: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Craniometaphyseal dysplasia, MIM#123000; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.0 ALG9 Zornitza Stark reviewed gene: ALG9: Rating: GREEN; Mode of pathogenicity: None; Publications: 28932688; Phenotypes: Congenital disorder of glycosylation, type Il, MIM#608776; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.0 ALG14 Zornitza Stark gene: ALG14 was added
gene: ALG14 was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: ALG14 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ALG14 were set to 30221345; 23404334; 28733338
Phenotypes for gene: ALG14 were set to Myasthenic syndrome, congenital, 15, without tubular aggregates, MIM#616227; Intellectual disability
Review for gene: ALG14 was set to GREEN
gene: ALG14 was marked as current diagnostic
Added comment: 5 individuals from unrelated families described in the literature: one with myasthenic syndrome, no report of ID; second with predominantly ID phenotype; and three more with a neurodegenerative phenotype.
Sources: Expert list
Intellectual disability v3.0 ALDOB Zornitza Stark changed review comment from: Metabolic decompensation on exposure to fructose, including hypoglycaemia, but ID is not an intrinsic feature of this condition.; to: Metabolic decompensation on exposure to fructose, including hypoglycaemia, but ID is not an intrinsic feature of this condition. ID only reported in the absence of treatment.
Intellectual disability v3.0 ALDOB Zornitza Stark reviewed gene: ALDOB: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Fructose intolerance, hereditary, MIM# 229600; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.0 AHCY Zornitza Stark reviewed gene: AHCY: Rating: ; Mode of pathogenicity: None; Publications: 31957987, 27671891, 30121674, 28779239; Phenotypes: Hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase, MIM#613752; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.0 AGPS Zornitza Stark reviewed gene: AGPS: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Rhizomelic chondrodysplasia punctata, type 3, MIM#600121; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.0 AGMO Zornitza Stark gene: AGMO was added
gene: AGMO was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: AGMO was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AGMO were set to 31555905
Phenotypes for gene: AGMO were set to microcephaly; intellectual disability; epilepsy
Review for gene: AGMO was set to GREEN
gene: AGMO was marked as current diagnostic
Added comment: Three unrelated families and functional data.
Sources: Expert list
Intellectual disability v3.0 AGL Zornitza Stark reviewed gene: AGL: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Glycogen storage disease IIIa, MIM# 232400; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.0 AFG3L2 Zornitza Stark reviewed gene: AFG3L2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Spastic ataxia 5, autosomal recessive, MIM#614487; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.0 ADGRG6 Zornitza Stark reviewed gene: ADGRG6: Rating: RED; Mode of pathogenicity: None; Publications: 30549416; Phenotypes: Lethal congenital contracture syndrome 9, OMIM #616503; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.0 ADD3 Zornitza Stark gene: ADD3 was added
gene: ADD3 was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: ADD3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ADD3 were set to 29768408; 23836506
Phenotypes for gene: ADD3 were set to Cerebral palsy, spastic quadriplegic, 3, MIM#617008
Review for gene: ADD3 was set to GREEN
gene: ADD3 was marked as current diagnostic
Added comment: Four families reported in the literature with bi-allelic variants in this gene causing intellectual disability.
Sources: Expert list
Intellectual disability v3.0 ADCY5 Zornitza Stark reviewed gene: ADCY5: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Dyskinesia, familial, with facial myokymia, MIM#606703; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.0 ADAMTS10 Zornitza Stark gene: ADAMTS10 was added
gene: ADAMTS10 was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: ADAMTS10 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: ADAMTS10 were set to Weill-Marchesani syndrome 1, recessive, MIM#277600
Review for gene: ADAMTS10 was set to AMBER
Added comment: Mild intellectual disability is described in around 10% of affected individuals.
Sources: Expert list
Intellectual disability v3.0 ACADSB Zornitza Stark reviewed gene: ACADSB: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: 2-methylbutyrylglycinuria, MIM# 610006; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.0 ABCC6 Zornitza Stark reviewed gene: ABCC6: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Arterial calcification, generalized, of infancy, 2, MIM#614473, Pseudoxanthoma elasticum, MIM#264800; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.0 ABAT Zornitza Stark reviewed gene: ABAT: Rating: GREEN; Mode of pathogenicity: None; Publications: 10407778, 20052547, 27596361, 28411234,; Phenotypes: GABA-transaminase deficiency, MIM#613163; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability v3.0 ZSWIM6 Louise Daugherty commented on gene: ZSWIM6
Intellectual disability v3.0 ZSWIM6 Louise Daugherty Tag watchlist was removed from gene: ZSWIM6.
Intellectual disability v3.0 UFM1 Louise Daugherty Tag watchlist was removed from gene: UFM1.
Intellectual disability v3.0 TRMT1 Louise Daugherty Tag watchlist was removed from gene: TRMT1.
Intellectual disability v3.0 TRMT1 Louise Daugherty commented on gene: TRMT1
Intellectual disability v3.0 TRAF7 Louise Daugherty Tag watchlist was removed from gene: TRAF7.
Intellectual disability v3.0 TRAF7 Louise Daugherty commented on gene: TRAF7
Intellectual disability v3.0 TCF20 Louise Daugherty edited their review of gene: TCF20: Changed rating: GREEN
Intellectual disability v3.0 TCF20 Louise Daugherty Tag watchlist was removed from gene: TCF20.
Intellectual disability v3.0 TCF20 Louise Daugherty commented on gene: TCF20: As a result of watchlist tag audit the watchlist tag was removed from TCF20 this is now a green gene with sufficient evidence/review
Intellectual disability v3.0 SYNJ1 Louise Daugherty Tag watchlist was removed from gene: SYNJ1.
Intellectual disability v3.0 SYNJ1 Louise Daugherty commented on gene: SYNJ1
Intellectual disability v3.0 SLC6A9 Louise Daugherty edited their review of gene: SLC6A9: Changed rating: GREEN
Intellectual disability v3.0 SLC6A9 Louise Daugherty Tag watchlist was removed from gene: SLC6A9.
Intellectual disability v3.0 SLC6A9 Louise Daugherty commented on gene: SLC6A9: As a result of watchlist tag audit the watchlist tag was removed from SLC6A9- this is now a green gene with sufficient evidence/review
Intellectual disability v3.0 SETD1B Louise Daugherty Tag watchlist was removed from gene: SETD1B.
Intellectual disability v3.0 SETD1B Louise Daugherty commented on gene: SETD1B: As a result of watchlist tag audit the watchlist tag was removed from SETD1B- this is now a green gene with sufficient evidence/review
Intellectual disability v3.0 RLIM Louise Daugherty commented on gene: RLIM: As a result of watchlist tag audit the watchlist tag was removed from RLIM- this is now a green gene with sufficient evidence/review
Intellectual disability v3.0 RLIM Louise Daugherty Tag watchlist was removed from gene: RLIM.
Intellectual disability v3.0 MSL3 Louise Daugherty commented on gene: MSL3: As a result of watchlist tag audit the watchlist tag was removed from MSL3- this is now a green gene with sufficient evidence/review
Intellectual disability v3.0 MSL3 Louise Daugherty Tag watchlist was removed from gene: MSL3.
Intellectual disability v3.0 MSL3 Louise Daugherty commented on gene: MSL3: As a result of watchlist tag audit the watchlist tag was removed from MSL3- this is now a green gene with sufficient evidence/review
Intellectual disability v3.0 MED25 Louise Daugherty Tag watchlist was removed from gene: MED25.
Intellectual disability v3.0 MED25 Louise Daugherty commented on gene: MED25: As a result of watchlist tag audit the watchlist tag was removed from MED25- this is now a green gene with sufficient evidence/review
Intellectual disability v3.0 KDM1A Louise Daugherty Tag watchlist was removed from gene: KDM1A.
Intellectual disability v3.0 KDM1A Louise Daugherty commented on gene: KDM1A: As a result of watchlist tag audit the watchlist tag was removed from KDM1A- this is now a green gene with sufficient evidence/review
Intellectual disability v3.0 GRIA2 Louise Daugherty Tag watchlist was removed from gene: GRIA2.
Intellectual disability v3.0 GRIA2 Louise Daugherty commented on gene: GRIA2: As a result of watchlist tag audit the watchlist tag was removed from GRIA2- this is now a green gene with sufficient evidence/review
Intellectual disability v3.0 DLG4 Louise Daugherty Tag watchlist was removed from gene: DLG4.
Intellectual disability v3.0 DLG4 Louise Daugherty commented on gene: DLG4
Intellectual disability v3.0 CTDP1 Louise Daugherty Tag watchlist was removed from gene: CTDP1.
Intellectual disability v3.0 CTDP1 Louise Daugherty commented on gene: CTDP1
Intellectual disability v3.0 CSNK2A1 Louise Daugherty Tag watchlist was removed from gene: CSNK2A1.
Intellectual disability v3.0 CSNK2A1 Louise Daugherty commented on gene: CSNK2A1
Intellectual disability v3.0 CLCN4 Louise Daugherty Tag watchlist was removed from gene: CLCN4.
Intellectual disability v3.0 CLCN4 Louise Daugherty commented on gene: CLCN4
Intellectual disability v3.0 ALG11 Louise Daugherty Tag watchlist was removed from gene: ALG11.
Intellectual disability v3.0 ALG11 Louise Daugherty commented on gene: ALG11
Intellectual disability v3.0 VAMP1 Louise Daugherty Tag watchlist was removed from gene: VAMP1.
Intellectual disability v3.0 VAMP1 Louise Daugherty commented on gene: VAMP1: As a result of watchlist tag audit the watchlist tag was removed from VAMP1- this is now a green gene.
Intellectual disability v3.0 SUPT16H Konstantinos Varvagiannis gene: SUPT16H was added
gene: SUPT16H was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: SUPT16H was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SUPT16H were set to http://dx.doi.org/10.1136/jmedgenet-2019-106193
Phenotypes for gene: SUPT16H were set to Global developmental delay; Intellectual disability; Abnormality of the corpus callosum
Penetrance for gene: SUPT16H were set to Complete
Review for gene: SUPT16H was set to AMBER
Added comment: Bina et al (2020 - http://dx.doi.org/10.1136/jmedgenet-2019-106193) report on 4 unrelated individuals with heterozygous SNVs affecting SUPT16H as well as 1 further with microdeletion spanning this gene.

The phenotype consisted of DD with subsequent ID in a subset of them (ages of the cohort: 2y-14y), autistic features in few, abnormalities of the corpus callosum (for 3 with available MRI images), variable gastrointestinal problems in some, and possibly minor dysmorphic features.

SUPT16H encodes a subunit of the FACT (facilitates chromatin transcription) complex, a chromatin-specific factor required for transcription elongation as well as for DNA replication and repair (OMIM citing Belotserkovskaya et al. 2003 - PMID: 12934006). The 2 subunits of the complex [Spt16 (encoded by SUPT16H) and SSRP1] are essential for histone regulation. As the authors note, Spt16 interacts with the histone dimer H2A-H2B during transcription to allow RNA polymerase access to previously coiled DNA [cited PMIDs : 9489704, 10421373 / A recent study by Liu et al 2019 (PMID: 31775157) appears highly relevant].

SUPT16H has a Z-score of 5.1 in gnomAD and a pLI of 1 (%HI of 22.56 in Decipher).

SNVs :
4 de novo missense SNVs were identified following exome sequencing (NM_007192.3:c.484A>G or I162V / L432P / N571S / R734W), all absent from gnomAD and mostly predicted to be deleterious (I162V predicted benign, tolerated, disease-causing by PolyPhen2, SIFT, MutationTaster respectively and had a CADD score of 13.61). Prior work-up for these individuals (incl. CMA in some / MS-MLPA for Angelman s. in 1 / metabolic investigations) had (probably) not revealed an apparent cause, with small CNVs inherited from healthy parents (a 4q13.3 dup / 20q13.2 del - coordinates not provided).

There were no studies performed for the identified variants.

CNVs :
A 5th individual reported by Bina et al was found to harbor a 2.05 Mb 14q11.2 deletion spanning SUPT16H. The specific deletion also spanned CHD8 while the same individual harbored also a 30.17 Mb duplication of 18p11.32q12.1.

CNVs spanning SUPT16H reported to date, also span the (very) proximal CHD8. [Genomic coordinates (GRCh38) for SUPT16H and CHD8 as provided by OMIM : 14:21,351,471-21,384,018 / 14:21,385,198-21,456,122]. Haploinsufficiency of CHD8 is associated with a distinctive syndrome with overgrowth and ID (Douzgou et al 2019 - PMID: 31001818). The phenotype of SUPT16H-CHD8 duplications is discussed in other studies/reviews. [Smol et al 2020 - PMID: 31823155 / Smyk et al 2016 - PMID: 26834018].

Animal models were not commented on by Bina et al (possibly not available for mouse : http://www.informatics.jax.org/marker/MGI:1890948 / https://www.mousephenotype.org/data/genes/MGI:1890948 ).
Sources: Literature
Intellectual disability v3.0 TET3 Konstantinos Varvagiannis gene: TET3 was added
gene: TET3 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: TET3 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: TET3 were set to https://doi.org/10.1016/j.ajhg.2019.12.007
Phenotypes for gene: TET3 were set to Global developmental delay; Intellectual disability; Macrocephaly; Growth abnormality; Seizures; Autistic behavior; Abnormality of movement; Abnormality of the face
Penetrance for gene: TET3 were set to Complete
Review for gene: TET3 was set to GREEN
Added comment: Beck et al (2020 - DOI: https://doi.org/10.1016/j.ajhg.2019.12.007) report on individuals with monoallelic de novo or biallelic pathogenic TET3 variants.

For both inheritance modes (AR/AD) DD/ID were among the observed features (mild-severe - individuals from families 2, 4 and 6 for whom presence of ID was not commented, relevance to the current panel is suggested from the developmental milestones in the supplement. One individual presented DD without ID). Other features included hypotonia (in 8), ASD/autistic features (in 5), seizures (2 unrelated subjects for each inheritance mode). Postnatal growth abnormalities were observed in many, in most cases involving head size (with/without abnormal stature) and few presented abnormal prenatal growth. Variable movement disorders were observed in some. Some facial features appeared to be more common (eg. long face, tall forehead, etc).

Most were referred for their DD. Extensive prior genetic investigations had (mostly) come out normal (with possible contribution of a 16p11.2 dup in an individual with monoallelic variant or a 16q22 dup in another with biallelic TET3 variants). Monoallelic / biallelic variants in all subjects were identified following exome sequencing.

TET3 encodes a methylcytosine dioxygenase (the TET family consisting of 3 enzymes, TET1, TET2, TET3). These enzymes are involved in DNA demethylation through a series of reactions beginning with the conversion of 5-methyl cytosine [5mc] to 5-hydromethylcytosine [5hmC].

5 individuals from 3 families (1/3 consanguineous) harbored biallelic missense variants. 5 different missense variants were observed. Heterozygous parents appeared to be mildly affected (eg. having learning difficulties, etc).

6 individuals from 5 families harbored monoallelic variants [3 truncating (of which 2 localizing in the last exon), 2 missense SNVs]. In one family the variant was inherited from a similarly affected parent. In all other cases the variant had occured de novo. No additional TET3 variants were identified, with the limitations of WES.

All missense mutations, whether observed in individuals with biallelic or monoallelic variants, were located within the catalytic domain or - for a single variant (NM_001287491.1:c.2254C>T / p.Arg752Cys) - adjacent to it.

Functional studies were carried out only for (all) missense variants observed in individuals with biallelic variants. Conversion of 5mC to 5hmC is the first step in DNA demethylation. In HEK293 cells overexpressing either wt or variants, production of 5hmc was measured. 4/5 missense variants evaluated demonstrated a defect in converting 5mC to 5hmC, Arg752Cys being an exception (as also predicted by its localization).

DD/ID and abnormal growth are also features of disorders of the epigenetic machinery (DNA methylation machinery, histone machinery, chromatin remodelers, other chromatin-associated proteins). Similarly to TET3, both monoallelic and biallelic variants in KDM5B, encoding for another component of the epigenetic machinery, have been identified in individuals with ID.

Mouse models discussed by the authors [several Refs provided though not here reviewed] : The gene has been shown to be highly expressed in oocytes, zygotes and neurons and to play a role in demethylation of the paternal genome after fertilization. (From the MGI: 'mice inheriting a null allele from a germ cell conditional null mother display impaired reprogramming of the paternal genome resulting in reduced embryo viability'). Beck et al also note that Tet3 inhibition or depletion in differentiated neurons can impact synaptic function [PMIDs cited: 25915473, 24757058, 26711116].
Sources: Literature
Intellectual disability v3.0 PIGP Konstantinos Varvagiannis changed review comment from: Please consider upgrading this gene to Green.

A recent study Vetro et al. (2020 - https://doi.org/10.1212/NXG.0000000000000387) identified 4 additional affected individuals with severe EIEE, belonging to a large inbred family. Following extensive genetic investigations (all of which were non-diagnostic) these subjects were found to harbor in homozygosity the frameshift variant also reported in the 2 previous studies (NM_153681.2:c.456delA / p.Glu153AsnfsTer34 or NM_153682.2:c.384delA / p.Glu129AsnfsTer34). Reduced expression of the GPI-anchor protein CD16 was demonstrated in granulocytes of affected individuals.; to: Please consider upgrading this gene to Green.

In a recent study, Vetro et al. (2020 - https://doi.org/10.1212/NXG.0000000000000387) identified 4 additional affected individuals with severe EIEE, belonging to a large inbred family. Following extensive genetic investigations (all of which were non-diagnostic) these subjects were found to harbor in homozygosity the frameshift variant also reported in the 2 previous studies (NM_153681.2:c.456delA / p.Glu153AsnfsTer34 or NM_153682.2:c.384delA / p.Glu129AsnfsTer34). Reduced expression of the GPI-anchor protein CD16 was demonstrated in granulocytes of affected individuals.
Intellectual disability v3.0 PIGP Konstantinos Varvagiannis edited their review of gene: PIGP: Added comment: Please consider upgrading this gene to Green.

A recent study Vetro et al. (2020 - https://doi.org/10.1212/NXG.0000000000000387) identified 4 additional affected individuals with severe EIEE, belonging to a large inbred family. Following extensive genetic investigations (all of which were non-diagnostic) these subjects were found to harbor in homozygosity the frameshift variant also reported in the 2 previous studies (NM_153681.2:c.456delA / p.Glu153AsnfsTer34 or NM_153682.2:c.384delA / p.Glu129AsnfsTer34). Reduced expression of the GPI-anchor protein CD16 was demonstrated in granulocytes of affected individuals.; Changed publications: 28334793, 31139695, https://doi.org/10.1212/NXG.0000000000000387
Intellectual disability v3.0 ZNF292 Konstantinos Varvagiannis commented on gene: ZNF292: Correction to the phrase "Manual review of some relevant LoF variants in gnomAD suggested that they represent false positive calls":

Irrespective of the variants identified in their cohort, Mirzaa et al. reviewed many pLoF variants which are listed in gnomAD. The authors suggested that some of these variants may not represent true LoF variants.

Eg. NM_015021.3:c.2690C>A ( https://gnomad.broadinstitute.org/variant/6-87966037-C-A ) which appears to be a stopgain variant (Ser[TCA]>Ter[TAA]) is probably not a true LoF variant. It always occurred in cis (/the same reads) with NM_015021.3:c.2689T>C (Ser[TCA] to Pro[CCA]). This is visible in the IGV graph of gnomAD (url above).

Thus, gnomAD lists 2 single-nucleotide variants affecting the same codon, one next to the other. However, as the 2 SNVs always occurred in cis, this represents a single missense multi-nucleotide variant (Ser[TCA]>Gln[CAA]) [ NM_015021.3(ZNF292_v001):c.2689_2690delinsCA ].

Similar observations were made for other variants seen in gnomAD.
Intellectual disability v3.0 NUS1 Konstantinos Varvagiannis edited their review of gene: NUS1: Added comment: Please consider upgrading this gene (NUS1 is also rated Green in the epilepsy panel).

Den et al (2019 - PMID: 31656175) reported on 2 additional unrelated individuals (aged 17 and 59y) both presenting intellectual disability, epilepsy , involuntary movements, ataxia and scoliosis. Both were found to harbor the same splicing variant in NUS1 (NM_138459.4:c.691+1C>A) following exome sequencing. Using lymphoblastoid cell lines from both individuals it was demonstrated that the variant creates a new splice donor site in exon 3 further creating a new reading frame and producing a premature termination codon [c.601_691del or p.(Arg202Glnfs*9)]. Using cyclohexamide, it was further shown that the mutant mRNA is partially subjected to NMD. [Additional variants identified by exome for the 2 subjects were non diagnostic (/VUS). An SPTAN1 nonsense variant identified in one was inherited from an unaffected parent (dominant-negative mechanism listed in G2P for this gene / in ClinVar all pLoF variants are submitted as VUS)].
-----; Changed rating: GREEN; Changed publications: 25066056, 29100083, 24824130, 30348779, 31656175
Intellectual disability v3.0 RNF113A Konstantinos Varvagiannis reviewed gene: RNF113A: Rating: GREEN; Mode of pathogenicity: None; Publications: 25612912, 31880405, 31793730, 29133357, 30506991, 15256591, 24026126, 23555887; Phenotypes: ; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Intellectual disability v3.0 MTHFS Konstantinos Varvagiannis changed review comment from: Biallelic pathogenic MTHFS variants cause Neurodevelopmental disorder with microcephaly, epilepsy, and hypomyelination (# 618367).

The gene encodes 5,10-Methenyltetrahydrofolate synthetase which catalyzes conversion of 5-formyltetrahydrofolate (5-FTHF or folinic acid) to 5,10-methenyltetrahydrofolate (5,10-MTHF).

At least 3 unrelated individuals have been reported. The phenotype appears to be relevant to both epilepsy and ID gene panels and the role of variants/the gene supported by enzymatic activity studies, 5-FTHF accumulation, 5,10-MTHF levels (low/low-normal), the role of folate metabolism pathway overall and some supporting (metabolic) evidence from the mouse model.
---
Rodan et al (2018 - PMID: 30031689) reported on 2 individuals both presenting with microcephaly, severe global DD, epilepsy, progressive spasticity and cerebral hypomyelination upon MRI imaging. Short stature was also feature in both.

The 1st patient was an 8-year-old male who following exome sequencing was found to harbor 2 missense variants each inherited from a carrier parent. (NM_006441.3:c.434G>A / p.R145Q and c.107T>C / p.L36P). A further AFG3L2 indel was not felt to fit with his phenotype (and the onset of the related disorder appears to occur later).

Previous investigations included extensive metabolic testing, CMA, Angelman syndrome methylation analysis, GFAP, POLG1, TYMP sequencing, mitochondrial genome analysis and an XL-ID gene panel (further suggesting relevance of this gene to the current panel) were all non-diagnostic.

CSF 5-MTHF levels were initially on the low-normal range, subsequently found to be decreased (upon folinic acid supplementation) and later normalized upon use of another regimen.

MTHFS activity was measured in control fibroblasts as well as fibroblasts from this individual, with the latter demonstrating no enzyme activity. Accumulation (30x elevation) of 5-FTHF (the substrate of MTHFS) was demonstrated in patient fibroblasts.

The 2nd patient was a 11-year-old male with similar features incl. global DD (standing/walking/single words at/after 4 years of age, limited vocabulary and articulation upon last examination).

Extensive metabolic work-up as well as genetic testing for an epilepsy panel, vanishing white matter disease gene panel, mitochondrial genome as well as specific gene sequencing (LAMA2, POLR3A, POLR3B) were all non-diagnostic. Trio exome revealed 2 MTHFS variants in trans configuration (c.484C>T / p.Q162X and c.434G>A / p.R145Q).
---
Romero et al (2019 - PMID: 31844630) reported on a 4-year-old female with congenital microcephaly, severe global DD (nonverbal/nonambulatory at the age of 4), spasticity, epilepsy and cerebral hypomyelination.

Extensive investigations prior to exome sequencing revealed macrocytic anemia, decreased CSF 5-MTHF and elevated neopterin, 2 CNVs of uncertain significance upon CMA with additional long ROH on chr15. Methylation studies were negative. The child was homozygous for c.220C>T / p.R74X (RefSeq is probably NM_006441.3. MTHFS lies on chr15. The parents were unrelated but came from the same town). There were no other candidate variants from the exome analysis.

Both articles discuss extensively the role of the folate metabolism pathway overall in nucleic acid synthesis, AA metabolism, neurotransmitter synthesis, methylation as well as 5-FTHF / 5,10-MTHF in particular in myelin stabilization and DNA synthesis (eg. according to Romero et al. a defect in MTHFS would impair myelin production and also lead to decreased myelin stability).
---
A book chapter cited by Rodan et al (in N. Blau et al. (eds.), Physician’s Guide to the Diagnosis, Treatment, and Follow-Up of Inherited Metabolic Diseases - DOI: 10.1007/978-3-642-40337-8_10) included limited details on a patient with 'MTHFS gene mutation'. This individual had early speech delay, seizures beginning in infancy, ID, autistic features, recurrent infections and was found to have very low CSF 5-MTHF levels. [Details in p169 and table 10.6 - p173].
---
In a mouse model reported by Field et al (2011 - PMID: 22303332), Mthfs was disrupted through insertion of a gene trap vector between the first 2 exons. Heterozygous [Mthfs(gt/+)] mice were fertile and viable. Mthfs protein levels were slightly but not statistically significantly reduced in tissues measured. No homozygous embryos were recovered following intercrosses of heterozygous mice, suggesting that Mthfs is an essential gene. Mouse embryonic fibroblasts from heterozygous mice [Mthfs (gt/+)] exhibited reduced de novo purine biosynthesis, but did not exhibit altered de novo thymidylate biosynthesis. Plasma folate levels were altered in heterozygous mice on a standard (/control) diet.
Sources: Literature; to: Biallelic pathogenic MTHFS variants cause Neurodevelopmental disorder with microcephaly, epilepsy, and hypomyelination (# 618367).

The gene encodes 5,10-Methenyltetrahydrofolate synthetase which catalyzes conversion of 5-formyltetrahydrofolate (5-FTHF or folinic acid) to 5,10-methenyltetrahydrofolate (5,10-MTHF).

At least 3 unrelated individuals have been reported. The phenotype appears to be relevant to both epilepsy and ID gene panels and the role of variants/the gene supported by enzymatic activity studies, 5-FTHF accumulation, 5,10-MTHF levels (low/low-normal), the role of folate metabolism pathway overall and some supporting (metabolic) evidence from the mouse model.
---
Rodan et al (2018 - PMID: 30031689) reported on 2 individuals both presenting with microcephaly, severe global DD, epilepsy, progressive spasticity and cerebral hypomyelination upon MRI imaging. Short stature was also feature in both.

The 1st patient was an 8-year-old male who following exome sequencing was found to harbor 2 missense variants each inherited from a carrier parent. (NM_006441.3:c.434G>A / p.R145Q and c.107T>C / p.L36P). A further AFG3L2 indel was not felt to fit with his phenotype (and the onset of the related disorder appears to occur later).

Previous investigations included extensive metabolic testing, CMA, Angelman syndrome methylation analysis, GFAP, POLG1, TYMP sequencing, mitochondrial genome analysis and an XL-ID gene panel (further suggesting relevance of this gene to the current panel) were all non-diagnostic.

CSF 5-MTHF levels were initially on the low-normal range, subsequently found to be decreased (upon folinic acid supplementation) and later normalized upon use of another regimen.

MTHFS activity was measured in control fibroblasts as well as fibroblasts from this individual, with the latter demonstrating no enzyme activity. Accumulation (30x elevation) of 5-FTHF (the substrate of MTHFS) was demonstrated in patient fibroblasts.

The 2nd patient was a 11-year-old male with similar features incl. global DD (standing/walking/single words at/after 4 years of age, limited vocabulary and articulation upon last examination).

Extensive metabolic work-up as well as genetic testing for an epilepsy panel, vanishing white matter disease gene panel, mitochondrial genome as well as specific gene sequencing (LAMA2, POLR3A, POLR3B) were all non-diagnostic. Trio exome revealed 2 MTHFS variants in trans configuration (c.484C>T / p.Q162X and c.434G>A / p.R145Q).
---
Romero et al (2019 - PMID: 31844630) reported on a 4-year-old female with congenital microcephaly, severe global DD (nonverbal/nonambulatory at the age of 4), spasticity, epilepsy and cerebral hypomyelination.

Extensive investigations prior to exome sequencing revealed macrocytic anemia, decreased CSF 5-MTHF and elevated neopterin, 2 CNVs of uncertain significance upon CMA with additional long ROH on chr15. Methylation studies were negative. The child was homozygous for c.220C>T / p.R74X (RefSeq is probably NM_006441.3. MTHFS lies on chr15. The parents were unrelated but came from the same town). There were no other candidate variants from the exome analysis.

Both articles discuss extensively the role of the folate metabolism pathway overall in nucleic acid synthesis, AA metabolism, neurotransmitter synthesis, methylation as well as 5-FTHF / 5,10-MTHF in particular in myelin stabilization and DNA synthesis (eg. according to Romero et al. a defect in MTHFS would impair myelin production and also lead to decreased myelin stability).
---
A book chapter cited by Rodan et al (in N. Blau et al. (eds.), Physician’s Guide to the Diagnosis, Treatment, and Follow-Up of Inherited Metabolic Diseases - DOI: 10.1007/978-3-642-40337-8_10) included limited details on a patient with 'MTHFS gene mutation'. This individual had early speech delay, seizures beginning in infancy, ID, autistic features, recurrent infections and was found to have very low CSF 5-MTHF levels. [Details in p169 and table 10.6 - p173].
---
In a mouse model reported by Field et al (2011 - PMID: 22303332), Mthfs was disrupted through insertion of a gene trap vector between the first 2 exons. Heterozygous [Mthfs(gt/+)] mice were fertile and viable. Mthfs protein levels were slightly but not statistically significantly reduced in tissues measured. No homozygous embryos were recovered following intercrosses of heterozygous mice, suggesting that Mthfs is an essential gene. Mouse embryonic fibroblasts from heterozygous mice [Mthfs (gt/+)] exhibited reduced de novo purine biosynthesis, but did not exhibit altered de novo thymidylate biosynthesis. Plasma folate levels were altered in heterozygous mice on a standard (/control) diet.

[Please consider inclusion in other possibly relevant panels e.g. for metabolic disorders]
Sources: Literature
Intellectual disability v3.0 MTHFS Konstantinos Varvagiannis gene: MTHFS was added
gene: MTHFS was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: MTHFS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MTHFS were set to 30031689; 31844630; 22303332; https://doi.org/10.1007/978-3-642-40337-8_10
Phenotypes for gene: MTHFS were set to Neurodevelopmental disorder with microcephaly, epilepsy, and hypomyelination, 618367
Penetrance for gene: MTHFS were set to Complete
Review for gene: MTHFS was set to GREEN
Added comment: Biallelic pathogenic MTHFS variants cause Neurodevelopmental disorder with microcephaly, epilepsy, and hypomyelination (# 618367).

The gene encodes 5,10-Methenyltetrahydrofolate synthetase which catalyzes conversion of 5-formyltetrahydrofolate (5-FTHF or folinic acid) to 5,10-methenyltetrahydrofolate (5,10-MTHF).

At least 3 unrelated individuals have been reported. The phenotype appears to be relevant to both epilepsy and ID gene panels and the role of variants/the gene supported by enzymatic activity studies, 5-FTHF accumulation, 5,10-MTHF levels (low/low-normal), the role of folate metabolism pathway overall and some supporting (metabolic) evidence from the mouse model.
---
Rodan et al (2018 - PMID: 30031689) reported on 2 individuals both presenting with microcephaly, severe global DD, epilepsy, progressive spasticity and cerebral hypomyelination upon MRI imaging. Short stature was also feature in both.

The 1st patient was an 8-year-old male who following exome sequencing was found to harbor 2 missense variants each inherited from a carrier parent. (NM_006441.3:c.434G>A / p.R145Q and c.107T>C / p.L36P). A further AFG3L2 indel was not felt to fit with his phenotype (and the onset of the related disorder appears to occur later).

Previous investigations included extensive metabolic testing, CMA, Angelman syndrome methylation analysis, GFAP, POLG1, TYMP sequencing, mitochondrial genome analysis and an XL-ID gene panel (further suggesting relevance of this gene to the current panel) were all non-diagnostic.

CSF 5-MTHF levels were initially on the low-normal range, subsequently found to be decreased (upon folinic acid supplementation) and later normalized upon use of another regimen.

MTHFS activity was measured in control fibroblasts as well as fibroblasts from this individual, with the latter demonstrating no enzyme activity. Accumulation (30x elevation) of 5-FTHF (the substrate of MTHFS) was demonstrated in patient fibroblasts.

The 2nd patient was a 11-year-old male with similar features incl. global DD (standing/walking/single words at/after 4 years of age, limited vocabulary and articulation upon last examination).

Extensive metabolic work-up as well as genetic testing for an epilepsy panel, vanishing white matter disease gene panel, mitochondrial genome as well as specific gene sequencing (LAMA2, POLR3A, POLR3B) were all non-diagnostic. Trio exome revealed 2 MTHFS variants in trans configuration (c.484C>T / p.Q162X and c.434G>A / p.R145Q).
---
Romero et al (2019 - PMID: 31844630) reported on a 4-year-old female with congenital microcephaly, severe global DD (nonverbal/nonambulatory at the age of 4), spasticity, epilepsy and cerebral hypomyelination.

Extensive investigations prior to exome sequencing revealed macrocytic anemia, decreased CSF 5-MTHF and elevated neopterin, 2 CNVs of uncertain significance upon CMA with additional long ROH on chr15. Methylation studies were negative. The child was homozygous for c.220C>T / p.R74X (RefSeq is probably NM_006441.3. MTHFS lies on chr15. The parents were unrelated but came from the same town). There were no other candidate variants from the exome analysis.

Both articles discuss extensively the role of the folate metabolism pathway overall in nucleic acid synthesis, AA metabolism, neurotransmitter synthesis, methylation as well as 5-FTHF / 5,10-MTHF in particular in myelin stabilization and DNA synthesis (eg. according to Romero et al. a defect in MTHFS would impair myelin production and also lead to decreased myelin stability).
---
A book chapter cited by Rodan et al (in N. Blau et al. (eds.), Physician’s Guide to the Diagnosis, Treatment, and Follow-Up of Inherited Metabolic Diseases - DOI: 10.1007/978-3-642-40337-8_10) included limited details on a patient with 'MTHFS gene mutation'. This individual had early speech delay, seizures beginning in infancy, ID, autistic features, recurrent infections and was found to have very low CSF 5-MTHF levels. [Details in p169 and table 10.6 - p173].
---
In a mouse model reported by Field et al (2011 - PMID: 22303332), Mthfs was disrupted through insertion of a gene trap vector between the first 2 exons. Heterozygous [Mthfs(gt/+)] mice were fertile and viable. Mthfs protein levels were slightly but not statistically significantly reduced in tissues measured. No homozygous embryos were recovered following intercrosses of heterozygous mice, suggesting that Mthfs is an essential gene. Mouse embryonic fibroblasts from heterozygous mice [Mthfs (gt/+)] exhibited reduced de novo purine biosynthesis, but did not exhibit altered de novo thymidylate biosynthesis. Plasma folate levels were altered in heterozygous mice on a standard (/control) diet.
Sources: Literature
Intellectual disability v3.0 PUM1 Konstantinos Varvagiannis commented on gene: PUM1: 5 unrelated individuals with de novo pathogenic PUM1 variants have been reported in the literature. DD (5/5), ID (4/5 - relevant severity to the current panel), seizures (4/4 - absence/tonic-clonic, abnormal EEG) and variable other features (incl. facial dysmorphism, ataxia, cryptorchidism) appear to be part of the phenotype. 9 individuals with deletions spanning PUM1 and proximal genes presented similar features.

[1] PMID: 29474920 - Gennarino et al (2018)
[2] PMID: 30903679 - Bonnemason-Carrere et al (2019)
[3] PMID: 31859446 - Voet et al (2019) [with review of the literature]

SNVs in relevant individuals were identified by exome sequencing and were in all cases de novo.

Arg1147Trp was a recurrent variant reported in 3 unrelated subjects with ID and seizures (Refs 1,2,3 / NM_001020658.1:c.3439C>T). A nonsense variant was reported in an additional one with DD, ID, seizures and additional features (c.2509C>T / p.Arg837* - Ref3). One individual with a de novo missense variant (c.3416G>A / p.Arg1139Trp) with DD and ataxia, though without ID was reported in Ref1.

Details on 9 individuals with 0.3 - 5.6 Mb deletions spanning PUM1 and other genes are provided in Ref1. Features also included DD, ID, seizures, ataxia, etc.

Extensive initial investigations were reported for individuals in Refs 2 and 3 (various investigations incl. karyotype, SNP-array, targeted sequencing of OPHN1, KANSL1 or of a small panel of ID genes, biopsies and/or metabolic work-up) to rule out alternative causes. These only revealed a likely benign CNV and a GRIA3 SNV of uncertain significance in the case of an individual harboring the recurrent Arg1147Trp variant [Ref2].

Role of the gene (from OMIM):
Pumilio proteins, such as PUM1, negatively regulate gene expression by repressing translation of mRNAs to which they bind (Lee et al., 2016). A clinically significant PUM1 target is ataxin (ATXN1; 601556), mutation in which causes spinocerebellar ataxia-1 (SCA1; 601556).

Variant studies:
- Arg1147Trp was shown to be associated with normal PUM1 mRNA levels, but reduced (to ~43%) PUM1 protein levels in patient fibroblasts. ATXN1 mRNA and protein levels, as well as protein and/or mRNA levels of other PUM1 targets were shown to be increased (Ref1).
- In Ref1, in vitro transfection assays with wt or mt PUM1 were performed in HEK293T cells to evaluate repression of ATXN1 and E2F3. While overexpression of wt and Arg1147Trp were able to reduce ATXN1 and E2F3 levels, Arg1139Trp was not able to repress ATXN1 or E2F3.
- Upon overexpression in mouse hippocampal neurons, PUM1 missense mutations (among others Arg1139Trp and Arg1147Trp) were shown to alter neuronal morphology.

Overall haploinsufficiency is the proposed mechanism for the disorder for which the acronym PADDAS is used (Pumilio1-associated developmental disability, ataxia and seizure).

Milder mutations reducing PUM1 levels by 25% are associated with adult-onset ataxia without ID (PRCA or Pumilio1-related cerebellar ataxia) [Ref1].

Mouse models:
The role of PUM1 was first suggested in mouse models where Pum1 mutations were shown to lead to a SCA1-like phenotype (PMID cited : 12086639 - Watase et al 2002) further shown to be caused by increased Atxn1 mRNA and protein levels (PMID cited : 25768905 - Gennarino et al 2015).
The mouse model seems to recapitulate several of the features observed in affected individuals : Pum1 homozygous ko mice display among others hyperactivity, progressive cerebellar signs, spontaneous seizures as also observed in affected individuals (PMID cited : 25768905 - Gennarino et al 2015). Cryptorchidism was observed in 2 patients similar to testicular hypoplasia reported in Pum1 ko mice (PMID cited : 22342750 - Chen et al 2012).
- Heterozygous mice were evaluated in Ref1 with 69% or 75% exhibiting spontaneous seizures by the end of 30 or 35 wks respectively, with abnormal EEG activity already by 16 wks.

Additional individuals with PUM1 variants and a relevant phenotype of ID with or without seizures have been reported as part of the DDD study or as external submissions to Decipher and ClinVar :

https://decipher.sanger.ac.uk/search?q=PUM1#research-variants/results [ DDD4K.01387 participant ]
https://decipher.sanger.ac.uk/search?q=pum1#consented-patients/results [ external submission(s) ]
https://www.ncbi.nlm.nih.gov/clinvar/variation/431110/ [ splice-site variant in an individual with ID submitted prior to the 1st publication on the disorder ]
Intellectual disability v3.0 PUM1 Konstantinos Varvagiannis gene: PUM1 was added
gene: PUM1 was added to Intellectual disability. Sources: Literature,Radboud University Medical Center, Nijmegen
Mode of inheritance for gene: PUM1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: PUM1 were set to 29474920; 30903679; 31859446
Phenotypes for gene: PUM1 were set to Global developmental delay; Intellectual disability; Seizures; Abnormality of the face; Ataxia; Cryptorchidism
Penetrance for gene: PUM1 were set to unknown
Review for gene: PUM1 was set to GREEN
Added comment: Please consider inclusion in both ID and epilepsy panels with probably green rating.
Sources: Literature, Radboud University Medical Center, Nijmegen
Intellectual disability v3.0 DLL1 Konstantinos Varvagiannis gene: DLL1 was added
gene: DLL1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: DLL1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: DLL1 were set to 31353024
Phenotypes for gene: DLL1 were set to Global developmental delay; Intellectual disability; Morphological abnormality of the central nervous system; Seizures; Behavioral abnormality; Autism; Scoliosis
Penetrance for gene: DLL1 were set to unknown
Review for gene: DLL1 was set to GREEN
Added comment: Heterozygous DLL1 pathogenic variants cause Neurodevelopmental disorder with nonspecific brain abnormalities and with or without seizures (# 618709).

Fischer-Zirnsak et al (2019 - PMID: 31353024) reported on 15 affected individuals from 12 unrelated families.

Most common features included DD/ID (12/14), ASD (6/14 - belonging to 6 families) or other behavioral abnormalities, seizures (6/14 - from 6 unrelated families) and various brain MRI abnromalities. As commented by OMIM (based on the same ref) "Cognitive function ranges from severely impaired to the ability to attend schools with special assistance". Among other features, scoliosis was observed in 4. The authors could not identify a distinctive facial gestalt.

Variable initial investigations (where discussed/performed - also suggesting relevance to the current panel) included CMA, FMR1, FLNA, mitochondrial DNA analysis and metabolic work-up but had not revealed an alternative cause.

The DLL1 variants were identified by WES (with the exception of a 122-kb microdeletion spanning DLL1 and FAM120B detected by CMA). Nonsense, frame-shift, splice-site variants in positions predicted to result to NMD were identified in most. One individual was found to harbor a missense variant (NM_005618.3:c.536G>T / p.Cys179Phe) and another the aforementioned microdeletion.

The variant in several individuals had occurred as a de novo event. In 2 families, it was inherited from an also affected parent (an unaffected sib was non-carrier) while in 3 families parental studies were not possible/complete.

In frame insertion of 4 residues was demonstrated for a splice site variant, from LCLs of the corresponding individual. For another individual, material was unavailable for mRNA studies. The missense variant affected a cysteine (of the DSL domain) conserved in all Notch ligands while AA changes affecting the same position of JAG1 (another Notch ligand) have been described in patients with Alagille s.

Based on the variants identified and reports of deletions spanning DLL1 in the literature, haploinsufficiency is the proposed underlying mechanism. The gene has also a pLI of 1 and %HI of 4.65.

DLL1 encodes the Delta-like canonical Notch ligand 1. Notch signaling is an established pathway for brain morphogenesis. Previous in vivo and in vitro studies have demonstrated the role of DLL1 in CNS. The gene is highly expressed in neuronal precursor cells during embryogenesis. Expression of Dll1 (and other molecules of the Notch signalling pathway) in an oscillatory/sustained pattern and cell-cell interactions important for this pathway have been demonstrated to play a role in neuronal differentiation. [Most discussed by Fischer-Zirnsak et al with several refs provided / also Gray et al., 1999 - PMID: 10079256 & OMIM].

Animal models as summarized by the authors:
[Mouse] Loss of Dll1 in mice has been shown to increase neuronal differentiation, cause CNS hyperplasia and increased number of neurons (PMIDs cited: 9109488, 12397111, 20081190). Reduced Dll1 expression was associated with scoliosis and mild vertebral defects (cited PMIDs: 19562077, 14960495, 22484060 / among others Dll1 haploinsufficiency and dominant negative models studied). Scoliosis and vertebral segmentation defects were features in 4 and 1 individual, respectively in the cohort of 15.
[Zebrafish] Homozygous mutations in dlA, the zebrafish ortholog, disrupted the Delta-Notch signaling and led to patterning defects in the hindbrain and overproduction of neurons (cited: 15366005).

Please consider inclusion in other possibly relevant panels e.g. for ASD.
Sources: Literature
Intellectual disability v3.0 TFE3 Konstantinos Varvagiannis reviewed gene: TFE3: Rating: GREEN; Mode of pathogenicity: Other; Publications: 30595499, 31833172, https://doi.org/10.1126/scisignal.aax0926; Phenotypes: Global developmental delay, Intellectual disability, Abnormality of skin pigmentation, Coarse facial features, Seizures; Mode of inheritance: Other
Intellectual disability v3.0 MN1 Konstantinos Varvagiannis gene: MN1 was added
gene: MN1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: MN1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: MN1 were set to 31834374; 31839203; 15870292
Phenotypes for gene: MN1 were set to Central hypotonia; Feeding difficulties; Global developmental delay; Intellectual disability; Hearing impairment; Abnormality of facial skeleton; Craniosynostosis; Abnormality of the face; Abnormality of the cerebellum; Abnormality of the corpus callosum; Polymicrogyria
Penetrance for gene: MN1 were set to Complete
Review for gene: MN1 was set to GREEN
Added comment: Two studies by Mak et al (2019 - PMID: 31834374 / Ref1) and Miyake et al (2019 - PMID: 31839203 / Ref2) provide sufficient evidence for heterozygous MN1 C-terminal truncating variants (predicted to escape NMD - localizing within the last nucleotides of exon 1 or in exon 2) being associated with a distinctive phenotype and DD and ID among the features.

Mak et al also discuss on the phenotype of individuals with variants causing N-terminal truncation or with MN1 deletions (discussed at the end of this review).

Overlapping features for C-terminal truncating variants included hypotonia, feeding difficulties, global DD and ID, hearing loss, cranial shape defects (/craniosynostosis in few), highly suggestive/distinctive facial features (eg. frontal bossing, hypertelorism, downslanting palpebral-fissures, shallow orbits, short upturned nose, low-set/posteriorly rotated/dysplastic ears, etc) and brain MRI abnormalities (eg. rhomboencephalosynapsis or cerebellar dysplasia, polymicrogyria, dysplastic CC).

The majority of the affected individuals were investigated by WES/WGS with a single one tested by targeted MN1 Sanger sequencing due to highly suggestive features. Variable previous investigations incl. CMA in several, gene panel testing (Rasopathies, hearing loss, craniofacial panels, FMR1, etc) and metabolic work were normal in most. In a single case a likely pathogenic ACSL4 also explained part of the phenotype (Ref2). In the majority of these individuals, the variant had occured as a de novo event. Two sibs had inherited the truncating variant from a milder affected mosaic parent. A parental sample was not available for an additional individual.

p.(Arg1295*) or NM_002430.2:c.3883C>T was a recurrent variant, seen in several individuals and in both studies.

Several lines of evidence are provided for the MN1 variants and the role of the gene including:
- For few individuals for whom cell lines were available, variants were shown to escape NMD by cDNA/RT-PCR/RNA-seq [Ref1 & 2].
- The gene has a high expression in fetal brain [Ref2 / fig S2]
- MN1 (* 156100 - MN1 protooncogene, transcriptional regulator) has been proposed to play a role in cell proliferation and shown to act as transcription cofactor (increasing its transactivation capacity in synergy with coactivators EP300 and RAC3) [Discussion and Refs provided in Ref2].
- In vitro studies suggested increased protein stability (upon transfection of wt/mut constructs in HEK293T cells), enhanced MN1 aggregation in nuclei (when wt/mut GFP-tagged MN1 was expressed in HeLa cells), increased inhibitory effect on cell growth (MG63 cells - role of MN1 in cell proliferation discussed above) and retained transactivation activity (upon transient MN1 overexpression of wt/mt MN1 in HEK293T cells) for the variants. These seem to support a gain-of-function effect for the C-terminal truncating variants [Ref2].
- The truncating variants are proposed to raise the fraction of Intrinsically disordered regions (IDRs = regions without fixed tertiary structure) probably contributing to the above effects [Ref2].
- Expression of FLAG-tagged MN1 wt/mut MN1 followed by immunoprecipitation and mass spectrometry analysis (mCAT-Hela cells), provided evidence that MN1 is involved in transcriptional regulation: a. through binding ZBTB24 and RING1 E3 ubiquitin ligase (with mutant MN1 displaying impaired interaction with ZBTB24 and no binding to RING1) and/or b. through interaction with DNA-binding transcription factors PBX1 and PKNOX1. Proper MN1 degradation is proposed to mediate precise transcriptional regulation. [Ref2]
- Transcriptome analysis in LCLs from an affected individual suggested dysregulation of genes relevant to neuronal development (eg. LAMP, ITGA, etc) and GO analysis suggested enrichment for pathways possibly linked to the observed phenotypes [Ref2].
- Discussed in both Refs1/2, homozygous Mn1-ko mice display abnormal skull bone development and die at/shortly after birth as a result of cleft palate. Heterozygous Mn1-ko mice display hypoplastic membranous bones of the cranial skeleton and cleft palate (CP), the latter with incomplete penetrance [Meester-Smoor et al 2005 - PMID: 15870292]. This is thus compatible with the cranial shape defects observed in C-terminal truncations (while CP has been reported in gene deletions, bifid uvula was reported once in C-terminal and N-terminal truncating variants, in the latter case with submucous CP).
-----
The phenotype of other MN1 variants is discussed by Mak et al (Ref1) :
- 3 individuals with MN1 N-terminal truncating variants (eg. Ser179*, Pro365Thrfs*120, Ser472*) presented speech delay, mild conductive hearing loss and facial features different from C-terminal truncations. None of these individuals had significant ID.
- Microdeletions: One individual (#27) with 130 kb deletion harboring only MN1, presented microcephaly, DD and ID and mildly dysmorphic facial features. Deletions spanning MN1 and other genes (eg a 1.17 Mb deletion in ind. #28) and relevant cases from the literature reviewed, with mild DD/ID, variable palatal defects and/or facial dysmorphisms (distinct from the C-terminal truncating variants) among the frequent findings.

[Please consider inclusion in other possibly relevant gene panels eg. for hearing loss (conductive/sensorineural in 16/20 reported by Mak et al) or craniosynostosis, etc].
Sources: Literature
Intellectual disability v3.0 CXorf56 Konstantinos Varvagiannis gene: CXorf56 was added
gene: CXorf56 was added to Intellectual disability. Sources: Literature,Radboud University Medical Center, Nijmegen
Mode of inheritance for gene: CXorf56 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: CXorf56 were set to 29374277; 31822863
Phenotypes for gene: CXorf56 were set to ?Mental retardation, X-linked 107, 301013
Penetrance for gene: CXorf56 were set to unknown
Review for gene: CXorf56 was set to AMBER
Added comment: Verkerk et al (2018 - PMID: 29374277) reported on a three-generation family with five males and one female presenting mild non-syndromic ID. Segregation was compatible with X-linked inheritance.

Multipoint linkage analysis with XL microsatellite markers demonstrated a linkage peak at Xq23-24 with LOD score of 3.3. Haplotype analysis and utilization of additional STR markers allowed narrowing to a region of 7.6 Mb containing 92 genes.

WGS in 3 affected males (spanning 3 generations) and 1 unaffected male and application of relevant filters for rare protein affecting variants within this region - present only in affected but absent in the unaffected individual - suggested a CXorf56 frameshift variant in exon 2 [NM_022101.3:c.159_160insTA / p.(Asp54*)] as the only relevant for this phenotype.

Sanger sequencing was performed for 25 family members with all 5 affected males and 1 affected female harboring this insertion and 8 unaffected females (also) shown to be carriers.

X-chromosome inactivation studies demonstrated that unaffected females had skewed inactivation (76-93%) of the variant allele, while the single affected female did not have a skewed XCI pattern (54%).

In EBV-transformed lymphoblasts grown with/without cycloheximide, mRNA levels were shown to be significantly lower in the affected female compared to unaffected ones (and corrected upon treatment with cycloheximide). mRNA levels were also significantly lower in cell lines from an affected male, with expression showing significant increase after treatment with cycloheximide. These results confirmed that nonsense-mediated decay applies.

The variant was absent from ExAC (where CXorf56 has a pLI of 0.93) and 188 healthy Dutch individuals.

The function of CXorf56 is not known. The gene appears to be expressed in brain and a (broad) range of other tissues [ https://gtexportal.org/home/gene/CXORF56 ].

Immunostaining in 8-week old murine brain, showed that the protein is present in the nucleus and cell soma of most neurons in brain cortex and cerebellum. Upon transfection of human CXorf56 cDNA in mouse primary hippocampal neurons, the protein localized in the nucleus, dendrites (co-localizing with Map2) and dendritic spines. As the authors note, the latter may suggest a role in synaptic function.

Overexpression in HEK293T cells demonstrated predominantly nuclear localization.

Mouse : Based on MGI (and an article by Cox et al. - PMID: 20548051 / both cited by the authors) male chimeras hemizygous for a gene trapped allele have abnormal midbrain-hindbrain boundary morphology, decreased forebrain size, while a subset hemizygous for a different gene trapped allele show growth delay [ http://www.informatics.jax.org/marker/MGI:1924894 ].

-----

Rocha et al (2019 - PMID: 31822863) report on 9 affected individuals with mild to severe ID belonging to 3 unrelated families. Additional features in this cohort - observed in some - included abnormal reflexes, fine tremor, seizures (in 3), abnormal gait, etc.

In the 1st family, 3 males presented with (severe/severe/moderate) ID and 2 females with mild ID. Following a normal CMA and FMR1 testing, trio plus exome sequencing revealed a CXorf56 in-frame deletion [NM_022101.3:c.498_503del / p.(Glu167_Glu168del)]. Sanger sequencing in 9 members, confirmed presence of the variant in one unaffected mother, all her affected sons (2) and daughers(2) and an affected grandson and absence in 2 remaining unaffected daughters. Skewing of XCI was seen in blood cells from affected females (97 and 83%) while the unaffected mother had complete inactivation of the carrier X-chromosome. The authors commented that even minor reductions in CXorf56 (suggested by XCI in affected females) may be detrimental and/or that inactivation for this gene may be different than that of AR gene (which was studied instead) or in other tissues.

In family 2, an affected mother (with learning difficulties) and her 2 sons - the most severely affected presenting moderate ID - harbored a frameshift variant [c.303_304delCTinsACCC / p.(Phe101Leufs*20)].

A male with ID belonging to a 3rd family, for which no further information was available, was found to harbor the c.498_503del variant (also discussed above) as a de novo event.

It has been commented that individuals with Xq24 deletions spanning CXorf56 present with ID, although (all) such deletions reported in the literature also span the neighboring UBE2A gene, associated with Mental retardation, X-linked syndromic, Nascimento-type (MIM #300860).

-----

In OMIM, the CXorf56-related phenotype is ?Mental retardation, X-linked 107 (# 301013), based only on the report by Verkerk et al.

This gene is included in gene panels for ID offered by some diagnostic laboratories (incl. Radboudumc).

-----

Overall, CXorf56 can be considered for inclusion in the ID panel either with amber (function of the gene unknown, skewed XCI also in affected females in the 2nd reference) or with green rating (several individuals from 4 families, compatible segregation studies and females presenting a milder phenotype than males or unaffected, LOD score in the 1st report, studies confirming lower mRNA levels and NMD, gene expressed in human brain, expression in mouse brain cortex and cerebellum, evidence from transfection studies in mouse hippocampal neurons).

[Note : penetrance was here set to unknown / It was complete for males, incomplete for females].
Sources: Literature, Radboud University Medical Center, Nijmegen
Intellectual disability v3.0 UGP2 Konstantinos Varvagiannis gene: UGP2 was added
gene: UGP2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: UGP2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: UGP2 were set to 31820119
Phenotypes for gene: UGP2 were set to Seizures; Global developmental delay; Intellectual disability; Feeding difficulties; Abnormality of vision; Abnormality of the face
Penetrance for gene: UGP2 were set to Complete
Review for gene: UGP2 was set to GREEN
Added comment: Perenthaler et al. (2019 - PMID: 31820119) provide evidence that homozygosity for a variant abolishing the start codon of the UGP2 transcript (NM_001001521.1) encoding the predominant (short) protein isoform in brain, leads to a severe epileptic encephalopathy.

This variant (chr2:64083454A>G / NM_001001521.1:c.1A>G - p.?) is also predicted to result in a substitution of a methionine at position 12 by a valine of the longer UGP2 transcript (NM_006759.3:c.34A>G - p.Met12Val).

The 2 isoforms differ only by 11 amino acids at the N-terminal and are otherwise expected to be functionally equivalent.

The authors provide details on 22 individuals from 15 families (some of which consanguineous).

Features included intractable seizures (in all), absence of developmental milestones (in all), progressive microcephaly, visual impairment. The authors reported also presence of somewhat similar facial features. Some of these individuals passed away early.

Previous work-up in several of them (incl. SNP-array, gene panel testing and metabolic investigations) had not revealed any abnormality, apart from ROH in some individuals. In all cases, the homozygous UGP2 SNV was the only P/LP variant for the neurodevelopmental phenotype following exome/genome sequencing. Segregation studies in affected/unaffected family members were compatible.

Families came from the Netherlands (but mostly from) India, Pakistan and Iran. Presence of a region of homozygosity shared between individuals from different families suggested that the variant might represent a mutation that originated several generations ago (in the area of Balochistan). The variant is present 15x in gnomAD, only in heterozygous state (in Asian mostly, reported once in Ashkenazi Jewish or Europeans) [ https://gnomad.broadinstitute.org/variant/2-64083454-A-G ].

UGP2 encodes UDP-glucose pyrophosphorylase which is an essential enzyme in sugar metabolism, catalyzing conversion of glucose-1-phosphate to UDP-glucose. UDP-glucose, in turn, serves as precursor for production of glycogen by glycogen synthase.

The authors provide several lines of evidence for a the role of the gene in the CNS as well as for the deleterious effect of the specific variant :
- In patient fibroblasts total UGP2 levels were not signifficantly different compared to parent / control fibroblasts, the longer isoform being upregulated (and stable) when the shorter is missing. Immunocytochemistry demonstrated similar localization of UGP2 in the case of mutant or wt cells. Enzymatic activity (/capacity to produce UDP-glucose) was similar between homozygous mut, heterozygous and wt fibroblasts.
- In H9-derived neural stem cells, Western Blot, RT-PCR and qRT-PCR suggested that the short isoform is the predominant one. (In embryonic stem cells, or fibroblasts the ratio between short and long isoform was lower).
- Analysis of RNA-seq data from human fetal tissues suggested that the short isoform is the predominant in brain.
- UGP2 was detected upon immunohistochemistry in fetal brain tissues from first to third trimester of pregnancy while Western Blot confirmed preferential expression of the shorter isoform.
- Homozygous embryonic (ESC) or neural stem cells (NSC) for the variant (knock-in/KI) or for a frameshift variant (knock-out/KO) were generated. Study of NSCs demonstrated reduced total UGP2 protein expression upon Western Blot in the case of KI cells and depleted in KO ones. Transcriptome analysis did not show major transcriptome alterations in KI/KO ESCs compared to wt. In NSC KI/KO cells transcriptome alterations were observed compared to wt with upregulation among others of genes for synaptic processes and genes implicated in epilepsy.
- The absence of UGP2 was shown to result in reduced ability of KO/KI NSCs to produce UDP-glucose, reduced capacity to synthesize glycogen under hypoxia (rescued in the case of KO cells by overexpression of wt or long isoform), defects of protein glycosylation as well as in increased unfolded protein response (/susceptibility to ER stress). These alterations are commented to be possibly implicated in pathogenesis of epilepsy, progressive microcephaly, etc.
- A CRISPR-Cas9 zebrafish model leading with loss of ugp2a and hypomorphic ugp2b (the zebrafish homologs of UGP2) demonstrated abnormal behavior, reduced eye movements and increased frequency/duration of movements upon stimulation with a potent convulsant (suggestive of increased seizure susceptibility).
- UGP knockout in drosophila is lethal while flies compound heterozygous for hypomorphic alleles are viable but show a movement defects due to altered synaptogenesis secondary to glycosylation defects (cited PMID: 27466186).
- The authors make speculations as for the occurrence of a single variant (and not others) eg. absence of UGP2 (in the case of LoF variants affecting both isoforms) would possibly be incompatible with life, Met12Val being tolerable for the long transcript not affecting stability/enzymatic activity (which may not be the case for other substitutions affecting Met12), etc.
Sources: Literature
Intellectual disability v3.0 ADPRHL2 Louise Daugherty Tag new-gene-name tag was added to gene: ADPRHL2.
Intellectual disability v3.0 ADPRHL2 Louise Daugherty commented on gene: ADPRHL2: Added new-gene-name tag, new approved HGNC gene symbol for ADPRHL2 is ADPRS
Intellectual disability v3.0 KAT8 Konstantinos Varvagiannis gene: KAT8 was added
gene: KAT8 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: KAT8 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: KAT8 were set to 31794431
Phenotypes for gene: KAT8 were set to Global developmental delay; Intellectual disability; Seizures; Abnormality of vision; Feeding difficulties; Abnormality of the cardiovascular system; Autism
Penetrance for gene: KAT8 were set to unknown
Review for gene: KAT8 was set to GREEN
Added comment: Heterozygous pathogenic missense KAT8 variants have been reported in individuals with DD, ID and epilepsy. Variants occurred as de novo events within the chromobarrel or the acetyltransferase domain and were all shown to affect H4K16 acetylation, as would be predicted by the gene's function (lysine acetyltransferase). Evidence from brain specific Kat8 knockout in mouse, supports the role of the gene in brain development. One similarly affected individual compound heterozygous for a nonsense and a missense variant (the former affecting subnuclear localization and the latter H4K16ac) was also reported, with carrier relatives being unaffected. Mutations in genes of the MSL/NSL complexes (with which KAT8 forms multisubunit complexes) or genes in other acetyltransferases of the same subfamily (MYST) as KAT8 cause neurodevelopmental disorders [Details provided below].
-----
Li et al. (2019 - PMID: 31794431) report on 8 unrelated individuals with heterozygous de novo pathogenic KAT8 variants, as well as an additional one compound heterozygous for a nonsense and a missense one.

Overlapping phenotype consisted of DD/ID (8/8), seizures/epilepsy (6/8), brain MRI anomalies as well as presence of variable facial dysmorphic features. Less frequent features included abnormal vision (5/8), feeding difficulties (3/8), cardiac anomalies (3/8), autism (in 1).

The (9th) individual with biallelic variants had similar phenotype of DD/ID, epilepsy, autism and dysmorphic facial features. Heterozygous parents and sister, the latter carrier for the missense variant, were all unaffected.

All individuals had undergone exome sequencing, while extensive other investigations for at least 7/9 had only revealed variants of uncertain significance/contribution to the phenotype or were normal.

KAT8 encodes lysine acetyltransferase 8, which acetylates histone H4 at lysine 16 (H4K16). It belongs to the MYST subfamily of lysine acetyltransferases, the other members of which include KAT6A, KAT6B (both involved in neurodevelopmental disorders) and KAT5.

KAT8 forms two stoichiometric multisubunitcomplexes, one with the MSL complex and the other with the NSL. Mutations in genes encoding for subunits of the NSL or MSL complex (eg. KANSL1 and MSL3) are associated with neurodevelopmental disorders.

Overall 6 missense SNVs were reported among the heterozygous patients, p.Tyr90Cys (NM_032188.2:c.269A>G) being a recurrent one seen in 3. The compound heterozygous patient had a missense (c.973C>T / p.Arg325Cys) and a nonsense variant (c.523A>T / p.Lys175*). All missense variants lied either in the chromobarrel domain or the acetyltransferase domain. Variants in the latter domain localized within the KAT8/Mof-specific region or - in the case of the compound heterozygous individual - within the acetyl-CoA binding motif.

FLAG-tagged KAT8 (either wt or for all missense SNVs) was transfected in HEK293 cells with vectors for HA-tagged MSL proteins. While the nonsense variant was difficult to express, missense SNVs were expressed to similar levels to wt, promoted expression of MSL proteins but resulted in defective H4K16 acetylation and to a lesser extent H4K5 acetylation. As a result all missense variants impaired acetylation. This was also the case for chromobarrel domain variants, while expression of a KAT8 lacking the chromobarrel domain confirmed its ability to form complex with the MSL proteins and the impairment of H4K16 acetylation.

The nonsense variant demonstrated abnormal subnuclear localization.

The mouse model provides extensive evidence for the involvement of KAT8 in cerebral development. Cerebrum-specific Kat8 knockout mice presented postnatal growth retardation, hyperactivity/irritability, pre-weaning lethality, and cerebral hypoplasia upon autopsy. Loss of Kat8 reduced the number of neural stem and progenitor cells available for embryonic cerebrocortical development, impaired cell proliferation and stimulated apoptosis. The article also provides additional evidence from mouse model.
Sources: Literature
Intellectual disability v3.0 RARS Konstantinos Varvagiannis gene: RARS was added
gene: RARS was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: RARS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RARS were set to 31814314; 28905880; 24777941
Phenotypes for gene: RARS were set to Cerebral hypomyelination; Global developmental delay; Intellectual disability; Seizures; Cerebral atrophy; Nystagmus; Ataxia; Feeding difficulties
Penetrance for gene: RARS were set to Complete
Review for gene: RARS was set to GREEN
Added comment: Biallelic pathogenic RARS1 variants cause Leukodystrophy, hypomyelinating, 9 (# 616140).

The current review was based primarily on PMID: 31814314 (Mendes et al, 2019) providing details on 20 affected individuals from 15 families. 5 of these patients were included in a previous publication (Wolf et al, 2014 - PMID: 24777941) sharing authors with this study.

Clinical presentation and severity can be highly variable. However, among the 15 patients of relevant age (5/20 deceased at an early age), ID was observed in 13 (in 6/13 mild-moderate, in 7/13 severe/profound). Epilepsy was reported in half (10/20) with seizures being refractory to treatment in most and the phenotype corresponding to an infantile epileptic encephalopathy. DD and seizures were the presenting feature in 7 and 5 patients respectively, while in other cases presenting features were less specific (eg. failure to thrive in 1/20, irritabilty in 2/20). As a result the gene appears to be relevant to both DD/ID and epilepsy panels.

RARS1 encodes the cytoplasmic arginyl-tRNA synthetase 1, which is a component of the aminoacyl-tRNA synthetase complex (OMIM and Wolf et al, 2014 - PMID: 24777941). Aminoacyl-tRNA synthetases catalyze the aminoacylation ('charging') of tRNA by (with) their cognate amino acid.

Utilisation of alternative initiation codons, from a single mRNA transcript, results in translation of a long and a short protein isoform (Zheng et al 2006 - PMID: 16430231). The long isoform is needed for the formation of the multi-synthetase complex (MSC), while the short is free in the cytoplasm and does not have any interaction with the MSC. The long isoform appears to be essential for protein synthesis (discussed with several refs provided in PMID: 28905880 - Nafisinia et al, 2017).

The role of variants has been supported in several patients by additional studies - among others :
[PMID 31814314] Impaired Arginyl-tRNA synthetase activity was demonstrated in fibroblasts from 3 patients. Activity was normal in one additional individual compound heterozygous for a variant affecting initiation codon and a missense one. Western blot however demonstrated presence mainly of the short protein isoform. The authors suggest that this isoform possibly contributed to enzymatic activity. The long isoform which is needed for the MSC complex was only represented by a faint band in the Western Blot of the same individual.
[PMID: 28905880] Using fibroblasts from an affected subject homozygous for a missense variant (NM_002887.3:c.5A>G / p.Asp2Gly) and controls, a 75% reduction of the long isoform was shown upon WB. The short isoform was present at similar levels. As the N-terminus (of the long isoform) mediates interaction with the MSC (and AIMP1), assembly of the latter was 99% reduced in patient fibroblasts. Proliferation of patient fibroblasts was significantly reduced when cultured in a medium with limited arginine, a finding which was thought to reflect inefficient protein synthesis.

Mutations in other genes encoding for aminoacyl-tRNA synthetases (eg. AARS1, VARS1) or scaffolding proteins of the multisynthetase complex (eg. AIMP1 and AIMP2) lead to neurodevelopmental disorders with overlapping phenotype [most genes rated green in both the ID and epilepsy panel].
Sources: Literature
Intellectual disability v3.0 SUZ12 Konstantinos Varvagiannis changed review comment from: ID can be a feature in individuals heterozygous for SUZ12 pathogenic variants. 13 affected individuals (from 12 families) have been reported:

[1] PMID 28229514 (Imagawa et al, 2017) : 1 individual
[2] PMID 30019515 (Imagawa et al, 2018) : 2 further unrelated subjects
[3] PMID 31736240 (Cyrus et al, 2019) : 10 additional subjects (from 9 families)

Reviewed by Cyrus et al, features observed in more than half of the (13) affected individuals included prenatal and/or postnatal overgrowth (in some only prenatal, others only postnatal, others did not manifest overgrowth at all), some suggestive facial features (eg. prominent forehead, hypertelorism, downslanting palpebral fissures, round face, broad/low nasal bridge), DD and ID (the latter in 7/13, in most cases mild), advanced bone age, musculoskeletal abnormalities and cryptorchidism. Less frequent features included brain MRI abnormalities (eg. CC hypoplasia/agenesis, etc.), umbilical hernias, respiratory abnormalities, cardiac anomalies (in one).

All were diagnosed with WES/WGS/panel testing, with few having additional findings upon this or prior testing (eg. CNVs/SNVs).

SUZ12 encodes one of the 4 core proteins of the PRC2 complex (the 3 other being encoded by EZH1/2, EED and RBBP4/7). The complex has a methyltransferase activity, catalyzing addition of up to 3 methyl groups on histone 3 at lysine residue 27 (H3K27), leading to chromatin compaction and further to gene silencing.

Mutations in genes encoding 2 other core components of the PRC2 complex - namely EZH2 and EED - cause Weaver and Cohen-Gibson syndrome with overlapping phenotype incl. overgrowth, advanced bone age, craniofacial features and DD/ID.

The SET domain of EZH1/2 and EED as well as the VEFS domain of SUZ12 are contributing to the catalytic activity.

SUZ12 variants reported to date include missense and pLoF variants (frameshift, nonsense, splice site ones) predicted to disrupt or eliminate the VEFS-box domain [almost all missense within this domain with the exception of one proximal to it (Arg535Gln) / pLoF causing truncation prior or within this domain (Arg654Ter might be an exception)] {NP_056170.2}.

Variants either occurred de novo or were inherited (~1/3), on some occasions from a mildly affected parent. Parental mosaicism has also been reported (eg. in ref1, and one or possibly two additional families in ref3).

Some preliminary assumptions on possible genotype-phenotype correlations (for overgrowth and ID related to missense/pLoF variants) are discussed in ref3.

SUZ12 is also be deleted in some patients with NF1 deletion (and a diagnosis of neurofibromatosis type 1). Deletion of SUZ12 has been proposed to contribute to the phenotype of these individuals (eg. overgrowth, cognitive development, facial features). [Discussed in ref1].

Functional studies have been carried out only in the first report (ref1) and demonstrated decreased trimethylation of H3K27 in the case of a missense variant. Overall a partial loss-of-function mechanism has been proposed for the variants.

Mouse models: A study by Pasini et al (PMID: 15385962) did not report phenotypic differences between wt and heterozygous Suz12 knockout mice (gene-trap vector) as for size, morphology and fertility. Total knockout resulted in embryonic lethality, significant growth retardation and several developmental defects. Loss of Suz12 was shown to result in absence of di- and tri-methylated H3K27 in the ko embryos. In another study cited (Miro et al - PMID: 19535498) heterozygous mice (replacement of exons 12-16 with a lacZ gene and neo cassette) displayed variable CNS defects with incomplete penetrance.

The role of the PRC2 complex and the phenotypes related to mutations in genes encoding its core components, are discussed in PMID: 31724824 (also by Cyrus et al, 2019).

SUZ12 is not associated with any phenotype in OMIM. In G2P it is included in the DD panel associated with Weaver-like overgrowth syndrome (disease confidence : confirmed). The gene is also included in gene panels for ID offered by some diagnostic laboratories (eg. GeneDx).
Sources: Literature; to: ID can be a feature in individuals heterozygous for SUZ12 pathogenic variants. 13 affected individuals (from 12 families) have been reported:

[1] PMID 28229514 (Imagawa et al, 2017) : 1 individual
[2] PMID 30019515 (Imagawa et al, 2018) : 2 further unrelated subjects
[3] PMID 31736240 (Cyrus et al, 2019) : 10 additional subjects (from 9 families)

Reviewed by Cyrus et al, features observed in more than half of the (13) affected individuals included prenatal and/or postnatal overgrowth (in some only prenatal, others only postnatal, others did not manifest overgrowth at all), some suggestive facial features (eg. prominent forehead, hypertelorism, downslanting palpebral fissures, round face, broad/low nasal bridge), DD and ID (the latter in 7/13, in most cases mild), advanced bone age, musculoskeletal abnormalities and cryptorchidism. Less frequent features included brain MRI abnormalities (eg. CC hypoplasia/agenesis, etc.), umbilical hernias, respiratory abnormalities, cardiac anomalies (in one).

All were diagnosed with WES/WGS/panel testing, with few having additional findings upon this or prior testing (eg. CNVs/SNVs).

SUZ12 encodes one of the 4 core proteins of the PRC2 complex (the 3 other being encoded by EZH1/2, EED and RBBP4/7). The complex has a methyltransferase activity, catalyzing addition of up to 3 methyl groups on histone 3 at lysine residue 27 (H3K27), leading to chromatin compaction and further to gene silencing.

Mutations in genes encoding 2 other core components of the PRC2 complex - namely EZH2 and EED - cause Weaver and Cohen-Gibson syndrome with overlapping phenotype incl. overgrowth, advanced bone age, craniofacial features and DD/ID.

The SET domain of EZH1/2 and EED as well as the VEFS domain of SUZ12 are contributing to the catalytic activity.

SUZ12 variants reported to date include missense and pLoF variants (frameshift, nonsense, splice site ones) predicted to disrupt or eliminate the VEFS-box domain [almost all missense within this domain with the exception of one proximal to it (Arg535Gln) / pLoF causing truncation prior or within this domain (Arg654Ter might be an exception)] {NP_056170.2}.

Variants either occurred de novo or were inherited (~1/3), on some occasions from a mildly affected parent. Parental mosaicism has also been reported (eg. in ref1, and one or possibly two additional families in ref3).

Some preliminary assumptions on possible genotype-phenotype correlations (for overgrowth and ID related to missense/pLoF variants) are discussed in ref3.

SUZ12 may also be deleted in some patients with NF1 deletion (and a diagnosis of neurofibromatosis type 1). Deletion of SUZ12 has been proposed to contribute to the phenotype of these individuals (eg. overgrowth, cognitive development, facial features). [Discussed in ref1].

Functional studies have been carried out only in the first report (ref1) and demonstrated decreased trimethylation of H3K27 in the case of a missense variant. Overall a partial loss-of-function mechanism has been proposed for the variants.

Mouse models: A study by Pasini et al (PMID: 15385962) did not report phenotypic differences between wt and heterozygous Suz12 knockout mice (gene-trap vector) as for size, morphology and fertility. Total knockout resulted in embryonic lethality, significant growth retardation and several developmental defects. Loss of Suz12 was shown to result in absence of di- and tri-methylated H3K27 in the ko embryos. In another study cited (Miro et al - PMID: 19535498) heterozygous mice (replacement of exons 12-16 with a lacZ gene and neo cassette) displayed variable CNS defects with incomplete penetrance.

The role of the PRC2 complex and the phenotypes related to mutations in genes encoding its core components, are discussed in PMID: 31724824 (also by Cyrus et al, 2019).

SUZ12 is not associated with any phenotype in OMIM. In G2P it is included in the DD panel associated with Weaver-like overgrowth syndrome (disease confidence : confirmed). The gene is also included in gene panels for ID offered by some diagnostic laboratories (eg. GeneDx).
Sources: Literature
Intellectual disability v3.0 SUZ12 Konstantinos Varvagiannis changed review comment from: ID can be a feature in individuals heterozygous for SUZ12 pathogenic variants. 13 affected individuals (from 12 families) have been reported:

[1] PMID 28229514 (Imagawa et al, 2017) : 1 individual
[2] PMID 30019515 (Imagawa et al, 2018) : 2 further unrelated subjects
[3] PMID 31736240 (Cyrus et al, 2019) : 10 newly diagnosed subjects (from 9 families)

Reviewed by Cyrus et al, features observed in more than half of the (13) affected individuals included prenatal and/or postnatal overgrowth (in some only prenatal, others only postnatal, others did not manifest overgrowth at all), some suggestive facial features (eg. prominent forehead, hypertelorism, downslanting palpebral fissures, round face, broad/low nasal bridge), DD and ID (the latter in 7/13, in most cases mild), advanced bone age, musculoskeletal abnormalities and cryptorchidism. Less frequent features included brain MRI abnormalities (eg. CC hypoplasia/agenesis, etc.), umbilical hernias, respiratory abnormalities, cardiac anomalies (in one).

All were diagnosed with WES/WGS/panel testing, with few having additional findings upon this or prior testing (eg. CNVs/SNVs).

SUZ12 encodes one of the 4 core proteins of the PRC2 complex (the 3 other being encoded by EZH1/2, EED and RBBP4/7). The complex has a methyltransferase activity, catalyzing addition of up to 3 methyl groups on histone 3 at lysine residue 27 (H3K27), leading to chromatin compaction and further to gene silencing.

Mutations in genes encoding 2 other core components of the PRC2 complex - namely EZH2 and EED - cause Weaver and Cohen-Gibson syndrome with overlapping phenotype incl. overgrowth, advanced bone age, craniofacial features and DD/ID.

The SET domain of EZH1/2 and EED as well as the VEFS domain of SUZ12 are contributing to the catalytic activity.

SUZ12 variants reported to date include missense and pLoF variants (frameshift, nonsense, splice site ones) predicted to disrupt or eliminate the VEFS-box domain [almost all missense within this domain with the exception of one proximal to it (Arg535Gln) / pLoF causing truncation prior or within this domain (Arg654Ter might be an exception)] {NP_056170.2}.

Variants either occurred de novo or were inherited (~1/3), on some occasions from a mildly affected parent. Parental mosaicism has also been reported (eg. in ref1, and one or possibly two additional families in ref3).

Some preliminary assumptions on possible genotype-phenotype correlations (for overgrowth and ID related to missense/pLoF variants) are discussed in ref3.

SUZ12 is also be deleted in some patients with NF1 deletion (and a diagnosis of neurofibromatosis type 1). Deletion of SUZ12 has been proposed to contribute to the phenotype of these individuals (eg. overgrowth, cognitive development, facial features). [Discussed in ref1].

Functional studies have been carried out only in the first report (ref1) and demonstrated decreased trimethylation of H3K27 in the case of a missense variant. Overall a partial loss-of-function mechanism has been proposed for the variants.

Mouse models: An study by Pasini et al (PMID: 15385962) did not report phenotypic differences between wt and heterozygous Suz12 knockout mice (gene-trap vector) as for size, morphology and fertility. Total knockout resulted in embryonic lethality, significant growth retardation and several developmental defects. Loss of Suz12 was shown to result in absence of di- and tri-methylated H3K27 in the ko embryos. In another study cited (Miro et al - PMID: 19535498) heterozygous mice (replacement of exons 12-16 with a lacZ gene and neo cassette) displayed variable CNS defects with incomplete penetrance.

The role of the PRC2 complex and the phenotypes related to mutations in genes encoding its core components, are discussed in PMID: 31724824 (also by Cyrus et al, 2019).

SUZ12 is not associated with any phenotype in OMIM. In G2P it is included in the DD panel associated with Weaver-like overgrowth syndrome (disease confidence : confirmed). The gene is also included in gene panels for ID offered by some diagnostic laboratories (eg. GeneDx).
Sources: Literature; to: ID can be a feature in individuals heterozygous for SUZ12 pathogenic variants. 13 affected individuals (from 12 families) have been reported:

[1] PMID 28229514 (Imagawa et al, 2017) : 1 individual
[2] PMID 30019515 (Imagawa et al, 2018) : 2 further unrelated subjects
[3] PMID 31736240 (Cyrus et al, 2019) : 10 additional subjects (from 9 families)

Reviewed by Cyrus et al, features observed in more than half of the (13) affected individuals included prenatal and/or postnatal overgrowth (in some only prenatal, others only postnatal, others did not manifest overgrowth at all), some suggestive facial features (eg. prominent forehead, hypertelorism, downslanting palpebral fissures, round face, broad/low nasal bridge), DD and ID (the latter in 7/13, in most cases mild), advanced bone age, musculoskeletal abnormalities and cryptorchidism. Less frequent features included brain MRI abnormalities (eg. CC hypoplasia/agenesis, etc.), umbilical hernias, respiratory abnormalities, cardiac anomalies (in one).

All were diagnosed with WES/WGS/panel testing, with few having additional findings upon this or prior testing (eg. CNVs/SNVs).

SUZ12 encodes one of the 4 core proteins of the PRC2 complex (the 3 other being encoded by EZH1/2, EED and RBBP4/7). The complex has a methyltransferase activity, catalyzing addition of up to 3 methyl groups on histone 3 at lysine residue 27 (H3K27), leading to chromatin compaction and further to gene silencing.

Mutations in genes encoding 2 other core components of the PRC2 complex - namely EZH2 and EED - cause Weaver and Cohen-Gibson syndrome with overlapping phenotype incl. overgrowth, advanced bone age, craniofacial features and DD/ID.

The SET domain of EZH1/2 and EED as well as the VEFS domain of SUZ12 are contributing to the catalytic activity.

SUZ12 variants reported to date include missense and pLoF variants (frameshift, nonsense, splice site ones) predicted to disrupt or eliminate the VEFS-box domain [almost all missense within this domain with the exception of one proximal to it (Arg535Gln) / pLoF causing truncation prior or within this domain (Arg654Ter might be an exception)] {NP_056170.2}.

Variants either occurred de novo or were inherited (~1/3), on some occasions from a mildly affected parent. Parental mosaicism has also been reported (eg. in ref1, and one or possibly two additional families in ref3).

Some preliminary assumptions on possible genotype-phenotype correlations (for overgrowth and ID related to missense/pLoF variants) are discussed in ref3.

SUZ12 is also be deleted in some patients with NF1 deletion (and a diagnosis of neurofibromatosis type 1). Deletion of SUZ12 has been proposed to contribute to the phenotype of these individuals (eg. overgrowth, cognitive development, facial features). [Discussed in ref1].

Functional studies have been carried out only in the first report (ref1) and demonstrated decreased trimethylation of H3K27 in the case of a missense variant. Overall a partial loss-of-function mechanism has been proposed for the variants.

Mouse models: A study by Pasini et al (PMID: 15385962) did not report phenotypic differences between wt and heterozygous Suz12 knockout mice (gene-trap vector) as for size, morphology and fertility. Total knockout resulted in embryonic lethality, significant growth retardation and several developmental defects. Loss of Suz12 was shown to result in absence of di- and tri-methylated H3K27 in the ko embryos. In another study cited (Miro et al - PMID: 19535498) heterozygous mice (replacement of exons 12-16 with a lacZ gene and neo cassette) displayed variable CNS defects with incomplete penetrance.

The role of the PRC2 complex and the phenotypes related to mutations in genes encoding its core components, are discussed in PMID: 31724824 (also by Cyrus et al, 2019).

SUZ12 is not associated with any phenotype in OMIM. In G2P it is included in the DD panel associated with Weaver-like overgrowth syndrome (disease confidence : confirmed). The gene is also included in gene panels for ID offered by some diagnostic laboratories (eg. GeneDx).
Sources: Literature
Intellectual disability v3.0 SUZ12 Konstantinos Varvagiannis gene: SUZ12 was added
gene: SUZ12 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: SUZ12 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SUZ12 were set to 28229514; 30019515; 31736240; 15385962; 19535498; 31724824
Phenotypes for gene: SUZ12 were set to Overgrowth; Global developmental delay; Intellectual disability; Accelerated skeletal maturation; Abnormality of the skeletal system; Abnormality of the genitourinary system; Abnormality of the corpus callosum; Abnormality of the respiratory system; Abnormality of the abdominal wall
Penetrance for gene: SUZ12 were set to unknown
Review for gene: SUZ12 was set to GREEN
Added comment: ID can be a feature in individuals heterozygous for SUZ12 pathogenic variants. 13 affected individuals (from 12 families) have been reported:

[1] PMID 28229514 (Imagawa et al, 2017) : 1 individual
[2] PMID 30019515 (Imagawa et al, 2018) : 2 further unrelated subjects
[3] PMID 31736240 (Cyrus et al, 2019) : 10 newly diagnosed subjects (from 9 families)

Reviewed by Cyrus et al, features observed in more than half of the (13) affected individuals included prenatal and/or postnatal overgrowth (in some only prenatal, others only postnatal, others did not manifest overgrowth at all), some suggestive facial features (eg. prominent forehead, hypertelorism, downslanting palpebral fissures, round face, broad/low nasal bridge), DD and ID (the latter in 7/13, in most cases mild), advanced bone age, musculoskeletal abnormalities and cryptorchidism. Less frequent features included brain MRI abnormalities (eg. CC hypoplasia/agenesis, etc.), umbilical hernias, respiratory abnormalities, cardiac anomalies (in one).

All were diagnosed with WES/WGS/panel testing, with few having additional findings upon this or prior testing (eg. CNVs/SNVs).

SUZ12 encodes one of the 4 core proteins of the PRC2 complex (the 3 other being encoded by EZH1/2, EED and RBBP4/7). The complex has a methyltransferase activity, catalyzing addition of up to 3 methyl groups on histone 3 at lysine residue 27 (H3K27), leading to chromatin compaction and further to gene silencing.

Mutations in genes encoding 2 other core components of the PRC2 complex - namely EZH2 and EED - cause Weaver and Cohen-Gibson syndrome with overlapping phenotype incl. overgrowth, advanced bone age, craniofacial features and DD/ID.

The SET domain of EZH1/2 and EED as well as the VEFS domain of SUZ12 are contributing to the catalytic activity.

SUZ12 variants reported to date include missense and pLoF variants (frameshift, nonsense, splice site ones) predicted to disrupt or eliminate the VEFS-box domain [almost all missense within this domain with the exception of one proximal to it (Arg535Gln) / pLoF causing truncation prior or within this domain (Arg654Ter might be an exception)] {NP_056170.2}.

Variants either occurred de novo or were inherited (~1/3), on some occasions from a mildly affected parent. Parental mosaicism has also been reported (eg. in ref1, and one or possibly two additional families in ref3).

Some preliminary assumptions on possible genotype-phenotype correlations (for overgrowth and ID related to missense/pLoF variants) are discussed in ref3.

SUZ12 is also be deleted in some patients with NF1 deletion (and a diagnosis of neurofibromatosis type 1). Deletion of SUZ12 has been proposed to contribute to the phenotype of these individuals (eg. overgrowth, cognitive development, facial features). [Discussed in ref1].

Functional studies have been carried out only in the first report (ref1) and demonstrated decreased trimethylation of H3K27 in the case of a missense variant. Overall a partial loss-of-function mechanism has been proposed for the variants.

Mouse models: An study by Pasini et al (PMID: 15385962) did not report phenotypic differences between wt and heterozygous Suz12 knockout mice (gene-trap vector) as for size, morphology and fertility. Total knockout resulted in embryonic lethality, significant growth retardation and several developmental defects. Loss of Suz12 was shown to result in absence of di- and tri-methylated H3K27 in the ko embryos. In another study cited (Miro et al - PMID: 19535498) heterozygous mice (replacement of exons 12-16 with a lacZ gene and neo cassette) displayed variable CNS defects with incomplete penetrance.

The role of the PRC2 complex and the phenotypes related to mutations in genes encoding its core components, are discussed in PMID: 31724824 (also by Cyrus et al, 2019).

SUZ12 is not associated with any phenotype in OMIM. In G2P it is included in the DD panel associated with Weaver-like overgrowth syndrome (disease confidence : confirmed). The gene is also included in gene panels for ID offered by some diagnostic laboratories (eg. GeneDx).
Sources: Literature
Intellectual disability v3.0 Rebecca Foulger promoted panel to version 3.0
Intellectual disability v2.1143 AFF3 Konstantinos Varvagiannis changed review comment from: Voisin et al. (2019 - https://doi.org/10.1101/693937) report on 10 individuals with de novo missense AFF3 variants affecting a 9-amino-acid sequence (degron) important for the protein's degradation and summarize the phenotype of an additional individual previously described by Steichen-Gersdorf et al. (2008 - PMID: 18616733) with a 500 kb affecting only AFF3 (LAF4) and removing also this sequence.

The phenotype of missense variants consisted of kidney anomalies, mesomelic dysplasia, seizures, hypertrichosis, intellectual disability and pulmonary problems and was overlapping with that of the deletion. [10 of 11 subjects exhibited severe developmental epileptic encephalopathy].

9 probands harbored missense variants affecting the codon 258 while one individual had a variant affecting codon 260 [c.772G>T or p.Ala258Ser (x2), c.772G>A or p.Ala258Thr (x6), c.773C>T or p.Ala258Val (x1) and c.779T>G or p.(Val260Gly) (x1) - NM_001025108.1 / NP_001020279.1]. The deletion removed exons 4-13.

AFF1-4 are ALF transcription factor paralogs, components of the transcriptional super elongation complex regulating expression of genes involved in neurogenesis and development.

Using HEK293T cells expressing FLAG-tagged AFF3 (and AFF4) wt or mutants, accumulation of mutated forms was shown upon immunoblot.

Aff3+/- and/or -/- mice exhibit skeletal defects. These were more pronounced in homozygous mice which demonstrated also some elements in favor of kidney dysfunction and/or metabolic deregulation and possible neurological dysfunction (signs of impaired hearing and diminished grip strength). Homozygous mice had CNS anomalies (enlarged lateral ventricles and decreased corpus callosum size) similar to some affected individuals, although these were not observed in another Aff3-/- model. Knock-in mice modeling the microdeletion and the Ala258Thr variant displayed lower mesomelic limb deformities and early lethality respectively [cited PMIDs : 21677750, 25660031, knock-in model was part of the present study].

Accumulation of the protein in zebrafish (by overexpression of the human wt AFF3 mRNA), led to morphological defects.

Reanalysis of transcriptome data from previously generated HEK293T cell lines knocked down for AFF2, AFF3 and AFF4 by shRNAs (study) suggested that these transcription factors are not redundant.

Finally, CHOPS syndrome (#616368) due to mutations of AFF4 also leading to increased protein stability presents a partially overlapping phenotype (incl. cognitive impairment) to that of AFF3.
----
Shimizu et al. (8/2019 - PMID: 31388108) describe an additional individual with de novo AFF3 missense variant. The phenotype overlaps with that summarized by Voisin et al. incl. mesomelic dysplasia with additional skeletal anomalies, bilateral kidney hypoplasia and severe DD at the age of 2.5 years. Seizures and pulmonary problems were not observed. Although a different RefSeq is used the variant is among those also reported by Voisin et al. [NM_002285.2:c.697G>A (p.Ala233Thr) corresponding to NM_001025108.1:c.772G>A (p.Ala258Thr)].
----
In G2P, AFF3 is associated with Skeletal dysplasia with severe neurological disease (disease confidence : probable / ID and seizures among the assigned phenotypes). There is no associated phenotype in OMIM.
Some diagnostic laboratories include AFF3 in their ID panel (eg. among the many co-authors' affiliations GeneDx and Victorian Clinical Genetics - which was already listed as source for AFF3 in the current panel).
----
As a result this gene can be considered for upgrade to green (relevant phenotype and severity, sufficient cases, evidence for accumulation similar to AFF4, animal models, etc) or amber (pending publication of the article).

[Review modified to add additional reference/case report]; to: Voisin et al. (2019 - https://doi.org/10.1101/693937) report on 10 individuals with de novo missense AFF3 variants affecting a 9-amino-acid sequence (degron) important for the protein's degradation and summarize the phenotype of an additional individual previously described by Steichen-Gersdorf et al. (2008 - PMID: 18616733) with a 500 kb deletion affecting only AFF3 (LAF4) and removing also this sequence.

The phenotype of missense variants consisted of kidney anomalies, mesomelic dysplasia, seizures, hypertrichosis, intellectual disability and pulmonary problems and was overlapping with that of the deletion. [10 of 11 subjects exhibited severe developmental epileptic encephalopathy].

9 probands harbored missense variants affecting the codon 258 while one individual had a variant affecting codon 260 [c.772G>T or p.Ala258Ser (x2), c.772G>A or p.Ala258Thr (x6), c.773C>T or p.Ala258Val (x1) and c.779T>G or p.(Val260Gly) (x1) - NM_001025108.1 / NP_001020279.1]. The deletion removed exons 4-13.

AFF1-4 are ALF transcription factor paralogs, components of the transcriptional super elongation complex regulating expression of genes involved in neurogenesis and development.

Using HEK293T cells expressing FLAG-tagged AFF3 (and AFF4) wt or mutants, accumulation of mutated forms was shown upon immunoblot.

Aff3+/- and/or -/- mice exhibit skeletal defects. These were more pronounced in homozygous mice which demonstrated also some elements in favor of kidney dysfunction and/or metabolic deregulation and possible neurological dysfunction (signs of impaired hearing and diminished grip strength). Homozygous mice had CNS anomalies (enlarged lateral ventricles and decreased corpus callosum size) similar to some affected individuals, although these were not observed in another Aff3-/- model. Knock-in mice modeling the microdeletion and the Ala258Thr variant displayed lower mesomelic limb deformities and early lethality respectively [cited PMIDs : 21677750, 25660031, knock-in model was part of the present study].

Accumulation of the protein in zebrafish (by overexpression of the human wt AFF3 mRNA), led to morphological defects.

Reanalysis of transcriptome data from previously generated HEK293T cell lines knocked down for AFF2, AFF3 and AFF4 by shRNAs (study) suggested that these transcription factors are not redundant.

Finally, CHOPS syndrome (#616368) due to mutations of AFF4 also leading to increased protein stability presents a partially overlapping phenotype (incl. cognitive impairment) to that of AFF3.
----
Shimizu et al. (8/2019 - PMID: 31388108) describe an additional individual with de novo AFF3 missense variant. The phenotype overlaps with that summarized by Voisin et al. incl. mesomelic dysplasia with additional skeletal anomalies, bilateral kidney hypoplasia and severe DD at the age of 2.5 years. Seizures and pulmonary problems were not observed. Although a different RefSeq is used the variant is among those also reported by Voisin et al. [NM_002285.2:c.697G>A (p.Ala233Thr) corresponding to NM_001025108.1:c.772G>A (p.Ala258Thr)].
----
In G2P, AFF3 is associated with Skeletal dysplasia with severe neurological disease (disease confidence : probable / ID and seizures among the assigned phenotypes). There is no associated phenotype in OMIM.
Some diagnostic laboratories include AFF3 in their ID panel (eg. among the many co-authors' affiliations GeneDx and Victorian Clinical Genetics - which was already listed as source for AFF3 in the current panel).
----
As a result this gene can be considered for upgrade to green (relevant phenotype and severity, sufficient cases, evidence for accumulation similar to AFF4, animal models, etc) or amber (pending publication of the article).

[Review modified to add additional reference/case report]
Intellectual disability v2.1143 Rebecca Foulger List of related panels changed from Coarse facial features including Coffin-Siris-like disorders; ID; Moderate; severe or profound intellectual disability; Schizophrenia plus additional features; Intellectual disability - microarray; fragile X and sequencing to Coarse facial features including Coffin-Siris-like disorders; ID; Moderate; severe or profound intellectual disability; Schizophrenia plus additional features; Intellectual disability - microarray; fragile X and sequencing; R29
Panel types changed to Rare Disease 100K; GMS Rare Disease Virtual; Component Of Super Panel; GMS signed-off
Intellectual disability v2.1141 AKAP17A Rebecca Foulger Mode of inheritance for gene: AKAP17A was changed from BIALLELIC, autosomal or pseudoautosomal to Unknown
Intellectual disability v2.1140 AKAP17A Rebecca Foulger Deleted their review
Intellectual disability v2.1140 AKAP17A Rebecca Foulger Deleted their comment
Intellectual disability v2.1140 AKAP17A Rebecca Foulger changed review comment from: Comment on mode of inheritance: Set MOI to BIALLELIC. Pseudoautosomal region 1. Mode of inheritance has not been thoroughly checked, but assumed to be biallelic.; to: Comment on mode of inheritance: This gene is in the pseudoautosomal region shared between chromosomes X and Y. The mode of inheritance should therefore be set to Biallelic or Monoallelic once more cases establish the inheritance pattern.
Intellectual disability v2.1140 CSF2RA Rebecca Foulger Added comment: Comment on mode of inheritance: Changed MOI to BIALLELIC. Pseudoautosomal region 1. Mode of inheritance has been checked.
Intellectual disability v2.1140 CSF2RA Rebecca Foulger Mode of inheritance for gene: CSF2RA 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 BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v2.1139 AKAP17A Rebecca Foulger Added comment: Comment on mode of inheritance: Set MOI to BIALLELIC. Pseudoautosomal region 1. Mode of inheritance has not been thoroughly checked, but assumed to be biallelic.
Intellectual disability v2.1139 AKAP17A Rebecca Foulger Mode of inheritance for gene: AKAP17A was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v2.1138 FA2H Rebecca Foulger Phenotypes for gene: FA2H were changed from Spastic paraplegia 35, autosomal recessive, 612319 to Spastic paraplegia 35, autosomal recessive, 612319; spastic paraplegia with ID; cognitive defects; Seizures
Intellectual disability v2.1137 FA2H Rebecca Foulger Publications for gene: FA2H were set to 24833714; 20104589
Intellectual disability v2.1136 FA2H Rebecca Foulger Classified gene: FA2H as Green List (high evidence)
Intellectual disability v2.1136 FA2H Rebecca Foulger Added comment: Comment on list classification: Upgraded from Amber to Green based on Green review by Alistair Pagnamenta: PMID:31135052 analysed a cohort of 19 cases with biallelic FA2H variants. Phenotype includes spastic paraplegia associated with ID: mild cognitive deficits were noted from childhood in 93% of cases, and were considered progressive in all but two cases.
Intellectual disability v2.1136 FA2H Rebecca Foulger Gene: fa2h has been classified as Green List (High Evidence).
Intellectual disability v2.1135 TRAPPC4 Konstantinos Varvagiannis gene: TRAPPC4 was added
gene: TRAPPC4 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: TRAPPC4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TRAPPC4 were set to 31794024
Phenotypes for gene: TRAPPC4 were set to Feeding difficulties; Progressive microcephaly; Intellectual disability; Seizures; Spastic tetraparesis; Abnormality of the face; Scoliosis; Cortical visual impairment; Hearing impairment
Penetrance for gene: TRAPPC4 were set to Complete
Review for gene: TRAPPC4 was set to GREEN
Added comment: Van Bergen et al. (2019 - PMID: 31794024) report on 7 affected individuals from 3 famillies (only 1 of which consanguineous), all homozygous for a TRAPPC4 splicing variant.

Overlapping features included feeding difficulties, progressive microcephaly, severe to profound developmental disability (7/7 - DD also prior to the onset of seizures / regression also reported in 3), epilepsy (7/7 - onset in the first year), spastic quadriparesis. Other findings in some/few incl. scoliosis, cortical visual and hearing impairment. Some facial features were shared (eg. bitemporal narrowing, long philtrum, open mouth with thin tented upper lip, pointed chin, etc). Brain imaging demonstrated abnormalities in those performed (among others cerebral with/without cerebellar atrophy).

Work-up prior to exome sequencing was normal (highly variable incl. metabolic testing, CMA, MECP2, CDKL5, mitochondrial depletion studies, etc).

Exome of affected individuals (and parents +/- affected sibs in some families) revealed a homozygous TRAPPC4 splicing variant [NM_016146.5:c.454+3A>G / chr11:g.118890966A>G (hg19)]. Sanger sequencing confirmed variant in affecteds, heterozygosity in parents and compatible genotypes with disease status in sibs/other members.

Families were of Caucasian/Turkish and French-Canadian ethnicities. SNP array to compare haplotypes between affecteds in 2 families did not reveal a shared haplotype (/founder effect) and the variant is present in gnomAD (68/281054 - no hmz) in many populations (European/Asian/African/Latino) [https://gnomad.broadinstitute.org/variant/11-118890966-A-G].

mRNA studies in fibroblasts from an affected individual confirmed the splicing defect (2 RT-PCR products corresponding to wt and a shorter due to skipping of exon 3, the latter further confirmed by Sanger sequencing. The shorter transcript is not present in controls). qPCR revealed that the normal transript in patient fibroblasts was present at 6% of the level observed in control fibroblasts (or 54% in the case of a heterozygote parent compared to controls).

Western blot in patient fibroblasts, revealed presence of full-length protein in significantly reduced levels compared to fibroblasts from carrier parents or controls. There was no band using an antibody targeting the N-terminal region of the protein prior to exon 3, suggesting that NMD applies (skipping of ex3 is also predicted to lead to frameshift).

TRAPPC4 encodes one of the core proteins of the TRAPP complex. Use of different accessory proteins leads to formation of 2 distinct complexes (TRAPPII / III). The complex has an important role in intracellular trafficking. Both TRAPPII & TRAPPIII have a function in the secretory pathway, while complex III has a role also in autophagy. Core proteins are important for the complex stability. The TRAPP complex serves as a GEF for Ypt/Rab GTPases [several refs in article].

Mutations in genes for other proteins of the complex lead to neurodevelopmental disorders with associated ID ('TRAPPopathies' used by the authors / TRAPPC12, C6B, C9 green in the current panel).

Western blot suggested that levels of other TRAPP subunits (TRAPPC2 or C12) under denaturing conditions, although PAGE/size exclusion chromatography suggested that the levels of fully-assembled TRAPP complexes were lower in affected individuals.

Studies in patient fibroblasts showed a secretory defect (between ER, Golgi and the plasma membrane) which was restored upon lentiviral transduction with wt TRAPPC4 construct. Basal and starvation-induced autophagy were also impaired in patient fibroblasts (increased LC3 marker and LC3-positive structures / impaired co-localization with lysosomes) partly due to defective autophagosome formation (/sealing).

TRAPPC4 is the human orthologue of the yeast Trs23. In a yeast model of reduced Trs23 (due to temperature instability) the authors demonstrated impaired assembly of the TRAPP core. The yeast model recapitulated the autophagy as well as well as the secretory defect observed in patient fibroblasts.
Sources: Literature
Intellectual disability v2.1135 SNX27 Konstantinos Varvagiannis gene: SNX27 was added
gene: SNX27 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: SNX27 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SNX27 were set to 25894286; 31721175; 21300787; 23524343
Phenotypes for gene: SNX27 were set to Generalized hypotonia; Global developmental delay; Intellectual disability; Seizures
Penetrance for gene: SNX27 were set to Complete
Review for gene: SNX27 was set to GREEN
gene: SNX27 was marked as current diagnostic
Added comment: Evidence from 2 publications suggests that DD, ID and seizures are part of the phenotype of individuals with biallelic SNX27 pathogenic variants :
---------
Damseh, Danson et al (2015 - PMID: 25894286) first reported on a consanguineous family with 4 affected sibs, homozygous for an SNX27 pathogenic variant. Features incl. hypotonia soon after birth, failure to thrive, severely delayed psychomotor development with no milestone acquisition, occurrence of myoclonic seizures with 3 individuals deceased early. Exome sequencing in one revealed a few candidate variants, with an SNX27 frameshift one [NM_030918.6:c.515_516del - p.(His172Argfs*6) / absent from ExAC] being the only retained following Sanger segregation studies. Using fibroblasts from an affected individual, Western blot with an antibody which would also bind prior to the truncation site, was consistent with dramatically reduced/absent SNX27 truncated mutant protein. Protein levels of VPS35, a component of the retromer responsible for direct cargo binding (not mediated by a cargo adaptor as SNX27), were normal.
---------
Parente et al (2019 - PMID: 31721175) reported on a 13-year-old male with motor and language delay, ADHD, ID (kindergarten academic level at the age of 13) and seizures with onset at the age of 9 years (GTC, with abnormal EEG and postical SV tachycardia). Variable physical findings were reported. White matter hyperintesities were noted upon initial brain MRI (but were less marked in subsequent ones). Initial genetic testing (Alexander's disease, CMA, FMR1) was normal. Exome revealed compound heterozygosity for 2 SNX27 variants (NM_030918.5/NM_001330723.1 both apply c.510C>G - p.Tyr170* and c.1295G>A - p.Cys432Tyr) each inherited from healthy carrier parents. There were no other potentially causative variants. A parental history of - isolated - late onset seizures was reported (so this individual may not be considered for the seizure phenotype here).

The authors also reported on a further 31-year old affected male. This individual had infantile hypotonia, poor eye contact with subsequent significant DD, seizures (febrile/afebrile T-C with onset at the age of 14m) and ID estimated in the severe range. Variable - though somewhat different - physical findings were reported. Initial work-up included basic metabolic testing, standard karyotype, FISH for 15q11 and subtelomeric regions and PHF6 genetic testing - all normal. Exome (and subsequent Sanger confirmation/parental studies) revealed compound heterozygosity for a missense and a frameshift variant (c.989G>A / p.Arg330His and c.782dupT / p.Leu262Profs*6 same in NM_001330723.1, NM_030918.6).
---------
SNX27 encodes sorting nexin 27, a cargo adaptor for the retromer. The latter is a multi-protein complex essential for regulating the retrieval and recycling of transmembrane cargos from endosomes to the trans-Golgi network or the plasma membrane [Lucas et al 2016 - PMID: 27889239 / McNally et al 2018 - PMID: 30072228].

As summarized by Parente et al, the encoded protein by regulating composition of the cell surface influences several processes eg. neuronal excitability, synaptic plasticity, Wnt signaling etc. It has been shown to interact with surface receptors and their ligands including GIRK channels, 5-HT4, ionotropic glutamate receptors (incl. NMDA- and AMPA-type receptors) and mGluR5 [several refs. provided].

Knockout of Snx27 in mice resulted in embryonic lethality (16% hmz of the 25% expected), severe postnatal growth retardation and death within the first 3 weeks. Snx27(+/-) mice have normal neuroanatomy but exhibit cognitive deficits (in learning and memory) and defects in synaptic function/plasticity with reduced amounts of NMDA and AMPA receptors (Cai et al - PMID: 21300787, Wang et al - PMID: 23524343).
---------
The gene is included in gene panels for ID offered by some diagnostic laboratories (eg. GeneDx) and a current primary ID gene in SysID. There is no associated phenotype in OMIM/G2P.
Sources: Literature
Intellectual disability v2.1135 FA2H Alistair Pagnamenta reviewed gene: FA2H: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 31135052, 20104589; Phenotypes: HSP, ID, Seizures; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v2.1135 SLC5A6 Konstantinos Varvagiannis changed review comment from: SLC5A6 encodes the sodium dependent multivitamin transporter (SMVT), a transporter of biotin, pantothenate and lipoate. The transporter has a major role in vitamin uptake in the digestive system (among others is the sole transporter for intestinal uptake of biotin which is not synthesized and but must be obtained from exogenous sources) as well as transport across the blood-brain barrier (SMVT being responsible for 89% of biotin transport) [several refs provided by Subramanian et al and Byrne et al].

4 affected individuals from 3 families have been reported.

Subramanian et al (2017 - PMID: 27904971) et al reported on a girl with feeding difficulties and failure to thrive (requiring nasogastric tube placement), microcephaly, DD (at 15m developmental age corresponding to 6m with features suggestive of spastic cerebral palsy), occurrence of multiple infections, osteoporosis and pathologic bone fractures. MRIs suggested brain atrophy, thin CC and hypoplasia of the pons. Metabolic (AA, OA) investigations and array-CGH were normal. Whole exome sequencing revealed presence of a missense (Arg123Leu - RefSeq not provided) and a nonsense (Arg94Ter) SLC5A6 variant. Serum biotin was normal although - at the time - the child was on parenteral and G-T nutrition. Following administration of biotin, pantothenic acid and lipoic acid the child demonstrated among others improved motor and verbal skills, head growth and normalization of immunoglobulin levels. Transfection of mutants in human derived intestinal HuTu-80 cells and brain U87 cells was carried out and a 3H-biotin assay showed no induction in biotin uptake confirming impaired functionality of the transporter. While wt protein displayed normal expression/membrane localization, Arg94Ter was poorly expressed with ectopic localization (cytoplasm). Arg123Leu was retained predominantly intracellularly, probably in the ER as was further supported by colocalization with DsRed-ER. Evidence from the literature is provided that deficiencies of the specific vitamins explain the clinical features (DD, microcephaly, immunological defect, osteopenia, etc).

Schwantje et al (2019 - PMID: 31392107) described a girl with severe feeding problems, vomiting with blood (suspected Mallory-Weiss syndrome), poor weight gain and delayed gross motor development. The child presented an episode of gastroenteritis associated with reduced consciousness, circulatory insufficiency and metabolic derangement (hypoglycemia, severe metabolic acidosis, hyperammonemia, mild lactate elevation, ketonuria). Investigations some months prior to the admission (?) were suggestive of a metabolic disorder due to elevated plasma C3-carnitine, C5-OH-carnitine and elevated urinary excretion of 3-OH-isovaleric acid (biotinidase deficiency was considered in the DD but enzymatic activity was only marginally decreased). Biotin supplementation was initiated. Trio-exome sequencing (at 3yrs) demonstrated compound heterozygosity for 2 frameshift variants [NM_021095.2:c.422_423del / p.(Val141Alafs*34) and c.1865_1866del]. Following this result, increase of biotin supplementation and introduction of pantothenic acid, GI symptoms (incl. chronic diarrhea) resolved and the child displayed improved appetite and growth, yet a stable motor delay. The authors cite previous studies of conditional ko mice, displaying intestinal mucosal abnormalities and growth defects (similar to the child's problems), prevented by biotin and pantothenic acid supplementation.

Byrne et al (2019 - PMID: 31754459) reported on a sibling pair with severe motor/speech developmental regression following a plateau (at 12m and 14m), development of ataxia and dyskinetic movements (both), seizures (one). Feeding difficulties, reflux and failure to thrive required N-G/gastrostomy feeding while both presented GI hemorrhage (in the case of the older sib, lethal). Other features in the youngest sib included brain MRI abnormalities (cerebral/cerebellar atrophy, thin CC, etc) and IgG deficiency. Biochemical, single-gene testing and mtDNA sequencing were not diagnostic. Exome in one, revealed presence of a frameshift [c.422_423del as above] and a missense variant (Arg400Thr). Sanger sequencing confirmed variants in both sibs and heterozygosity in parents. HeLa cells transfected with empty vector, wt or mut expression constructs confirmed significantly decreased 3H-biotin uptake for mut constructs compared to wt (and similar to empty vector). Parenteral triple vitamin replacement at the age of ~7 years resulted in improved overall condition, regain of some milestones, attenuation of vomiting, and resolution of peripheral neuropathy. Seizure were well-controlled (as was the case before treatment) despite persistence of epileptiform discharges. Again the authors cite studies of conditional (intestine-specific) SLC5A6 ko mice, with those viable (~1/3) demonstrating growth retardation, decreased boned density and GI abnormalities (similar to affected individuals). The phenotype could be rescued by oversupplementation of biotin and pantothenic acid (PMIDs cited: 23104561, 29669219).

[Please consider inclusion in other relevant panels eg. metabolic disorders]
Sources: Literature; to: SLC5A6 encodes the sodium dependent multivitamin transporter (SMVT), a transporter of biotin, pantothenate and lipoate. The transporter has a major role in vitamin uptake in the digestive system (among others is the sole transporter for intestinal uptake of biotin which is not synthesized but must be obtained from exogenous sources) as well as transport across the blood-brain barrier (SMVT being responsible for 89% of biotin transport) [several refs provided by Subramanian et al and Byrne et al].

4 affected individuals from 3 families have been reported.

Subramanian et al (2017 - PMID: 27904971) et al reported on a girl with feeding difficulties and failure to thrive (requiring nasogastric tube placement), microcephaly, DD (at 15m developmental age corresponding to 6m with features suggestive of spastic cerebral palsy), occurrence of multiple infections, osteoporosis and pathologic bone fractures. MRIs suggested brain atrophy, thin CC and hypoplasia of the pons. Metabolic (AA, OA) investigations and array-CGH were normal. Whole exome sequencing revealed presence of a missense (Arg123Leu - RefSeq not provided) and a nonsense (Arg94Ter) SLC5A6 variant. Serum biotin was normal although - at the time - the child was on parenteral and G-T nutrition. Following administration of biotin, pantothenic acid and lipoic acid the child demonstrated among others improved motor and verbal skills, head growth and normalization of immunoglobulin levels. Transfection of mutants in human derived intestinal HuTu-80 cells and brain U87 cells was carried out and a 3H-biotin assay showed no induction in biotin uptake confirming impaired functionality of the transporter. While wt protein displayed normal expression/membrane localization, Arg94Ter was poorly expressed with ectopic localization (cytoplasm). Arg123Leu was retained predominantly intracellularly, probably in the ER as was further supported by colocalization with DsRed-ER. Evidence from the literature is provided that deficiencies of the specific vitamins explain the clinical features (DD, microcephaly, immunological defect, osteopenia, etc).

Schwantje et al (2019 - PMID: 31392107) described a girl with severe feeding problems, vomiting with blood (suspected Mallory-Weiss syndrome), poor weight gain and delayed gross motor development. The child presented an episode of gastroenteritis associated with reduced consciousness, circulatory insufficiency and metabolic derangement (hypoglycemia, severe metabolic acidosis, hyperammonemia, mild lactate elevation, ketonuria). Investigations some months prior to the admission (?) were suggestive of a metabolic disorder due to elevated plasma C3-carnitine, C5-OH-carnitine and elevated urinary excretion of 3-OH-isovaleric acid (biotinidase deficiency was considered in the DD but enzymatic activity was only marginally decreased). Biotin supplementation was initiated. Trio-exome sequencing (at 3yrs) demonstrated compound heterozygosity for 2 frameshift variants [NM_021095.2:c.422_423del / p.(Val141Alafs*34) and c.1865_1866del]. Following this result, increase of biotin supplementation and introduction of pantothenic acid, GI symptoms (incl. chronic diarrhea) resolved and the child displayed improved appetite and growth, yet a stable motor delay. The authors cite previous studies of conditional ko mice, displaying intestinal mucosal abnormalities and growth defects (similar to the child's problems), prevented by biotin and pantothenic acid supplementation.

Byrne et al (2019 - PMID: 31754459) reported on a sibling pair with severe motor/speech developmental regression following a plateau (at 12m and 14m), development of ataxia and dyskinetic movements (both), seizures (one). Feeding difficulties, reflux and failure to thrive required N-G/gastrostomy feeding while both presented GI hemorrhage (in the case of the older sib, lethal). Other features in the youngest sib included brain MRI abnormalities (cerebral/cerebellar atrophy, thin CC, etc) and IgG deficiency. Biochemical, single-gene testing and mtDNA sequencing were not diagnostic. Exome in one, revealed presence of a frameshift [c.422_423del as above] and a missense variant (Arg400Thr). Sanger sequencing confirmed variants in both sibs and heterozygosity in parents. HeLa cells transfected with empty vector, wt or mut expression constructs confirmed significantly decreased 3H-biotin uptake for mut constructs compared to wt (and similar to empty vector). Parenteral triple vitamin replacement at the age of ~7 years resulted in improved overall condition, regain of some milestones, attenuation of vomiting, and resolution of peripheral neuropathy. Seizure were well-controlled (as was the case before treatment) despite persistence of epileptiform discharges. Again the authors cite studies of conditional (intestine-specific) SLC5A6 ko mice, with those viable (~1/3) demonstrating growth retardation, decreased boned density and GI abnormalities (similar to affected individuals). The phenotype could be rescued by oversupplementation of biotin and pantothenic acid (PMIDs cited: 23104561, 29669219).

[Please consider inclusion in other relevant panels eg. metabolic disorders]
Sources: Literature
Intellectual disability v2.1135 SLC5A6 Konstantinos Varvagiannis gene: SLC5A6 was added
gene: SLC5A6 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: SLC5A6 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC5A6 were set to 27904971; 31392107; 31754459; 23104561; 29669219
Phenotypes for gene: SLC5A6 were set to Feeding difficulties; Failure to thrive; Global developmental delay; Developmental regression; Intellectual disability; Seizures; Microcephaly; Cerebral atrophy; Abnormality of the corpus callosum; Vomiting; Chronic diarrhea; Gastrointestinal hemorrhage; Abnormal immunoglobulin level; Osteopenia; Abnormality of metabolism/homeostasis
Penetrance for gene: SLC5A6 were set to Complete
Review for gene: SLC5A6 was set to GREEN
Added comment: SLC5A6 encodes the sodium dependent multivitamin transporter (SMVT), a transporter of biotin, pantothenate and lipoate. The transporter has a major role in vitamin uptake in the digestive system (among others is the sole transporter for intestinal uptake of biotin which is not synthesized and but must be obtained from exogenous sources) as well as transport across the blood-brain barrier (SMVT being responsible for 89% of biotin transport) [several refs provided by Subramanian et al and Byrne et al].

4 affected individuals from 3 families have been reported.

Subramanian et al (2017 - PMID: 27904971) et al reported on a girl with feeding difficulties and failure to thrive (requiring nasogastric tube placement), microcephaly, DD (at 15m developmental age corresponding to 6m with features suggestive of spastic cerebral palsy), occurrence of multiple infections, osteoporosis and pathologic bone fractures. MRIs suggested brain atrophy, thin CC and hypoplasia of the pons. Metabolic (AA, OA) investigations and array-CGH were normal. Whole exome sequencing revealed presence of a missense (Arg123Leu - RefSeq not provided) and a nonsense (Arg94Ter) SLC5A6 variant. Serum biotin was normal although - at the time - the child was on parenteral and G-T nutrition. Following administration of biotin, pantothenic acid and lipoic acid the child demonstrated among others improved motor and verbal skills, head growth and normalization of immunoglobulin levels. Transfection of mutants in human derived intestinal HuTu-80 cells and brain U87 cells was carried out and a 3H-biotin assay showed no induction in biotin uptake confirming impaired functionality of the transporter. While wt protein displayed normal expression/membrane localization, Arg94Ter was poorly expressed with ectopic localization (cytoplasm). Arg123Leu was retained predominantly intracellularly, probably in the ER as was further supported by colocalization with DsRed-ER. Evidence from the literature is provided that deficiencies of the specific vitamins explain the clinical features (DD, microcephaly, immunological defect, osteopenia, etc).

Schwantje et al (2019 - PMID: 31392107) described a girl with severe feeding problems, vomiting with blood (suspected Mallory-Weiss syndrome), poor weight gain and delayed gross motor development. The child presented an episode of gastroenteritis associated with reduced consciousness, circulatory insufficiency and metabolic derangement (hypoglycemia, severe metabolic acidosis, hyperammonemia, mild lactate elevation, ketonuria). Investigations some months prior to the admission (?) were suggestive of a metabolic disorder due to elevated plasma C3-carnitine, C5-OH-carnitine and elevated urinary excretion of 3-OH-isovaleric acid (biotinidase deficiency was considered in the DD but enzymatic activity was only marginally decreased). Biotin supplementation was initiated. Trio-exome sequencing (at 3yrs) demonstrated compound heterozygosity for 2 frameshift variants [NM_021095.2:c.422_423del / p.(Val141Alafs*34) and c.1865_1866del]. Following this result, increase of biotin supplementation and introduction of pantothenic acid, GI symptoms (incl. chronic diarrhea) resolved and the child displayed improved appetite and growth, yet a stable motor delay. The authors cite previous studies of conditional ko mice, displaying intestinal mucosal abnormalities and growth defects (similar to the child's problems), prevented by biotin and pantothenic acid supplementation.

Byrne et al (2019 - PMID: 31754459) reported on a sibling pair with severe motor/speech developmental regression following a plateau (at 12m and 14m), development of ataxia and dyskinetic movements (both), seizures (one). Feeding difficulties, reflux and failure to thrive required N-G/gastrostomy feeding while both presented GI hemorrhage (in the case of the older sib, lethal). Other features in the youngest sib included brain MRI abnormalities (cerebral/cerebellar atrophy, thin CC, etc) and IgG deficiency. Biochemical, single-gene testing and mtDNA sequencing were not diagnostic. Exome in one, revealed presence of a frameshift [c.422_423del as above] and a missense variant (Arg400Thr). Sanger sequencing confirmed variants in both sibs and heterozygosity in parents. HeLa cells transfected with empty vector, wt or mut expression constructs confirmed significantly decreased 3H-biotin uptake for mut constructs compared to wt (and similar to empty vector). Parenteral triple vitamin replacement at the age of ~7 years resulted in improved overall condition, regain of some milestones, attenuation of vomiting, and resolution of peripheral neuropathy. Seizure were well-controlled (as was the case before treatment) despite persistence of epileptiform discharges. Again the authors cite studies of conditional (intestine-specific) SLC5A6 ko mice, with those viable (~1/3) demonstrating growth retardation, decreased boned density and GI abnormalities (similar to affected individuals). The phenotype could be rescued by oversupplementation of biotin and pantothenic acid (PMIDs cited: 23104561, 29669219).

[Please consider inclusion in other relevant panels eg. metabolic disorders]
Sources: Literature
Intellectual disability v2.1135 TMX2 Rebecca Foulger Classified gene: TMX2 as Green List (high evidence)
Intellectual disability v2.1135 TMX2 Rebecca Foulger Added comment: Comment on list classification: Promoted TMX2 from Amber to Green to match Green review by Ivone Leong and new evidence from Konstantinos Varvagiannis.
Intellectual disability v2.1135 TMX2 Rebecca Foulger Gene: tmx2 has been classified as Green List (High Evidence).
Intellectual disability v2.1134 TMX2 Ivone Leong edited their review of gene: TMX2: Added comment: Based on the new evidence submitted from the expert reviewer, there is now enough evidence to promote this gene to Green status.; Changed rating: GREEN
Intellectual disability v2.1134 CNOT3 Konstantinos Varvagiannis reviewed gene: CNOT3: Rating: GREEN; Mode of pathogenicity: None; Publications: 28135719, 31201375, 24121232; Phenotypes: Intellectual developmental disorder with speech delay, autism, and dysmorphic facies, MIM 618672; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Intellectual disability v2.1134 OXR1 Konstantinos Varvagiannis gene: OXR1 was added
gene: OXR1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: OXR1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: OXR1 were set to https://doi.org/10.1016/j.ajhg.2019.11.002
Phenotypes for gene: OXR1 were set to Central hypotonia; Global developmental delay; Delayed speech and language development; Intellectual disability; Seizures; Abnormality of the cerebellum
Penetrance for gene: OXR1 were set to Complete
Review for gene: OXR1 was set to GREEN
Added comment: Wang et al (2019 - https://doi.org/10.1016/j.ajhg.2019.11.002 ) report on 5 individuals (from 3 families) with biallelic OXR1 LoF variants.

Common features included hypotonia (4/5), severe global DD (5/5) and speech delay (5/5), ID (5/5), epilepsy (5/5) with cerebellar dysplasia/atrophy (5/5) and in some scoliosis.

All were investigated by exome sequencing and were found to harbor biallelic loss-of-function variants (2 splice-site, a stopgain and a frameshift one) either in homozygosity (2 consanguineous families) or in compound heterozygosity. In all cases parental segregation studies were compatible and in one family, an unaffected sib shown to be carrier.

Althouhgh OXR1 has been shown to affect several processes (among others DNA lesions induced by oxidative stress in E.coli, neuronal maintenance, mitochondrial morphology and DNA maintenance, etc), its mechanism of action is still not well defined. There are 6 RefSeq transcripts, the longest (NM_018002.3) encoding 3 protein domains (LysM, GRAM, TLDc). The TLDc domain is encoded by all transcripts.

Identified variants affected (probably all - fig1D) transcripts expressed in the CNS, namely NM_018002.3, NM_001198532.1, NM_181354.4. The 3 transcripts not expressed in the CNS are NM_001198533.1, NM_001198534.1 and NM_001198535.1.

Western blot with 2 different antibodies which would bind upstream of the truncation site failed to detect presence of truncated proteins in 2 affected individuals from 2 families.

The Drosophila homolog of OXR is mustard (mtd). The authors provide evidence that loss of mtd is lethal. This was however rescued by expression of an 80kb fly BAC clone covering mtd, or the fly mtd-RH isoform cDNA, or a short human OXR1 cDNA containing only the TLDc domain or a human NCOA7 cDNA. The latter is another human mtd homolog which also contains the TLDc domain. As a result the TLDc domain compensated sufficiently for loss of mtd.

Flies that survived displayed bang sensitivity and climbing defects the former assay being suggestive of susceptibility to seizures and the latter of impaired neurological/muscular function.

The authors provided evidence that mtd is broadly expressed in the fly CNS. RNAi mediated mtd knockdown specific to neurons (elav/nSyb-GAL4 expression of mtd RNAi) led to lethal eclosion defects for RNAis targeting most (18)/all(23) mtd isoforms. Lifespan was increased upon expression of human OXR1 cDNA. Neuronal loss and vacuolization was demonstrated and additional experiments in R7 photoreceptors showed presence of aberrant lysosomal structures (autolysosomes, autophagosomes and/or endolysosomes).

Aberrant lysosomal structures were also observed in fibroblasts from affected individuals (accumulation of lysosomes and/or presence of highly aberrant compartments with content typical of lysosomal dysfunction).

Overall the data presented suggest a critical role for OXR1 in lysosomal biology.

Although previous reports suggested that OXR1 is involved in oxidative stress resistance, studies performed by the authors suggested that oxidative stress is probably not the driver of the mutant fly defects.
Sources: Literature
Intellectual disability v2.1134 PDE6D Ellen McDonagh Classified gene: PDE6D as Amber List (moderate evidence)
Intellectual disability v2.1134 PDE6D Ellen McDonagh Added comment: Comment on list classification: Gene added by external reviewer, and promoted to Amber due to one family and a recent additional case.
Intellectual disability v2.1134 PDE6D Ellen McDonagh Gene: pde6d has been classified as Amber List (Moderate Evidence).
Intellectual disability v2.1133 PCYT2 Ellen McDonagh Classified gene: PCYT2 as Green List (high evidence)
Intellectual disability v2.1133 PCYT2 Ellen McDonagh Added comment: Comment on list classification: This gene was added by an external reviewer and rated Green. This is currently Green on the Hereditary spastic paraplegia gene panel (Version 1.210), and confirmed with Zerin Hyder (Genomics England Clinical Team) that this is appropriate to be Green on the ID panel.
Intellectual disability v2.1133 PCYT2 Ellen McDonagh Gene: pcyt2 has been classified as Green List (High Evidence).
Intellectual disability v2.1132 SVBP Rebecca Foulger Classified gene: SVBP as Green List (high evidence)
Intellectual disability v2.1132 SVBP Rebecca Foulger Added comment: Comment on list classification: Updated rating to Green to match Green review by Catherine Snow. Phenotypes include global DD and intellectual disability in >3 families.
Intellectual disability v2.1132 SVBP Rebecca Foulger Gene: svbp has been classified as Green List (High Evidence).
Intellectual disability v2.1131 PNPT1 Rebecca Foulger commented on gene: PNPT1
Intellectual disability v2.1131 PNPT1 Rebecca Foulger Phenotypes for gene: PNPT1 were changed from Combined oxidative phosphorylation deficiency 13, 614932; Deafness, autosomal recessive 70, 614934 to Combined oxidative phosphorylation deficiency 13, 614932; Deafness, autosomal recessive 70, 614934; developmental delay; intellectual disability
Intellectual disability v2.1131 PNPT1 Rebecca Foulger Publications for gene: PNPT1 were set to
Intellectual disability v2.1129 PNPT1 Konstantinos Varvagiannis changed review comment from: Biallelic PNPT1 pathogenic variants cause Combined oxidative phosphorylation deficiency 13 (MIM 614932). Despite phenotypic variability - common to disorders resulting from mitochondrial dysfunction - DD and ID of relevant severity to the current panel have been reported in several individuals published in the literature. Seizures may also be observed.

Rius et al (2019 - PMID: 31752325) provide an overview of 24 affected individuals (7 new and 17 from previous studies). Neurodevelopmental features are summarized in fig.1 and additional details are provided in the supplement. Based on this review, seizures were present in 7 individuals (of the 18 for whom this information was available).

PNPT1 encodes the mitochondrial polynucleotide phosphorylase, involved in the import of nuclear-encoded RNA to mitochondria. Loss of its activity has been shown to result in combined respiratory chain deficiency. However, as discussed by Rius et al and previous articles as well, OXPHOS studies in affected individuals may be normal or suggestive of only mild impairement due to tissue specificity and different assay methods used (eg. spectrophotometric vs dipstick activity assays). The same applies to lactate which was normal or mildly elevated in some affected individuals.

Missense, pLoF function variants as well as a synonymous one leading to aberrant splicing (NM_033109.4:c.1818T>G) have been reported.

Overall, this gene might be considered for upgrade to green rating.; to: Biallelic PNPT1 pathogenic variants cause Combined oxidative phosphorylation deficiency 13 (MIM 614932). Despite phenotypic variability - common to disorders resulting from mitochondrial dysfunction - DD and ID of relevant severity to the current panel have been reported in several individuals published in the literature. Seizures may also be observed.

Rius et al (2019 - PMID: 31752325) provide an overview of 24 affected individuals (7 new and 17 from previous studies). Neurodevelopmental features are summarized in fig.1 and additional details are provided in the supplement. Based on this review, seizures were present in 7 individuals (of the 18 for whom this information was available).

PNPT1 encodes the mitochondrial polynucleotide phosphorylase, involved in the import of nuclear-encoded RNA to mitochondria. Loss of its activity has been shown to result in combined respiratory chain deficiency. However, as discussed by Rius et al and previous articles as well, OXPHOS studies in affected individuals may be normal or suggestive of only mild impairment due to tissue specificity and different assay methods used (eg. spectrophotometric vs dipstick activity assays). The same applies to lactate which was normal or mildly elevated in some affected individuals.

Missense, pLoF function variants as well as a synonymous one leading to aberrant splicing (NM_033109.4:c.1818T>G) have been reported.

Overall, this gene might be considered for upgrade to green rating.
Intellectual disability v2.1129 PNPT1 Konstantinos Varvagiannis reviewed gene: PNPT1: Rating: GREEN; Mode of pathogenicity: None; Publications: 31752325; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v2.1129 PIK3C2A Catherine Snow Classified gene: PIK3C2A as Amber List (moderate evidence)
Intellectual disability v2.1129 PIK3C2A Catherine Snow Gene: pik3c2a has been classified as Amber List (Moderate Evidence).
Intellectual disability v2.1128 NTNG2 Ellen McDonagh Classified gene: NTNG2 as Green List (high evidence)
Intellectual disability v2.1128 NTNG2 Ellen McDonagh Added comment: Comment on list classification: Gene added by external reviewer and rated Green. 11 unrelated families reported with homozygous variants in this gene with a neurodevelopmental disorder including global developmental delay, plus functional evidence. Promoted to Green.
Intellectual disability v2.1128 NTNG2 Ellen McDonagh Gene: ntng2 has been classified as Green List (High Evidence).
Intellectual disability v2.1128 PIK3C2A Catherine Snow gene: PIK3C2A was added
gene: PIK3C2A was added to Intellectual disability. Sources: Expert Review
Mode of inheritance for gene: PIK3C2A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PIK3C2A were set to 31034465
Phenotypes for gene: PIK3C2A were set to Oculoskeletodental syndrome, 618440
Review for gene: PIK3C2A was set to AMBER
Added comment: PIK3C2A is on a number of panels including a Green rating on Skeletal dysplasia (Version 1.244) clinical support advised that as PIK3C2A phenotype includes DD, gene should be rated as Amber on this panel.
Sources: Expert Review
Intellectual disability v2.1127 ZNF292 Catherine Snow Deleted their review
Intellectual disability v2.1127 ZNF292 Catherine Snow edited their review of gene: ZNF292: Changed rating: AMBER
Intellectual disability v2.1127 ZNF292 Catherine Snow reviewed gene: ZNF292: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v2.1127 FAM160B1 Ellen McDonagh Classified gene: FAM160B1 as Red List (low evidence)
Intellectual disability v2.1127 FAM160B1 Ellen McDonagh Added comment: Comment on list classification: Gene added by external reviewer, and promoted from grey to Red as the function of the protein/gene is still unknown at this stage. One family and another unrelated individual reported with developmental delay/ID and variants in this gene, however this will be kept red until further evidence arises.
Intellectual disability v2.1127 FAM160B1 Ellen McDonagh Gene: fam160b1 has been classified as Red List (Low Evidence).
Intellectual disability v2.1126 SCAMP5 Ellen McDonagh Classified gene: SCAMP5 as Amber List (moderate evidence)
Intellectual disability v2.1126 SCAMP5 Ellen McDonagh Added comment: Comment on list classification: Gene added by external Reviewer, and promoted to Amber due to review and overall evidence.
Intellectual disability v2.1126 SCAMP5 Ellen McDonagh Gene: scamp5 has been classified as Amber List (Moderate Evidence).
Intellectual disability v2.1125 ZNF292 Ellen McDonagh Classified gene: ZNF292 as Amber List (moderate evidence)
Intellectual disability v2.1125 ZNF292 Ellen McDonagh Added comment: Comment on list classification: Gene added by external reviewer. Promoted from grey to Amber due to the evidence presented, and reflecting the rating of 'probable' in Gene2Phenotype for ZNF292-related developmental disorder. At this stage, this has not been made Green due to uncertainty regarding the penetrance and the comment from the reviewer regarding manual review of some relevant LoF variants in gnomAD suggested that they represent false positive calls.
Intellectual disability v2.1125 ZNF292 Ellen McDonagh Gene: znf292 has been classified as Amber List (Moderate Evidence).
Intellectual disability v2.1124 AP1B1 Catherine Snow Classified gene: AP1B1 as Amber List (moderate evidence)
Intellectual disability v2.1124 AP1B1 Catherine Snow Gene: ap1b1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v2.1123 AP1B1 Catherine Snow reviewed gene: AP1B1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v2.1123 FDFT1 Catherine Snow Classified gene: FDFT1 as Amber List (moderate evidence)
Intellectual disability v2.1123 FDFT1 Catherine Snow Gene: fdft1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v2.1122 FDFT1 Catherine Snow reviewed gene: FDFT1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v2.1122 TMX2 Konstantinos Varvagiannis edited their review of gene: TMX2: Changed publications: 31586943, 31270415, 31735293
Intellectual disability v2.1122 TMX2 Konstantinos Varvagiannis edited their review of gene: TMX2: Added comment: A recent report by Vandervore, Schot et al. following the previous review (Am J Hum Genet. 2019 Nov 12 - PMID: 31735293), provides further evidence that biallelic TMX2 mutations cause malformations of cortical development, microcephaly, DD and ID and epilepsy.

As a result this gene should probably be considered for inclusion in the ID/epilepsy panels with green rating.

Overall, 14 affected subjects from 10 unrelated families are reported in the aforementioned study. The majority had severe DD/ID (failure to achieve milestones, absent speech/ambulation and signs of cerebral palsy) with few having a somewhat milder impairment. 12 (of the 14) presented with epilepsy (spasms, myoclonic seizures, focal seizures with/without generalization or generalized tonic-clonic seizures) with onset most often in early infancy. Upon brain MRI (in 12 individuals), 5 presented polymicrogyria, 2 others pachygyria, 4 with brain atrophy, etc.

All individuals were found to harbor biallelic TMX2 mutations by exome sequencing while previous investigations in several had ruled out alternative causes (infections, metabolic or chromosomal anomalies). Missense variants, an in-frame deletion as well as pLoF (stopgain/frameshift) variants were reported. [NM_015959.3 used as ref below].

The effect of variants was supported by mRNA studies, eg. RT-qPCR/allele specific RT-qPCR. The latter proved reduced expression for a frameshift variant (c.391dup / p.Leu131Profs*6) most likely due to NMD. Total mRNA levels were also 23% lower in an individual compound htz for a missense variant and a stopgain one localized in the last exon (c.757C>T / p.Arg253*). As for the previously reported c.614G>A (p.Arg205Gln), affecting the last nucleotide of exon 6, total mRNA in skin fibroblasts from a homozygous individual was not significantly decreased. RNA-Seq however demonstrated the presence of 4 different transcripts (roughly 25% each), one representing the regular mRNA, one with intron 6 retention (also present at low levels in healthy individuals), one with loss of 11 nucleotides within exon 6 and a fourth one due to in-frame skipping of exon 6.

*To the best of my understanding :

Thioredoxin (TRX)-related transmembrane proteins (TMX) belong to the broader family of oxidoreductases of protein disulfide isomerase (PDI) having an important role in protein folding.

Study of the data from the Allen Human Brain Atlas suggest relevant fetal expression also increasing during postnatal life.

As RNA-seq was carried out for 2 individuals, GO analysis suggested that the most deregulated clusters of genes are implicated in post-translational protein modifications (as would be expected for PDIs), membranes and synapse while pathway analysis suggested that relevant categories were inhibited eg. nervous system development/function and cell growth/proliferation/survival.

Upon transfection of HEK293T cells, exogenous TMX2 was shown to co-localize with calnexin (CNX) to the (ER) mitochondria-associated-membrane. Mass-spectrometry based analysis of co-immunoprecipitated proteins confirmed interaction with CNX but also other regulators of calcium homeostasis, mitochondrial membrane components and respiratory chain NADH dehydrogenase.

Study of the mitochondrial activity of TMX2-deficient fibroblasts suggested reduced respiratory reserve capacity, compensated by increased glycolytic activity.

TMX2 occurs in both reduced and oxidized monomeric form. It also forms (homo)dimers with the ratio of dimers/monomers increasing under conditions of oxidative stress. Variant TMX2 increased propensity to form dimers, thus mimicking increased oxidative state. This was observed under stress but also under native conditions.

---------; Changed rating: GREEN
Intellectual disability v2.1122 WDFY3 Ivone Leong Classified gene: WDFY3 as Amber List (moderate evidence)
Intellectual disability v2.1122 WDFY3 Ivone Leong Added comment: Comment on list classification: Gene promoted from Red to Amber based on evidence provided by expert reviewer. All affected individuals have mild-moderate ID, therefore the gene has been rated Amber.
Intellectual disability v2.1122 WDFY3 Ivone Leong Gene: wdfy3 has been classified as Amber List (Moderate Evidence).
Intellectual disability v2.1121 WDFY3 Ivone Leong Publications for gene: WDFY3 were set to 27008544
Intellectual disability v2.1120 IQSEC1 Catherine Snow Classified gene: IQSEC1 as Amber List (moderate evidence)
Intellectual disability v2.1120 IQSEC1 Catherine Snow Gene: iqsec1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v2.1119 IQSEC1 Catherine Snow reviewed gene: IQSEC1: Rating: AMBER; Mode of pathogenicity: None; Publications: 31607425; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v2.1119 SVBP Catherine Snow Phenotypes for gene: SVBP were changed from Neurodevelopmental disorder with ataxia, hypotonia, and microcephaly, 618569 to Neurodevelopmental disorder with ataxia, hypotonia, and microcephaly, 618569
Intellectual disability v2.1119 SVBP Catherine Snow Mode of inheritance for gene: SVBP was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v2.1119 SVBP Catherine Snow Phenotypes for gene: SVBP were changed from Neurodevelopmental disorder with ataxia, hypotonia, and microcephaly, 618569 to Neurodevelopmental disorder with ataxia, hypotonia, and microcephaly, 618569
Intellectual disability v2.1119 SVBP Catherine Snow Publications for gene: SVBP were set to 26350204; 31363758; 30607023
Intellectual disability v2.1119 SVBP Catherine Snow Phenotypes for gene: SVBP were changed from to Neurodevelopmental disorder with ataxia, hypotonia, and microcephaly, 618569
Intellectual disability v2.1118 SVBP Catherine Snow Publications for gene: SVBP were set to 26350204
Intellectual disability v2.1118 SVBP Catherine Snow Mode of inheritance for gene: SVBP was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v2.1117 SVBP Catherine Snow reviewed gene: SVBP: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with ataxia, hypotonia, and microcephaly, 618569; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v2.1117 NSF Ivone Leong Classified gene: NSF as Red List (low evidence)
Intellectual disability v2.1117 NSF Ivone Leong Added comment: Comment on list classification: New gene submitted by expert reviewed. Based on the evidence provided it was decided that there is currently not enough evidence to establish a gene-phenotype association. Therefore, this gene has been given a Red rating.
Intellectual disability v2.1117 NSF Ivone Leong Gene: nsf has been classified as Red List (Low Evidence).
Intellectual disability v2.1116 KCNT2 Ivone Leong Classified gene: KCNT2 as Green List (high evidence)
Intellectual disability v2.1116 KCNT2 Ivone Leong Added comment: Comment on list classification: New gene submitted by expert reviewer. Based on the evidence provided it was decided that there is enough evidence for this gene to be given Green status.
Intellectual disability v2.1116 KCNT2 Ivone Leong Gene: kcnt2 has been classified as Green List (High Evidence).
Intellectual disability v2.1115 KCNT2 Ivone Leong Added comment: Comment on mode of pathogenicity: Variants have gain-of-function effect.
Intellectual disability v2.1115 KCNT2 Ivone Leong Mode of pathogenicity for gene: KCNT2 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 v2.1114 KCNT2 Ivone Leong Phenotypes for gene: KCNT2 were changed from ?Epileptic encephalopathy, early infantile 57, MIM 617771 to ?Epileptic encephalopathy, early infantile 57, 617771
Intellectual disability v2.1113 TMX2 Ivone Leong Classified gene: TMX2 as Amber List (moderate evidence)
Intellectual disability v2.1113 TMX2 Ivone Leong Added comment: Comment on list classification: New gene submitted by expert reviewer. Based on the submitted evidence the gene has been given an Amber rating until further evidence is available to promote it to Green status.
Intellectual disability v2.1113 TMX2 Ivone Leong Gene: tmx2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v2.1112 CNOT2 Ivone Leong Classified gene: CNOT2 as Green List (high evidence)
Intellectual disability v2.1112 CNOT2 Ivone Leong Added comment: Comment on list classification: New gene added by expert reviewer. There is enough evidence to promote this gene to Green status.
Intellectual disability v2.1112 CNOT2 Ivone Leong Gene: cnot2 has been classified as Green List (High Evidence).
Intellectual disability v2.1111 CNOT2 Ivone Leong Phenotypes for gene: CNOT2 were changed from Intellectual developmental disorder with nasal speech, dysmorphic facies, and variable skeletal anomalies, MIM 618608 to Intellectual developmental disorder with nasal speech, dysmorphic facies, and variable skeletal anomalies, 618608
Intellectual disability v2.1110 DMXL2 Ivone Leong Classified gene: DMXL2 as Green List (high evidence)
Intellectual disability v2.1110 DMXL2 Ivone Leong Added comment: Comment on list classification: Promoted from Red to Green based on expert reviewer's comments/evidence.
Intellectual disability v2.1110 DMXL2 Ivone Leong Gene: dmxl2 has been classified as Green List (High Evidence).
Intellectual disability v2.1109 DMXL2 Ivone Leong Phenotypes for gene: DMXL2 were changed from Sensorineural Hearing Loss; ORPHA90636; OMIM:612186 to Sensorineural Hearing Loss; ORPHA90636; Epileptic encephalopathy, early infantile, 81, 618663; ?Polyendocrine-polyneuropathy syndrome, 616113
Intellectual disability v2.1108 DMXL2 Ivone Leong Publications for gene: DMXL2 were set to 25248098
Intellectual disability v2.1107 VAMP7 Eleanor Williams Added comment: Comment on mode of inheritance: This gene is in the pseudoautosomal region shared between chromosomes X and Y. The mode of inheritance should therefore be set to Biallelic or Monoallelic once more cases establish the inheritance pattern.
Intellectual disability v2.1107 VAMP7 Eleanor Williams Mode of inheritance for gene: VAMP7 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 Unknown
Intellectual disability v2.1106 SPRY3 Eleanor Williams Added comment: Comment on mode of inheritance: This gene is in the pseudoautosomal region shared between chromosomes X and Y. The mode of inheritance should therefore be set to Biallelic or Monoallelic once more cases establish the inheritance pattern.
Intellectual disability v2.1106 SPRY3 Eleanor Williams Mode of inheritance for gene: SPRY3 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 Unknown
Intellectual disability v2.1105 SLC25A6 Eleanor Williams Added comment: Comment on mode of inheritance: This gene is in the pseudoautosomal region shared between chromosomes X and Y. The mode of inheritance should therefore be set to Biallelic or Monoallelic once more cases establish the inheritance pattern.
Intellectual disability v2.1105 SLC25A6 Eleanor Williams Mode of inheritance for gene: SLC25A6 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 Unknown
Intellectual disability v2.1104 P2RY8 Eleanor Williams Added comment: Comment on mode of inheritance: This gene is in the pseudoautosomal region shared between chromosomes X and Y. The mode of inheritance should therefore be set to Biallelic or Monoallelic once more cases establish the inheritance pattern.
Intellectual disability v2.1104 P2RY8 Eleanor Williams Mode of inheritance for gene: P2RY8 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 Unknown
Intellectual disability v2.1103 PLCXD1 Eleanor Williams Added comment: Comment on mode of inheritance: This gene is in the pseudoautosomal region shared between chromosomes X and Y. The mode of inheritance should therefore be set to Biallelic or Monoallelic once more cases establish the inheritance pattern.
Intellectual disability v2.1103 PLCXD1 Eleanor Williams Mode of inheritance for gene: PLCXD1 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 Unknown
Intellectual disability v2.1102 DMXL2 Konstantinos Varvagiannis changed review comment from: This gene can be considered for upgrade to green rating (ID and epilepsy with >=4 relevant individuals/families/variants and >=2 studies, role of the protein, effect of variants in most cases demonstrated, phenotypic similarities with other disorders affecting autophagy, some evidence from animal models, etc).

Rare heterozygous variants disrupting DMXL2 (intragenic losses/gains, SNVs, CNVs affecting also additional genes) have been reported in individuals with variable neurodevelopmental disorders (ASD and ID) or psychiatric phenotypes [Costain et al. 2019 - PMID: 30732576 - summarized in Table 1]. (Highly) variable expressivity and possibly incomplete penetrance were proposed in the respective study. As a result evidence for ID/seizures due to monoallelic variants appears to be relatively limited.

DD, ID and (probably) epilepsy appear however to be features in several individuals with biallelic pathogenic variants as summarized in the studies below.

OMIM recently added a relevant entry with the DMXL2-associated phenotypes being the following:
- Epileptic encephalopathy, early infantile, 81; EIEE81 - 618663 (AD) [based on refs 2,3]
- ?Deafness, autosomal dominant 71 - 617605 (AD) [DD/ID/seizures are not part of the phenotype]
- ?Polyendocrine-polyneuropathy syndrome - 616113 (AR) [based on ref1]

DMXL2 is not associated with any phenotype in G2P. In SysID it is listed as a candidate ID gene based on the report by Tata et al (ref1). This gene is included in some gene panels for ID.

[1] Tata el al. (2014 - PMID: 25248098) reported on 3 sibs born to consanguineous Senegalese parents, presenting with a progressive endocrine and neurodevelopmental disorder. Features incl. incomplete puberty, central hypothyroidism, abnormal glucose regulation, moderate ID (3/3) and peripheral polyneuropathy. Seizures were not part of the phenotype. Linkage analysis suggested 2 candidate regions on chromosomes 13 and 15 with a LOD score of 2.5. High throughput sequencing of genes within these regions (~500) in an affected member and parent revealed a 15 bp in-frame deletion of DMXL2 (NM_015263.4:c.5827_5841del / p.Asp1943_Ser1947del). Sanger sequencing of other affected and unaffected members supported AR inheritance. RT-qPCR demonstrated that DMXL2 mRNA levels in blood lymphocytes were significantly lower in homozygous patients compared to heterozygous or wt family members or controls. The authors demonstrated that the encoded protein (rabconnectin-3a) is a synaptic protein (expressed in exocytosis vesicles) at the ends of axons of GnRH producing neurons. Neuron-specific deletion of one allele in mice resulted in delayed puberty and very low fertility. Adult mice had lower number of GnRH neurons in hypothalamus. siRNA-mediated downregulation of Dmxl2 expression in an insulin-secreting cell line resulted in only slight insulin secretion in response to augmenting concentrations of glucose, providing evidence of involvement of the protein in control of regulated insulin secretion.
-----------
[2] Maddirevula et al. (2019 - PMID: 30237576) reported briefly on a 36 months old boy, born to consanguineous parents, homozygous for a frameshift DMXL2 variant [individual 17-3220 | NM_001174117.1:c.4349_4350insTTACATGA or p.(Glu1450Aspfs*23)]. Features included focal seizures (onset at the age of 3m) with subsequent global DD, absent eye contact, cerebral atrophy and macrocephaly. This individual was identified following re-evaluation of exome data in a database of ~1550 exomes specifically for homozygous variants that would have been classified earlier as LP/P if the respective gene had sufficient evidence for association with a disorder. The family was not reported to have other affected members. As the authors noted, the boy was not known to have the multi-endocrine abnormalities reported by Tata et al. There are no additional information provided (eg. on confirmation of variants, etc).
-----------
[3] Esposito et al. (2019 - PMID: 31688942) report on 3 sibling pairs (all 3 families unrelated) with biallelic DMXL2 mutations and summarize previous evidence on the gene and the DMXL2-related phenotypes.

All presented a highly similar phenotype of Ohtahara syndrome (seizures with onset in the first days of life, tonic/myoclonic/occasionaly focal, burst-suppression upon EEG), profound DD/ID, quadriparesis, sensorineural hearing loss and presence of dysmorphic features. Sibs from 2 families presented evidence of peripheral polyneuropathy. Early brain MRIs revealed thin CC and hypomyelination in all, with later scans suggestive of gray and white matter shrinkage with leukoencephalopathy. None achieved developmental skills following birth with 5/6 deceased by the age of 9 years.

Exome sequencing revealed biallelic DMXL2 variants in all, with compatible parental segregation studies (NM_015263.3):
- Fam1 (2 sibs) : c.5135C>T (p.Ala1712Val) in trans with c.4478C>G (p.Ser1493*)
- Fam2 (2 sibs) : homozygosity for c.4478C>A (p.Ser1493*)
- Fam3 (2 sibs) : homozygosity for c.7518-1G>A

Heterozygous parents (aged 39-59) did not exhibit hearing impairment [report of a single multigenerational family by Chen et al (2017 - PMID: 27657680) where a heterozygous missense variant segregated with hearing loss - respective OMIM entry: ?Deafness, autosomal dominant 71 - 617605].

In patients' fibroblasts, effect of the variants on mRNA/protein expression was demonstrated with mRNA expressed only in a patient from family 1, and degraded/absent for the 2 stopgain SNVs affecting codon 1493. Skipping of ex31 leading to frameshift/introduction of a PTC was shown for the splice variant (p.Trp2508Argfs*4 secondary to c.7518-1G>A). Protein was also absent upon western-blot.

DMXL2 encodes a vesicular protein, DmX-Like protein 2 or rabconnectin-3a (cited Tata et al).

The gene is expressed in brain ( https://www.gtexportal.org/home/gene/DMXL2 ).

As Esposito et al comment, it is known to regulate the trafficking and activity of v-ATPase the latter having a role in acidifying intracellular organelles and promoting endosomal maturation (cited PMIDs : 25248098, 19758563, 22875945, 24802872).

In line with this, staining of patients' fibroblasts using the acidotropic dye LysoTracker demonstrated increased signal, reversed by re-expression of DMXL2 protein. Overall an acidic shift in pH with impairment of lysosomal structures and function was suggested. The authors provided additional evidence for altered lysosomal function and associated autophagy with accumulation of autophagy receptors (eg p62) and substrates (polyubiquitinated proteins). Vacuolization and accumulation of atypical fusion-like structures was shown upon ultrastractural analysis.

shRNA-mediated downregulation/silencing of Dmxl2 in mouse hippocampal neurons resulted also in altered lysosomal structures and defective autophagy. The neurons exhibited impaired neurite elongation and synapse formation.

The authors suggest similarities with Vici syndrome, where biallelic EPG5 mutations result in autophagic defects and clinical manifestations of DD/ID/epilepsy.

Dmxl2 homozygous ko mice display embryonic lethality with heterozygous mice displaying macrocephaly and corpus callosum dysplasia (cited PMIDs: 25248098, 30735494) .; to: This gene can be considered for upgrade to green rating (ID and epilepsy with >=4 relevant individuals/families/variants and >=2 studies, role of the protein, effect of variants in most cases demonstrated, phenotypic similarities with other disorders affecting autophagy, some evidence from animal models, etc).

Rare heterozygous variants disrupting DMXL2 (intragenic losses/gains, SNVs, CNVs affecting also additional genes) have been reported in individuals with variable neurodevelopmental disorders (ASD and ID) or psychiatric phenotypes [Costain et al. 2019 - PMID: 30732576 - summarized in Table 1]. (Highly) variable expressivity and possibly incomplete penetrance were proposed in the respective study. As a result evidence for ID/seizures due to monoallelic variants appears to be relatively limited.

DD, ID and (probably) epilepsy appear however to be features in several individuals with biallelic pathogenic variants as summarized in the studies below.

OMIM recently added a relevant entry with the DMXL2-associated phenotypes being the following:
- Epileptic encephalopathy, early infantile, 81; EIEE81 - 618663 (AR) [based on refs 2,3]
- ?Deafness, autosomal dominant 71 - 617605 (AD) [DD/ID/seizures are not part of the phenotype]
- ?Polyendocrine-polyneuropathy syndrome - 616113 (AR) [based on ref1]

DMXL2 is not associated with any phenotype in G2P. In SysID it is listed as a candidate ID gene based on the report by Tata et al (ref1). This gene is included in some gene panels for ID.

[1] Tata el al. (2014 - PMID: 25248098) reported on 3 sibs born to consanguineous Senegalese parents, presenting with a progressive endocrine and neurodevelopmental disorder. Features incl. incomplete puberty, central hypothyroidism, abnormal glucose regulation, moderate ID (3/3) and peripheral polyneuropathy. Seizures were not part of the phenotype. Linkage analysis suggested 2 candidate regions on chromosomes 13 and 15 with a LOD score of 2.5. High throughput sequencing of genes within these regions (~500) in an affected member and parent revealed a 15 bp in-frame deletion of DMXL2 (NM_015263.4:c.5827_5841del / p.Asp1943_Ser1947del). Sanger sequencing of other affected and unaffected members supported AR inheritance. RT-qPCR demonstrated that DMXL2 mRNA levels in blood lymphocytes were significantly lower in homozygous patients compared to heterozygous or wt family members or controls. The authors demonstrated that the encoded protein (rabconnectin-3a) is a synaptic protein (expressed in exocytosis vesicles) at the ends of axons of GnRH producing neurons. Neuron-specific deletion of one allele in mice resulted in delayed puberty and very low fertility. Adult mice had lower number of GnRH neurons in hypothalamus. siRNA-mediated downregulation of Dmxl2 expression in an insulin-secreting cell line resulted in only slight insulin secretion in response to augmenting concentrations of glucose, providing evidence of involvement of the protein in control of regulated insulin secretion.
-----------
[2] Maddirevula et al. (2019 - PMID: 30237576) reported briefly on a 36 months old boy, born to consanguineous parents, homozygous for a frameshift DMXL2 variant [individual 17-3220 | NM_001174117.1:c.4349_4350insTTACATGA or p.(Glu1450Aspfs*23)]. Features included focal seizures (onset at the age of 3m) with subsequent global DD, absent eye contact, cerebral atrophy and macrocephaly. This individual was identified following re-evaluation of exome data in a database of ~1550 exomes specifically for homozygous variants that would have been classified earlier as LP/P if the respective gene had sufficient evidence for association with a disorder. The family was not reported to have other affected members. As the authors noted, the boy was not known to have the multi-endocrine abnormalities reported by Tata et al. There are no additional information provided (eg. on confirmation of variants, etc).
-----------
[3] Esposito et al. (2019 - PMID: 31688942) report on 3 sibling pairs (all 3 families unrelated) with biallelic DMXL2 mutations and summarize previous evidence on the gene and the DMXL2-related phenotypes.

All presented a highly similar phenotype of Ohtahara syndrome (seizures with onset in the first days of life, tonic/myoclonic/occasionaly focal, burst-suppression upon EEG), profound DD/ID, quadriparesis, sensorineural hearing loss and presence of dysmorphic features. Sibs from 2 families presented evidence of peripheral polyneuropathy. Early brain MRIs revealed thin CC and hypomyelination in all, with later scans suggestive of gray and white matter shrinkage with leukoencephalopathy. None achieved developmental skills following birth with 5/6 deceased by the age of 9 years.

Exome sequencing revealed biallelic DMXL2 variants in all, with compatible parental segregation studies (NM_015263.3):
- Fam1 (2 sibs) : c.5135C>T (p.Ala1712Val) in trans with c.4478C>G (p.Ser1493*)
- Fam2 (2 sibs) : homozygosity for c.4478C>A (p.Ser1493*)
- Fam3 (2 sibs) : homozygosity for c.7518-1G>A

Heterozygous parents (aged 39-59) did not exhibit hearing impairment [report of a single multigenerational family by Chen et al (2017 - PMID: 27657680) where a heterozygous missense variant segregated with hearing loss - respective OMIM entry: ?Deafness, autosomal dominant 71 - 617605].

In patients' fibroblasts, effect of the variants on mRNA/protein expression was demonstrated with mRNA expressed only in a patient from family 1, and degraded/absent for the 2 stopgain SNVs affecting codon 1493. Skipping of ex31 leading to frameshift/introduction of a PTC was shown for the splice variant (p.Trp2508Argfs*4 secondary to c.7518-1G>A). Protein was also absent upon western-blot.

DMXL2 encodes a vesicular protein, DmX-Like protein 2 or rabconnectin-3a (cited Tata et al).

The gene is expressed in brain ( https://www.gtexportal.org/home/gene/DMXL2 ).

As Esposito et al comment, it is known to regulate the trafficking and activity of v-ATPase the latter having a role in acidifying intracellular organelles and promoting endosomal maturation (cited PMIDs : 25248098, 19758563, 22875945, 24802872).

In line with this, staining of patients' fibroblasts using the acidotropic dye LysoTracker demonstrated increased signal, reversed by re-expression of DMXL2 protein. Overall an acidic shift in pH with impairment of lysosomal structures and function was suggested. The authors provided additional evidence for altered lysosomal function and associated autophagy with accumulation of autophagy receptors (eg p62) and substrates (polyubiquitinated proteins). Vacuolization and accumulation of atypical fusion-like structures was shown upon ultrastractural analysis.

shRNA-mediated downregulation/silencing of Dmxl2 in mouse hippocampal neurons resulted also in altered lysosomal structures and defective autophagy. The neurons exhibited impaired neurite elongation and synapse formation.

The authors suggest similarities with Vici syndrome, where biallelic EPG5 mutations result in autophagic defects and clinical manifestations of DD/ID/epilepsy.

Dmxl2 homozygous ko mice display embryonic lethality with heterozygous mice displaying macrocephaly and corpus callosum dysplasia (cited PMIDs: 25248098, 30735494) .
Intellectual disability v2.1102 DMXL2 Konstantinos Varvagiannis reviewed gene: DMXL2: Rating: GREEN; Mode of pathogenicity: None; Publications: 25248098, 30237576, 31688942; Phenotypes: Epileptic encephalopathy, early infantile, 81, MIM 618663, ?Polyendocrine-polyneuropathy syndrome, MIM 616113; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Intellectual disability v2.1102 IL3RA Eleanor Williams Added comment: Comment on mode of inheritance: This gene is in the pseudoautosomal region shared between chromosomes X and Y. The mode of inheritance should therefore be set to Biallelic or Monoallelic once more cases establish the inheritance pattern.
Intellectual disability v2.1102 IL3RA Eleanor Williams Mode of inheritance for gene: IL3RA 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 Unknown
Intellectual disability v2.1101 DHRSX Eleanor Williams Added comment: Comment on mode of inheritance: This gene is in the pseudoautosomal region shared between chromosomes X and Y. The mode of inheritance should therefore be set to Biallelic or Monoallelic once more cases establish the inheritance pattern.
Intellectual disability v2.1101 DHRSX Eleanor Williams Mode of inheritance for gene: DHRSX 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 Unknown
Intellectual disability v2.1100 CRLF2 Eleanor Williams Added comment: Comment on mode of inheritance: This gene is in the pseudoautosomal region shared between chromosomes X and Y. The mode of inheritance should therefore be set to Biallelic or Monoallelic once more cases establish the inheritance pattern.
Intellectual disability v2.1100 CRLF2 Eleanor Williams Mode of inheritance for gene: CRLF2 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 Unknown
Intellectual disability v2.1099 AKAP17A Eleanor Williams Added comment: Comment on mode of inheritance: This gene is in the pseudoautosomal region shared between chromosomes X and Y. The mode of inheritance should therefore be set to Biallelic or Monoallelic once more cases establish the inheritance pattern.
Intellectual disability v2.1099 AKAP17A Eleanor Williams Mode of inheritance for gene: AKAP17A 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 Unknown
Intellectual disability v2.1098 ZNF292 Konstantinos Varvagiannis gene: ZNF292 was added
gene: ZNF292 was added to Intellectual disability. Sources: Radboud University Medical Center, Nijmegen,Literature
Mode of inheritance for gene: ZNF292 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ZNF292 were set to 31723249; 29904178
Phenotypes for gene: ZNF292 were set to Intellectual disability; Autism; Attention deficit hyperactivity disorder; Abnormality of the face; Abnormal muscle tone; Abnormality of nervous system morphology; Growth abnormality; Feeding difficulties; Abnormality of the skeletal system; Abnormality of the cardiovascular system; Microcephaly; Seizures
Penetrance for gene: ZNF292 were set to Incomplete
Review for gene: ZNF292 was set to GREEN
gene: ZNF292 was marked as current diagnostic
Added comment: Mirzaa et al. (2019 - PMID: 31723249) report on 28 individuals (from 27 families) with putatively pathogenic ZNF292 variants.

Main features consisted of DD and ID (27/28 - mild in 40%, moderate in 22%, severe in 11%) with or without ASD and ADHD. A single individual had no evidence of ID but had speech delay and ASD at the age of 6. Additional features (by diminishing order of frequency) included presence of non-specific dysmorphic features (~45%), abnormal tone, brain MRI abnormalities, growth failure, feeding difficulties, skeletal and cardiac anomalies, microcephaly and epilepsy (~11%).

As the authors comment, ZNF292 encodes a zinc finger protein, acting as a transcription factor.

Evidence is provided that gene has high expression in the developing human brain, with its expression being higher in prenatal development and diminishing postnatally. Znf292 is also expressed in adult mouse brain (highest in hippocampus/Purkinje cells).

Variants were identified by exome or targeted panel sequencing (targeted capture/molecular inversion probes). Previous investigations (eg. aCGH, analysis of relevant genes) had probably ruled out alternative causes in most with few having VUS or possibly relevant additional variants (eg. a KDM5C stopgain variant in a male).

24 putatively pathogenic variants were observed in this cohort, all predicting LoF (stopgain, frameshift or splice variants). All were de novo with the exception of one family where the variant was inherited from an affected parent. Almost all were absent from gnomAD and had CADD scores > 35.

Most variants lied within the last and largest exon that encodes a DNA binding domain. RT-PCR on RNA from 2 individuals harboring such variants confirmed that NMD does not apply. This exon however represents ~88% of the total coding length so the distribution of variants in this (NMD escaping) region was consistent with what would also be expected by chance.

ZNF292 has a pLI of 1 in gnomAD. Manual review of some relevant LoF variants in gnomAD suggested that they represent false positive calls.

As a result, the effect of variants is not clear although haploinsufficiency is still possible based also on phenotype of (larger) deletions spanning this gene (cited: Engwerda et al - PMID: 29904178 / The study focuses on deletions of the broader 6q. A possible role of ZNF292 is discussed as autism was present in 4/10 individuals with deletions encompassing this gene).

Based on the aforementioned cohort with one individual being diagnosed with mild ID only as an adult and/or presence of 5 pLoF variants in gnomAD the authors propose that some variants may be incompletely penetrant or associated with only mild features.

Finally, 15 additional individuals (belonging to 12 families) harbored variants for which pathogenicity was suspected (but could not be concluded) due to insufficient phenotypic information, lack of sufficient parental studies or missense variants. In this cohort variants were mostly pLoF, while 3 individuals (incl. 2 sibs) had a de novo missense SNV.
------
Other studies were not here reviewed as some of the individuals reported were published previously in larger cohorts.
------
There is no associated phenotype in OMIM / G2P. SysID includes this gene among the candidate ID ones.
ZNF292 is included in gene panels for ID offered by some diagnostic laboratories (incl. Radboudumc and GeneDx).
------
Overall ZNF292 could be added to the ID panel probably with green (or amber) rating.

[Please consider inclusion in other possibly relevant panels eg. autism, epilepsy]
Sources: Radboud University Medical Center, Nijmegen, Literature
Intellectual disability v2.1098 CNOT2 Konstantinos Varvagiannis gene: CNOT2 was added
gene: CNOT2 was added to Intellectual disability. Sources: Literature,Radboud University Medical Center, Nijmegen
Mode of inheritance for gene: CNOT2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CNOT2 were set to 31512373; 31145527; 28135719; 28159701; 30768759; 21505450; 18076123; 22247066
Phenotypes for gene: CNOT2 were set to Intellectual developmental disorder with nasal speech, dysmorphic facies, and variable skeletal anomalies, MIM 618608
Penetrance for gene: CNOT2 were set to unknown
Review for gene: CNOT2 was set to GREEN
gene: CNOT2 was marked as current diagnostic
Added comment: Heterozygous pathogenic CNOT2 variants cause Intellectual developmental disorder with nasal speech, dysmorphic facies, and variable skeletal anomalies (MIM 618608 - recently added disorder in OMIM). Larger 12q15 deletions, spanning CNOT2 have been reported in patients with similar phenotype.

Relevant individuals - most discussed below - include 2 patients with truncating de novo mutation, 1 with de novo intragenic deletion, few with small deletions spanning also 2-3 additional proximal genes and others with larger 12q15 deletions encompassing CNOT2 and several other genes.

Overall the phenotype - summarized by Uehara et al. (Ref1 - below) - seems to consist of language delay, mild motor delay (in most), some suggestive facial features (upslanted palpebral fissures, anteverted nares, thin upper lip and micrognathia). Nasal speech has also been reported in some individuals.

As commented by Uehara et al. (Ref1), CNOT2 (CCR4-NOT transcription complex subunit 2) is a member of the carbon catabolite repressor 4 complex (CCR4-NOT), the latter having an important role in deadenylation of mRNA and global mRNA expression. Disruption of the complex - which can be caused by loss of one of its components - results in various human disorders incl. neural diseases. siRNA CNOT2 depletion has been shown to induce CCR4-NOT disruption (cited PMIDs: 16284618, 29438013, 31006510, 21299754).

The type of variants (truncating, intragenic deletion, larger deletions) and the highly overlapping phenotypes in the respective patients suggest happloinsufficiency as the underlying mechanism. CNOT2 has also a pLI of 1 in gnomAD (o/e =0.06) and a %HI in Decipher of 4.39.

The gene appears to have relevant expression (https://www.proteinatlas.org/ENSG00000111596-CNOT2/tissue).
Animal models have not been discussed (or phenotypes possibly not sufficiently studied - MGI for Cnot2 : http://www.informatics.jax.org/marker/MGI:1919318).

CNOT2 is not associated with any phenotype in G2P. It is listed among the ID candidate genes in SysID.
This gene is included in gene panels for ID offered by some diagnostic laboratories (incl. Radboudumc).

Overall CNOT2 could be considered for inclusion in the ID panel with amber (DD although outcome is not known, presumed dysfunction of the CCR4-NOT complex, variant studies or animal models not available) or green rating (sufficient cases and variants, consistent phenotype).
-----
Individuals with CNOT2-only disruption:
[1] PMID: 31512373 (Uehara et al., 2019) - A 6 y.o. male investigated for hypotonia, feeding problems, DD (speech and motor), macrocephaly (+3 SD) and some possibly suggestive facial/other features was found to harbor a de novo stopgain variant (NM_001199302.1: c.946A>T, p.Lys316Ter) after trio exome sequencing. The variant and its de novo occurrence were confirmed by Sanger sequencing. NMD was the predicted effect (variant in ex11 of 21 / effect not further studied). Previous metabolic work-up and chromosomal testing had not revealed an alternative diagnosis.
[2] PMID: 31145527 (Alesi et al. 2019) - A 13 y.o. boy with hypotonia, failure to thrive, DD and following a specific schooling program for children with learning difficulties is reported. The authors comment on the facial phenotype (incl. upslanted p-f, anteverted nares, etc). Other features included valvular/supravalvular pulm. stenosis, mid aortic insufficiency, renal anomalies/failure, skeletal anomalies. Speech was nasal. CMA revealed an 85-kb 12q15 deletion spanning only CNOT2 (exons 3-15). Real-time PCR in proband and parents confirmed the variant and its de novo occurrence.
[3] PMID: 28135719 (DDD study, 2017) - An individual with developmental disorder and a de novo (validated) frameshift variant was identified [DDD4K.00807 - NM_014515.5:c.1158del / p.(L387Sfs*3)]. Phenotype in Decipher incl. abnormality of head/neck, nervous, skeletal system and growth. [https://decipher.sanger.ac.uk/ddd/research-variant/16b4f7866652f08e25a194f65535b4c5#overview].

Individuals with disruption of additional proximal genes due to CNVs:
[4] PMID: 28159701 (Alesi et al. 2017) - The authors report on a 29 y.o. individual with history of DD, learning difficulties, ID (WAIS-R IQ of 48 at the age of 17 y), some dysmorphic facial features. Additional features incl. recurrent infections, nasal voice as well as skeletal anomalies. CMA revealed a 742 kb microdeletion spanning CNOT2, KCNMB4 and PTPRB. Real-time PCR confirmed deletion and it's de novo occurrence in the proband.
[5] PMID: 30768759 (Uehara et al. 2019) - A female investigated among others for global DD (walking/1st words at 24m), mild ID, submucosal cleft palate with some distinctive facial features (upslanted p-f, micrognathia, etc) was found to harbor a 1.32-Mb deletion of 12q15 encompassing CNOT2 and 14 other genes. Given the phenotypic resemblance to patients with 12q15 deletions, the previously defined smallest region of overlap (ref 4,6), the LoF SNV in Decipher the authors suggested that CNOT2 is the critical gene for the phenotype of 12q15 deletion syndrome.

Larger deletions defining the smallest region of overlap
[6] PMID: 21505450 (Vergult et al. 2011) - 3 patients with de novo microdeletions of ~ 2.5 Mb in size with a 1.34 MB common region of overlap are reported. Learning diability, DD, nasal speech and hypothyroidism were among the common features.
[7] PMID: 18076123 (Schluth et al. 2008) - A girl with large (~10 Mb) de novo deletion of 12q15 - q21.2 identified by BAC array was described. The phenotype consisted of hypotonia, DD, moderate ID, growth delay and facial dysmorphic features.
[8] PMID: 22247066 (Lopez et al. 2012) - A patient with ID and features of Floating-Harbor syndrome was found to harbor a 4.7 Mb de novo 12q15-q21.1 deletion spanning CNOT2 and 18 additional genes.
[..]
Sources: Literature, Radboud University Medical Center, Nijmegen
Intellectual disability v2.1098 TMX2 Konstantinos Varvagiannis gene: TMX2 was added
gene: TMX2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: TMX2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TMX2 were set to 31586943; 31270415
Phenotypes for gene: TMX2 were set to Global developmental delay; Intellectual disability; Seizures; Microcephaly; Abnormal cortical gyration
Penetrance for gene: TMX2 were set to Complete
Review for gene: TMX2 was set to AMBER
Added comment: PMID: 31586943 - Ghosh et al. 2019 - reported on 8 individuals from 4 consanguineous families from the Middle East and Central Asia, all with a phenotype of DD/ID, seizures and microcephaly with lissencephaly (microlissencephaly is the term applying to the combination of two) upon brain MRI.

All patients were investigated by exome sequencing and the variant localized within a region of ROH which was common to all 4 families. All were homozygous for a TMX2 missense variant (NM_001144012.2:c.500G>A or p.Arg167Gln / NM_015959.4:c.614G>A p.Arg205Gln or hg38 - Chr11:g.57739039G>A). The variant was considered to be the best candidate, upon review of all other homozygous ones.

Sanger sequencing confirmed homozygosity for the variant in affected subjects, with additional compatible segregation studies including parents in all families as well as unaffected sibs (in two families).

Despite presence of the same mutation in all, several proximal to this variant SNPs did not appear to be shared among the families studied, thus suggesting that the variant had arisen within different haplotype blocks.

The authors comment that the variant was not previously identified in public databases. (The variant seems to correspond to rs370455806, present in 10 htz individuals in gnomAD, as well as in the GME database [GME Genotype Count 992:0:1 (hmz?) | Allele Count: 2,1984] . GME includes primarily - although not necessarily - healthy individuals).

This SNV affecting the last nucleotide of an exon of several transcripts (correct ref. is NM_001144012.2 as appears in the supplement / using NM_001347898.1 as in the fig./text the variant would lie within an intron), an eventual splicing effect was studied. mRNA transcript levels were assessed following RT-PCR using different sets of primers. There was no evidence of novel splice isoforms but mRNA levels were reduced compared to controls (15-50% in affected individuals, to a lesser level in carriers). This led to the hypothesis that NMD of an aberrantly spliced mRNA might apply, although this was not proven.

TMX2 encodes a protein disulfide isomerase (PDI). PDIs are transmembrane ER proteins which have a critical role in protein folding (PMID cited: 12670024). There were no relevant studies carried out in the article.

As for animal models, the authors comment that mice homozygous for null mutations display preweaning lethality with complete penetrance.(http://www.informatics.jax.org/diseasePortal/popup?isPhenotype=true&markerID=MGI:1914208&header=mortality/aging).
-------
Previously, Schot el al. (ESHG Conference 2018 Oral Presentation - Mutations in the thioredoxin related gene TMX2 cause primary microcephaly, polymicrogyria and severe neurodegeneration with impaired mitochondrial energy metabolism - available in PMID: 31270415 / https://www.nature.com/articles/s41431-019-0407-4 ) reported on 7 individuals from 5 unrelated families with biallelic TMX2 mutations. A newborn with microcephaly, polymicrogyria who died of refractory epilepsy, was compound heterozygous for 2 TMX2 variants. 6 additional individuals (from 4 unrelated families) with similar phenotype were found to harbor biallelic TMX2 mutations. It was commented that TMX2 is enriched in mitochondria-associated membrane of the ER with a role in ER stress protection and regulation of neuronal apoptosis. In line with this, fibroblasts from 2 unrelated patients showed secondary OXPHOS deficiency and increased glycolytic activity (the latter possibly as a compensatory mechanism).
-------
There is no associated phenotype in OMIM/G2P/SysID.
-------
Overall this gene could be considered for inclusion in the ID/epilepsy panel probably with amber (/red) rating pending further evidence.
Sources: Literature
Intellectual disability v2.1098 KCNT2 Konstantinos Varvagiannis gene: KCNT2 was added
gene: KCNT2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: KCNT2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: KCNT2 were set to 29069600; 29740868
Phenotypes for gene: KCNT2 were set to ?Epileptic encephalopathy, early infantile 57, MIM 617771
Penetrance for gene: KCNT2 were set to unknown
Review for gene: KCNT2 was set to GREEN
Added comment: Heterozygous pathogenic KCNT2 variants cause ?Epileptic encephalopathy, early infantile, 57 (MIM 617771).

At least 3 unrelated affected individuals have been reported :

- PMID: 29069600 - Gururaj et al. 2017 : a male child with EOEE (hypotonia, profound DD and intractable infantile seizures) due to a de novo KCNT2 missense variant (NM_001287819.1:c.720T>A or p.Phe240Leu) identified by exome sequencing.

- PMID: 29740868 - Ambrosino et al. 2018 : A girl with phenotype corresponding to West syndrome later evolving to Lennox-Gastaut syndrome. At the age of 9 years the girl displayed severe ID. Trio exome sequencing revealed a de novo missense KCNT2 variant (NM_001287820.2:c.569G>A or p.Arg190His). A 14 y.o. female recruited through the DDD study with phenotype corresponding to epilepsy of infancy with migrating focal seizures. The girl had poor language development and severe learning disability. Infective and metabolic causes were initially ruled out. Trio exome sequencing revealed a de novo missense SNV (c.569G>C or Arg190Pro).

Overall KCNT2 has been commented to contribute to a phenotypic spectrum similar and overlapping to that of KCNT1 (Ambrosino et al.). [KCNT1 is rated green in both epilepsy and ID panels].

KCNT2 was recently included in the epilepsy panel as green (functional studies summarized in the respective reviews). The gene was also recently added to G2P, associated with 'Developmental and infantile epileptic encephalopathy'. It is not commonly included in gene panels for ID offered by diagnostic laboratories.

As a result, KCNT2 could be considered for inclusion in the ID panel with green (or amber) rating.
Sources: Literature
Intellectual disability v2.1098 NSF Konstantinos Varvagiannis gene: NSF was added
gene: NSF was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: NSF was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: NSF were set to 31675180
Phenotypes for gene: NSF were set to Seizures; EEG with burst suppression; Global developmental delay; Intellectual disability
Penetrance for gene: NSF were set to unknown
Mode of pathogenicity for gene: NSF 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: NSF was set to AMBER
Added comment: Suzuki et al. (2019 - PMID: 31675180) report on 2 unrelated individuals with de novo missense NSF variants. Overall the phenotype corresponded to an early infantile epileptic encephalopathy. The first patient developed vomiting and tonic seizures immediately after birth, with burst-suppression pattern upon EEG. Trio exome sequencing, followed by Sanger sequencing of proband and parents, revealed a de novo missense variant (NM_006178.3:c.1375G>A / p.Ala459Thr), absent from public databases and predicted in silico to be deleterious (CADD score of 30). The girl died 36 days after birth due to respiratory failure. Another subject, having necessitated mechanical ventilation due to absence of spontaneous respiration after birth, developed myoclonic seizures. EEG showed a burst-suppression pattern. At the age of 3, she was noted to have persistence of seizures and profound ID. Trio exome sequencing identified a missense NSF variant (c.1688C>T / p.Pro563Leu) also confirmed and shown to be de novo by Sanger sequencing. Again the variant was absent from public datasets and had a CADD score of 34. While expression of wt NSF allele in the developing eye of Drosophila had no effect, expression of mutants severely affected eye development - suggesting a dominant negative effect. NSF encodes a homo-hexameric AAA ATPase, which is recruited by SNAPs (Soluble NSF Attachment Proteins) - and the latter by SNAREs (SNAP REceptors) - thus having a role in vesicular transport and membrane fusion. There is currently no associated phenotype in OMIM/G2P. Overall, this gene could be considered for inclusion probably with amber/red rating pending further evidence (eg. additional work-up or alternative causes/explanations not discussed).
Sources: Literature
Intellectual disability v2.1098 WDFY3 Konstantinos Varvagiannis reviewed gene: WDFY3: Rating: GREEN; Mode of pathogenicity: None; Publications: 27008544, 31327001, 25198012, 28191889; Phenotypes: ?Microcephaly 18, primary, autosomal dominant - MIM 617520; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Intellectual disability v2.1098 SCAMP5 Konstantinos Varvagiannis gene: SCAMP5 was added
gene: SCAMP5 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: SCAMP5 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SCAMP5 were set to 31439720; 20071347
Phenotypes for gene: SCAMP5 were set to Global developmental delay; Intellectual disability; Seizures; Abnormality of nervous system morphology; Behavioral abnormality
Penetrance for gene: SCAMP5 were set to unknown
Mode of pathogenicity for gene: SCAMP5 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: SCAMP5 was set to AMBER
Added comment: PMID: 31439720 (Hubert et al. 2019) reported on 2 unrelated individuals with severe ID, seizures behavioral and brain MRI abnormalities (white matter hyperintensity and mesial temporal sclorosis), both harboring the same missense SCAMP5 mutation as a de novo event (NM_001178111.1:c.538G>T or p.Gly180Trp).

Previously aCGH +/- metabolic workup were non diagnostic.

The occurrence of the same de novo variant in both as well as the similar presentation (incl. MRI images) suggested SCAMP5 as the most probable candidate gene, despite presence of few other variants in both.

SCAMP5 is highly expressed in brain (https://www.proteinatlas.org/ENSG00000198794-SCAMP5) and previous studies have suggested a role in synaptic vesicle trafficking (PMIDs cited: 29562188, 25057210, etc).

Cultured skin fibroblasts from affected individuals failed to express SCAMP5.

Scamp is the Drosophila orthologue, with previous studies having demonstrated that mutants display defects in climbing, olfactory-assisted memory and susceptibility to heat induced seizures (PMIDs cited: 25478561, 19144841). Expression of the Scamp Gly302Trp variant in Drosophila ('equivalent' to the SCAMP5 Gly180Trp) revealed strongly reduced levels for the variant compared with wt upon Western Blot, either due to reduced expression or due to increased turnover. Overall the effect of Gly302Trp expression was similar to Scamp knockdown by RNAi (eg. rough eye phenotype, reduced ability to climb the walls of a graded tube after tapping, less/no flies reaching adult stage) but significantly different compared to wt.

As a result, a dominant-negative effect was presumed.
----------
PMID: 20071347 (Castermans et al. 2010) is cited as a previous report of a relevant affected individual. In this study a 40 y.o. male with early DD, mild ID (IQ of 63) and ASD was found to harbor a de novo apparently balanced t(1;15) translocation affecting CLIC4 and PPCDC (both not associated with ID). [1-Mb resolution aCGH revealed no relevant CNVs].

Studies were however focused on SCAMP5 given that the gene is located downstream of / proximal to PPCDC, has brain-enriched expression as well as involvement in synaptic trafficking and demonstrated:
- Less than 50% expression upon quantitative RT-PCR in patients leukocytes, compared to control.
- Silencing and overexpression of Scamp5 in mouse β-TC3 cells resulted in increased and suppressed respectively secretion of large dense-core vesicles (LDCVs).
- Given conservation of some components involved in secretion of dense core granules (DCGs) in platelets and LDCVs in neuronal cells, study of patient platelets - where SCAMP5 was confirmed to be expressed - suggested an altered pattern of DCGs.
----------
SCAMP5 is not associated with any phenotype in OMIM/G2P/SysID and not commonly included in gene panels for ID.
----------
Overall, this gene could be considered for inclusion in the ID and epilepsy panels probably with amber (# of unrelated individuals, 1 recurrent de novo variant and 1 regulatory effect, gene expressed in brain with a role in synaptic vesicle trafficking) or red rating (pending further evidence).
Sources: Literature
Intellectual disability v2.1098 FAM160B1 Konstantinos Varvagiannis gene: FAM160B1 was added
gene: FAM160B1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: FAM160B1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FAM160B1 were set to 27431290; 31353455
Phenotypes for gene: FAM160B1 were set to Central hypotonia; Global developmental delay; Intellectual disability; Abnormality of the face
Penetrance for gene: FAM160B1 were set to Complete
Review for gene: FAM160B1 was set to AMBER
Added comment: Anazi et al. (2017 - PMID: 27431290) in a study of 337 subjects with ID, reported on a consanguineous family (15DG2696) with 3 affected sibs. The proband, a 7 y.o. boy had hypotonia, DD, mild ID (IQ of 69), some facial dysmorphic features as well as increased skin elasticity and joint hypermobility. Initial investigations included metabolic testing for OA and CDGs, FMR1 and aCGH. A 4 y.o. sister and a 3 y.o. brother of the proband had similar presentation of DD. Exome sequencing, autozygosity mapping and segregation studies suggested a FAM160B1 hmz missense SNV as the likely causal variant (NM_001135051.1:c.248T>C or p.Leu83Pro). There were no other candidate variants. As the encoded protein has a yet unknown function, with uncertain in silico 3D modeling, the authors speculated disruption of helices affecting fold/(ligand binding) function as the underlying effect of this variant.

Mavioğlu et al. (2019 - PMID: 31353455) reported on a 38 y.o. female with history of motor and language delay, severe ID, ataxia, behavioral abrnormalities as well as some dysmorphic features. This individual was born to consanguineous parents (2nd cousins). There was history of a deceased, similarly affected sib. Initial investigations included metabolic work-up (plasma AA, urinary OA) and karyotyping. SNP genotyping in the family (parents, affected sib, 3 unaffected sibs) and multipoint linkage analysis for AR inheritance, yielded a maximum LOD score of 2.15. Selection of homozygous regions unique to the patient (but not present in unaffected sibs) did not suggest any known ID gene. Exome sequencing of the proband, with analysis of the variants in candidate regions revealed a homozygous stopgain SNV (NM_020940.4:c.115G>T or p.Glu39*) as the best candidate variant (with few others not considered to be relevant). FAM160B1 has a pLI of 1, LoF variants in public databases have MAFs below 0.000034 with no recorded homozygotes. In silico predictions suggested a deleterious effect (CADD score of 40, etc). The previous report by Anazi and fulfilment of the ACMG criteria for its classification of this variant as pathogenic led to its consideration as causal of the patient's phenotype.

Study of the expression of the 2 isoforms of the gene (isoform1: NM_020940, 2:NM_001135051) revealed that the first is ubiquitously expressed and the second only in testes. [To my understanding the 2 isoforms seem to differ only in their last exon, the 2 reported variants affecting both isoforms - http://genome.ucsc.edu/cgi-bin/hgTracks?db=hg19&lastVirtModeType=default&lastVirtModeExtraState=&virtModeType=default&virtMode=0&nonVirtPosition=&position=chr10%3A116577123%2D116663023&hgsid=777553295_dPP9DgaheaF82gTRTfZO6XS5lEzA ]

The function of this gene remains unknown. Animal models/phenotypes are probably not available.

There is no associated phenotype in OMIM/G2P. SysID lists FAM160B1 as a candidate ID gene.
FAM160B1 is not commonly included in gene panels for ID offered by diagnostic laboratories.

As a result this gene can be considered for inclusion in the current panel probably with amber (2 families/variants, variable ID as a feature) or red rating pending further evidence (given the partial phenotypic overlap, unknown function of the gene, variants not further studied, no animal models).
Sources: Literature
Intellectual disability v2.1098 PCYT2 Konstantinos Varvagiannis gene: PCYT2 was added
gene: PCYT2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: PCYT2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PCYT2 were set to 31637422
Phenotypes for gene: PCYT2 were set to Global developmental delay; Developmental regression; Intellectual disability; Spastic paraparesis; Seizures; Spastic tetraparesis; Cerebral atrophy; Cerebellar atrophy
Penetrance for gene: PCYT2 were set to Complete
Review for gene: PCYT2 was set to GREEN
Added comment: Vaz et al. (2019 - PMID: 31637422 - DDD study among the co-authors) report on 5 individuals - from 4 families - with biallelic PCYT2 mutations.

The phenotype corresponded to a complex hererditary paraplegia with global DD, regression (4/5), ID (mild in 3/5, severe in 2/5), spastic para-/tetraparesis, epilepsy (5/5 - variable onset 2-16 yrs - focal or tonic-clonic seizures) and progressive cerebral and cerebellar atrophy.

Exome sequencing in all revealed biallelic PCYT2 variants, confirmed with Sanger s. in probands and their parents (NM_001184917.2 - corresponding to the canonical transcript used as Ref below):
- P1 (Fam1) : 2 missense SNVs in trans configuration, c.730C>T or p.His244Tyr and c.920C>T or p.Pro307Leu
- P2 (Fam2 - consanguineous of White British origin), P3 (Fam3 - Consanguineous of Turkish origin), P4,5 (Fam4 - consanguineous, unspecified origin) : homozygosity for c.1129C>T or p.Arg377Ter) affecting the last exon of 8/12 transcripts, including the canonical one.

Individuals with the same genotype displayed variable degrees of ID (eg P3 - severe / P2, P4,5 - mild ID).

For sibs in Fam4, homozygosity for a missense SACS variant led to consideration of the respective disorder (AR spastic ataxia of Charlevoix-Saguenay) though the variant was predicted to be tolerated in silico and notably the MRI images not suggestive.

All variants were absent from / had extremely low AF in public databases, with no homozygotes.

Posphatidylethanolamine (PE) is a membrane lipid, particularly enriched in human brain (45% of phospholypid fraction). PE is synthesized either via the CDP-ethanolamine pathway or by decarboxylation of phosphatidylserine in mitochondria. PCYT2 encodes CTP:phosophoethanolamine cytidyltransferase (ET) which is an ubiquitously expressed rate-limiting enzyme for PE biosynthesis in the former pathway.

In silico, the 2 missense variants - localizing in the CTP catalytic domain 2 - were predicted to be damaging, as well as to affect protein stability.

Fibroblasts of 3 patients (P1, P2, P3) representing all variants were studied:
- Enzymatic activity was shown to be significantly reduced (though not absent) compared to controls. Abnormalities were noted upon Western Blot incl. absence in all 3 patients studied of one of the 2 bands normally found in controls (probably representing the longer isoform), reduced intensity in all 3 of another band probably corresponding to a shorter isoform, and presence of an additional band of intermediate molec. mass in patients with the truncating variant.
- RT-PCR on mRNA from patient fibroblasts did not reveal (significant) reduction compared to controls.
- Lipidomic profile of patient fibroblasts was compatible with the location of the block in the phospholipid biosynthesis pathway and different from controls.

The lipidomic profile had similarities with what has been reported for EPT1 deficiency, the enzyme directly downstream of ET. The SELENO1-related phenotype (/EPT1 deficiency) is also highly overlapping.

CRISPR-Cas9 was used to generate pcyt2 partial or complete knockout (ko) zebrafish, targeting either the final (ex13) or another exon (ex3) respectively. mRNA expression was shown to be moderately reduced in the first case and severely reduced/absent in the second, compared to wt. Similarly, complete-ko (ex3) led to significantly lower survival, with impaired though somewhat better survival of partial-ko (ex13) zebrafish.

Complete knockout of Pcyt2 in mice is embryonically lethal (PMID cited: 17325045) while heterozygous mice develop features of metabolic syndrome (PMID cited: 22764088).

Given lethality in knockout zebrafish / mice and the residual activity (15-20%) in patient fibroblasts, the variants reported were thought to be hypomorphic and complete loss of function possibly incompatible with life.

PCYT2 is not associated with any phenotype in OMIM/G2P/SysID and not commonly included in gene panels for ID.

As a result this gene could included in the ID / epilepsy panels with green (~/>3 indiv/fam/variants with the nonsense found in different populations, consistent phenotype, lipidomics, in silico/in vitro/in vivo evidence) or amber rating.

[Please consider inclusion in other possibly relevant panels eg. for metabolic disorders, etc].
Sources: Literature
Intellectual disability v2.1098 PDE6D Konstantinos Varvagiannis gene: PDE6D was added
gene: PDE6D was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: PDE6D was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PDE6D were set to 24166846; 30423442
Phenotypes for gene: PDE6D were set to ?Joubert syndrome 22 - MIM 615665
Penetrance for gene: PDE6D were set to Complete
Review for gene: PDE6D was set to AMBER
gene: PDE6D was marked as current diagnostic
Added comment: Thomas et al. (2014 - PMID: 24166846) reported on a consanguineous Pakistani family with 3 members presenting variable polydactyly, brain anomalies (incl. molar tooth sign), microphthalmia/coloboma with retinal disease, renal hypoplasia suggestive of Joubert syndrome.

Genotyping with a SNP array identified a unique 17-Mb region of homozygosity on chr2 with LOD score of 2.6. The region contained 208 genes, of which 15 present in ciliary gene databases. A homozygous splicing variant appeared to be the only relevant, PDE6D being a ciliary gene within this region [NM_002601.4:c.140-1G>A]. Status of all affected members, parents and 2 unaffected sibs was verified with Sanger sequencing.

PDE6D encodes a phosphodiesterase that binds to prenyl groups and has a critical role in ciliogenesis (Humbert et al. - PMID: 23150559 and OMIM).
Several lines of evidence provided support a role for PDE6D and the reported variants :
- Study of PDE6D expression during human embryogenesis suggests ubiquitous localization and highest levels in organs affected in ciliopathies (CNS, kidney tubules, respiratory tract epitherlial cells).
- RT-PCR of mRNA from control/patient fibroblasts and sequencing confirmed the splicing defect leading to an in-frame deletion of exon 3.
- Wt and mutant protein both localized in the basal body of primary cilia (patient/control fibroblasts). Cilia in both cases had normal morphology.
- Experiments in RPE cells confirmed that INPP5E (involved in Joubert/MORM syndrome) interacts (/is probably a cargo of) PDE6D, a process dependent on prenylation.
- Exon 3 deletion was confirmed to disrupt PDE6D binding to INPP5E.
- Analysis by immunofluoresence of INPP5E localization using control/patient fibroblasts and renal tissue showed absence of INPP5E from primary cilia in the case of patient cells (but not controls) suggesting that PDE6D is important for trafficking INPP5E to the cilium.
- Previous study in mice suggested altered photoreceptor physiology in Pde6d (-/-) animals, resulting in a slowly progressing rod/cone dystrophy. The effect was however limited to the eye. (PMID cited : 17496142 - Zhang et al., 2007).
- Morpholino knockdown of pde6d resulted in pericardial edema, eye abnormalities (microphthalmia and disorganized retinal cell layers) and kidney morphogenesis defects (distended, blocked pronephric openings and proximal tubule cysts). Edema was rescued upon coinjection of morpholino with wt (but not mutant) mRNA. Similarly coinjection led to complete or partial rescue of eye development in the case of wt and mutant mRNA respectively supporting pathogenicity and (partial) loss-of-function effect for the variant.
---------
Mégarbané et al. (2019 - PMID: 30423442) reported on an affected 6 month-old boy born to Lebanese first-cousin parents. Features included hypotonia, developmental delay, microcephaly, oculomotor apraxia, postaxial polydactyly of hands and feet and presence of a molar tooth sign upon brain MRI. Renal and retinal anomalies were absent (also given his age). Exome sequencing revealed homozygosity for a frameshift PDE6D variant [NM_002601.3:c.367_368insG or p.(Leu123Cysfs*13)]. Sanger sequencing confirmed presence of the variant in the proband and carrier status of the parents. The variant affected the penultimate exon (note : present in only this longest transcript) and was not predicted to trigger NMD but rather lead to elimination of a highly conserved PDZ-interaction domain.
---------
The phenotype associated with biallelic PDE6D variants in OMIM is ?Joubert syndrome 22 - MIM 615665 based only on the 1st report ('delayed psychomotor development' among the features). There is no relevant entry in G2P. PDE6D is listed as a Current primary (/confirmed) ID gene in SysID (the aforementioned PMIDs cited).

This gene is included in gene panels for ID offered by some diagnostic laboratories (eg. GeneDx).
---------
Overall PDE6D could be considered for inclusion in the ID panel probably with amber rating (2 families/variants, DD but outcome otherwise unknown - evidence for the the gene causing JS seems however sufficient).
Sources: Literature
Intellectual disability v2.1098 NTNG2 Konstantinos Varvagiannis gene: NTNG2 was added
gene: NTNG2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: NTNG2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NTNG2 were set to 31372774; 31668703
Phenotypes for gene: NTNG2 were set to Central hypotonia; Global developmental delay; Intellectual disability; Behavioral abnormality; Microcephaly; Seizures
Penetrance for gene: NTNG2 were set to Complete
Review for gene: NTNG2 was set to GREEN
Added comment: [1] Abu-Libdeh et al. (2019 - PMID: 31372774) reported 8 individuals from 4 unrelated consanguineous families of Arab Muslim origin, all homozygous for NM_032536.3:c.376dup - p.(Ser126PhefsTer241). Common features included hypotonia, failure to achieve milestones and developmental stagnation without regression during the first year (~9m) of life and severe ID. Minimal purposeful hand use (grasping and bringing objects to mouth), hand stereotypies and bruxism were also observed. Microcephaly and impaired growth were almost universal (with the exception of 2 having an OFC at ~10% percentile). Relevant previous investigations were normal in all and included MECP2, SMN1, aCGH, metabolic testing, etc. The variant was identified by exome in all, and Sanger confirmed with compatible segregation studies in parents and sibs. The variant was found within a shared haplotype of ~4.35 Mb, probably due to a founder effect.

[2] Dias et al. (2019 - PMID: 31668703) described 16 individuals from 7 unrelated families from Iran, Mexico, Turkey, Egypt and Bangladesh. Parents were known to be consanguineous or shown to be distantly related. All patients were homozygous for missense variants private to each family (7 variants) identified following exome sequencing. Shared features incl. hypotonia, GDD, severe to profound ID and behavioral anomalies incl. autistic features/stereotypies (most), screaming/laughing spells (most), bruxism. Microcephaly (5/14), growth below average/FTT and GI problems were also observed.

Epilepsy was reported in 5 individuals belonging to 4 different families in these 2 studies (5/24 overall / 4 variants).

Netrin-G2, the encoded protein, is bound to the plasma membrane by GPI-anchors. Netrins-G2 and G1 (another member of the Netrin-G subfamily) are enriched in presynaptic terminals. Interaction with their cognate Netrin-G ligand trans-synaptic partners / receptors (NGL2, NGL1 respectively) has been shown to promote axon outgrowth, induce and maintain excitatory synapse formation. Complementary and non-overlapping expression in the developping and mature CNS has been shown for Netrin-G2/1 in mice (several references provided by Abu-Libdeh / Dias).

Variant effect : The frameshift variant was not studied by Abu-Libdeh et al. Variants in the 2nd ref. were all missense, displayed no-specific localization and were suggested to affect protein stability and/or expression at the cell surface as 4/7 involved loss or addition of cystein residues (possibly creating unpaired cysteins) and 2 of the remaining 3 were predicted to affect the hydrophobic core. In line with this, overexpression of wt/variant constructs in HeLa cells demonstrated substantially decreased cell surface expression for all variants.

Mouse models/phenotypes : Dias et al. showed that siRNA-mediated Ntng2 knockdown in N2a cells led to significant reduction in neurite number and length. Studied previously, Ntng2 knockout mice display impaired learning, memory, visual and motor functioning (PMID cited : 26746425).

NTNG2 is not associated with any phenotype in OMIM/G2P. SysID lists it among the candidate ID genes, citing PMID: 29302074 (not here reviewed & NTNG2 not in the main text).

Overall this gene can be considered for inclusion in the ID panel probably as green (>3 individuals/families/variants, consistent phenotype in both reports, role of the gene, in silico and in vitro studies, animal model, etc) or amber.

[Please consider inclusion in other panels if relevant eg. ASD panel (many individuals having autistic / Rett-like features or epilepsy) or epilepsy (>3 individuals/families/variants although most families were also consanguineous)]
Sources: Literature
Intellectual disability v2.1098 AP1B1 Konstantinos Varvagiannis gene: AP1B1 was added
gene: AP1B1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: AP1B1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AP1B1 were set to 31630788; 31630791
Phenotypes for gene: AP1B1 were set to Failure to thrive; Abnormality of the skin; Hearing abnormality; Abnormality of copper homeostasis; Global developmental delay; Intellectual disability
Penetrance for gene: AP1B1 were set to Complete
Review for gene: AP1B1 was set to AMBER
Added comment: Boyden et al. (2019 - PMID: 31630788) and Alsaif et al (2019 - PMID: 31630791) report on the phenotype related to biallelic AP1B1 mutations.

Common features included failure to thrive, ichthyosis (with variable palmoplantar keratoderma/erythroderma/abnormal hair) and hearing loss. Each study focused on different additional features eg. thrombocytopenia or photophobia in all individuals reported by Boyden et al, while Alsaif et al. focused on abnormal copper metabolism (low plasma copper and ceruloplasmin) observed in all 3 affected individuals and enteropathy/hepatopathy observed in 2 sibs.

DD was observed in all 3 individuals (2 families) reported by Alsaif et al. and patient 424 reported by Boyden et al. ID was noted in all individuals of relevant age (2 from 2 families) in the study by Alsaif. Boyden commented that ID is not part of the phenotype. The adult (424) - despite his early DD - was noted to have normal intellect and had graduated college. The other patient (1325) was last followed up at 11 months (still DD was not reported).

AP1B1 encodes one of the large subunits (β1) of the adaptor protein complex 1. Each of the AP complexes is a heterotetramer composed of two large (one of γ, α, δ, ε and β1-β4 for AP-1 to AP-4 respectively), one medium (μ1-μ4) and one small (σ1-σ4) adaptin subunit. The complex is involved in vesicle-mediated transport.

Variants were confirmed in probands and carrier parents (NM_001127.3):
Boyden Pat424 (33y) : c.430T>C (p.Cys144Arg) in trans with c.2335delC (p.Leu779Serfs*26)
Boyden Pat1325 (11m) [consanguineous Ashkenazi Jewish family] : homozygosity for c.2374G>T (p.Glu792*)
Alsaif sibs P1,P2 (4y4m, 1y5m) [consanguineous - Pakistani origin] : homozygous for a chr22 75 kb deletion spanning only the promoter and ex1-2 of AP1B1
Alsaif P3 (4y6m) [consanguineous - Saudi origin] : homozygous for a c.38-1G>A

Variant / additional studies :
22q 75-kb deletion: PCR deletion mapping and Sanger delineated the breakpoints of the 22q12.2 del to chr22:29758984-29815476 (hg?). Complete absence of transcript upon RT-PCR (mRNA from fibrolasts).
Splicing variant (c.38-1G>A): RT-PCR confirmed replacement of the normal transcript by an aberrant harboring a 1 bp deletion (r.40del).
Stopgain variant (c.2374G>T): Western blot demonstrated loss of AP1B1 (and marked reduction also for AP1G1) in cultured keratinocytes of the homozygous patient.

Loss-of-function is the effect predicted by variants. Vesicular defects were observed in keratinocytes of an affected individual (homozygous for the nonsense variant). Rescue of these vesicular defects upon transduction with wt AP1B1 lentiviral construct confirmed the LoF effect. [Boyden et al.]

ATP7A and ATP7B, two copper transporters, have been shown to depend on AP-1 for their trafficking. Similar to MEDNIK syndrome, caused by mutations in AP1S1 and having an overlapping phenotype with AP1B1 (also including hypocupremia and hypoceruloplasminemia), fibroblasts from 2 affected individuals (from different families) demonstrated abnormal ATP7A trafficking. [Alsaif et al.]

Proteomic analysis of clathrin coated vesicles (2 ind from 2 fam) demonstrated that AP1B1 was the only AP1/AP2 CCV component consistently reduced in 2 individuals (from 2 families). [Alsaif et al.]

Boyden et al. provided evidence for abnormal differentiation and proliferation in skin from an affected individual. In addition E-cadherin and β-catenin were shown to be mislocalized in keratinocytes from this affected individual.

Loss of ap1b1 in zebrafish is not lethal but lead to auditory defects (/vestibular deficits). The inner ears appear to develop normally, although there is progressive degeneration of ear epithelia. There are no behavioral/neurological phenotypes listed for mouse models. [ http://www.informatics.jax.org/marker/MGI:1096368 ].

AP1B1 is not associated with any phenotype in OMIM/G2P/SysID.

Overall this gene could be considered for inclusion in the ID panel probably with amber rating.
Sources: Literature
Intellectual disability v2.1098 FDFT1 Konstantinos Varvagiannis gene: FDFT1 was added
gene: FDFT1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: FDFT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FDFT1 were set to 29909962
Phenotypes for gene: FDFT1 were set to Profound global developmental delay; Intellectual disability; Seizures; Abnormality of nervous system morphology; Cortical visual impairment; Abnormality of the skin; Abnormality of the face
Penetrance for gene: FDFT1 were set to Complete
Review for gene: FDFT1 was set to AMBER
Added comment: Biallelic pathogenic FDFT1 variants cause Squalene synthase deficiency (MIM 618156). 3 individuals from 2 families (and 3 variants) have been reported. DD, ID and seizures are part of the phenotype (3/3). The metabolic profile observed is specific and highly suggestive of disruption of the cholesterol biosynthesis pathway (at the specific level) while the clinical presentation is similar to other disorders of the pathway (SLO). The effect of 2 variants has been studied in detail (in one case mis-splicing demonstrated and in the other regulatory effect). Overall, this gene could be considered for inclusion in the ID/epilepsy panel with amber rating. As the gene is currently present only in the DDG2P panel, please consider adding it to relevant ones (eg. IEMs, undiagnosed metabolic disorders, etc). [Details provided below].
----
Coman et al. (2018 - PMID: 29909962) reported on 3 relevant individuals from 2 unrelated families.

The phenotype consisted of seizures (3/3 - neonatal onset - generalized), profound DD (ID can be inferred from the description in the supplement), variable brain MRI abnormalities (white matter loss, hypoplastic CC), cortical visual impairment, dry skin with photosensitivity as well facial dysmorphic features. Male subjects presented genital anomalies (cryptorchidism/hypospadias).

FDFT1 encodes squalene synthase, the enzyme which catalyzes conversion of farnesyl-pyrophosphate to squalene - the first specific step in cholesterol biosynthesis.

A specific pattern of metabolites was observed in all, similar to a pattern previously observed in animal models/humans treated with squalene synthase inhibitor or upon loading with farnesol (in animals). Overall the pattern was suggestive of a cholesterol biosynthesis defect at the level of squalene synthase as suggested by increased total farnesol levels (farnesyl-pyrophosphate + free farnesol), reduced/normal squalene, low plasma cholesterol as well as other metabolites.

Clinical features also resembled those observed in Smith-Lemli-Opitz syndrome (another disorder of cholesterol biosynthesis).

WES was carried out in affected individuals and their parents and revealed for sibs of the first family, compound heterozygosity for a maternally inherited 120-kb deletion spanning exons 6-10 of FDFT1 and CTSB and a paternally inherited FDFT1 variant in intron 8 (TC deletion/AG insertion). Variant studies for the latter included:
- Minigene splice assay demonstrating retention of 22 bp in intron 8.
- Partial splicing defect with both nl and mis-spliced cDNA (patient fibroblasts)
- Reduced protein levels in lymphoblasts/fibroblasts from both sibs upon Western blot.
Contribution of the CTSB deletion was considered unlikely (carrier mother was unaffected).

As for the 2nd family, WES data allowed identification of a homozygous deep-intronic (although this is transcript-specific) 16-bp deletion in the proband. Parents were carriers. For the specific variant :
- cDNA studies failed to detect 3 (of 10) isoforms which are normally present in control fibroblasts. Eventual NMD (which would be predicted if the deletion resulted in splicing defect) was eliminated given the absent effect of cyclohexamide addition, thus suggesting a regulatory effect.
- Given a predicted promoter/enhancer effect of the deleted region, a luciferase assay performed, suggested that the sequence had promoter capacity, with the construct containing the 16-bp deletion showing reduced promoter activity.

Fdft1 knockout mice demonstrate embryonic lethality around mid-gestation while they exhibit severe growth retardation and defective neural tube closure.

In G2P FDFT1 is associated with 'Defect in Cholesterol Biosynthesis' (confidence:possible/biallelic/LoF). The gene belongs to the Current primary ID gene group of SysID. It is not commonly included in gene panels for ID offered by diagnostic laboratories.
Sources: Literature
Intellectual disability v2.1098 IQSEC1 Konstantinos Varvagiannis gene: IQSEC1 was added
gene: IQSEC1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: IQSEC1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: IQSEC1 were set to 31607425
Phenotypes for gene: IQSEC1 were set to Central hypotonia; Global developmental delay; Intellectual disability; Behavioral abnormality; Short stature
Penetrance for gene: IQSEC1 were set to Complete
Review for gene: IQSEC1 was set to AMBER
Added comment: Ansar et al. (2019 - PMID: 31607425) reported on 5 individuals with biallelic IQSEC1 variants.

Common features included hypotonia, DD, speech impairment, severe ID, behavioral problems as well as short stature. Early-onset seizures were observed in 3 sibs (for whom there was also a paternal family history of seizures).

These subjects belonging to 2 consanguineous families from Pakistan and S. Arabia were found to harbor homozygous missense variants private to each family (Fam1: NM_001134382.2:c.1028C>T or p.Thr354Met following SNP genotyping of several members and exome of the proband | Fam2: c.962G>A or p.Arg321Gln following exome in 2 affected members). Sanger confirmation and study of parents (+/- sibs) were compatible.

The homozygous variant was the only candidate in the 1st family (also following exclusion of other causes of ID/short stature), and most likely/compatible with the patient's phenotype in the 2nd.

As the authors note, IQSEC1-3 encode guanine exchange factors (GEFs) for the ARF family of GTPases. IQSEC2 is a known XLID gene, while biallelic IQSEC3 mutations in ID have been recently reported (PMID: 31130284), all presenting phenotypic similarities (ID, short stature, speech defect).

Previous studies cited had shown that IQSEC1 & 2 are concentrated at the postsynaptic density of glutamatergic synapses in mammalian brain, playing a role in actin-dependent processes incl. AMPA receptor trafficing at synapses (all refs in article).

Drosophila model: The ortholog of IQSEC1, 2 and 3 is schizo and the phenotype associated with its loss is a growth cone guidance defect through dysregulation of the Slit-Robo pathway (all refs in article). The authors studied overexpression of either reference IQSEC1 cDNA or variant cDNAs in wt flies, the former only being toxic/lethal. Loss of schizo was also embryonically lethal but was partially rescued by expression of reference IQSEC1 cDNA. Expression of cDNA for the 2 variants did not rescue lethality. As a result LoF appears to be the underlying effect of both variants. The authors provided evidence that schizo is localized in glia and neurons at various stages of development and is important for proper axon guidance in both CNS and PNS. In Drosophila, schizo is also localized in photoreceptors and RNAi-mediated knockdown resulted in severely impaired sight (also observed in 1 patient).

Mouse model: Through generation of Iqsec1-floxed mice, it was demonstrated that targeted depletion of Iqsec1 in the cortex resulted in increased density/immature morphology of dendritic spines.

IQSEC1 is not associated with any phenotype in OMIM / G2P / SysID and not commonly included in gene panels for ID.

As a result, this gene could be considered for inclusion in the ID panel as probably as amber (2 families/variants).
Sources: Literature
Intellectual disability v2.1098 TAOK1 Rebecca Foulger Phenotypes for gene: TAOK1 were changed from to INTELLECTUAL DISABILITY; developmental delay
Intellectual disability v2.1097 TAOK1 Rebecca Foulger Publications for gene: TAOK1 were set to
Intellectual disability v2.1096 TAOK1 Rebecca Foulger Added comment: Comment on mode of inheritance: Set MOI to MONOALLELIC, to match Gene2Phenotype and PMID:31230721.
Intellectual disability v2.1096 TAOK1 Rebecca Foulger Mode of inheritance for gene: TAOK1 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v2.1095 TAOK1 Ellen McDonagh reviewed gene: TAOK1: Rating: GREEN; Mode of pathogenicity: None; Publications: 31230721; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v2.1095 TAOK1 Ellen Thomas Classified gene: TAOK1 as Green List (high evidence)
Intellectual disability v2.1095 TAOK1 Ellen Thomas Added comment: Comment on list classification: Recently reported DD gene
Intellectual disability v2.1095 TAOK1 Ellen Thomas Gene: taok1 has been classified as Green List (High Evidence).
Intellectual disability v2.1095 TAOK1 Ellen Thomas Classified gene: TAOK1 as Green List (high evidence)
Intellectual disability v2.1095 TAOK1 Ellen Thomas Added comment: Comment on list classification: Recently reported DD gene
Intellectual disability v2.1095 TAOK1 Ellen Thomas Gene: taok1 has been classified as Green List (High Evidence).
Intellectual disability v2.1095 TAOK1 Ellen Thomas Classified gene: TAOK1 as Green List (high evidence)
Intellectual disability v2.1095 TAOK1 Ellen Thomas Added comment: Comment on list classification: Recently reported DD gene
Intellectual disability v2.1095 TAOK1 Ellen Thomas Gene: taok1 has been classified as Green List (High Evidence).
Intellectual disability v2.1094 TAOK1 Ellen Thomas Classified gene: TAOK1 as Green List (high evidence)
Intellectual disability v2.1094 TAOK1 Ellen Thomas Added comment: Comment on list classification: Recently reported DD gene
Intellectual disability v2.1094 TAOK1 Ellen Thomas Gene: taok1 has been classified as Green List (High Evidence).
Intellectual disability v2.1094 TAOK1 Ellen Thomas Classified gene: TAOK1 as Green List (high evidence)
Intellectual disability v2.1094 TAOK1 Ellen Thomas Added comment: Comment on list classification: Recently reported DD gene
Intellectual disability v2.1094 TAOK1 Ellen Thomas Gene: taok1 has been classified as Green List (High Evidence).
Intellectual disability v2.1093 SIX3 Rebecca Foulger Phenotypes for gene: SIX3 were changed from Holoprosencephaly-2, 157170Schizensephaly, 269160; HOLOPROSENCEPHALY to Holoprosencephaly-2, 157170; Schizensephaly, 269160; HOLOPROSENCEPHALY
Intellectual disability v2.1092 SVBP Alistair Pagnamenta reviewed gene: SVBP: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 31363758, 30607023; Phenotypes: brain abnormalities, microcephaly, intellectual disability, delayed gross motor development, spasticity, delayed speech development; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v2.1092 NKAP Catherine Snow Phenotypes for gene: NKAP were changed from to Global developmental delay; Intellectual disability
Intellectual disability v2.1091 NKAP Catherine Snow Classified gene: NKAP as Green List (high evidence)
Intellectual disability v2.1091 NKAP Catherine Snow Added comment: Comment on list classification: NKAP reviewed by Konstantinos Varvagiannis following publication by Fiordaliso et al. (PMID:31587868) who identified 10 males from 8 unrelated families with missense mutations in NKAP (on Xq24) Hypotonia and tall stature with Marfanoid habitus was predominant phenotype. One variant (NM_024528:c.988G>A / p.Arg333Gln) was seen in 4 families and although origin was not provided for all families this variant was seen in brothers with parents from Slovakia and an individual with parents from Japan.
NKAP is not currently in OMIM or Gene2Phenotype.
Rating NKAP as Green as consistent phenotype observed, >3 unrelated individuals and some functional work in Zebrafish.
Intellectual disability v2.1091 NKAP Catherine Snow Gene: nkap has been classified as Green List (High Evidence).
Intellectual disability v2.1090 NKAP Catherine Snow Tag missense tag was added to gene: NKAP.
Intellectual disability v2.1090 METTL5 Rebecca Foulger Classified gene: METTL5 as Amber List (moderate evidence)
Intellectual disability v2.1090 METTL5 Rebecca Foulger Added comment: Comment on list classification: METTL5 was added to the panel and rated Green by Konstantinos Varvagiannis. There are just sufficient (3) cases from the literature (siblings in PMID:29302074 plus 2 families in PMID:31564433), and animal models (mice and zebrafish) exhibit microcephaly similar to the human phenotype. However, the Gly61Asp variant found in the PMID:29302074 siblings is currently classed as VUS and PMID:31564433 failed to demonstrate a functional impact for this variant on the encoded protein.

METTL5 has been recently added (October 2019) to DD-G2P with a probable rating for 'Autosomal-Recessive Intellectual Disability and Microcephaly'. METTL5 is not yet associated with a disorder in OMIM. Given the uncertainty of the functional significance of the Gly61Asp variant, on balance an Amber rating is appropriate at this time, pending further cases or functional evidence.
Intellectual disability v2.1090 METTL5 Rebecca Foulger Gene: mettl5 has been classified as Amber List (Moderate Evidence).
Intellectual disability v2.1089 METTL5 Rebecca Foulger Publications for gene: METTL5 were set to 29302074; http://doi.org/10.1016/j.ajhg.2019.09.007; https://imgc2019.sciencesconf.org/data/abstract_book_complete.pdf
Intellectual disability v2.1088 METTL5 Rebecca Foulger Phenotypes for gene: METTL5 were changed from Delayed speech and language development; Intellectual disability; Microcephaly; Behavioral abnormality to Autosomal-Recessive Intellectual Disability and Microcephaly; Delayed speech and language development; Intellectual disability; Microcephaly; Behavioral abnormality
Intellectual disability v2.1088 NKAP Catherine Snow Publications for gene: NKAP were set to 26358559; 26350204
Intellectual disability v2.1087 TRAPPC6B Rebecca Foulger Classified gene: TRAPPC6B as Green List (high evidence)
Intellectual disability v2.1087 TRAPPC6B Rebecca Foulger Added comment: Comment on list classification: Updated rating from Amber to Green based on Aug 2019 review by Konstantinos Varvagiannis. Konstantinos notes an additional 2019 paper (Nair et al) who report a Lebanese patient with global DD and ID, who is homozygous for a nonsense variant in TRAPPC6B (p.Leu8*). The unaffected mother was a heterozygous carrier. In contrast to previous cases, the patient did not show any seizures, but the authors note he was only 3.5 years old at the time of writing, and will be monitored for seizure events. ID/DD is a consistent phenotype across cases. This takes the number of cases to 3 (with the 3 families in Marin-Valencia forming 1 case), with 3 separate variants. Therefore Green rating is appropriate.
Intellectual disability v2.1087 TRAPPC6B Rebecca Foulger Gene: trappc6b has been classified as Green List (High Evidence).
Intellectual disability v2.1086 CSDE1 Catherine Snow Classified gene: CSDE1 as Green List (high evidence)
Intellectual disability v2.1086 CSDE1 Catherine Snow Added comment: Comment on list classification: CSDE1 identified by Konstantinos Varvagiannis based on a publication by Guo et al. (PMID: 31579823) This is the first time CSDE1 has been associated with any diseases therefore it not currently in OMIM or Gene2Phenotype. However consistent phenotype of DD/ID and autism seen among all individuals with variants. With functional work on both mice and Drosophila.
Intellectual disability v2.1086 CSDE1 Catherine Snow Gene: csde1 has been classified as Green List (High Evidence).
Intellectual disability v2.1085 CSDE1 Catherine Snow Publications for gene: CSDE1 were set to http://doi.org/10.1126/sciadv.aax2166
Intellectual disability v2.1084 SMG9 Catherine Snow Publications for gene: SMG9 were set to 27018474; 30914295
Intellectual disability v2.1083 SMG9 Catherine Snow edited their review of gene: SMG9: Added comment: Maintaining Amber rating as although another individual with a variant has been identified in PMID: 31390136 there are still only full details of serve developmental delays for 2 unrelated families due to the young age of death of one reported individual in 27018474; Changed publications: 31390136
Intellectual disability v2.1083 PMPCB Catherine Snow changed review comment from: PMPCB identified by Konstantinos Varvagiannis following publication by Vögtle et al. (2018 - PMID: 29576218) who reported on by Vögtle et al. (2018 - PMID: 29576218) who identified 5 individuals from 4 unrelated families (in one case consanguineous) who have biallelic pathogenic PMPCB variants.
PMPCB is in OMIM and Gene2Phenotype with relevant phenotype. Individuals reported have stagnation in their development before onset of symptoms. PMPCB is Green on relevant Mitochondrial disorders panel (Version 2.1). As phenotype of DD is relevant to ID panel PMPCB is classified as Green.; to: PMPCB identified by Konstantinos Varvagiannis following publication by Vögtle et al. (2018 - PMID: 29576218) who identified 5 individuals from 4 unrelated families (in one case consanguineous) who have biallelic pathogenic PMPCB variants.
PMPCB is in OMIM and Gene2Phenotype with relevant phenotype. Individuals reported have stagnation in their development before onset of symptoms including, delayed psychomotor development and ID. PMPCB is Green on relevant Mitochondrial disorders panel (Version 2.1). As phenotype of DD is relevant to ID panel PMPCB is classified as Green.
Intellectual disability v2.1083 PMPCB Catherine Snow Publications for gene: PMPCB were set to
Intellectual disability v2.1083 PMPCB Catherine Snow Classified gene: PMPCB as Green List (high evidence)
Intellectual disability v2.1083 PMPCB Catherine Snow Gene: pmpcb has been classified as Green List (High Evidence).
Intellectual disability v2.1082 PMPCB Catherine Snow reviewed gene: PMPCB: Rating: GREEN; Mode of pathogenicity: None; Publications: 29576218; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v2.1082 PCDH12 Catherine Snow Phenotypes for gene: PCDH12 were changed from intellectual disability; microcephaly; epilepsy; perithalamic hyperechogenicity; periventricular hyperechogenicity; midbrain abnormalities; hypothalamic abnormalities to intellectual disability; microcephaly; epilepsy; perithalamic hyperechogenicity; periventricular hyperechogenicity; midbrain abnormalities; hypothalamic abnormalities; Microcephaly, seizures, spasticity, and brain calcification, 251280
Intellectual disability v2.1081 PCDH12 Catherine Snow Classified gene: PCDH12 as Green List (high evidence)
Intellectual disability v2.1081 PCDH12 Catherine Snow Added comment: Comment on list classification: Following review by Konstantinos Varvagiannis on PCDH12, highlighted that here is now a sufficient number of published variants from unrelated families to classify PCDH12 as Green with ID reported in all.
Intellectual disability v2.1081 PCDH12 Catherine Snow Gene: pcdh12 has been classified as Green List (High Evidence).
Intellectual disability v2.1081 PCDH12 Catherine Snow Publications for gene: PCDH12 were set to 27164683
Intellectual disability v2.1080 CDH2 Catherine Snow Classified gene: CDH2 as Amber List (moderate evidence)
Intellectual disability v2.1080 CDH2 Catherine Snow Gene: cdh2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v2.1079 CDH2 Catherine Snow reviewed gene: CDH2: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v2.1079 APC2 Catherine Snow Classified gene: APC2 as Green List (high evidence)
Intellectual disability v2.1079 APC2 Catherine Snow Gene: apc2 has been classified as Green List (High Evidence).
Intellectual disability v2.1078 APC2 Catherine Snow Classified gene: APC2 as No list
Intellectual disability v2.1078 APC2 Catherine Snow Added comment: Comment on list classification: APC2 is in OMIM with a relevant clinical features but not in Gene2Phenotype. APC2 was identified by Konstantinos Varvagiannis who reviewed all variants. Sufficient number of individuals from unrelated families reported upon in the literature and three different variants identified. Therefore APC2 can be classified as Green
Intellectual disability v2.1078 APC2 Catherine Snow Gene: apc2 has been removed from the panel.
Intellectual disability v2.1077 TDP2 Catherine Snow Classified gene: TDP2 as Green List (high evidence)
Intellectual disability v2.1077 TDP2 Catherine Snow Gene: tdp2 has been classified as Green List (High Evidence).
Intellectual disability v2.1076 TDP2 Catherine Snow commented on gene: TDP2
Intellectual disability v2.1076 TANC2 Rebecca Foulger edited their review of gene: TANC2: Changed rating: AMBER
Intellectual disability v2.1076 TANC2 Rebecca Foulger changed review comment from: Comment on list classification: Updated rating from Red to Amber based on PMID:31616000 2019 article suggested by Andrea Haworth. Sufficient unrelated cases (19/20) with an ID/DD phenotype but the pathogenicity of the variants has not yet been verified. Therefore Amber with 'watchlist' tag is appropriate pending functional studies.; to: Comment on list classification: Updated rating from Red to Amber based on PMID:31616000 2019 article suggested by Andrea Haworth. Sufficient unrelated cases (19/20) with an ID/DD phenotype but the pathogenicity of the variants has not yet been verified. Not yet associated with a disorder in Gene2Phenotype or OMIM. Currently only 1 paper, therefore Amber with 'watchlist' tag is appropriate pending functional studies.
Intellectual disability v2.1076 TANC2 Rebecca Foulger Classified gene: TANC2 as Amber List (moderate evidence)
Intellectual disability v2.1076 TANC2 Rebecca Foulger Added comment: Comment on list classification: Updated rating from Red to Amber based on PMID:31616000 2019 article suggested by Andrea Haworth. Sufficient unrelated cases (19/20) with an ID/DD phenotype but the pathogenicity of the variants has not yet been verified. Therefore Amber with 'watchlist' tag is appropriate pending functional studies.
Intellectual disability v2.1076 TANC2 Rebecca Foulger Gene: tanc2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v2.1075 TANC2 Rebecca Foulger commented on gene: TANC2: Summary of PMID:31616000 (PMC:6794285) suggested by Andrea Haworth reviewer: Guo et al assembled phenotypic data for 19 probands and 1 affected sibling with TANC2 variants. Variants include 16 LGD (likely gene-disruptive) variants and three intragenic microdeletions. Phenotypes included ASD, ID, speech-language delay and childhood motor delay:
- 15/20 individuals had ASD/autism features (7 with a formal diagnosis).
- 19/20 individuals had some form of ID (17 with a formal diagnosis of borderline to severe ID, and 2 with learning difficulties without a formal diagnosis).
- 18/20 showed speech-language delay.
- 13/19 individuals had childhood motor delay.
- 11/20 individuals had a formal diagnosis of epilepsy (9) or suffered recurrent seizures (2).
Intellectual disability v2.1075 TANC2 Rebecca Foulger Phenotypes for gene: TANC2 were changed from to NDD syndrome; Neurodevelopmental Disorder; Intellectual disability; Childhood speech delay; Childhood motor delay
Intellectual disability v2.1074 TANC2 Rebecca Foulger Added comment: Comment on mode of inheritance: Set MOI as MONOALLELIC based on PMID:31616000 (Figure 2).
Intellectual disability v2.1074 TANC2 Rebecca Foulger Mode of inheritance for gene: TANC2 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v2.1073 TDP2 Catherine Snow Mode of inheritance for gene: TDP2 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v2.1072 TANC2 Rebecca Foulger Publications for gene: TANC2 were set to 26350204
Intellectual disability v2.1071 PIGP Rebecca Foulger Classified gene: PIGP as Amber List (moderate evidence)
Intellectual disability v2.1071 PIGP Rebecca Foulger Added comment: Comment on list classification: PIGP was added to the panel and rated Green by Konstantinos Varvagiannis. Upgraded rating from Grey to Amber, and added watchlist tag, following review of literature and Amber rating on the Genetic epilepsy syndromes panel. Not yet associated with a disorder in Gene2Phenotype. 2 unrelated cases from the literature plus a third case from LOVD. Therefore Amber rating is appropriate.
Intellectual disability v2.1071 PIGP Rebecca Foulger Gene: pigp has been classified as Amber List (Moderate Evidence).
Intellectual disability v2.1070 PMPCA Rebecca Foulger Classified gene: PMPCA as Amber List (moderate evidence)
Intellectual disability v2.1070 PMPCA Rebecca Foulger Added comment: Comment on list classification: Updated rating from Grey to Amber. PMPCA was added and rated Green by Konstantinos Varvagiannis. Although there are sufficient (3) literature cases overall, the phenotype is variable across cases: 3 families with a possible Founder variant in PMID:25808372, no ID reported in PMID:26657514, 1 family in PMID:27148589 and 1 individual in PMID:30617178. Therefore rated Amber awaiting further cases.
Intellectual disability v2.1070 PMPCA Rebecca Foulger Gene: pmpca has been classified as Amber List (Moderate Evidence).
Intellectual disability v2.1069 PMPCA Rebecca Foulger commented on gene: PMPCA
Intellectual disability v2.1069 CA5A Rebecca Foulger commented on gene: CA5A
Intellectual disability v2.1069 CA5A Rebecca Foulger Mode of inheritance for gene: CA5A was changed from to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v2.1068 CA5A Rebecca Foulger Phenotypes for gene: CA5A were changed from to Hyperammonemia due to carbonic anhydrase VA deficiency, 615751
Intellectual disability v2.1067 CA5A Rebecca Foulger Publications for gene: CA5A were set to
Intellectual disability v2.1066 TANC2 Andrea Haworth commented on gene: TANC2
Intellectual disability v2.1066 MED25 Rebecca Foulger Classified gene: MED25 as Green List (high evidence)
Intellectual disability v2.1066 MED25 Rebecca Foulger Added comment: Comment on list classification: Updated rating from Amber to Green based on the recent Lebanese cases reported by Nair et al (DOI:10.1159/000501114 and PMID:30800049). Advice and a Green review by Helen Brittain supports the upgrade to Green.
Intellectual disability v2.1066 MED25 Rebecca Foulger Gene: med25 has been classified as Green List (High Evidence).
Intellectual disability v2.1065 FBXW11 Catherine Snow Classified gene: FBXW11 as Green List (high evidence)
Intellectual disability v2.1065 FBXW11 Catherine Snow Gene: fbxw11 has been classified as Green List (High Evidence).
Intellectual disability v2.1064 FBXW11 Catherine Snow reviewed gene: FBXW11: Rating: GREEN; Mode of pathogenicity: None; Publications: 31402090, 16865294; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v2.1064 SMPD4 Louise Daugherty Classified gene: SMPD4 as Green List (high evidence)
Intellectual disability v2.1064 SMPD4 Louise Daugherty Added comment: Comment on list classification: Changed from Amber to Green. Appropriate phenotypes, sufficient cases, support gene-disease association.
Intellectual disability v2.1064 SMPD4 Louise Daugherty Gene: smpd4 has been classified as Green List (High Evidence).
Intellectual disability v2.1063 SMPD4 Louise Daugherty Tag watchlist was removed from gene: SMPD4.
Intellectual disability v2.1063 SMPD4 Louise Daugherty Added comment: Comment on publications: Magini P et al. (October 2019) Loss of SMPD4 Causes a Developmental Disorder Characterized by Microcephaly and Congenital Arthrogryposis.
Intellectual disability v2.1063 SMPD4 Louise Daugherty Publications for gene: SMPD4 were set to
Intellectual disability v2.1062 TDP2 Konstantinos Varvagiannis gene: TDP2 was added
gene: TDP2 was added to Intellectual disability. Sources: Literature,Radboud University Medical Center, Nijmegen
Mode of inheritance for gene: TDP2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TDP2 were set to 24658003; 30109272; 31410782
Phenotypes for gene: TDP2 were set to Spinocerebellar ataxia, autosomal recessive 23, 616949)
Penetrance for gene: TDP2 were set to unknown
Review for gene: TDP2 was set to GREEN
gene: TDP2 was marked as current diagnostic
Added comment: Biallelic pathogenic TGP2 variants cause Spinocerebellar ataxia, autosomal recessive 23 (MIM 616949). At least 6 affected individuals from 4 families have been reported, in all cases homozygous for LoF variants (3 different). ID, epilepsy and ataxia are consistent features of the disorder.

TDP2 encodes a phosphodiesterase that is required for efficient repair of double strand breaks (DSBs) produced by abortive topoisomerase II (TOP2) activity.

The gene is expressed in fetal and adult human brain.

Evidence at the variant level (mRNA, protein levels) and additional studies for impairment of TOP2-induced DSB repair support a role.

Animal models (primarily mice) reproduce the DSB repair defect, provide some histopathological evidence, show transcriptional dysregulation of genes (in line with the role of TOP2 in transcription). They have however failed to reproduce relevant neurological phenotypes.

Published studies are summarized below.

TDP2 is included in gene panels for ID offered by some diagnostic laboratories (incl. Radboudumc and GeneDx). There is no associated phenotype in G2P. TDP2 is listed among the current primary ID genes in SysID.

Overall, this gene could be considered for inclusion in the ID and epilepsy panels probably as green (>=3 patients/families/variants, relevant ID and seizures in all, expression in brain, mRNA/protein levels tested, impaired activity) or amber (absence of neurological phenotypes in mouse model).
------------

[1] - PMID: 24658003 (Gómez-Herreros et al. 2014):
Reports 3 individuals from a consanguineous Irish family. Features included seizures (onset by 2m, 6m and 12y), ID (3/3) and ataxia (3/3).

A splicing variant (NM_016614.3:c.425+1G>A) was found in a 9.08-Mb region of homozygosity shared by all. A further ZNF193 missense variant localizing in the same region was thought unlikely to contribute to the phenotype (evidence also provided in subsequent study).

The effect of the specific variant was proven by abnormal mRNA size, lower mRNA levels due to NMD (corrected upon cyclohexamide treatment), loss of TDP2 protein upon WB, loss of protein activity in lymphoblastoid cells from affected individuals, decreased repair of DSBs and increased cell death upon addition of etoposide (which promotes TOP2 abortive activity).

The authors report very briefly on a further patient (from Egypt), with ID, 'reports of fits' and ataxia. This individual, with also affected sibs, was homozygous LoF (c.413_414delinsAA / p.Ser138*). Again, the authors were not able to detect TDP2 activity in blood from this subject.

As also commented:
- TDP2 has relevant expression in human (particularly adult) brain.
- Mouse model : Tdp2 is expressed in relevant tissues, absence of Tdp2 activity was observed in neural tissue of mice homoyzgous for an ex1-3 del, with impairment of DSB repair. The authors were unable to detect a neurological phenotype with behavioral analyses, preliminary assesment of seizure propensity. Mice did not show developmental defects. Histopathology however, revealed ~25% reduction in the density of interneurons in cerebellum (a 'hallmark of DSB repair' and associated with seizures and ataxia). Transcription of several genes was shown to be disregulated.
- Knockdown in zebrafish appears to affect left-right axis detremination (cited PMID: 18039968).

[2] - PMID: 30109272 (Zagnoli-Vieira et al. 2018):
A 6 y.o. male with seizures (onset by 5m), hypotonia, DD and ID, microcephaly and some additional clinical features and testing (ETC studies on muscle biopsy, +lactate, +(lactate/pyruvate) ratio) which could be suggestive of mitochondrial disorder. This individual from the US was homozygous for the c.425+1G>A variant but lacked the ZNF193 one (despite a shared haplotype with the Irish patients). Again absence of the protein was shown upon WB in patient fibroblasts, also supported by its activity. Complementation studies restored the DSB repair defect. The defect was specific to TOP2-induced DSBs as suggested by hypersensitivity to etoposide but not to ionizing radiation. CRISPR/Cas9 generated mutant human A549 cells demonstrated abnormal DSB repair. Fibroblasts / edited A549 cells failed to show mitochondrial defects (which were noted in muscle).

[3] - PMID: 31410782 (Ciaccio et al. 2019):
A girl born to consanguineous Italian parents, presented with moderate/severe ID, seizures (onset at 12y) and - among others - gait ataxia, tremor and dysmetria. MRI at the age of 12, demonstrated cerebellar atrophy (although previous exams were N). WES revealed a homozygous nonsense variant (c.400C>T / p.Arg134Ter) for which each parent was found to be carrier. Previous investigations included aCGH, NGS testing for epilepsy and metabolic testing.
Sources: Literature, Radboud University Medical Center, Nijmegen
Intellectual disability v2.1062 PCDH12 Konstantinos Varvagiannis reviewed gene: PCDH12: Rating: ; Mode of pathogenicity: None; Publications: 27164683, 28804758, 29556033, 30178464, 30459466, 18477666; Phenotypes: Microcephaly, seizures, spasticity, and brain calcification, 251280; Mode of inheritance: None; Current diagnostic: yes
Intellectual disability v2.1062 NKAP Konstantinos Varvagiannis reviewed gene: NKAP: Rating: GREEN; Mode of pathogenicity: None; Publications: DOI: 10.1016/j.ajhg.2019.09.009; Phenotypes: Global developmental delay, Intellectual disability, Tall stature, Scoliosis, Pectus excavatum, Pectus carinatum, Arachnodactyly, Camptodactyly, Abnormality of the cardiovascular system, Abnormality of the genitourinary system, Abnormality of the face, Obesity; 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 v2.1062 APC2 Konstantinos Varvagiannis gene: APC2 was added
gene: APC2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: APC2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: APC2 were set to 31585108; 25753423; 19759310; 22573669
Phenotypes for gene: APC2 were set to Global developmental delay; Intellectual disability; Seizures; Morphological abnormality of the central nervous system
Penetrance for gene: APC2 were set to Complete
Review for gene: APC2 was set to GREEN
gene: APC2 was marked as current diagnostic
Added comment: Probably 14 individuals from 9 families (8 consanguineous) with biallelic APC2 LoF variants have been reported.

ID and brain abnormalities were features in all, although the presentation was quite different between sibs in the first report (PMID: 25753423 - mild/mod ID, ventriculomegaly and CC anomalies, macrocephaly with variable height, Sotos-like facial features) and 12 subsequently described patients (PMID: 31585108 - severe ID, P>A lissencephaly/CC anomalies/ventriculomegaly/paucity of white matter in (almost) all, gT-C/myoclonic seizures in 8/12 with onset 3m-6y, OFC in the low percentiles).

In all cases relevant alternative diagnoses (eg. macrocephaly/overgrowth syndromes - 1st report, mutations in other lissencephaly genes, metabolic disorders - 2nd) were ruled out.

APC2 encodes Adenomatous polyposis coli protein 2, expressed in the CNS.

All variants reported to date were LoF (stopgain/frameshift/splicing) and were supported by parental-only studies. Mutations in the 1st report as well as 4/8 variants from the 2nd report localized within the last exon (NM_005883.2 / longest of >=3 isoforms), although the 2nd report did not observe obvious genotype-phenotype correlations.

Despite a pLI of 1 in gnomAD, Lee et al. comment that heterozygous carriers did not have any noticeable phenotype. They further note that carriers were not examined by brain MRI, though. 27 heterozygous high-confidence variants appear in individuals in gnomAD. Finally as commented on, APC2 is not mutated in colon cancer.

Animal models: Apc -/- mice displayed disrupted neuronal migration, with defects of lamination of cerebral cortex and cerebellum supporting the observed brain abnormalities. In addition Apc2-deficient mice also presented impaired learning and memory abilities. Extensive additional studies have shown Apc2 co-localization with microtubules affecting their stabilization, distribution along actin fibers (all supporting a role in cytoskeletal organization) and regulation of Rac1 (a Rho GTPase). Generation of Neuro2a cells demonstrated abnormal localization mainly in cell bodies of mutant hAPC2 proteins (due to frameshift in the last exon / deletion of the C-terminal part) - different from wt (neurites, growth cones, cell bodies). The first patient report also provided evidence for Apc2 being a downstream effector of Nsd1, with Nsd1 knockdown brains displaying impaired migration / laminar positioning of cortical neurons (similar to Apc2-/- model) and rescued by forced expression of Apc2.

Relevant articles:
PMIDs: 19759310 and 22573669 (Shintani et al. 2009 & 2012) [mouse model]
PMID: 25753423 (Almuriekhi et al. 2015) [2 individuals + mouse model]
PMID: 31585108 (Lee et al. 2019) [12 individuals from 8 families]
-----
In OMIM, the APC2-related phenotype is ?Sotos syndrome 3 (MIM 617169 - AR). G2P does not have any associated phenotype for this gene. In SysID, APC2 belongs to the Current primary ID genes.
APC2 is included in gene panels for ID offered by some diagnostic laboratories (eg. Radboudumc, GeneDx).
-----
Overall, this gene could be considered for inclusion in the ID panel probably as green (>3 individuals/families/variants, highly specific pattern of lissencephaly in 12/14, mouse model supporting migration defects and impaired learning/memory) rather than amber (differences between the 1st and the other families reported as for the OFC and presence of lissencephaly).
Sources: Literature
Intellectual disability v2.1062 CDH2 Konstantinos Varvagiannis changed review comment from: Accogli et al. (2019 - PMID: 31585109) report on 9 individuals with de novo pathogenic CDH2 variants.

Overlapping features included axon pathfinding defects (corpus callosum agenesis/hypoplasia, mirror movements, Duane anomaly), cardiac, ocular and genital anomalies. Neurodevelopmental phenotypes included DD (8/9), ID (2/8 mild and 2/8 moderate, the remaining had either low-average/borderline int. functioning (2), did not present ID (2) or did not have relevant age for evaluation) and ASD (in 2).

CDH2 encodes cadherin-2 (N-cadherin) with high expression in neural tissue. As the authors note, the gene has important role in neural development, incl. proliferation and differentiation of neural progenitor cells, neural tube formation, synaptogenesis, neuronal migration and axon elongation. N-cadherin, similar to other classical cadherins has an extracellular domain with 5 extracellular cadherin (EC) domain repeats that mediate cell adhesion either in cis or in trans (between molecules of the same / different cells).

Mutations in other cadherins have been associated among others with neurodevelopmental disorders (eg. PCDH19, PCDH12, etc).

Variants in all cases were de novo, identified following trio-WES. 7 missense variants (6 of which clustering within the EC4-EC5 linker region or the EC5 domain - calculated p=1.37x10-4) and 2 frameshift ones predicted not to lead to NMD were identified.

One individual had an additional DNM1 variant, formally fulfilling ACMG criteria for pathogenic. The authors however felt that presentation of the specific subject (low-average/borderline int. functioning, absence of seizures and microcephaly) was not compatible with the phenotype of DNM1-encephalopathy .

Missense SNVs within the EC4-EC5 region, were shown to impair cell-cell adhesion by affecting both self-binding and trans adhesion to wt N-cadherin (in L cells studied). This supported a possible dominant-negative effect. A single variant in the EC2 domain - previously shown to be critical for adhesion - was thought to have a similar effect. The authors speculated that truncating variants may also act in a dominant-negative manner (as has been demonstrated for other cadherins) although LoF remains possible.

Cdh2 knockout in mice is embryonically lethal. Mouse with conditional inactivation of Cdh2 in the cerebral cortex leads to cortical disorganization and CCA similar to the human phenotypes (PMIDs cited: 9015265, 17222817). Other animal studies (mouse, zebrafish, chicken, dog, etc) are also cited to link with specific defects.

Heterozygous CDH2 variants affecting the ectodomain have been associated with ARVC (2 variants, one of which segregated with the disorder in a 3-generation family, the other identified in two unrelated families with several affecteds - refs. provided in the article). Cardiac abnormalities were noted in several subjects (incl. electrical activity in 2). [Amber rating of this gene in Arrhythmogenic cardiomyopathy panel].
------
The gene is not associated with any phenotype in OMIM / G2P / SysID and not commonly included in panels for ID.
------
As a result CDH2 could be considered for inclusion in the ID panel probably as amber (mild/moderate ID in 4/8, uncertainty regarding the underlying effect of some variants or additional phenotypes (ARVC)) or green (>3 individuals/variants/families, ID is a feature and in some cases of moderate degree).
Sources: Literature; to: Accogli et al. (2019 - PMID: 31585109) report on 9 individuals with de novo pathogenic CDH2 variants.

Overlapping features included axon pathfinding defects (corpus callosum agenesis/hypoplasia, mirror movements, Duane anomaly), cardiac, ocular and genital anomalies. Neurodevelopmental phenotypes included DD (8/9), ID (2/8 mild and 2/8 moderate, the remaining had either low-average/borderline int. functioning (2), did not present ID (2) or did not have relevant age for evaluation) and ASD (in 2).

CDH2 encodes cadherin-2 (N-cadherin) with high expression in neural tissue. As the authors note, the gene has important role in neural development, incl. proliferation and differentiation of neural progenitor cells, neural tube formation, synaptogenesis, neuronal migration and axon elongation. N-cadherin, similar to other classical cadherins has an extracellular domain with 5 extracellular cadherin (EC) domain repeats that mediate cell adhesion either in cis or in trans (between molecules of the same / different cells).

Mutations in other cadherins have been associated among others with neurodevelopmental disorders (eg. PCDH19, PCDH12, etc).

Variants in all cases were de novo, identified following trio-WES. 7 missense variants (6 of which clustering within the EC4-EC5 linker region or the EC5 domain - calculated p=1.37x10-4) and 2 frameshift ones predicted not to lead to NMD were identified.

One individual had an additional DNM1 variant, formally fulfilling ACMG criteria for pathogenic. The authors however felt that presentation of the specific subject (low-average/borderline int. functioning, absence of seizures and microcephaly) was not compatible with the phenotype of DNM1-encephalopathy .

Missense SNVs within the EC4-EC5 region, were shown to impair cell-cell adhesion by affecting both self-binding and trans adhesion to wt N-cadherin (in L cells studied). This supported a possible dominant-negative effect. A single variant in the EC2 domain - previously shown to be critical for adhesion - was thought to have a similar effect. The authors speculated that truncating variants may also act in a dominant-negative manner (as has been demonstrated for other cadherins) although LoF remains possible.

Cdh2 knockout in mice is embryonically lethal. Conditional inactivation of Cdh2 in the cerebral cortex leads to cortical disorganization and CCA similar to the human phenotypes (PMIDs cited: 9015265, 17222817). Other animal studies (mouse, zebrafish, chicken, dog, etc) are also cited to link with specific defects.

Heterozygous CDH2 variants affecting the ectodomain have been associated with ARVC (2 variants, one of which segregated with the disorder in a 3-generation family, the other identified in two unrelated families with several affecteds - refs. provided in the article). Cardiac abnormalities were noted in several subjects (incl. electrical activity in 2). [Amber rating of this gene in Arrhythmogenic cardiomyopathy panel].
------
The gene is not associated with any phenotype in OMIM / G2P / SysID and not commonly included in panels for ID.
------
As a result CDH2 could be considered for inclusion in the ID panel probably as amber (mild/moderate ID in 4/8, uncertainty regarding the underlying effect of some variants or additional phenotypes (ARVC)) or green (>3 individuals/variants/families, ID is a feature and in some cases of moderate degree).
Sources: Literature
Intellectual disability v2.1062 CDH2 Konstantinos Varvagiannis gene: CDH2 was added
gene: CDH2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: CDH2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CDH2 were set to 31585109; 9015265; 17222817
Phenotypes for gene: CDH2 were set to Abnormality of the corpus callosum; Abnormality of neuronal migration; Bimanual synkinesia; Duane anomaly; Abnormality of cardiovascular system; Abnormality of the eye; Abnormality of the genital system; Global developmental delay; Intellectual disability
Penetrance for gene: CDH2 were set to unknown
Review for gene: CDH2 was set to AMBER
Added comment: Accogli et al. (2019 - PMID: 31585109) report on 9 individuals with de novo pathogenic CDH2 variants.

Overlapping features included axon pathfinding defects (corpus callosum agenesis/hypoplasia, mirror movements, Duane anomaly), cardiac, ocular and genital anomalies. Neurodevelopmental phenotypes included DD (8/9), ID (2/8 mild and 2/8 moderate, the remaining had either low-average/borderline int. functioning (2), did not present ID (2) or did not have relevant age for evaluation) and ASD (in 2).

CDH2 encodes cadherin-2 (N-cadherin) with high expression in neural tissue. As the authors note, the gene has important role in neural development, incl. proliferation and differentiation of neural progenitor cells, neural tube formation, synaptogenesis, neuronal migration and axon elongation. N-cadherin, similar to other classical cadherins has an extracellular domain with 5 extracellular cadherin (EC) domain repeats that mediate cell adhesion either in cis or in trans (between molecules of the same / different cells).

Mutations in other cadherins have been associated among others with neurodevelopmental disorders (eg. PCDH19, PCDH12, etc).

Variants in all cases were de novo, identified following trio-WES. 7 missense variants (6 of which clustering within the EC4-EC5 linker region or the EC5 domain - calculated p=1.37x10-4) and 2 frameshift ones predicted not to lead to NMD were identified.

One individual had an additional DNM1 variant, formally fulfilling ACMG criteria for pathogenic. The authors however felt that presentation of the specific subject (low-average/borderline int. functioning, absence of seizures and microcephaly) was not compatible with the phenotype of DNM1-encephalopathy .

Missense SNVs within the EC4-EC5 region, were shown to impair cell-cell adhesion by affecting both self-binding and trans adhesion to wt N-cadherin (in L cells studied). This supported a possible dominant-negative effect. A single variant in the EC2 domain - previously shown to be critical for adhesion - was thought to have a similar effect. The authors speculated that truncating variants may also act in a dominant-negative manner (as has been demonstrated for other cadherins) although LoF remains possible.

Cdh2 knockout in mice is embryonically lethal. Mouse with conditional inactivation of Cdh2 in the cerebral cortex leads to cortical disorganization and CCA similar to the human phenotypes (PMIDs cited: 9015265, 17222817). Other animal studies (mouse, zebrafish, chicken, dog, etc) are also cited to link with specific defects.

Heterozygous CDH2 variants affecting the ectodomain have been associated with ARVC (2 variants, one of which segregated with the disorder in a 3-generation family, the other identified in two unrelated families with several affecteds - refs. provided in the article). Cardiac abnormalities were noted in several subjects (incl. electrical activity in 2). [Amber rating of this gene in Arrhythmogenic cardiomyopathy panel].
------
The gene is not associated with any phenotype in OMIM / G2P / SysID and not commonly included in panels for ID.
------
As a result CDH2 could be considered for inclusion in the ID panel probably as amber (mild/moderate ID in 4/8, uncertainty regarding the underlying effect of some variants or additional phenotypes (ARVC)) or green (>3 individuals/variants/families, ID is a feature and in some cases of moderate degree).
Sources: Literature
Intellectual disability v2.1062 MED25 Helen Brittain edited their review of gene: MED25: Added comment: There are now different variants (potentially each founders) in three populations, and several families, that have been reported in association with ID. Therefore the evidence for a green rating in terms of a gene:disease association now seems sufficient. To determine the extent of the phenotype, in terms of associated features, further cases would be beneficial. Therefore I would currently recommend a green rating for the ID panel.; Changed rating: GREEN; Changed phenotypes: Basel-Vanagait-Smirin-Yosef syndrome 616449; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v2.1062 INTS1 Rebecca Foulger Phenotypes for gene: INTS1 were changed from Hypotonia; Global developmental delay; Cataract; Abnormality of the skeletal system to Neurodevelopmental disorder with cataracts, poor growth, and dysmorphic facies, 618571; Hypotonia; Global developmental delay; Cataract; Abnormality of the skeletal system
Intellectual disability v2.1061 AP2M1 Rebecca Foulger Phenotypes for gene: AP2M1 were changed from Seizures; Ataxia; Generalized hypotonia; Intellectual disability; Global developmental delay; Autistic behavior to Intellectual developmental disorder 60 with seizures, 618587; Seizures; Ataxia; Generalized hypotonia; Intellectual disability; Global developmental delay; Autistic behavior
Intellectual disability v2.1060 RAC3 Rebecca Foulger Phenotypes for gene: RAC3 were changed from Abnormality of brain morphology, Abnormal muscle tone, Neurodevelopmental delay, Intellectual disability; Abnormality of brain morphology; Abnormal muscle tone; Neurodevelopmental delay; Intellectual disability to Neurodevelopmental disorder with structural brain anomalies and dysmorphic facies, 618577; Abnormality of brain morphology, Abnormal muscle tone, Neurodevelopmental delay, Intellectual disability; Abnormality of brain morphology; Abnormal muscle tone; Neurodevelopmental delay; Intellectual disability
Intellectual disability v2.1059 PIGU Rebecca Foulger Phenotypes for gene: PIGU were changed from Global developmental delay; Intellectual disability; Seizures; Cerebral atrophy; Cerebellar hypoplasia; Scoliosis to Glycosylphosphatidylinositol biosynthesis defect 2, 618590; Global developmental delay; Intellectual disability; Seizures; Cerebral atrophy; Cerebellar hypoplasia; Scoliosis
Intellectual disability v2.1058 PIGQ Rebecca Foulger Phenotypes for gene: PIGQ were changed from SEVERE EARLY-ONSET EPILEPSY to SEVERE EARLY-ONSET EPILEPSY; Epileptic encephalopathy, early infantile, 77, 618548
Intellectual disability v2.1057 PIGB Rebecca Foulger Phenotypes for gene: PIGB were changed from Generalized hypotonia; Global developmental delay; Intellectual disability; Seizures; Hearing abnormality; Abnormality of vision; Elevated alkaline phosphatase; Abnormality of the head; Abnormality of the hand; Abnormality of the foot to Epileptic encephalopathy, early infantile, 80, 618580; Generalized hypotonia; Global developmental delay; Intellectual disability; Seizures; Hearing abnormality; Abnormality of vision; Elevated alkaline phosphatase; Abnormality of the head; Abnormality of the hand; Abnormality of the foot
Intellectual disability v2.1056 HNRNPR Catherine Snow Classified gene: HNRNPR as Green List (high evidence)
Intellectual disability v2.1056 HNRNPR Catherine Snow Gene: hnrnpr has been classified as Green List (High Evidence).
Intellectual disability v2.1055 HNRNPR Catherine Snow reviewed gene: HNRNPR: Rating: GREEN; Mode of pathogenicity: None; Publications: 31079900, 26795593; Phenotypes: Intellectual Disability; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v2.1055 DDX6 Catherine Snow Classified gene: DDX6 as Green List (high evidence)
Intellectual disability v2.1055 DDX6 Catherine Snow Gene: ddx6 has been classified as Green List (High Evidence).
Intellectual disability v2.1054 DDX6 Catherine Snow reviewed gene: DDX6: Rating: GREEN; Mode of pathogenicity: None; Publications: 31422817; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v2.1054 TIMM50 Rebecca Foulger Classified gene: TIMM50 as Green List (high evidence)
Intellectual disability v2.1054 TIMM50 Rebecca Foulger Added comment: Comment on list classification: TIMM50 was added to the ID panel and rated Green by Konstantinos Varvagiannis. Not yet associated with a disorder in Gene2Phenotype but upgraded rating from Grey to Green following review of literature evidence. PMID:27573165 and PMID:31058414 report 5 patients from 3 families with a consistent ID and epilepsy phenotype accompanied by 3-methylglutaconic aciduria. In addition, PMID:30190335 report pyschomotor regression in their patient, and a conference abstract (Serajee et al. 2015) adds an additional case of developmental delay. Therefore ID appears a consistent phenotype of 3-methylglutaconic aciduria and with sufficient reported cases, a Green rating is appropriate.
Intellectual disability v2.1054 TIMM50 Rebecca Foulger Gene: timm50 has been classified as Green List (High Evidence).
Intellectual disability v2.1053 TIMM50 Rebecca Foulger commented on gene: TIMM50
Intellectual disability v2.1053 TIMM50 Rebecca Foulger Phenotypes for gene: TIMM50 were changed from 3-methylglutaconic aciduria, type IX (MIM 617698) to 3-methylglutaconic aciduria, type IX, 617698
Intellectual disability v2.1052 GABRA5 Rebecca Foulger Classified gene: GABRA5 as Green List (high evidence)
Intellectual disability v2.1052 GABRA5 Rebecca Foulger Added comment: Comment on list classification: Upgraded from Amber to Green following advice from Genomics England clinical team. The case reported in PMID:29961870 (Butler et al 2018) had delayed milestones and is reported to be non-verbal, which is a relevant phenotype for this panel. Overall 3 unrelated cases from 2 papers.
Intellectual disability v2.1052 GABRA5 Rebecca Foulger Gene: gabra5 has been classified as Green List (High Evidence).
Intellectual disability v2.1051 KCNMA1 Catherine Snow Phenotypes for gene: KCNMA1 were changed from GENERALIZED EPILEPSY AND PAROXYSMAL DYSKINESIA to Cerebellar atrophy, developmental delay, and seizures, 617643; Paro