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Intellectual disability v2.1015 SOX4 Louise Daugherty Added comment: Comment on phenotypes: added OMIM MIM id
Intellectual disability v2.1015 SOX4 Louise Daugherty Phenotypes for gene: SOX4 were changed from Syndromic intellectual disability; Global developmental delay; Intellectual disability; Growth delay; Clinodactyly of the 5th finger; facial dysmorphism to Coffin-Siris syndrome 10, 618506; Syndromic intellectual disability; Global developmental delay; Intellectual disability; Growth delay; Clinodactyly of the 5th finger; facial dysmorphism
Intellectual disability v2.1014 KMT2E Louise Daugherty Added comment: Comment on phenotypes: added OMIM MIM id
Intellectual disability v2.1014 KMT2E Louise Daugherty Phenotypes for gene: KMT2E were changed from Global developmental delay; Intellectual disability; Autism; Seizures; Abnormality of skull size to O'Donnell-Luria-Rodan syndrome, 618512; Global developmental delay; Intellectual disability; Autism; Seizures; Abnormality of skull size
Intellectual disability v2.1013 CNOT1 Louise Daugherty Added comment: Comment on phenotypes: added OMIM MIM id
Intellectual disability v2.1013 CNOT1 Louise Daugherty Phenotypes for gene: CNOT1 were changed from global developmental delay to Holoprosencephaly 12, with or without pancreatic agenesis, 618500; global developmental delay
Intellectual disability v2.1012 CACNA1B Louise Daugherty Added comment: Comment on phenotypes: added OMIM MIM id
Intellectual disability v2.1012 CACNA1B Louise Daugherty Phenotypes for gene: CACNA1B were changed from Progressive Epilepsy-Dyskinesia; Seizures; Abnormality of movement; Intellectual disability; Developmental regression; Global developmental delay to Neurodevelopmental disorder with seizures and nonepileptic hyperkinetic movements, 618497; Progressive Epilepsy-Dyskinesia; Seizures; Abnormality of movement; Intellectual disability; Developmental regression; Global developmental delay
Intellectual disability v2.1011 PUF60 Rebecca Foulger Phenotypes for gene: PUF60 were changed from Verheij syndrome, 615583; VRJS; Chromosome 8q24.3 deletion syndrome; PUF60 syndrome; Intellectual disability to Syndromic intellectual disability; Verheij syndrome, 615583; VRJS; Chromosome 8q24.3 deletion syndrome; PUF60 syndrome; Intellectual disability
Intellectual disability v2.1010 COLEC10 Rebecca Foulger commented on gene: COLEC10
Intellectual disability v2.1010 COLEC10 Rebecca Foulger Phenotypes for gene: COLEC10 were changed from to 3MC syndrome 3, 248340
Intellectual disability v2.1009 COLEC10 Rebecca Foulger Publications for gene: COLEC10 were set to
Intellectual disability v2.1008 FRMPD4 Rebecca Foulger Classified gene: FRMPD4 as Green List (high evidence)
Intellectual disability v2.1008 FRMPD4 Rebecca Foulger Added comment: Comment on list classification: Updated rating from Amber to Green on advice of Genomics England clinical team: four families with a relevant phenotype meets the criteria for a Green rating.
Intellectual disability v2.1008 FRMPD4 Rebecca Foulger Gene: frmpd4 has been classified as Green List (High Evidence).
Intellectual disability v2.1007 FRMPD4 Rebecca Foulger Added comment: Comment on mode of inheritance: MOI set to X-linked dominant on advice of Genomics England clinical team, in view of the single reported female heterozygote with a relevant phenotype.
Intellectual disability v2.1007 FRMPD4 Rebecca Foulger Mode of inheritance for gene: FRMPD4 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 v2.1006 GRIA2 Rebecca Foulger commented on gene: GRIA2
Intellectual disability v2.1006 POLR2A Rebecca Foulger Classified gene: POLR2A as Green List (high evidence)
Intellectual disability v2.1006 POLR2A Rebecca Foulger Gene: polr2a has been classified as Green List (High Evidence).
Intellectual disability v2.1005 POLR2A Rebecca Foulger Phenotypes for gene: POLR2A were changed from Generalized hypotonia; Global developmental delay; Feeding difficulties to Global developmental delay; Generalized hypotonia; Feeding difficulties
Intellectual disability v2.1004 POLR2A Rebecca Foulger commented on gene: POLR2A
Intellectual disability v2.1004 AFF3 Rebecca Foulger changed review comment from: As noted by Konstantinos Varvagiannis, Voisin et al., 2019 (not yet in PubMed) describe de novo missense variants in the degron of AFF3 (a region required for its degradation) in 10 unrelated individuals with symptoms including ID. 4 different missense variants were identified (p.A258S, p.A258T, p.A258V and p.V260G). Although there are sufficient cases with a relevant phenotype, I have rated as Amber pending publication of the 2019 article: as OMIM note in their correspondance on AFF3, information changes from the initial bioRxiv upload to peer-reviewed publication. Therefore updated rating of AFF3 from Red to Amber, added 'watchlist' tag (in addition to missense tag), and will re-curate when the paper is published.; to: As noted by Konstantinos Varvagiannis, Voisin et al., 2019 (not yet in PubMed) describe de novo missense variants in the degron of AFF3 (a region required for its degradation) in 10 unrelated individuals with symptoms including ID. 4 different missense variants were identified (p.A258S, p.A258T, p.A258V and p.V260G). Although there are sufficient cases with a relevant phenotype (plus the individual reported in PMID:18616733), I have rated as Amber pending publication of the Voisin 2019 article: as OMIM note in their correspondance on AFF3, information changes from the initial bioRxiv upload to peer-reviewed publication. Therefore updated rating of AFF3 from Red to Amber, added 'watchlist' tag and 'missense' tag, and will re-curate when the paper is published.
Intellectual disability v2.1004 AFF3 Rebecca Foulger Publications for gene: AFF3 were set to
Intellectual disability v2.1003 AFF3 Rebecca Foulger Phenotypes for gene: AFF3 were changed from to Intellectual disability; Seizures
Intellectual disability v2.1002 AFF3 Rebecca Foulger Mode of inheritance for gene: AFF3 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v2.1001 AFF3 Rebecca Foulger Mode of pathogenicity for gene: AFF3 was changed from to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Intellectual disability v2.1001 AFF3 Rebecca Foulger Classified gene: AFF3 as Amber List (moderate evidence)
Intellectual disability v2.1001 AFF3 Rebecca Foulger Gene: aff3 has been classified as Amber List (Moderate Evidence).
Intellectual disability v2.1000 AFF3 Rebecca Foulger Tag watchlist tag was added to gene: AFF3.
Intellectual disability v2.1000 AFF3 Rebecca Foulger Tag missense tag was added to gene: AFF3.
Intellectual disability v2.1000 AFF3 Rebecca Foulger commented on gene: AFF3
Intellectual disability v2.1000 WDR37 Rebecca Foulger commented on gene: WDR37: Added missense tag: only missense variants reported so far (PMID:31327510 and PMID:31327508).
Intellectual disability v2.1000 WDR37 Rebecca Foulger Classified gene: WDR37 as Green List (high evidence)
Intellectual disability v2.1000 WDR37 Rebecca Foulger Gene: wdr37 has been classified as Green List (High Evidence).
Intellectual disability v2.1000 WDR37 Rebecca Foulger Mode of pathogenicity for gene: WDR37 was changed from None to Other
Intellectual disability v2.999 WDR37 Rebecca Foulger commented on gene: WDR37: WDR37 was added to the ID panel and rated Green by Konstantinos Varvagiannis. Although WDR37 is not yet associated with a disorder in OMIM or Gene2Phenotype, there are sufficient unrelated cases in two recent papers (PMID:31327510 and PMID:31327508) with a severe ID/DD phenotype for inclusion on the panel. Plus it was agreed at the Webex call on Thurs 8th August with members of the GMS Neurology Specialist Test Group that WDR37 should be rated Green on the epilepsy panel (402). Therefore updated rating from Grey to Green.
Intellectual disability v2.999 WDR37 Rebecca Foulger Tag missense tag was added to gene: WDR37.
Intellectual disability v2.999 WDR37 Rebecca Foulger commented on gene: WDR37
Intellectual disability v2.999 PIGU Rebecca Foulger Classified gene: PIGU as Green List (high evidence)
Intellectual disability v2.999 PIGU Rebecca Foulger Gene: pigu has been classified as Green List (High Evidence).
Intellectual disability v2.998 PIGU Rebecca Foulger commented on gene: PIGU: PIGU (together with other PIGx genes) were discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019 to discuss R59 Early onset or syndromic epilepsy. Agreed that there is enough evidence to rate PIGU Green on the 'Genetic epilepsy syndromes' panel (402). Therefore applied Green rating to the ID panel also: although PIGU is not yet associated with a disorder in OMIM or Gene2Phenotype, there are sufficient unrelated cases described in PMID:31353022.
Intellectual disability v2.998 PIGU Rebecca Foulger commented on gene: PIGU: Added 'missense' tag as missense variants only reported so far (PMID:31353022).
Intellectual disability v2.998 PIGU Rebecca Foulger Tag missense tag was added to gene: PIGU.
Intellectual disability v2.998 PIGU Rebecca Foulger commented on gene: PIGU: PMID:31353022 (Knaus et al. 2019) report two homozygous missense mutations (c.209T>A [p.Ile70Lys] and c.1149C>A [p.Asn383Lys]) in 5 individuals from 3 unrelated families. All individuals presented with global DD severe-to-profound ID, muscular hypotonia, seizures, brain anomalies, scoliosis, and mild facial dysmorphism. Sequencing confirmed that all parents were healthy carriers. c.209T>A has not been observed in gnomAD while c.1149C>A has been observed only in the heterozygous state (7/277194).
Intellectual disability v2.998 PIGU Rebecca Foulger commented on gene: PIGU
Intellectual disability v2.998 NFASC Sarah Leigh Classified gene: NFASC as Green List (high evidence)
Intellectual disability v2.998 NFASC Sarah Leigh Added comment: Comment on list classification: Associated with phenotype in OMIM and not in Gen2Phen. At least 3 variants identified in unrelated cases.
Intellectual disability v2.998 NFASC Sarah Leigh Gene: nfasc has been classified as Green List (High Evidence).
Intellectual disability v2.997 NFASC Sarah Leigh gene: NFASC was added
gene: NFASC was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: NFASC was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NFASC were set to 28940097; 30124836; 30850329
Phenotypes for gene: NFASC were set to Neurodevelopmental disorder with central and peripheral motor dysfunction 618356
Review for gene: NFASC was set to GREEN
Added comment: Sources: Literature
Intellectual disability v2.996 POLR2A Konstantinos Varvagiannis gene: POLR2A was added
gene: POLR2A was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: POLR2A was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: POLR2A were set to 31353023
Phenotypes for gene: POLR2A were set to Generalized hypotonia; Global developmental delay; Feeding difficulties
Penetrance for gene: POLR2A were set to unknown
Review for gene: POLR2A was set to GREEN
gene: POLR2A was marked as current diagnostic
Added comment: Haijes et al. (2019 - PMID: 31353023) report on 16 individuals with heterozygous de novo POLR2A variants.

DD in all domains was observed in all individuals, ranging from mild to severe (in 8/16 moderate or more severe). The developmental scores were stable over time (as for eventual catch-up/decline) supporting relevance to the current panel.

POLR2A encodes RPB1, the largest subunit of RNA polymerase II (pol II). Pol II is responsible for the transcription of all protein coding genes as well as several long/short non-coding RNA genes.

Missense, in-frame deletions as well as truncating mutations were observed. POLR2A has a pLI of 1 and a Z-score for missense variants of 7.13 (one of the highest ones). The reported variants did not cluster in specific domains of the protein although many were in regions relatively depleted in benign variants in gnomAD (stretches of desert Z-scores). Measures such as the CADD scores did not discriminate between deleterious ones and those in gnomAD.

Different layers of structural analyses, functional analyses (impaired growth in S. cerevisiae in genetic background lacking transcr. factors Dst1 / Sub1 - suggesting reduced transcriptional fidelity / reduced HeLa cell viability) or phenotypic overlap were used to classify variants in probably disease causing (11), possibly disease causing (4 - only based on phenotypic overlap) or of unknown effect (1 variant - due to unavailable/incomplete phenotype).

Some variants were predicted to act by haploinsufficiency while others (missense ones) by a dominant-negative mechanism, the latter being more likely to result in severe phenotypes.

Mutations in genes encoding subunits of pol III (responsible for tRNA synthesis) are associated with leukodystrophy phenotypes with some limited overlap with POLR2A (delayed myelination/white-matter loss/tooth misalignment). Mutations in genes encoding other subunits of pol II (other than RPB1 encoded by POLR2A) have not been implicated in disease though.

POLR2A is not associated with any phenotype in OMIM/G2P. This gene is included in panels for ID offered by some diagnostic laboratories [eg. Utrecht UMC - affiliation of many co-authors of this study or GeneDx].

As a result, this gene can be considered for inclusion in the ID panel probably as green, or amber.
Sources: Literature
Intellectual disability v2.996 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.
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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).
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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).; 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 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.
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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)].
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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).
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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 v2.996 GRIA2 Konstantinos Varvagiannis reviewed gene: GRIA2: Rating: GREEN; Mode of pathogenicity: None; Publications: 31300657; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v2.996 AFF3 Konstantinos Varvagiannis reviewed gene: AFF3: 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: https://doi.org/10.1101/693937, 18616733; Phenotypes: Intellectual disability, Seizures, Abnormality of skeletal morphology, Abnormality of the urinary system, Hypertrichosis, Abnormality of the respiratory system; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Intellectual disability v2.996 PIGU Konstantinos Varvagiannis gene: PIGU was added
gene: PIGU was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: PIGU was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PIGU were set to 31353022
Phenotypes for gene: PIGU were set to Global developmental delay; Intellectual disability; Seizures; Cerebral atrophy; Cerebellar hypoplasia; Scoliosis
Penetrance for gene: PIGU were set to Complete
Review for gene: PIGU was set to GREEN
Added comment: Knaus et al. (2019 - PMID: 31353022) report on 5 affected individuals (from 3 unrelated families) with biallelic pathogenic PIGU variants.

Common features included tone abnormalities, global DD, ID, seizures, CNS anomalies (cerebral atrophy and/or cerebellar hypoplasia), scoliosis. Affected individuals presented also with facial similarities. DD/ID were universal features and their severity appears to be relevant to the panel. Seizures were also reported in all individuals (myoclonic in 3, for whom this was specified). ALP was normal in all.

Three individuals from 2 non-consanguineous families (one from Norway, the other not specified) were homozygous for a missense variant NM_080476.4:c.1149C>A (or p.Asn383Lys) present with an AF of 7/277197 in Europeans. Two individuals born to consanguineous parents from Turkey were homozygous for another missense variant (c.209T>A or p.Ile70Lys - same RefSeq).

Segregation analyses in parents and unaffected sibs were carried out.

PIGU encodes a subunit of the GPI transaminidase, a heteropentameric complex (other subunits encoded by PIGK, PIGS, PIGT and GPAA1) that mediates attachment in the endoplasmic reticulum of glycosylphosphatidylinositol (GPI) to the C-termini of proteins which are subsequently anchored to the cell surface.

Pathogenic variants in 18 of 29 genes implicated in biosynthesis of the GPI anchor have been identified as a cause of GPI biosynthesis disorders, with ID and seizures as principal features. Mutations in other genes encoding components of the GPI transaminidase complex (GPAA1, PIGT and PIGS) lead to neurodevelopmental disorders.

Functional impairment of PIGU was supported by flow-cytometric analysis showing significant reduction of cell surface expression of GPI anchored proteins (mainly FLAER, CD16 and CD24) on granulocytes from affected individuals. In addition accumulation of free GPI anchors on the cell surface of B cells from affected individuals further suggested deficiency of the GPI transaminidase.

Transient expression of mutant (Asn383Lys) protein failed to rescue expression of GPI-APs to the same extent as wt in a CHO cell line deficient for PIGU.

Feature analysis demonstrated similarities among individuals with mutations in other genes of the GPI transamidase complex (GPAA1 and PIGT) as well as with GPI biosynthesis disorders. Facial analysis was also suggestive of facial similarities between individuals with GPAA1 and PIGU mutations.

PIGU is not associated with any phenotype in OMIM or G2P.

As a result this gene can be considered for inclusion in the ID and epilepsy panels probably as green (3 families, ID of relevant severity and seizures in all affected individuals, known group of disorders and supportive evidence) or amber.
Sources: Literature
Intellectual disability v2.996 WDR37 Konstantinos Varvagiannis reviewed gene: WDR37: 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: 31327510, 31327508; Phenotypes: Global developmental delay, Intellectual disability, Seizures, Abnormality of the eye, Abnormality of nervous system morphology, Hearing abnormality, Abnormality of the cardiovascular system, Abnormality of the skeletal system, Abnormality of the genitourinary system; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v2.996 WDR37 Konstantinos Varvagiannis Deleted their review
Intellectual disability v2.996 WDR37 Konstantinos Varvagiannis gene: WDR37 was added
gene: WDR37 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: WDR37 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: WDR37 were set to 31327510; 31327508
Phenotypes for gene: WDR37 were set to Global developmental delay; Intellectual disability; Seizures; Abnormality of the eye; Abnormality of nervous system morphology; Hearing abnormality; Abnormality of the cardiovascular system; Abnormality of the skeletal system; Abnormality of the genitourinary system
Penetrance for gene: WDR37 were set to unknown
Review for gene: WDR37 was set to GREEN
Added comment: Two concurrent publications by Reis et al. and Kanca et al. (2019 - PMIDs: 31327510, 31327508) report on the phenotype of individuals with de novo WDR37 mutations.

The study by Reis et al. provides clinical details on 4 affected individuals, while 5 further are described by Kanca et al.

4 different de novo variants were reported in these individuals who appear to be unrelated in (and between) the 2 studies [NM_014023.3]:
- c.356C>T (p.Ser119Phe) [Reis indiv. 1 - 3y, Kanca proband 3 - 5m2w]
- c.389C>T (p.Thr130Ile) [Reis indiv. 2 - 22m , Kanca proband 5 - 6w]
- c.374C>T (p.Thr125Ile) [Reis indiv. 3 - 8y , Kanca proband 1 - 7y]
- c.386C>G (p.Ser129Cys) [Reis indiv. 4 - unkn age, Kanca probands 2 and 4, 6.5y and 19y]

Common features included DD/ID (severity relevant for the current panel), seizures (9/9), ocular anomalies (corneal opacity/Peters anomaly, coloboma, microphthalmia etc.) and variable brain, hearing, cardiovascular, skeletal and genitourinary anomalies. Some facial and/or other dysmorphic features (incl. excess nuchal skin / webbed neck) were also frequent among affected individuals. Feeding difficulties and growth deficiency were also among the features observed.

The function of WDR37 is not known. Variants demonstrated comparable protein levels and cellular localization compared to wt.

Reis et al. provide evidence using CRISPR-Cas9 mediated genome editing in zebrafish, to introduce the Ser129Cys variant observed in affected individuals as well as novel missense and frameshift variants. Poor growth (similar to the human phenotype) and larval lethality were noted for missense variants. Head size was proportionately small. Ocular (coloboma/corneal) or craniofacial anomalies were not observed. Zebrafish heterozygous for LoF variants survived to adulthood.

Based on these a dominant-negative mechanism was postulated for missense alleles.

RNA-seq analysis in zebrafish showed upregulation of cholesterol biosynthesis pathways (among the most dysregulated ones).

Previous data in mice, suggest a broad expression pattern for Wdr37 with enrichment in ocular and brain tissues, significant associations in homozygous mutant mice for decreased body weight, grip strength, skeletal anomalies and possible increase (p =< 0.05) in ocular (lens/corneal) and other anomalies [BioGPS and International Mouse Phenotyping Consortium cited].

CG12333 loss (the Drosophila WDR37 ortholog) causes increased bang sensitivity in flies (analogous to the human epilepsy phenotype), defects in copulation and grip strength, phenotypes that were rescued by human reference but not variant cDNAs.

As discussed by Kanca et al. based on data from Drosophila and mice, limited phenotypic similarity of CNVs spanning WDR37 and adjacent genes with the reported individuals and the presence of LoF variants in control populations haploinsufficiency appears unlikely. Gain-of-function is also unlikely, as expression of human variants in flies did not exacerbate the observed phenotypes. A dominant-negative effect is again proposed.

WDR37 is not associated with any phenotype in OMIM/G2P.

As a result WDR37 can be considered for inclusion in the ID and epilepsy panels with green (relevant phenotype, sufficient cases, animal models) or amber rating.
Sources: Literature
Intellectual disability v2.996 POU3F3 Catherine Snow Classified gene: POU3F3 as Green List (high evidence)
Intellectual disability v2.996 POU3F3 Catherine Snow Gene: pou3f3 has been classified as Green List (High Evidence).
Intellectual disability v2.995 POU3F3 Catherine Snow reviewed gene: POU3F3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v2.995 IARS Sarah Leigh commented on gene: IARS
Intellectual disability v2.995 IARS Sarah Leigh Tag new-gene-name tag was added to gene: IARS.
Intellectual disability v2.995 POU3F3 Catherine Snow Publications for gene: POU3F3 were set to https://doi.org/10.1016/j.ajhg.2019.06.007; 24550763
Intellectual disability v2.994 SHANK1 Catherine Snow Classified gene: SHANK1 as Red List (low evidence)
Intellectual disability v2.994 SHANK1 Catherine Snow Gene: shank1 has been classified as Red List (Low Evidence).
Intellectual disability v2.993 SHANK1 Catherine Snow reviewed gene: SHANK1: Rating: RED; Mode of pathogenicity: None; Publications: 30053575, 20868654; Phenotypes: ; Mode of inheritance: None
Intellectual disability v2.993 PIGB Catherine Snow Classified gene: PIGB as Green List (high evidence)
Intellectual disability v2.993 PIGB Catherine Snow Gene: pigb has been classified as Green List (High Evidence).
Intellectual disability v2.993 PIGB Catherine Snow Classified gene: PIGB as Green List (high evidence)
Intellectual disability v2.993 PIGB Catherine Snow Gene: pigb has been classified as Green List (High Evidence).
Intellectual disability v2.992 PIGB Catherine Snow reviewed gene: PIGB: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v2.992 DLG4 Catherine Snow Classified gene: DLG4 as Green List (high evidence)
Intellectual disability v2.992 DLG4 Catherine Snow Gene: dlg4 has been classified as Green List (High Evidence).
Intellectual disability v2.991 CTBP1 Rebecca Foulger Tag missense tag was added to gene: CTBP1.
Intellectual disability v2.991 AP2M1 Catherine Snow Tag missense tag was added to gene: AP2M1.
Intellectual disability v2.991 CYP27A1 Catherine Snow Tag watchlist tag was added to gene: CYP27A1.
Intellectual disability v2.991 CYP27A1 Catherine Snow commented on gene: CYP27A1: Advice from clinical team "the phenotypic relevance is borderline. I would opt for amber in view of the small number of cases of school age, or earlier, intellectual impairment. This phenotype is the mainstay of this panel, but not clearly the common presentation for this disorder. Therefore I would prefer to opt to await further cases with a relevant phenotype before reviewing this".
CYP27A1 will therefore remain Amber on the panel and the watchlist tag been added.
Intellectual disability v2.991 PHF21A Catherine Snow Classified gene: PHF21A as Green List (high evidence)
Intellectual disability v2.991 PHF21A Catherine Snow Gene: phf21a has been classified as Green List (High Evidence).
Intellectual disability v2.990 PHF21A Catherine Snow changed review comment from: Potocki-Shaffer syndrome thought to caused by a deletion of 11p11.2, the minimum deleted region contains at least five genes, including PHF21A.
Hamanaka et al in PMID: 30487643 reported on three individuals who all underwent trio WES to have de novo, variants in PHF21A. All individuals had DD and ID although mild in one case.
PHF21A is not currently associated with any phenotypes in OMIM but is classed probable and associated with Disease: POTOCKI-SHAFFER SYNDROME in Gene2Phenotype.
Combined with the functional evidence and two expert reviews, there is now enough evidence for PHF21A to be classed as Green.; to: Potocki-Shaffer syndrome thought to caused by a deletion of 11p11.2, the minimum deleted region contains at least five genes, including PHF21A.
Hamanaka et al in PMID: 30487643 reported on three individuals who all underwent trio WES to have de novo, variants in PHF21A. All individuals had DD and ID although mild in one case. This is the first reporting of LOF variants solely in PHF21A.
PHF21A is not currently associated with any phenotypes in OMIM but is classed probable and associated with Disease: POTOCKI-SHAFFER SYNDROME in Gene2Phenotype.
Combined with the functional evidence and two expert reviews, there is now enough evidence for PHF21A to be classed as Green.
Intellectual disability v2.990 PHF21A Catherine Snow reviewed gene: PHF21A: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v2.990 GTF3C3 Catherine Snow Classified gene: GTF3C3 as Amber List (moderate evidence)
Intellectual disability v2.990 GTF3C3 Catherine Snow Gene: gtf3c3 has been classified as Amber List (Moderate Evidence).
Intellectual disability v2.989 GTF3C3 Catherine Snow reviewed gene: GTF3C3: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v2.989 PPP1R21 Catherine Snow Phenotypes for gene: PPP1R21 were changed from Hepatosplenomegaly; Abnormality of the respiratory system; Generalized hypotonia, Feeding difficulties, Profound global developmental delay, Abnormality of the face, Abnormality of vision, Abnormal heart morphology, Abnormality of the respiratory system to Hepatosplenomegaly; Abnormality of the respiratory system; Generalized hypotonia, Feeding difficulties, Profound global developmental delay, Abnormality of the face, Abnormality of vision, Abnormal heart morphology
Intellectual disability v2.988 PPP1R21 Catherine Snow Phenotypes for gene: PPP1R21 were changed from Hepatosplenomegaly; Abnormality of the respiratory system; Generalized hypotonia, Feeding difficulties, Profound global developmental delay, Abnormality of the face, Abnormality of vision, Abnormal heart morphology, Abnormality of the respiratory system, Hepatosplenomegaly; Profound global developmental delay; Abnormal heart morphology; Generalized hypotonia; Feeding difficulties; Abnormality of the face; Abnormality of vision to Hepatosplenomegaly; Abnormality of the respiratory system; Generalized hypotonia, Feeding difficulties, Profound global developmental delay, Abnormality of the face, Abnormality of vision, Abnormal heart morphology, Abnormality of the respiratory system
Intellectual disability v2.987 GTF3C3 Catherine Snow Tag watchlist tag was added to gene: GTF3C3.
Intellectual disability v2.987 GTF3C3 Catherine Snow Phenotypes for gene: GTF3C3 were changed from to Global developmental delay; Intellectual disability; Seizures
Intellectual disability v2.987 GTF3C3 Catherine Snow Publications for gene: GTF3C3 were set to 28940097, 28097321
Intellectual disability v2.986 KMT2B Catherine Snow Publications for gene: KMT2B were set to 25529582; 27839873; 27992417; 29276005; 25405613; 29289525; 31216378
Intellectual disability v2.985 MTO1 Catherine Snow Publications for gene: MTO1 were set to
Intellectual disability v2.984 PHF21A Catherine Snow Publications for gene: PHF21A were set to 22770980; 26333423; 8456828; 8882796; 14872200; 9489802; 11017806; 11903336; 15852040; 23239541; 28127865
Intellectual disability v2.983 MTO1 Catherine Snow Classified gene: MTO1 as Green List (high evidence)
Intellectual disability v2.983 MTO1 Catherine Snow Gene: mto1 has been classified as Green List (High Evidence).
Intellectual disability v2.982 MTO1 Catherine Snow reviewed gene: MTO1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v2.982 KMT2B Catherine Snow commented on gene: KMT2B
Intellectual disability v2.982 KMT2B Catherine Snow Publications for gene: KMT2B were set to 25529582; 27839873; 27992417; 29276005; 25405613; 29289525
Intellectual disability v2.981 ZBTB11 Catherine Snow Tag watchlist tag was added to gene: ZBTB11.
Intellectual disability v2.981 VPS11 Catherine Snow Tag watchlist tag was added to gene: VPS11.
Intellectual disability v2.981 TKT Catherine Snow Tag watchlist tag was added to gene: TKT.
Intellectual disability v2.981 SUFU Catherine Snow Tag watchlist tag was added to gene: SUFU.
Intellectual disability v2.981 SRP54 Catherine Snow Tag watchlist tag was added to gene: SRP54.
Intellectual disability v2.981 SMG9 Catherine Snow Tag watchlist tag was added to gene: SMG9.
Intellectual disability v2.981 SLC5A7 Catherine Snow Tag watchlist tag was added to gene: SLC5A7.
Intellectual disability v2.981 SCYL1 Catherine Snow Tag watchlist tag was added to gene: SCYL1.
Intellectual disability v2.981 RSPRY1 Catherine Snow Tag watchlist tag was added to gene: RSPRY1.
Intellectual disability v2.981 RNF13 Catherine Snow Tag watchlist tag was added to gene: RNF13.
Intellectual disability v2.981 RAB11A Catherine Snow Tag watchlist tag was added to gene: RAB11A.
Intellectual disability v2.981 PTRHD1 Catherine Snow Tag watchlist tag was added to gene: PTRHD1.
Intellectual disability v2.981 PTRH2 Catherine Snow Tag watchlist tag was added to gene: PTRH2.
Intellectual disability v2.981 PLEKHG2 Catherine Snow Tag watchlist tag was added to gene: PLEKHG2.
Intellectual disability v2.981 LSS Catherine Snow Tag watchlist tag was added to gene: LSS.
Intellectual disability v2.981 LIPT2 Catherine Snow Tag watchlist tag was added to gene: LIPT2.
Intellectual disability v2.981 GTF2E2 Catherine Snow Tag watchlist tag was added to gene: GTF2E2.
Intellectual disability v2.981 FUK Catherine Snow Tag watchlist tag was added to gene: FUK.
Intellectual disability v2.981 EMG1 Catherine Snow Tag watchlist tag was added to gene: EMG1.
Intellectual disability v2.981 DYNC1I2 Catherine Snow Tag watchlist tag was added to gene: DYNC1I2.
Intellectual disability v2.981 DONSON Catherine Snow Tag watchlist tag was added to gene: DONSON.
Intellectual disability v2.981 GMNN Catherine Snow Tag watchlist tag was added to gene: GMNN.
Intellectual disability v2.981 UFM1 Catherine Snow Tag de novo tag was added to gene: UFM1.
Intellectual disability v2.980 CTBP1 Rebecca Foulger Classified gene: CTBP1 as Green List (high evidence)
Intellectual disability v2.980 CTBP1 Rebecca Foulger Added comment: Comment on list classification: Gene added to panel and rated Green by Chris Buxton. Changed rating to Green after agreement from Genomics England clinical team- sufficient cases and relevant phenotype. Have added missense tag, because only one missense tag reported so far.
Intellectual disability v2.980 CTBP1 Rebecca Foulger Gene: ctbp1 has been classified as Green List (High Evidence).
Intellectual disability v2.979 CTBP1 Rebecca Foulger commented on gene: CTBP1
Intellectual disability v2.979 MAP3K7 Catherine Snow Mode of inheritance for gene MAP3K7 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v2.979 TKT Catherine Snow Mode of inheritance for gene TKT was changed from to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v2.979 SUFU Catherine Snow Mode of inheritance for gene SUFU was changed from to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v2.979 SRP54 Catherine Snow Mode of inheritance for gene SRP54 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v2.979 SMG9 Catherine Snow Mode of inheritance for gene SMG9 was changed from to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v2.979 SLC5A7 Catherine Snow Mode of inheritance for gene SLC5A7 was changed from to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v2.979 SCYL1 Catherine Snow Mode of inheritance for gene SCYL1 was changed from to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v2.979 RSPRY1 Catherine Snow Mode of inheritance for gene RSPRY1 was changed from to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v2.979 LIPT2 Catherine Snow Mode of inheritance for gene LIPT2 was changed from to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v2.979 LIAS Catherine Snow Mode of inheritance for gene LIAS was changed from to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v2.979 GTF2E2 Catherine Snow Mode of inheritance for gene GTF2E2 was changed from to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v2.979 GMNN Catherine Snow Mode of inheritance for gene GMNN was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v2.979 EMG1 Catherine Snow Mode of inheritance for gene EMG1 was changed from to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v2.979 TRAIP Catherine Snow Mode of inheritance for gene TRAIP was changed from to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v2.979 PRR12 Catherine Snow Mode of inheritance for gene PRR12 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v2.979 MRPS34 Catherine Snow Mode of inheritance for gene MRPS34 was changed from to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v2.979 EMC1 Catherine Snow Mode of inheritance for gene EMC1 was changed from BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v2.978 MAP3K7 Catherine Snow gene: MAP3K7 was added
gene: MAP3K7 was added to Intellectual disability. Sources: Literature,Expert Review Red
Mode of inheritance for gene: MAP3K7 was set to
Publications for gene: MAP3K7 were set to 27426733; 30914295
Phenotypes for gene: MAP3K7 were set to Frontometaphyseal dysplasia 2, 617137
Intellectual disability v2.978 ZBTB11 Catherine Snow Source Expert Review was added to ZBTB11.
Source Expert Review Amber was added to ZBTB11.
Added phenotypes Intellectual developmental disorder, autosomal recessive 69, 618383 for gene: ZBTB11
Rating Changed from No List (delete) to Amber List (moderate evidence)
Intellectual disability v2.978 VPS11 Catherine Snow Source Expert Review was added to VPS11.
Source Expert Review Amber was added to VPS11.
Added phenotypes Leukodystrophy, hypomyelinating, 12, 616683 for gene: VPS11
Publications for gene VPS11 were changed from 27120463; 26307567; 27473128 to 27473128; 26307567; 27120463
Rating Changed from No List (delete) to Amber List (moderate evidence)
Intellectual disability v2.978 UFC1 Catherine Snow Added phenotypes Neurodevelopmental disorder with spasticity and poor growth, 618076 for gene: UFC1
Publications for gene UFC1 were changed from 29868776; 27431290; 30237576 to 30914295
Intellectual disability v2.978 TSEN15 Catherine Snow Added phenotypes Pontocerebellar hypoplasia, type 2F, 617026 for gene: TSEN15
Publications for gene TSEN15 were changed from 27392077; 25558065 to 27392077; 30914295; 25558065
Intellectual disability v2.978 TKT Catherine Snow gene: TKT was added
gene: TKT was added to Intellectual disability. Sources: Literature,Expert Review Amber
Mode of inheritance for gene: TKT was set to
Publications for gene: TKT were set to 27259054; 30914295
Phenotypes for gene: TKT were set to Short stature, developmental delay, and congenital heart defects, 617044
Intellectual disability v2.978 SUFU Catherine Snow gene: SUFU was added
gene: SUFU was added to Intellectual disability. Sources: Literature,Expert Review Amber
Mode of inheritance for gene: SUFU was set to
Publications for gene: SUFU were set to 28965847; 30914295
Phenotypes for gene: SUFU were set to Joubert syndrome 32, 617757
Intellectual disability v2.978 SRP54 Catherine Snow gene: SRP54 was added
gene: SRP54 was added to Intellectual disability. Sources: Literature,Expert Review Amber
Mode of inheritance for gene: SRP54 was set to
Publications for gene: SRP54 were set to 28972538; 30914295
Phenotypes for gene: SRP54 were set to Syndromic neutropenia with Shwachman-Diamond-like features
Intellectual disability v2.978 SMG9 Catherine Snow gene: SMG9 was added
gene: SMG9 was added to Intellectual disability. Sources: Literature,Expert Review Amber
Mode of inheritance for gene: SMG9 was set to
Publications for gene: SMG9 were set to 27018474; 30914295
Phenotypes for gene: SMG9 were set to Heart and brain malformation syndrome, 616920
Intellectual disability v2.978 SLC5A7 Catherine Snow gene: SLC5A7 was added
gene: SLC5A7 was added to Intellectual disability. Sources: Literature,Expert Review Amber
Mode of inheritance for gene: SLC5A7 was set to
Publications for gene: SLC5A7 were set to 30914295; 27569547
Phenotypes for gene: SLC5A7 were set to Myasthenic syndrome, congenital, 20, presynaptic,CMS20, 617143
Intellectual disability v2.978 SCYL1 Catherine Snow gene: SCYL1 was added
gene: SCYL1 was added to Intellectual disability. Sources: Literature,Expert Review Amber
Mode of inheritance for gene: SCYL1 was set to
Publications for gene: SCYL1 were set to 26581903; 30914295
Phenotypes for gene: SCYL1 were set to Spinocerebellar ataxia, autosomal recessive 21, 616719
Intellectual disability v2.978 RSPRY1 Catherine Snow gene: RSPRY1 was added
gene: RSPRY1 was added to Intellectual disability. Sources: Literature,Expert Review Amber
Mode of inheritance for gene: RSPRY1 was set to
Publications for gene: RSPRY1 were set to 26365341; 30914295
Phenotypes for gene: RSPRY1 were set to Spondyloepimetaphyseal dysplasia, Faden-Alkuraya type, 616585
Intellectual disability v2.978 RNF13 Catherine Snow Source Expert Review was added to RNF13.
Source Expert Review Amber was added to RNF13.
Added phenotypes Epileptic encephalopathy, early infantile, 73, 618379 for gene: RNF13
Publications for gene RNF13 were changed from to 30595371
Rating Changed from No List (delete) to Amber List (moderate evidence)
Intellectual disability v2.978 RAB11A Catherine Snow Source Expert Review was added to RAB11A.
Source Expert Review Amber was added to RAB11A.
Added phenotypes Global developmental delay, Intellectual disability for gene: RAB11A
Rating Changed from No List (delete) to Amber List (moderate evidence)
Intellectual disability v2.978 PTRHD1 Catherine Snow Source Expert Review was added to PTRHD1.
Source Expert Review Amber was added to PTRHD1.
Added phenotypes Parkinsonism, Intellectual disability for gene: PTRHD1
Publications for gene PTRHD1 were changed from 30398675; 27134041; 29143421; 27753167 to 30398675; 27134041; 27753167; 29143421
Rating Changed from No List (delete) to Amber List (moderate evidence)
Intellectual disability v2.978 PTRH2 Catherine Snow Source Expert Review was added to PTRH2.
Source Expert Review Amber was added to PTRH2.
Added phenotypes Infantile-onset multisystem neurologic, endocrine, and pancreatic disease, 616263 for gene: PTRH2
Publications for gene PTRH2 were changed from 25574476; 27129381; 25558065; 28328138; 28175314 to 25574476; 28175314; 28328138; 25558065; 27129381
Rating Changed from No List (delete) to Amber List (moderate evidence)
Intellectual disability v2.978 PLEKHG2 Catherine Snow Source Expert Review was added to PLEKHG2.
Source Expert Review Amber was added to PLEKHG2.
Added phenotypes Leukodystrophy and acquired microcephaly with or without dystonia, 616763 for gene: PLEKHG2
Publications for gene PLEKHG2 were changed from 26539891; 26573021; 24001768 to 26539891; 24001768; 26573021
Rating Changed from No List (delete) to Amber List (moderate evidence)
Intellectual disability v2.978 LSS Catherine Snow Source Expert Review was added to LSS.
Source Expert Review Amber was added to LSS.
Added phenotypes Cataract 44, Hypotrichosis 14, 616509, 618275 for gene: LSS
Publications for gene LSS were changed from 30723320; 30401459 to 30723320; 26200341; 30401459; 29016354
Rating Changed from No List (delete) to Amber List (moderate evidence)
Intellectual disability v2.978 LIPT2 Catherine Snow gene: LIPT2 was added
gene: LIPT2 was added to Intellectual disability. Sources: Literature,Expert Review Amber
Mode of inheritance for gene: LIPT2 was set to
Publications for gene: LIPT2 were set to 28628643; 30914295
Phenotypes for gene: LIPT2 were set to Encephalopathy, neonatal severe, with lactic acidosis and brain abnormalities, 617668
Intellectual disability v2.978 LIAS Catherine Snow gene: LIAS was added
gene: LIAS was added to Intellectual disability. Sources: Literature,Expert Review Amber
Mode of inheritance for gene: LIAS was set to
Publications for gene: LIAS were set to 22152680; 26108146; 24334290; 30914295
Phenotypes for gene: LIAS were set to Hyperglycinemia, lactic acidosis, and seizures, 614462
Intellectual disability v2.978 GTF2E2 Catherine Snow gene: GTF2E2 was added
gene: GTF2E2 was added to Intellectual disability. Sources: Literature,Expert Review Amber
Mode of inheritance for gene: GTF2E2 was set to
Publications for gene: GTF2E2 were set to 30914295; 26996949
Phenotypes for gene: GTF2E2 were set to Trichothiodystrophy 6, nonphotosensitive, 616943
Intellectual disability v2.978 GMNN Catherine Snow gene: GMNN was added
gene: GMNN was added to Intellectual disability. Sources: Literature,Expert Review Amber
Mode of inheritance for gene: GMNN was set to
Publications for gene: GMNN were set to 26637980; 30914295
Phenotypes for gene: GMNN were set to Meier-Gorlin syndrome 6, 616835
Intellectual disability v2.978 FUK Catherine Snow Source Expert Review was added to FUK.
Source Expert Review Amber was added to FUK.
Added phenotypes Congenital disorder of glycosylation with defective fucosylation 2, 618324 for gene: FUK
Rating Changed from No List (delete) to Amber List (moderate evidence)
Intellectual disability v2.978 FRRS1L Catherine Snow Source Expert Review Amber was added to FRRS1L.
Added phenotypes Epileptic encephalopathy, early infantile, 37, 616981 for gene: FRRS1L
Publications for gene FRRS1L were changed from 27236917; 27239025; 21147040; 29276473 to 29276473; 27239025; 21147040; 27236917; 30914295
Rating Changed from No List (delete) to Amber List (moderate evidence)
Intellectual disability v2.978 EMG1 Catherine Snow gene: EMG1 was added
gene: EMG1 was added to Intellectual disability. Sources: Literature,Expert Review Amber
Mode of inheritance for gene: EMG1 was set to
Publications for gene: EMG1 were set to 30914295
Phenotypes for gene: EMG1 were set to Bowen-Conradi syndrome, 211180
Intellectual disability v2.978 DYNC1I2 Catherine Snow Source Expert Review was added to DYNC1I2.
Source Expert Review Amber was added to DYNC1I2.
Added phenotypes Abnormality of head or neck; Microcephaly; Abnormality of nervous system morphology; Intellectual disability for gene: DYNC1I2
Rating Changed from No List (delete) to Amber List (moderate evidence)
Intellectual disability v2.978 DONSON Catherine Snow Source Expert Review was added to DONSON.
Source Expert Review Amber was added to DONSON.
Added phenotypes Microcephaly, short stature, and limb abnormalities 617604; Microcephaly-micromelia syndrome 251230 for gene: DONSON
Rating Changed from No List (delete) to Amber List (moderate evidence)
Intellectual disability v2.978 ZNF462 Catherine Snow Source Expert Review Green was added to ZNF462.
Source Expert Review was added to ZNF462.
Added phenotypes Ptosis, Prominent metopic ridge, Craniosynostosis, Global developmental delay, Intellectual disability, Autistic behavior for gene: ZNF462
Publications for gene ZNF462 were changed from 28513610; 29427787; 14564155; 12825074 to 28513610; 12825074; 29427787; 14564155
Rating Changed from No List (delete) to Green List (high evidence)
Intellectual disability v2.978 ZNF142 Catherine Snow Source Expert Review Green was added to ZNF142.
Source Expert Review was added to ZNF142.
Added phenotypes Neurodevelopmental disorder with impaired speech and hyperkinetic movements, 618425 for gene: ZNF142
Rating Changed from No List (delete) to Green List (high evidence)
Intellectual disability v2.978 ZMIZ1 Catherine Snow Source Expert Review Green was added to ZMIZ1.
Source Expert Review was added to ZMIZ1.
Added phenotypes Global developmental delay, Intellectual disability, Feeding difficulties, Growth abnormality, Microcephaly, Abnormality of the skeletal system, Abnormality of the urinary system, Abnormality of the cardiovascular system, Abnormality of head or neck for gene: ZMIZ1
Publications for gene ZMIZ1 were changed from 29754769; 18053775; 17967885; 26163108; 27479843 to 29754769; 18053775; 17967885; 30639322; 26163108; 27479843
Rating Changed from No List (delete) to Green List (high evidence)
Intellectual disability v2.978 WARS2 Catherine Snow Source Expert Review Green was added to WARS2.
Source Expert Review was added to WARS2.
Added phenotypes Neurodevelopmental disorder, mitochondrial, with abnormal movements and lactic acidosis, with or without seizures, 617710 for gene: WARS2
Publications for gene WARS2 were changed from 28236339; 28650581; 28905505; 29783990; 29120065 to 29783990; 28236339; 29120065; 28650581; 28905505
Rating Changed from No List (delete) to Green List (high evidence)
Intellectual disability v2.978 VARS Catherine Snow Source Expert Review Green was added to VARS.
Added phenotypes Neurodevelopmental disorder with microcephaly, seizures, and cortical atrophy, 617802 for gene: VARS
Publications for gene VARS were changed from 26539891; 29691655; 30275004 to 26539891; 30275004; 29691655
Rating Changed from No List (delete) to Green List (high evidence)
Intellectual disability v2.978 VAMP2 Catherine Snow Source Expert Review Green was added to VAMP2.
Source Expert Review was added to VAMP2.
Added phenotypes Generalized hypotonia, Global developmental delay, Intellectual disability, Autistic behavior, Stereotypic behavior, Seizures, Abnormality of movement, Cortical visual impairment for gene: VAMP2
Rating Changed from No List (delete) to Green List (high evidence)
Intellectual disability v2.978 UFM1 Catherine Snow Source Expert Review Green was added to UFM1.
Added phenotypes Leukodystrophy, hypomyelinating, 14, 617899 for gene: UFM1
Publications for gene UFM1 were changed from 28931644; 29868776; 30237576 to 28931644; 29868776; 30914295
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v2.978 TRRAP Catherine Snow Source Expert Review Green was added to TRRAP.
Source Expert Review was added to TRRAP.
Added phenotypes Developmental delay with or without dysmorphic facies and autism, 603015 for gene: TRRAP
Publications for gene TRRAP were changed from 30827496 to 30827496; 30424743
Rating Changed from No List (delete) to Green List (high evidence)
Intellectual disability v2.978 TRAIP Catherine Snow gene: TRAIP was added
gene: TRAIP was added to Intellectual disability. Sources: Expert Review Green,Literature
Mode of inheritance for gene: TRAIP was set to
Publications for gene: TRAIP were set to 26595769; 30914295
Phenotypes for gene: TRAIP were set to Seckel syndrome 9, 616777
Intellectual disability v2.978 SNAP25 Catherine Snow Source Expert Review Green was added to SNAP25.
Added phenotypes ?Myasthenic syndrome, congenital, 18, 616330 for gene: SNAP25
Publications for gene SNAP25 were changed from 29491473; 28135719; 29100083; 25381298; 25003006 to 29100083; 28135719; 25003006; 29491473; 25381298; 30914295
Rating Changed from No List (delete) to Green List (high evidence)
Intellectual disability v2.978 RPIA Catherine Snow Source Expert Review Green was added to RPIA.
Source Expert Review was added to RPIA.
Added phenotypes ?Ribose 5-phosphate isomerase deficiency, 608611 for gene: RPIA
Publications for gene RPIA were changed from 14988808; 20499043; 28801340; 30088433 to 20499043; 31056085; 14988808; 30088433; 28801340
Rating Changed from No List (delete) to Green List (high evidence)
Intellectual disability v2.978 RALA Catherine Snow Source Expert Review Green was added to RALA.
Source Expert Review was added to RALA.
Added phenotypes Global developmental delay, Intellectual disability, Seizures, Abnormality of nervous system morphology for gene: RALA
Publications for gene RALA were changed from to 30500825
Rating Changed from No List (delete) to Green List (high evidence)
Intellectual disability v2.978 RAC3 Catherine Snow Source Expert Review Green was added to RAC3.
Source Expert Review was added to RAC3.
Added phenotypes Abnormality of brain morphology, Abnormal muscle tone, Neurodevelopmental delay, Intellectual disability for gene: RAC3
Publications for gene RAC3 were changed from 30293988; 29276006 to 29276006; 30293988
Rating Changed from No List (delete) to Green List (high evidence)
Intellectual disability v2.978 PUS7 Catherine Snow Source Expert Review Green was added to PUS7.
Source Expert Review was added to PUS7.
Added phenotypes Intellectual developmental disorder with abnormal behavior, microcephaly, and short stature, 618342 for gene: PUS7
Publications for gene PUS7 were changed from to 30778726; 30526862
Rating Changed from No List (delete) to Green List (high evidence)
Intellectual disability v2.978 PUS3 Catherine Snow Source Expert Review Green was added to PUS3.
Source Expert Review was added to PUS3.
Added phenotypes Mental retardation, autosomal recessive 55, 617051 for gene: PUS3
Publications for gene PUS3 were changed from 27055666; 30308082 to 30697592; 30308082; 27055666
Rating Changed from No List (delete) to Green List (high evidence)
Intellectual disability v2.978 PRR12 Catherine Snow Source Expert Review Green was added to PRR12.
Source Expert Review was added to PRR12.
Added phenotypes Global developmental delay, Intellectual disability, Abnormality of the iris, Abnormality of vision, Behavioral abnormality for gene: PRR12
Publications for gene PRR12 were changed from 29556724; 26163108 to 28135719; 26163108; 29556724
Rating Changed from No List (delete) to Green List (high evidence)
Intellectual disability v2.978 PPP2CA Catherine Snow Source Expert Review Green was added to PPP2CA.
Source Expert Review was added to PPP2CA.
Added phenotypes Neurodevelopmental disorder and language delay with or without structural brain abnormalities, 618354 for gene: PPP2CA
Publications for gene PPP2CA were changed from 29274472; 30030003 to 29274472; 30030003; 30595372
Rating Changed from No List (delete) to Green List (high evidence)
Intellectual disability v2.978 PPP1R21 Catherine Snow Source Expert Review Green was added to PPP1R21.
Source Expert Review was added to PPP1R21.
Added phenotypes Generalized hypotonia, Feeding difficulties, Profound global developmental delay, Abnormality of the face, Abnormality of vision, Abnormal heart morphology, Abnormality of the respiratory system, Hepatosplenomegaly for gene: PPP1R21
Rating Changed from No List (delete) to Green List (high evidence)
Intellectual disability v2.978 PITRM1 Catherine Snow Source Expert Review Green was added to PITRM1.
Source Expert Review was added to PITRM1.
Added phenotypes Ataxia; Intellectual disability for gene: PITRM1
Rating Changed from No List (delete) to Green List (high evidence)
Intellectual disability v2.978 PIGG Catherine Snow Source Expert Review Green was added to PIGG.
Added phenotypes Mental retardation, autosomal recessive 53, 616917 for gene: PIGG
Publications for gene PIGG were changed from 26996948; 28581210 to 28581210; 26996948; 30914295
Rating Changed from No List (delete) to Green List (high evidence)
Intellectual disability v2.978 P4HTM Catherine Snow Source Expert Review Green was added to P4HTM.
Source Expert Review was added to P4HTM.
Added phenotypes Central hypotonia, Muscular hypotonia, Global developmental delay, Intellectual disability, Seizures, Abnormality of the eye, Hypoventilation, Sleep apnea, Dysautonomia for gene: P4HTM
Rating Changed from No List (delete) to Green List (high evidence)
Intellectual disability v2.978 MRPS34 Catherine Snow gene: MRPS34 was added
gene: MRPS34 was added to Intellectual disability. Sources: Expert Review Green,Literature
Mode of inheritance for gene: MRPS34 was set to
Publications for gene: MRPS34 were set to 30914295; 28777931
Phenotypes for gene: MRPS34 were set to Combined oxidativephosphorylation deficiency 32, 617664
Intellectual disability v2.978 GPT2 Catherine Snow Source Expert Review Green was added to GPT2.
Source Expert Review was added to GPT2.
Added phenotypes Mental retardation, autosomal recessive 49, 138210 for gene: GPT2
Publications for gene GPT2 were changed from PMID: 25758935; 27601654; 28130718; 29226631 to 27601654; 28130718; 29226631; 25758935
Rating Changed from No List (delete) to Green List (high evidence)
Intellectual disability v2.978 GNB5 Catherine Snow Source Expert Review Green was added to GNB5.
Added phenotypes Language delay and ADHD/cognitive impairment with or without cardiac arrhythmia, 617182; Intellectual developmental disorder with cardiac arrhythmia, 617173 for gene: GNB5
Publications for gene GNB5 were changed from 27523599; 27677260; 28697420; 29368331 to 27677260; 28697420; 29368331; 30914295; 27523599
Rating Changed from No List (delete) to Green List (high evidence)
Intellectual disability v2.978 FBXL3 Catherine Snow Source Expert Review Green was added to FBXL3.
Added phenotypes Intellectual developmental disorder with short stature, facial anomalies, and speech defects, 606220 for gene: FBXL3
Rating Changed from No List (delete) to Green List (high evidence)
Intellectual disability v2.978 FARS2 Catherine Snow Source Expert Review Green was added to FARS2.
Source Expert Review was added to FARS2.
Added phenotypes Spastic paraplegia 77, autosomal recessive, 617046; Combined oxidative phosphorylation deficiency 14, 614946 for gene: FARS2
Rating Changed from No List (delete) to Green List (high evidence)
Intellectual disability v2.978 EMC1 Catherine Snow Source Expert Review Green was added to EMC1.
Added phenotypes Cerebellar atrophy, visual impairment, and psychomotor retardation, 616875 for gene: EMC1
Publications for gene EMC1 were changed from 26942288; 29271071 to 29271071; 26942288; 30914295
Rating Changed from No List (delete) to Green List (high evidence)
Intellectual disability v2.978 DPH1 Catherine Snow Source Expert Review Green was added to DPH1.
Added phenotypes Developmental delay with short stature, dysmorphic features, and sparse hair, 616901 for gene: DPH1
Publications for gene DPH1 were changed from 25558065; 26220823; 29362492; 29410513 to 29362492; 29410513; 26220823; 25558065
Rating Changed from No List (delete) to Green List (high evidence)
Intellectual disability v2.978 DHPS Catherine Snow Source Expert Review Green was added to DHPS.
Source Expert Review was added to DHPS.
Added phenotypes Abnormal muscle tone, Global developmental delay, Intellectual disability, Seizures, EEG abnormality, Behavioral abnormality, Abnormality of head or neck for gene: DHPS
Publications for gene DHPS were changed from 21389784; 21850436 to 21389784; 30661771; 21850436
Rating Changed from No List (delete) to Green List (high evidence)
Intellectual disability v2.978 DDX59 Catherine Snow Source Expert Review Green was added to DDX59.
Added phenotypes Orofaciodigital syndrome V, 174300 for gene: DDX59
Publications for gene DDX59 were changed from 23972372; 28711741; 29127725 to 28711741; 29127725; 23972372; 30914295
Rating Changed from No List (delete) to Green List (high evidence)
Intellectual disability v2.978 DCPS Catherine Snow Source Expert Review Green was added to DCPS.
Added phenotypes Al-Raqad syndrome, 616459 for gene: DCPS
Publications for gene DCPS were changed from 25712129; 25701870; 30289615 to 25701870; 30289615; 25712129
Rating Changed from No List (delete) to Green List (high evidence)
Intellectual disability v2.978 CYFIP2 Catherine Snow Source Expert Review Green was added to CYFIP2.
Source Expert Review was added to CYFIP2.
Added phenotypes Epileptic encephalopathy, early infantile, 65, 618008 for gene: CYFIP2
Publications for gene CYFIP2 were changed from 29534297; 29667327; 30664714; 25432536; 27524794; 12818175; 20537992 to 12818175; 30664714; 20537992; 29534297; 25432536; 27524794; 29667327
Rating Changed from No List (delete) to Green List (high evidence)
Intellectual disability v2.978 CUX1 Catherine Snow Source Expert Review Green was added to CUX1.
Source Expert Review was added to CUX1.
Added phenotypes Global developmental delay with or without impaired intellectual development, 618330 for gene: CUX1
Publications for gene CUX1 were changed from 30014507; 20510857; 25059644 to 25059644; 20510857; 30014507
Rating Changed from No List (delete) to Green List (high evidence)
Intellectual disability v2.978 CARS Catherine Snow Source Expert Review Green was added to CARS.
Source Expert Review was added to CARS.
Added phenotypes Brittle hair; Fragile nails; Microcephaly; Neurodevelopmental delay for gene: CARS
Publications for gene CARS were changed from to 30824121
Rating Changed from No List (delete) to Green List (high evidence)
Intellectual disability v2.978 CAD Catherine Snow Source Expert Review Green was added to CAD.
Added phenotypes Epileptic encephalopathy, early infantile, 50 - MIM 616457 for gene: CAD
Publications for gene CAD were changed from 25678555; 28007989 to 25678555; 28007989; 30914295
Rating Changed from No List (delete) to Green List (high evidence)
Intellectual disability v2.978 CACNA1B Catherine Snow Source Expert Review was added to CACNA1B.
Added phenotypes Global developmental delay; Seizures; Intellectual disability; Abnormality of movement; Developmental regression for gene: CACNA1B
Publications for gene CACNA1B were changed from 30982612; 25296916 to 26157024; 30982612
Intellectual disability v2.978 BRSK2 Catherine Snow Source Expert Review Green was added to BRSK2.
Source Expert Review was added to BRSK2.
Added phenotypes Global developmental delay, Intellectual disability, Autism, Behavioral abnormality for gene: BRSK2
Publications for gene BRSK2 were changed from https://doi.org/10.1016/j.ajhg.2019.02.002 to 15705853; 23715323; 30879638; 25363768; 28135719
Rating Changed from No List (delete) to Green List (high evidence)
Intellectual disability v2.978 AP2M1 Catherine Snow Source Expert Review Green was added to AP2M1.
Source Expert Review was added to AP2M1.
Added phenotypes Seizures; Ataxia; Generalized hypotonia; Intellectual disability; Global developmental delay; Autistic behavior for gene: AP2M1
Rating Changed from No List (delete) to Green List (high evidence)
Intellectual disability v2.978 ALKBH8 Catherine Snow Source Expert Review Green was added to ALKBH8.
Source Expert Review was added to ALKBH8.
Added phenotypes Global developmental delay; Seizures; Intellectual disability for gene: ALKBH8
Publications for gene ALKBH8 were changed from 31079898 to 31130284; 31079898
Rating Changed from No List (delete) to Green List (high evidence)
Intellectual disability v2.977 FRMPD4 Catherine Snow changed review comment from: Further paper identified to indicated FRMPD4 is relevant to ID. PMID: 29267967 provides details of four unrelated families, two families, family 1 and 4 had already been identified and reported in PMID:25644381.
Family 2, two brothers, had a micro deletion of exon 2, their mother was heterozygous for the same micro deletion.
Family 3, two half-siblings (p.Arg286Ter) Their unaffected mother was heterozygous for the same deletion, a hetrozygous sister was mildly disabled.
No further segregation information for the two families was reported.
Some functional work performed but only for the frameshift variant that was reported in family 1.
Requesting support from clinical team as limited information on the extended families and the female affected in family 3 is the only hetrozygous carrier who displays ID features.; to: Further paper identified to indicated FRMPD4 is relevant to ID. PMID: 29267967 provides details of four unrelated families, two families, family 1 and 4 had already been identified and reported in PMID:25644381.
Family 2, two brothers, had a micro deletion of exon 2, their mother was heterozygous for the same micro deletion.
Family 3, two half-siblings (p.Arg286Ter) Their unaffected mother was heterozygous for the same deletion, a hetrozygous sister was mildly disabled.
No further segregation information for the two families was reported.
Some functional work performed but only for the frameshift variant that was reported in family 1.
Requesting support from clinical team as limited information on the extended families and the female affected in family 3 is the only heterozygous carrier who displays ID features.
Intellectual disability v2.977 FRMPD4 Catherine Snow changed review comment from: Further paper identified to indicated FRMPD4 is relevant to ID. PMID: 29267967 provides details of four unrelated families, two families, family 1 and 4 had already been identified and reported in PMID:25644381.
Family 2, two brothers, had a micro deletion of exon 2, their mother was hetrozygous for the same micro deletion.
Family 3, two half-siblings, p.Arg286Ter . Their unaffected mother was heterozygous for the same deletion, a hetrozygous sister was mildly disabled.
No further segregation information for the two families was reported
Some functional work on mice performed.
Requesting support from clinical team as limited information on the extended families and the female affected in family 3 is the only hetrozygous carrier who displays ID features.; to: Further paper identified to indicated FRMPD4 is relevant to ID. PMID: 29267967 provides details of four unrelated families, two families, family 1 and 4 had already been identified and reported in PMID:25644381.
Family 2, two brothers, had a micro deletion of exon 2, their mother was heterozygous for the same micro deletion.
Family 3, two half-siblings (p.Arg286Ter) Their unaffected mother was heterozygous for the same deletion, a hetrozygous sister was mildly disabled.
No further segregation information for the two families was reported.
Some functional work performed but only for the frameshift variant that was reported in family 1.
Requesting support from clinical team as limited information on the extended families and the female affected in family 3 is the only hetrozygous carrier who displays ID features.
Intellectual disability v2.977 FRMPD4 Catherine Snow changed review comment from: Further paper identified to indicated FRMPD4 is relevant to ID. PMID: 29267967 provides details of four unrelated families, two families, family 1 and 4 had already been identified and reported in PMID:25644381.
Family 2, two brothers, had a micro deletion of exon 2, their mother was hetrozygous for the same micro deletion
Family 3, two half-siblings, p.Arg286Ter . Their unaffected mother was heterozygous for the same deletion, a hetrozygous sister was mildly disabled.
No further segregation information for the two families was reported
Some functional work on mice performed.
Requesting support from clinical team as limited information on the extended families and the female affected in family 3 is the only hetrozygous carrier who displays ID features.; to: Further paper identified to indicated FRMPD4 is relevant to ID. PMID: 29267967 provides details of four unrelated families, two families, family 1 and 4 had already been identified and reported in PMID:25644381.
Family 2, two brothers, had a micro deletion of exon 2, their mother was hetrozygous for the same micro deletion.
Family 3, two half-siblings, p.Arg286Ter . Their unaffected mother was heterozygous for the same deletion, a hetrozygous sister was mildly disabled.
No further segregation information for the two families was reported
Some functional work on mice performed.
Requesting support from clinical team as limited information on the extended families and the female affected in family 3 is the only hetrozygous carrier who displays ID features.
Intellectual disability v2.977 FRMPD4 Catherine Snow changed review comment from: PMID: 29267967 provides details of four unrelated families, two families, family 1 and 4 had already been identified and reported in PMID:25644381.
Family 2, two brothers, had a micro deletion of exon 2, their mother was hetrozygous for the same micro deletion
Family 3, two half-siblings, p.Arg286Ter . Their unaffected mother was heterozygous for the same deletion, a hetrozygous sister was mildly disabled.
No further segregation information for the two families was reported
Some functional work on mice performed.
Requesting support from clinical team as limited information on the extended families and the female affected in family 3 is the only hetrozygous carrier who displays ID features.; to: Further paper identified to indicated FRMPD4 is relevant to ID. PMID: 29267967 provides details of four unrelated families, two families, family 1 and 4 had already been identified and reported in PMID:25644381.
Family 2, two brothers, had a micro deletion of exon 2, their mother was hetrozygous for the same micro deletion
Family 3, two half-siblings, p.Arg286Ter . Their unaffected mother was heterozygous for the same deletion, a hetrozygous sister was mildly disabled.
No further segregation information for the two families was reported
Some functional work on mice performed.
Requesting support from clinical team as limited information on the extended families and the female affected in family 3 is the only hetrozygous carrier who displays ID features.
Intellectual disability v2.977 FRMPD4 Catherine Snow reviewed gene: FRMPD4: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v2.977 KIF2A Catherine Snow changed review comment from: Three further cases identified in the literature.
PMID:27747449 (Cavallin et al 2017) detected two de novo p.Ser317Asn and p.His321Pro mutations in KIF2A in two patients with lissencephaly and microcephaly. Case 1 had DD, no epilepsy but was only 9 months old at last reporting. Case 2 had neonatal seizures and severe DD.
PMID:27896282 (Tian et al 2016) report a patient with lissencephaly, developmental delay, and infantile spasms, due to de novo heterozygous variant in KIF2A (p.Thr320Ile).

Therefore upgrading rating from Amber to Green as now sufficient (>3) unrelated cases.; to: Three further cases identified in the literature.
PMID:27747449 (Cavallin et al 2017) detected two de novo p.Ser317Asn and p.His321Pro mutations in KIF2A in two patients with lissencephaly and microcephaly. Case 1 had DD, no epilepsy but was only 9 months old at last reporting. Case 2 had neonatal seizures and severe DD.
PMID:27896282 (Tian et al 2016) report a patient with lissencephaly, developmental delay, and infantile spasms, due to de novo heterozygous variant in KIF2A (p.Thr320Ile).
Most cases identified have epilepsy first however as one individual did not have seizures KIF2A is relevant for the ID panel.
Therefore upgrading rating from Amber to Green as now sufficient (>3) unrelated cases.
Intellectual disability v2.977 DLG4 Catherine Snow Publications for gene: DLG4 were set to 27479843; 25123844; 19617690; 29460436; 23020937; 28135719
Intellectual disability v2.976 DLG4 Catherine Snow Phenotypes for gene: DLG4 were changed from to Intellectual disability; Marfanoid habitus
Intellectual disability v2.976 DLG4 Catherine Snow Publications for gene: DLG4 were set to 27479843; 25123844; 19617690; 29460436; 23020937; 28135719
Intellectual disability v2.976 DLG4 Catherine Snow Publications for gene: DLG4 were set to 27479843; 25123844; 19617690
Intellectual disability v2.975 DLG4 Catherine Snow reviewed gene: DLG4: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v2.975 KIF2A Catherine Snow Classified gene: KIF2A as Green List (high evidence)
Intellectual disability v2.975 KIF2A Catherine Snow Gene: kif2a has been classified as Green List (High Evidence).
Intellectual disability v2.974 KIF2A Catherine Snow commented on gene: KIF2A
Intellectual disability v2.974 KIF2A Catherine Snow Phenotypes for gene: KIF2A were changed from Cortical dysplasia, complex, with other brain malformations 3, 615411 to Cortical dysplasia, complex, with other brain malformations 3, 615411
Intellectual disability v2.973 KIF2A Catherine Snow Phenotypes for gene: KIF2A were changed from Cortical dysplasia, complex, with other brain malformations 3, 615411 to Cortical dysplasia, complex, with other brain malformations 3, 615411
Intellectual disability v2.973 KIF2A Catherine Snow Phenotypes for gene: KIF2A were changed from MALFORMATIONS OF CORTICAL DEVELOPMENT AND MICROCEPHALY. to Cortical dysplasia, complex, with other brain malformations 3, 615411
Intellectual disability v2.972 KIF2A Catherine Snow Publications for gene: KIF2A were set to 23603762; 21594994; 27747449; 27896282
Intellectual disability v2.971 KIF2A Catherine Snow Publications for gene: KIF2A were set to 23603762; 21594994; 27747449; 27896282
Intellectual disability v2.971 KIF2A Catherine Snow Publications for gene: KIF2A were set to 23603762; 21594994
Intellectual disability v2.970 CYP27A1 Catherine Snow reviewed gene: CYP27A1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v2.970 CYP27A1 Catherine Snow Publications for gene: CYP27A1 were set to 24442603; 29484516
Intellectual disability v2.970 CYP27A1 Catherine Snow Publications for gene: CYP27A1 were set to
Intellectual disability v2.969 GRIA2 Catherine Snow changed review comment from: GRIA2 has been associated with ID in PMID: 31300657. The authors identified 28 unrelated individuals who had heterozygous de novo GRIA2 mutations. All individuals had experienced DD and moderate to severe ID, except 2 who had died at a young age. Epilepsy was identified in at least 10 individuals.
Multiple de-novo intragenic variants including missense (n = 15), splice-site (n = 2), in-frame deletion (n = 1), stop-gain (n = 1) and frameshift (n = 2) variants were reported. In all patients with intragenic variants they were first identified by WES, WGS or massively parallel targeted sequencing and confirmed as de-novo by trio Sanger sequencing. Also a further three patients were identified with a microdeletion involving GRIA2 using micro array analysis.

GRIA2 is currently not associated with a disease in OMIM or Gene2Phenotype and this is the first time that GRIA2 has been reported to be associated with ID but other AMPA receptors, GRIA3, and GRIA4 are Green on the ID panel.
Therefore there is not sufficient number of unrelated individuals and evidence to make GRIA2 Green.; to: GRIA2 has been associated with ID in PMID: 31300657. The authors identified 28 unrelated individuals who had heterozygous de novo GRIA2 mutations. All individuals had experienced DD and moderate to severe ID, except 2 who had died at a young age. Epilepsy was identified in at least 10 individuals.
Multiple de-novo intragenic variants including missense (n = 15), splice-site (n = 2), in-frame deletion (n = 1), stop-gain (n = 1) and frameshift (n = 2) variants were reported. In all patients with intragenic variants they were first identified by WES, WGS or massively parallel targeted sequencing and confirmed as de-novo by trio Sanger sequencing. Also a further three patients were identified with a microdeletion involving GRIA2 using micro array analysis.

GRIA2 is currently not associated with a disease in OMIM or Gene2Phenotype and this is the first time that GRIA2 has been reported to be associated with ID but other AMPA receptors, GRIA3, and GRIA4 are Green on the ID panel.
Therefore there is now sufficient number of unrelated individuals and evidence to make GRIA2 Green.
Intellectual disability v2.969 GRIA2 Catherine Snow Classified gene: GRIA2 as Green List (high evidence)
Intellectual disability v2.969 GRIA2 Catherine Snow Gene: gria2 has been classified as Green List (High Evidence).
Intellectual disability v2.968 GRIA2 Catherine Snow reviewed gene: GRIA2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v2.968 GRIA2 Catherine Snow Publications for gene: GRIA2 were set to 28725178; 26350204; 24896178; 22669415; 28630856
Intellectual disability v2.967 SHANK1 Chris Buxton commented on gene: SHANK1
Intellectual disability v2.967 DEGS1 Rebecca Foulger Phenotypes for gene: DEGS1 were changed from Leukodystrophy hypomyelinating 18, MIM 618404) to Leukodystrophy hypomyelinating 18, MIM 618404); developmental delay
Intellectual disability v2.966 DEGS1 Rebecca Foulger Classified gene: DEGS1 as Green List (high evidence)
Intellectual disability v2.966 DEGS1 Rebecca Foulger Added comment: Comment on list classification: DEGS1 was added to the panel and rated Green by Konstantinos Varvagiannis. Developmental delay and/or ID is a common phenotype (and initial presentation) of the Leukodystrophy. Sufficient cases from multiple papers (PMIDs:30620338,30620337,31186544) to support inclusion on the panel.
Intellectual disability v2.966 DEGS1 Rebecca Foulger Gene: degs1 has been classified as Green List (High Evidence).
Intellectual disability v2.965 DEGS1 Rebecca Foulger commented on gene: DEGS1: PMID:30620338: Karsai et al., 2019 identified a homozygous p.Ala280Val variant in DEGS1 in a Turkish patient of consanguineous parents. Both parents and healthy siblings were heterozygous carriers of the variant. Leading symptoms were early-onset developmental delay, movement disorder, progressive spasticity, and epilepsy.
Intellectual disability v2.965 DEGS1 Rebecca Foulger commented on gene: DEGS1: PMID:31186544: Dolgin et al., 2019 describe four individuals from a consanguineous family. All four had mild to severe ID, spastic quadriplegia, scoliosis and epilepsy in most. WES identified a homozygous missense variant in DEGS1 (in isoforms N219S, N255S).
Intellectual disability v2.965 DEGS1 Rebecca Foulger commented on gene: DEGS1
Intellectual disability v2.965 ATN1 Catherine Snow Phenotypes for gene: ATN1 were changed from Generalized hypotonia; Global developmental delay; Intellectual disability; Seizures; Feeding difficulties; Abnormality of the cardiovascular system; Cleft palate; Abnormality of the kidney to Generalized hypotonia; Global developmental delay; Intellectual disability; Seizures; Feeding difficulties; Abnormality of the cardiovascular system; Cleft palate; Abnormality of the kidney
Intellectual disability v2.965 ATN1 Catherine Snow Phenotypes for gene: ATN1 were changed from Dentatorubro-pallidoluysian atrophy 125370 to Generalized hypotonia; Global developmental delay; Intellectual disability; Seizures; Feeding difficulties; Abnormality of the cardiovascular system; Cleft palate; Abnormality of the kidney
Intellectual disability v2.964 ATN1 Catherine Snow Publications for gene: ATN1 were set to 24972706; 30827498
Intellectual disability v2.964 ATN1 Catherine Snow Publications for gene: ATN1 were set to 24972706
Intellectual disability v2.963 ATN1 Catherine Snow changed review comment from: As reviewed on the Genetic epilepsy syndromes (Version 1.178). Advice from the clinical team was that as phenotype is relevant it can be rated as Green.

Konstantinos Varvagiannis reviewed Palmer et al. (2019 - PMID: 30827498) who describes 8 individuals all with de novo variants in a specific and highly evolutionary conserved histidine-rich 16 amino acid motif encoded by exon 7 of ATN1. The pedigree analysis showed that all individuals are unrelated with different ancestry, all except one had undergone trio sequencing.

All individuals have DD/ID and 5/8 have seizures therefore making it applicable to the epilepsy panel. ATN1 is in OMIM but is associated with the STR, it is in Gene2Phenotype as probable based on this paper.

ATN1_CAG STR is Green in a large number of panels and there are a number of publications associated with the STR. This is the first publication where variants within the gene and not the STR have been associated with this phenotype; to: As reviewed on the Genetic epilepsy syndromes (Version 1.178). Advice from the clinical team was that as phenotype is relevant it can be rated as Green.

Konstantinos Varvagiannis reviewed Palmer et al. (2019 - PMID: 30827498) who describes 8 individuals all with de novo variants in a specific and highly evolutionary conserved histidine-rich 16 amino acid motif encoded by exon 7 of ATN1. The pedigree analysis showed that all individuals are unrelated with different ancestry, all except one had undergone trio sequencing.

All individuals have DD/ID. ATN1 is in OMIM but is associated with the STR, it is in Gene2Phenotype as probable based on this paper.

ATN1_CAG STR is Green in a large number of panels and there are a number of publications associated with the STR. This is the first publication where variants within the gene and not the STR have been associated with this phenotype
Intellectual disability v2.963 ATN1 Catherine Snow Mode of pathogenicity for gene: ATN1 was changed from to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Intellectual disability v2.962 ATN1 Catherine Snow Classified gene: ATN1 as Green List (high evidence)
Intellectual disability v2.962 ATN1 Catherine Snow Gene: atn1 has been classified as Green List (High Evidence).
Intellectual disability v2.962 ATN1 Catherine Snow Classified gene: ATN1 as Green List (high evidence)
Intellectual disability v2.962 ATN1 Catherine Snow Gene: atn1 has been classified as Green List (High Evidence).
Intellectual disability v2.961 ATN1 Catherine Snow reviewed gene: ATN1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v2.961 KCNJ11 Rebecca Foulger Publications for gene: KCNJ11 were set to
Intellectual disability v2.960 KCNJ11 Rebecca Foulger Added comment: Comment on mode of inheritance: Changed MOI from BIALLELIC to BOTH monoallelic and biallelic, based on most papers in the literature reporting heterozygous activating variants in KCNJ11 with DD/ID as features: (e.g. PMIDs 25678012, 16670688, 27681997, 28943513).
Intellectual disability v2.960 KCNJ11 Rebecca Foulger Mode of inheritance for gene: KCNJ11 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v2.959 ATRX Rebecca Foulger Added comment: Comment on mode of inheritance: Changed Mode of inheritance from XLR to XLD: Alpha-thalassemia/mental retardation syndrome, 301040 is listed as XLD in OMIM (in addition to Mental retardation-hypotonic facies syndrome, X-linked, 309580 listed as XLR). Although PMID:17503331 report that nearly all female carriers of ATRX syndrome have highly skewed X-chromosome inactivation in favour of cells expressing the normal ATRX allele and are essentially phenotypically normal, PMID:16955409 report a female carrier where the chromosome carrying the mutant allele was active and she therefore showed a phenotype.
Intellectual disability v2.959 ATRX Rebecca Foulger Mode of inheritance for gene: ATRX was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Intellectual disability v2.958 ATRX Rebecca Foulger Publications for gene: ATRX were set to 25529582; 24896178; 26860117; 26997013; 10995512; 7697714; 12116232; 15565397; 8644709; 9244431; 9598720
Intellectual disability v2.957 ATRX Rebecca Foulger commented on gene: ATRX: PMID:16955409: Badens et al. 2006 report a 4 year old female with a heterozygous R246C variant in ATRX and a skewed pattern of X-inactivation where her maternally-inherited X chromosome that carried the de novo variant remained active. Clinical features included severed DD.
Intellectual disability v2.957 ATRX Rebecca Foulger commented on gene: ATRX
Intellectual disability v2.957 ATRX Rebecca Foulger Phenotypes for gene: ATRX were changed from Alpha-thalassemia/mental retardation syndrome, 301040Alpha-thalassemia myelodysplasia syndrome, somatic, 300448Mental retardation-hypotonic facies syndrome, X-linked, 309580; MENTAL RETARDATION SYNDROMIC X-LINKED WITH HYPOTONIC FACIES SYNDROME TYPE 1 (MRXSHF1) to Alpha-thalassemia/mental retardation syndrome, 301040; Mental retardation-hypotonic facies syndrome, X-linked, 309580
Intellectual disability v2.956 ATRX Rebecca Foulger Publications for gene: ATRX were set to
Intellectual disability v2.955 SLC9A6 Rebecca Foulger Publications for gene: SLC9A6 were set to
Intellectual disability v2.954 SLC9A6 Rebecca Foulger changed review comment from: Comment on mode of inheritance: Changed the MOI from XLR to XLD based on Pescosolido et al., 2014 (PMID:25044251) who report mild to moderate ID in heterozygous female carriers.; to: Comment on mode of inheritance: Changed the MOI from XLR to XLD based on Pescosolido et al., 2014 (PMID:25044251) who report mild to moderate ID in heterozygous female carriers. Note that NHE6 is an alias for SLC9A6.
Intellectual disability v2.954 SLC9A6 Rebecca Foulger Added comment: Comment on mode of inheritance: Changed the MOI from XLR to XLD based on Pescosolido et al., 2014 (PMID:25044251) who report mild to moderate ID in heterozygous female carriers.
Intellectual disability v2.954 SLC9A6 Rebecca Foulger Mode of inheritance for gene: SLC9A6 was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Intellectual disability v2.953 CTBP1 Chris Buxton reviewed gene: CTBP1: Rating: GREEN; Mode of pathogenicity: Other; Publications: 27094857, 31041561; Phenotypes: intellectual disability, ataxia, hypotonia, tooth enamel defect; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v2.953 DEGS1 Konstantinos Varvagiannis gene: DEGS1 was added
gene: DEGS1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: DEGS1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DEGS1 were set to 30620337; 30620338; 31186544
Phenotypes for gene: DEGS1 were set to Leukodystrophy hypomyelinating 18, MIM 618404)
Penetrance for gene: DEGS1 were set to Complete
Review for gene: DEGS1 was set to GREEN
Added comment: Several individuals with biallelic pathogenic DEGS1 variants have been reported to date, in the following studies :
[1] Pant et al. 2019 (PMID: 30620337) : 19 patients from 13 unrelated families
[2] Karsai et al. 2019 (PMID: 30620338) : 1 individual
[3] Dolgin et al. 2019 (PMID: 31186544) : 4 individuals belonging to a large consanguineous kindred

As summarized in the first article and OMIM, affected individuals may have very poor psychomotor development, dystonia, spasticity, seizures with hypomyelinating leukodystrophy upon brain imaging and/or progressive atrophy of corpus callosum, thalami and cerebellum. Although a severe form overall was reported for many individuals in the first study, variable severity (eg. mild to severe ID) was reported among individuals belonging to the same kindred in the report by Dolgin et al.

DEGS1 encodes Δ4-dehydroceramide desaturase which catalyzes conversion of dihydroceramide (DhCer) to ceramide (Cer) in the de novo ceramide biosynthetic pathway. Ceramide is the central unit of all sphingolipids, which are components of cellular membranes and play key roles in several processes incl. cell differentiation, neuronal signaling and myelin sheath formation.

Sphingolipid balance is important for the CNS as demonstrated in the case of lysosomal disorders (eg. Gaucher, Niemann Pick, Farber) one enzymatic step away from DEGS1.

Variants of all types (missense, stopgain, frameshift) have been reported with the majority/almost all located in the fatty acid desaturase (FAD) domain.

Extensive studies have been carried out and demonstrated:
- impaired DEGS1 activity in patients' fibroblasts and muscle suggested by increased DhCer/Cer ratio and compatible broader biochemical effects (higher levels of dihydrosphingosine, dihydrosphingomyelins, etc. and lower levels of sphingosine, monohexosylceramides, etc).
- increased ROS production in patient fibroblasts (similar to a Drosophila model of excess DhCer),
- high expression of the gene in child and adult CNS tissues from control individuals (evaluated by RT-qPCR in Ref. 1). A previous study has suggested that DEGS1 expression is upregulated during the 4-9th week of human embryogenesis (PMID cited: 20430792) which may suggest an important role for neural system development.
- decreased expression for some variants either evaluated at the mRNA (RT-qPCR) / protein level (by Western Blot)
- In zebrafish loss of Degs1 resulted in increased DhCer/Cer ratio, locomotor disability and impaired myelination similar to the patients' phenotype. Fingolimod, a sphingosine analog inhibiting Cer synthase (one step prior to DEGS1 in the de novo ceramide biosynthesis pathway, and converting sphingosine to ceramide in the salvage pathway) reduced the DhCer/Cer imbalance, ameliorated the locomotor phenotype and increased the number of myelinating oligodendrocytes in zebrafish, while it reduced the ROS levels in patient fibroblasts.

Previous animal models:
Apart from the zebrafish model (Pant et al.), higher DhCer/Cer ratios have been shown in homozygous Degs1 -/- mice similar to what is also observed in D. melanogaster. As summarized in MGI (and the previous studies as well) "mice homozygous for a knock-out allele exhibit premature death, decreased to absent ceramide levels, decreased body weight, scaly skin, sparse hair, tremors, hematological and blood chemistry abnormalities, decreased bone mineral content and density and decreased liver function." (PMIDs cited: 17339025, 28507162).
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The respective OMIM entry is Leukodystrophy, hypomyelinating, 18 (#618404). DEGS1 is not associated with any phenotype in G2P.
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As a result, DEGS1 can be considered for inclusion in the ID and epilepsy panels probably as green (relevant phenotype, sufficient number of individuals, supportive expression and biochemical studies, animal models, etc).
Sources: Literature
Intellectual disability v2.953 PIGB Konstantinos Varvagiannis gene: PIGB was added
gene: PIGB was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: PIGB was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PIGB were set to 31256876
Phenotypes for gene: PIGB were set to 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
Penetrance for gene: PIGB were set to Complete
Review for gene: PIGB was set to GREEN
Added comment: Murakami et al. (2019 - PMID: 31256876) provide detailed information on 14 individuals from 10 families (4 of which consanguineous) with biallelic pathogenic PIGB variants.

Overlapping features included DD/ID (13/13), epilepsy (14/14), deafness (7/14), ophthalmological or brain anomalies, hand and feet anomalies as well as presence of dysmorphic features. ID was common, in those individuals with appropriate age. Some had a previous diagnosis of DOORS syndrome (deafness/onychodystrophy/osteodystrophy,retardation, seizures) and few showed 2-oxoglutatic aciduria which can also be seen in DOORS s.

PIGB encodes phosphatidylinositol glycan anchor biosynthesis class B protein.

Overall the phenotype was similar to other inherited glycosylphosphatidylinositol (GPI) deficiencies (IGDs). As happens to be the case in some other GPI deficiencies alkaline phosphatase was also elevated in those tested (8/9).

8 missense, 1 stopgain as well as an intronic SNV are reported. All variants were either absent or ultra-rare and with no homozygotes in gnomAD.

Affected individuals from 4 families, harbored an intronic SNV in the homozygous state. For this variant - with MAF of 0.0001592 or 6.51x10-5 in ExAC and gnomAD - activation of an aberrant splice acceptor site was shown [NM_004855.4:c.847-10A>G or p.Gln282_Trp283insArgCysGln].

Flow cytometric analysis of blood cells or fibroblasts showed decreased levels for various GPI-AP (GPI-anchored protein) markers in affected individuals. These levels were rescued upon transduction with a PIGB-encoding-Lx304 lentiviral vector of fibroblasts from one affected individual, suggesting that the PIGB defect was responsible.

The effect of the variants was evaluated using PIGB-deficient CHO cells, transfected with wt or mutant PIGB cDNAs. FACS analysis and immunoblotting demonstrated that variants were able to restore only slightly/partially - if at all - the surface presence of GPI-APs in the case of variants while the levels of mutant protein were reduced.

PIGB is not associated with any phenotype in OMIM/G2P. This gene 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 ID and epilepsy panels probably as green (or amber).
Sources: Literature
Intellectual disability v2.953 DEAF1 Rebecca Foulger Phenotypes for gene: DEAF1 were changed from MENTAL RETARDATION, AUTOSOMAL DOMINANT 24 to MENTAL RETARDATION, AUTOSOMAL DOMINANT 24; ?Dyskinesia, seizures, and intellectual developmental disorder, 617171; Mental retardation, autosomal dominant 24, 615828
Intellectual disability v2.952 DEAF1 Rebecca Foulger Added comment: Comment on mode of inheritance: Changed the MOI from 'MONOALLELIC' to 'BOTH monoallelic and biallelic' based on PMID:30923367. Nabais et al., 2019 investigated AD and AR DEAF1 variants in a cohort of 23 patients. With the exception of microcephaly, most phenotypes (including ID, DD and seizures) were reported in patients with biallelic and pathogenic de novo DEAF1 variants.
Intellectual disability v2.952 DEAF1 Rebecca Foulger Mode of inheritance for gene: DEAF1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v2.951 POU3F3 Konstantinos Varvagiannis gene: POU3F3 was added
gene: POU3F3 was added to Intellectual disability. Sources: Literature,Radboud University Medical Center, Nijmegen
Mode of inheritance for gene: POU3F3 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: POU3F3 were set to https://doi.org/10.1016/j.ajhg.2019.06.007; 24550763
Phenotypes for gene: POU3F3 were set to Generalized hypotonia; Delayed speech and language development; Global developmental delay; Intellectual disability; Autistic behavior
Penetrance for gene: POU3F3 were set to unknown
Review for gene: POU3F3 was set to GREEN
gene: POU3F3 was marked as current diagnostic
Added comment: Snijders Blok et al. (2019, DOI: https://doi.org/10.1016/j.ajhg.2019.06.007) report on 19 individuals with heterozygous POU3F3 variants.

Features included hypotonia in some, DD/ID (19/19) with impairment in speech and language skills, and autism-like symptoms with formal ASD diagnosis in 7(/19). Epilepsy was reported for 2 individuals. Overlapping facial features were noted among these individuals.

POU3F3 encodes a member of the class III POU family of transcription factors expressed in the central nervous system (Sumiyama et al. 1996, PMID: 8703082 cited in OMIM) and as the authors comment holds a role in regulation of key processes, eg. cortical neuronal migration, upper-layer specification and production and neurogenesis (PMIDs cited: 11859196, 12130536, 22892427, 17141158).

In almost all subjects (17/19) the variant had occurred as a de novo event, while one individual had inherited the variant from a similarly affected parent.

In total 12 nonsense/frameshift variants, 5 missense ones as well as 1 in-frame deletion were identified following (mostly) trio exome sequencing. All variants were absent from gnomAD, with in silico predictions in favour of pathogenicity.

The few missense variants and the in-frame deletion were found either in the POU-specific (NM_006236.2:c.1085G>T / p.Arg362Leu found in 2 subjects) or the POU-homeobox domain (where 2 variants affected the same residue, namely p.Arg407Gly/Leu, the other variant was p.Asn456Ser).

POU3F3 is an intronless gene and as a result truncating variants are not subject to NMD. The gene appears to be intolerant to LoF variants (pLI of 0.89 in gnomAD).

Western blot analysis of YFP-tagged POU3F3 variants (in HEK293 cell lysates) showed that the YFP-fusion proteins were expressed and had the expected molecular weights.

For several truncating variants tested as well as the in-frame deletion, aberrant subcellular localization pattern was demonstrated although this was not the case for 4 missense variants.

In vitro studies were carried out and suggested that POU3F3, as is known to be the case for POU3F2, is able to activate an intronic binding site in FOXP2. Using a luciferase assay, transcriptional activation was severely impaired for truncating variants tested, significantly lower for many missense ones with the exception of those affecting Arg407 in which case luciferase expression was either similar to wt (for Arg407Gly) or even increased in the case of Arg407Leu.

As the authors comment, both loss- and gain- of function mechanisms may underly pathogenicity of variants.

The ability of mutant proteins to form dimers either with wt or themselves was tested. Dimerization capacity was intact for most missense variants but was lost/decreased for truncating variants. The in-frame deletion resulted in impaired dimerization with wt, although homo-dimerization was found to be normal.
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Dheedene et al. (2014 - PMID: 24550763) had previously reported on a boy with ID. aCGH had demonstrated a de novo 360-kb deletion of 2q12.1 spanning only POU3F3 and MRPS9 the latter encoding a mitochondrial ribosomal protein (which would be most compatible with a - yet undescribed - recessive inheritance pattern / disorder).
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POU3F3 is not associated with any phenotype in OMIM/G2P.
The gene is included in gene panels for ID offered by some diagnostic laboratories (incl. Radboudumc, among the principal authors of the study).
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As a result POU3F3 seems to fulfill criteria for inclusion in the current panel probably as green [DD/ID was a universal feature - severity of ID was relevant in 5/10 individuals for whom details were available, functional evidence provided] or amber.
Sources: Literature, Radboud University Medical Center, Nijmegen
Intellectual disability v2.951 NEXMIF Rebecca Foulger Publications for gene: NEXMIF were set to
Intellectual disability v2.950 NEXMIF Rebecca Foulger Added comment: Comment on mode of inheritance: Changed MOI from XLR to XLD to match the XLD recorded for 'Mental retardation, X-linked 98' in OMIM (MIM:300912) and Gene2Phenotype, which records X-linked dominant inheritance for 'Intellectual disability and epilepsy' in addition to hemizgyous inheritance for 'KIAA2022'. An XLD inheritance is supported by PMID:27358180 which reports 14 female patients who carry a heterozygous de novo NEXMIF (KIAA2022) variant and share a phenotype characterised by intellectual disability and epilepsy.
Intellectual disability v2.950 NEXMIF Rebecca Foulger Mode of inheritance for gene: NEXMIF was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Intellectual disability v2.949 HK1 Ivone Leong Classified gene: HK1 as Green List (high evidence)
Intellectual disability v2.949 HK1 Ivone Leong Added comment: Comment on list classification: Promoted from red to green. This gene is associated with a phenotype in OMIM but not in Gene2Phenotype. There are sufficient cases for this gene to be promote to green status. Variants on the 5' end of the gene have been associated with neuropathy, hereditary motor and sensory, Russe type.
Intellectual disability v2.949 HK1 Ivone Leong Gene: hk1 has been classified as Green List (High Evidence).
Intellectual disability v2.948 HK1 Ivone Leong Added comment: Comment on mode of pathogenicity: A gain of function effect is presumed to cause disease.
Intellectual disability v2.948 HK1 Ivone Leong Mode of pathogenicity for gene: HK1 was changed from to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Intellectual disability v2.947 HK1 Ivone Leong Phenotypes for gene: HK1 were changed from Hemolytic anemia due to hexokinase deficiency, 235700; Neuropathy, hereditary motor and sensory, Russe type, 605285 to Hemolytic anemia due to hexokinase deficiency, 235700; Neuropathy, hereditary motor and sensory, Russe type, 605285; Abnormal muscle tone; Global developmental delay; Intellectual disability; Visual impairment; Neurological speech impairment; Ataxia
Intellectual disability v2.946 HK1 Ivone Leong Publications for gene: HK1 were set to
Intellectual disability v2.945 HK1 Ivone Leong Tag missense tag was added to gene: HK1.
Intellectual disability v2.945 NDUFAF5 Ivone Leong Classified gene: NDUFAF5 as Amber List (moderate evidence)
Intellectual disability v2.945 NDUFAF5 Ivone Leong Added comment: Comment on list classification: Promoted from red to amber. This gene is associated with a relevant phenotype in OMIM but not in Gene2Phenotype. After discussion with the Genomics England Clinical Team it was decided that there is currently not enough evidence to promote this gene to green. The clinical presentations reported in the papers are not classical for an ID cohort (except perhaps patient 1 in the Ashkenzi Jewish families). Therefore, this gene has been promoted to amber until further evidence emerges.
Intellectual disability v2.945 NDUFAF5 Ivone Leong Gene: ndufaf5 has been classified as Amber List (Moderate Evidence).
Intellectual disability v2.944 SMARCD1 Ivone Leong Classified gene: SMARCD1 as Green List (high evidence)
Intellectual disability v2.944 SMARCD1 Ivone Leong Added comment: Comment on list classification: Promoted from red to green. SMARCD1 is not associated with any phenotype in OMIM or Gene2Phenotype. After consulting with the Genomics England Clinical Team and based on the submitted expert review, it was decided that there is enough evidence to promote this gene to green status.
Intellectual disability v2.944 SMARCD1 Ivone Leong Gene: smarcd1 has been classified as Green List (High Evidence).
Intellectual disability v2.943 SMARCD1 Ivone Leong Mode of inheritance for gene: SMARCD1 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v2.942 SMARCD1 Ivone Leong Phenotypes for gene: SMARCD1 were changed from to Generalized hypotonia; Feeding difficulties; Global developmental delay; Intellectual disability; Abnormality of the hand; Abnormality of the foot
Intellectual disability v2.941 CTBP1 Rebecca Foulger Phenotypes for gene: CTBP1 were changed from Generalized hypotonia; Global developmental delay; Intellectual disability; Ataxia; Abnormality of dental enamel to Hypotonia, ataxia, developmental delay, and tooth enamel defect syndrome, 617915
Intellectual disability v2.940 TRPM3 Rebecca Foulger Classified gene: TRPM3 as Amber List (moderate evidence)
Intellectual disability v2.940 TRPM3 Rebecca Foulger Added comment: Comment on list classification: TRPM3 was added to the panel and rated Green by Konstantinos Varvagiannis based on PMID:31278393 (Dyment et al 2019). Although 8 probands were reported, 1 proband carries a VUS and an additional splice variant in DDB1. Therefore only variant is pathogenic, and this is missense, and de novo in all cases. The authors also note that heterozygous LOF variants in TRPM3 are observed in the general population. Not yet associated with a disorder in Gene2Phenotype or OMIM. Therefore have rated Amber and added 'watchlist' tag awaiting further cases or additional functional studies.
Intellectual disability v2.940 TRPM3 Rebecca Foulger Gene: trpm3 has been classified as Amber List (Moderate Evidence).
Intellectual disability v2.939 TRPM3 Rebecca Foulger Tag missense tag was added to gene: TRPM3.
Tag watchlist tag was added to gene: TRPM3.
Intellectual disability v2.939 TRPM3 Rebecca Foulger Publications for gene: TRPM3 were set to doi.org/10.1038/s41431-019-0462-x
Intellectual disability v2.938 TRPM3 Rebecca Foulger commented on gene: TRPM3
Intellectual disability v2.938 CTBP1 Konstantinos Varvagiannis changed review comment from: 12 individuals with a recurrent missense variant in CTBP1 have been reported, all summarized in the last article:
- Beck et al. 2016 (PMID: 27094857) : 4 individuals
- Sommerville et al. 2017 (PMID: 28955726) : 1 subject
- Beck et al. 2019 (PMID: 31041561) : 7 further individuals

Features included hypotonia, DD/ID, ataxia and tooth enamel defects. The degree of ID - when present - appeared to be highly variable based at least on the first two reports (3 individuals with severe ID, 1 with borderline-normal intellectual functioning, 1 did not exhibit ID) where this feature was further commented on.

A recurrent missense variant was found in all 12 affected individuals [NM_001328.2:c.1024C>T - p.(Arg342Trp) or NM_001012614.1:c.991C>T - p.(Arg331Trp)]. De novo occurrence this SNV was shown for (almost) all individuals, although in one case maternal sequencing reads were compatible with low-level somatic mosaicism (4/75 reads) not detected by Sanger sequencing. The mother of this individual was phenotypically normal. The variant is absent from gnomAD. Several in silico predictions (SIFT, PolyPhen2, MutationTaster, etc) suggest a deleterious effect.

Given recurrence of this specific variant, and presence of LoF ones in healthy individuals (pLI of 0.98 though in gnomAD) Beck et al. suggested a dominant negative or a gain-of-function effect rather than a loss of function mechanism.

Exclusion of alternative causes: was mainly discussed for the subject reported by Sommerville et al., due to the primary suspicion of a mitochondrial disorder (sequencing and research for mtDNA rearrangements, additional analysis of nuclear genes for mitochondrial disorders).

Expression: CTBP1 encodes C-terminal binding protein 1, with expression among others in brain and cerebellum (https://gtexportal.org/home/gene/CTBP1).

Role and Functional studies:
- The major nuclear isoform of CTBP1 (corresponding to NM_001328.2) and of its paralog CTBP2 function as transcriptional regulators (corepressors). The PLDLS(Pro-Leu-Asp-Leu-Ser)-binding cleft domain where this variant lies, acts as a high-affinity protein-binding interface to recruit DNA-binding repressors and chromatin modifying enzymes (PMID: 17967884).
- In a human glioblastoma cell line interaction of various cofactors with (Flag-tagged) CTBP1 was studied by immunoprecitipation with the Flag antibody and subsequent proteomic (LC-MS) analysis. This demonstrated reduced interaction in the case of R342W (compared to wt) with Zn-finger transcription factors, histone deacetylases, histone methyltransferases, histone H3-K4 demethylase etc. Western blot analyses also revealed reduced interaction of the R342W with several CTBP cofactors.
- RNA-seq analysis in glioblastoma cell line revealed similar overall transcriptional profiles between wt and R342W though multiple RNA species showed significant differences (eg. genes involved in the biological processes of mitotic nuclear division, DNA repair, transcription and regulation of transcription among those that were most upregulated and genes involved in brain development among the most downregulated).
- Patient fibroblasts under conditions of glucose deprivation exhibited strikingly more cell death compared to control fibroblasts. Study of mRNA levels of pro-apoptotic genes by q-RT-PCR revealed that Noxa expression under glucose deprivation vs under normal glucose was 8 to 10-fold enhanced for control fibroblasts, but more than 30-fold enhanced in the case patient fibroblasts. Western blot analyses were also in line with this.
- Mitochondrial dysfunction (probably secondary) with evidence of decreased complex I (and complex IV) activities in skeletal muscle was the case for 2 individuals among multiple patients who had muscle biopsies.

Animal models:
- Beck et al. discuss previously published mouse models where Ctbp1/2 both play overlapping transcriptional roles during development. Homozygous deletion of Ctbp2 is embryonically lethal (>E10.5). Homozygous deletion of Ctbp1 results in viable mice with reduced size and lifespan (Cited: Hildebrand et al. 2002 - PMID: 12101226)
- As commented on by Sommerville et al., Ctbp1 knockout in mouse embryonic fibroblasts resulted in elongated mitochondria, abnormal mitochondrial cristae, diminished ATP and O2 consumption and mitochondrial membrane potential.

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CTBP1 is associated with Hypotonia, ataxia, developmental delay, and tooth enamel defect syndrome (617915) in OMIM. It is not associated with any phenotype in G2P.
Some diagnostic laboratories (eg. GeneDx participating in the first study and others) include this gene in panels for intellectual disability.
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As a result, CTBP1 can be added in the current panel probably as green.; to: 12 individuals with a recurrent missense variant in CTBP1 have been reported, all summarized in the last article:
- Beck et al. 2016 (PMID: 27094857) : 4 individuals
- Sommerville et al. 2017 (PMID: 28955726) : 1 subject
- Beck et al. 2019 (PMID: 31041561) : 7 further individuals

Features included hypotonia, DD/ID, ataxia and tooth enamel defects. The degree of ID - when present - appeared to be highly variable based at least on the first two reports (3 individuals with severe ID, 1 with borderline-normal intellectual functioning, 1 did not exhibit ID) where this feature was further commented on.

A recurrent missense variant was found in all 12 affected individuals [NM_001328.2:c.1024C>T - p.(Arg342Trp) or NM_001012614.1:c.991C>T - p.(Arg331Trp)]. De novo occurrence this SNV was shown for (almost) all individuals, although in one case maternal sequencing reads were compatible with low-level somatic mosaicism (4/75 reads) not detected by Sanger sequencing. The mother of this individual was phenotypically normal. The variant is absent from gnomAD. Several in silico predictions (SIFT, PolyPhen2, MutationTaster, etc) suggest a deleterious effect.

Given recurrence of this specific variant, and presence of LoF ones in healthy individuals (pLI of 0.98 though in gnomAD) Beck et al. suggested a dominant negative or a gain-of-function effect rather than a loss of function mechanism.

Exclusion of alternative causes: was mainly discussed for the subject reported by Sommerville et al., due to the primary suspicion of a mitochondrial disorder (sequencing and research for mtDNA rearrangements, additional analysis of nuclear genes for mitochondrial disorders).

Expression: CTBP1 encodes C-terminal binding protein 1, with expression among others in brain and cerebellum (https://gtexportal.org/home/gene/CTBP1).

Role and Functional studies:
- The major nuclear isoform of CTBP1 (corresponding to NM_001328.2) and of its paralog CTBP2 function as transcriptional regulators (corepressors). The PLDLS(Pro-Leu-Asp-Leu-Ser)-binding cleft domain where this variant lies, acts as a high-affinity protein-binding interface to recruit DNA-binding repressors and chromatin modifying enzymes (PMID: 17967884).
- In a human glioblastoma cell line interaction of various cofactors with (Flag-tagged) CTBP1 was studied by immunoprecitipation with the Flag antibody and subsequent proteomic (LC-MS) analysis. This demonstrated reduced interaction in the case of R342W (compared to wt) with Zn-finger transcription factors, histone deacetylases, histone methyltransferases, histone H3-K4 demethylase etc. Western blot analyses also revealed reduced interaction of the R342W with several CTBP cofactors.
- RNA-seq analysis in glioblastoma cell line revealed similar overall transcriptional profiles between wt and R342W though multiple RNA species showed significant differences (eg. genes involved in the biological processes of mitotic nuclear division, DNA repair, transcription and regulation of transcription among those that were most upregulated and genes involved in brain development among the most downregulated).
- Patient fibroblasts under conditions of glucose deprivation exhibited strikingly more cell death compared to control fibroblasts. Study of mRNA levels of pro-apoptotic genes by q-RT-PCR revealed that Noxa expression under glucose deprivation vs under normal glucose was 8 to 10-fold enhanced for control fibroblasts, but more than 30-fold enhanced in the case patient fibroblasts. Western blot analyses were also in line with this.
- Mitochondrial dysfunction (probably secondary) with evidence of decreased complex I (and complex IV) activities in skeletal muscle was the case for 2 individuals among multiple patients who had muscle biopsies.

Animal models:
- Beck et al. discuss previously published mouse models where Ctbp1/2 both play overlapping transcriptional roles during development. Homozygous deletion of Ctbp2 is embryonically lethal (>E10.5). Homozygous deletion of Ctbp1 results in viable mice with reduced size and lifespan (Cited: Hildebrand et al. 2002 - PMID: 12101226)
- As commented on by Sommerville et al., Ctbp1 knockout in mouse embryonic fibroblasts resulted in elongated mitochondria, abnormal mitochondrial cristae, diminished ATP and O2 consumption and mitochondrial membrane potential (Cited: Kim and Youn 2009 - PMID: 19136938).

----
CTBP1 is associated with Hypotonia, ataxia, developmental delay, and tooth enamel defect syndrome (617915) in OMIM. It is not associated with any phenotype in G2P.
Some diagnostic laboratories (eg. GeneDx participating in the first study and others) include this gene in panels for intellectual disability.
----

As a result, CTBP1 can be added in the current panel probably as green.
Intellectual disability v2.938 CTBP1 Konstantinos Varvagiannis reviewed gene: CTBP1: 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: 27094857, 28955726, 31041561; Phenotypes: Hypotonia, ataxia, developmental delay, and tooth enamel defect syndrome (MIM 617915); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Intellectual disability v2.938 CTBP1 Konstantinos Varvagiannis Deleted their review
Intellectual disability v2.938 CTBP1 Konstantinos Varvagiannis changed review comment from: 12 individuals with a recurrent missense variant in CTBP1 have been reported, all summarized in the last article:
- Beck et al. 2016 (PMID: 27094857) : 4 individuals
- Sommerville et al. 2017 (PMID: 28955726) : 1 subject
- Beck et al. 2019 (PMID: 31041561) : 7 further individuals

Features included hypotonia, DD/ID, ataxia and tooth enamel defects. The degree of ID - when present - appeared to be highly variable based at least on the first two reports (3 individuals with severe ID, 1 with borderline-normal intellectual functioning, 1 did not exhibit ID) where this feature was further commented on.

A recurrent missense variant was found in all 12 affected individuals [NM_001328.2:c.1024C>T - p.(Arg342Trp) or NM_001012614.1:c.991C>T - p.(Arg331Trp)]. De novo occurrence this SNV was shown for (almost) all individuals, although in one case maternal sequencing reads were compatible with low-level somatic mosaicism (4/75 reads) not detected by Sanger sequencing. The mother of this individual was phenotypically normal. The variant is absent from gnomAD. Several in silico predictions (SIFT, PolyPhen2, MutationTaster, etc) suggest a deleterious effect.

Given recurrence of this specific variant, and presence of LoF ones in healthy individuals (pLI of 0.98 though in gnomAD) Beck et al. suggested a dominant negative or a gain-of-function effect rather than a loss of function mechanism.

Exclusion of alternative causes: was mainly discussed for the subject reported by Sommerville et al., due to the primary suspicion of a mitochondrial disorder (sequencing and research for mtDNA rearrangements, additional analysis of nuclear genes for mitochondrial disorders).

Expression: CTBP1 encodes C-terminal binding protein 1, with expression among others in brain and cerebellum (https://gtexportal.org/home/gene/CTBP1 ).

Role and Functional studies:
- The major nuclear isoform of CTBP1 (corresponding to NM_001328.2) and of its paralog CTBP2 function as transcriptional regulators (corepressors). The PLDLS(Pro-Leu-Asp-Leu-Ser)-binding cleft domain where this variant lies, acts as a high-affinity protein-binding interface to recruit DNA-binding repressors and chromatin modifying enzymes (PMID: 17967884).
- In a human glioblastoma cell line interaction of various cofactors with (Flag-tagged) CTBP1 was studied by immunoprecitipation with the Flag antibody and subsequent proteomic (LC-MS) analysis. This demonstrated reduced interaction in the case of R342W (compared to wt) with Zn-finger transcription factors, histone deacetylases, histone methyltransferases, histone H3-K4 demethylase etc. Western blot analyses also revealed reduced interaction of the R342W with several CTBP cofactors.
- RNA-seq analysis in glioblastoma cell line revealed similar overall transcriptional profiles between wt and R342W though multiple RNA species showed significant differences (eg. genes involved in the biological processes of mitotic nuclear division, DNA repair, transcription and regulation of transcription among those that were most upregulated and genes involved in brain development among the most downregulated).
- Patient fibroblasts under conditions of glucose deprivation exhibited strikingly more cell death compared to control fibroblasts. Study of mRNA levels of pro-apoptotic genes by q-RT-PCR revealed that Noxa expression under glucose deprivation vs under normal glucose was 8 to 10-fold enhanced for control fibroblasts, but more than 30-fold enhanced in the case patient fibroblasts. Western blot analyses were also in line with this.
- Mitochondrial dysfunction (probably secondary) with evidence of decreased complex I (and complex IV) activities in skeletal muscle was the case for 2 individuals among multiple patients who had muscle biopsies.

Animal models:
- Beck et al. discuss previously published mouse models where Ctbp1/2 both play overlapping transcriptional roles during development. Homozygous deletion of Ctbp2 is embryonically lethal (>E10.5). Homozygous deletion of Ctbp1 results in viable mice with reduced size and lifespan (Cited: Hildebrand et al. 2002 - PMID: 12101226)
- As commented on by Sommerville et al., Ctbp1 knockout in mouse embryonic fibroblasts resulted in elongated mitochondria, abnormal mitochondrial cristae, diminished ATP and O2 consumption and mitochondrial membrane potential.

----
CTBP1 is associated with Hypotonia, ataxia, developmental delay, and tooth enamel defect syndrome (617915) in OMIM. It is not associated with any phenotype in G2P.
Some diagnostic laboratories (eg. GeneDx participating in the first study and others) include this gene in panels for intellectual disability.
----

As a result, CTBP1 can be added in the current panel probably as green.
Sources: Literature; to: 12 individuals with a recurrent missense variant in CTBP1 have been reported, all summarized in the last article:
- Beck et al. 2016 (PMID: 27094857) : 4 individuals
- Sommerville et al. 2017 (PMID: 28955726) : 1 subject
- Beck et al. 2019 (PMID: 31041561) : 7 further individuals

Features included hypotonia, DD/ID, ataxia and tooth enamel defects. The degree of ID - when present - appeared to be highly variable based at least on the first two reports (3 individuals with severe ID, 1 with borderline-normal intellectual functioning, 1 did not exhibit ID) where this feature was further commented on.

A recurrent missense variant was found in all 12 affected individuals [NM_001328.2:c.1024C>T - p.(Arg342Trp) or NM_001012614.1:c.991C>T - p.(Arg331Trp)]. De novo occurrence this SNV was shown for (almost) all individuals, although in one case maternal sequencing reads were compatible with low-level somatic mosaicism (4/75 reads) not detected by Sanger sequencing. The mother of this individual was phenotypically normal. The variant is absent from gnomAD. Several in silico predictions (SIFT, PolyPhen2, MutationTaster, etc) suggest a deleterious effect.

Given recurrence of this specific variant, and presence of LoF ones in healthy individuals (pLI of 0.98 though in gnomAD) Beck et al. suggested a dominant negative or a gain-of-function effect rather than a loss of function mechanism.

Exclusion of alternative causes: was mainly discussed for the subject reported by Sommerville et al., due to the primary suspicion of a mitochondrial disorder (sequencing and research for mtDNA rearrangements, additional analysis of nuclear genes for mitochondrial disorders).

Expression: CTBP1 encodes C-terminal binding protein 1, with expression among others in brain and cerebellum (https://gtexportal.org/home/gene/CTBP1).

Role and Functional studies:
- The major nuclear isoform of CTBP1 (corresponding to NM_001328.2) and of its paralog CTBP2 function as transcriptional regulators (corepressors). The PLDLS(Pro-Leu-Asp-Leu-Ser)-binding cleft domain where this variant lies, acts as a high-affinity protein-binding interface to recruit DNA-binding repressors and chromatin modifying enzymes (PMID: 17967884).
- In a human glioblastoma cell line interaction of various cofactors with (Flag-tagged) CTBP1 was studied by immunoprecitipation with the Flag antibody and subsequent proteomic (LC-MS) analysis. This demonstrated reduced interaction in the case of R342W (compared to wt) with Zn-finger transcription factors, histone deacetylases, histone methyltransferases, histone H3-K4 demethylase etc. Western blot analyses also revealed reduced interaction of the R342W with several CTBP cofactors.
- RNA-seq analysis in glioblastoma cell line revealed similar overall transcriptional profiles between wt and R342W though multiple RNA species showed significant differences (eg. genes involved in the biological processes of mitotic nuclear division, DNA repair, transcription and regulation of transcription among those that were most upregulated and genes involved in brain development among the most downregulated).
- Patient fibroblasts under conditions of glucose deprivation exhibited strikingly more cell death compared to control fibroblasts. Study of mRNA levels of pro-apoptotic genes by q-RT-PCR revealed that Noxa expression under glucose deprivation vs under normal glucose was 8 to 10-fold enhanced for control fibroblasts, but more than 30-fold enhanced in the case patient fibroblasts. Western blot analyses were also in line with this.
- Mitochondrial dysfunction (probably secondary) with evidence of decreased complex I (and complex IV) activities in skeletal muscle was the case for 2 individuals among multiple patients who had muscle biopsies.

Animal models:
- Beck et al. discuss previously published mouse models where Ctbp1/2 both play overlapping transcriptional roles during development. Homozygous deletion of Ctbp2 is embryonically lethal (>E10.5). Homozygous deletion of Ctbp1 results in viable mice with reduced size and lifespan (Cited: Hildebrand et al. 2002 - PMID: 12101226)
- As commented on by Sommerville et al., Ctbp1 knockout in mouse embryonic fibroblasts resulted in elongated mitochondria, abnormal mitochondrial cristae, diminished ATP and O2 consumption and mitochondrial membrane potential.

----
CTBP1 is associated with Hypotonia, ataxia, developmental delay, and tooth enamel defect syndrome (617915) in OMIM. It is not associated with any phenotype in G2P.
Some diagnostic laboratories (eg. GeneDx participating in the first study and others) include this gene in panels for intellectual disability.
----

As a result, CTBP1 can be added in the current panel probably as green.
Sources: Literature
Intellectual disability v2.938 CTBP1 Konstantinos Varvagiannis gene: CTBP1 was added
gene: CTBP1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: CTBP1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CTBP1 were set to 27094857; 28955726; 31041561
Phenotypes for gene: CTBP1 were set to Generalized hypotonia; Global developmental delay; Intellectual disability; Ataxia; Abnormality of dental enamel
Penetrance for gene: CTBP1 were set to unknown
Mode of pathogenicity for gene: CTBP1 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: CTBP1 was set to GREEN
gene: CTBP1 was marked as current diagnostic
Added comment: 12 individuals with a recurrent missense variant in CTBP1 have been reported, all summarized in the last article:
- Beck et al. 2016 (PMID: 27094857) : 4 individuals
- Sommerville et al. 2017 (PMID: 28955726) : 1 subject
- Beck et al. 2019 (PMID: 31041561) : 7 further individuals

Features included hypotonia, DD/ID, ataxia and tooth enamel defects. The degree of ID - when present - appeared to be highly variable based at least on the first two reports (3 individuals with severe ID, 1 with borderline-normal intellectual functioning, 1 did not exhibit ID) where this feature was further commented on.

A recurrent missense variant was found in all 12 affected individuals [NM_001328.2:c.1024C>T - p.(Arg342Trp) or NM_001012614.1:c.991C>T - p.(Arg331Trp)]. De novo occurrence this SNV was shown for (almost) all individuals, although in one case maternal sequencing reads were compatible with low-level somatic mosaicism (4/75 reads) not detected by Sanger sequencing. The mother of this individual was phenotypically normal. The variant is absent from gnomAD. Several in silico predictions (SIFT, PolyPhen2, MutationTaster, etc) suggest a deleterious effect.

Given recurrence of this specific variant, and presence of LoF ones in healthy individuals (pLI of 0.98 though in gnomAD) Beck et al. suggested a dominant negative or a gain-of-function effect rather than a loss of function mechanism.

Exclusion of alternative causes: was mainly discussed for the subject reported by Sommerville et al., due to the primary suspicion of a mitochondrial disorder (sequencing and research for mtDNA rearrangements, additional analysis of nuclear genes for mitochondrial disorders).

Expression: CTBP1 encodes C-terminal binding protein 1, with expression among others in brain and cerebellum (https://gtexportal.org/home/gene/CTBP1 ).

Role and Functional studies:
- The major nuclear isoform of CTBP1 (corresponding to NM_001328.2) and of its paralog CTBP2 function as transcriptional regulators (corepressors). The PLDLS(Pro-Leu-Asp-Leu-Ser)-binding cleft domain where this variant lies, acts as a high-affinity protein-binding interface to recruit DNA-binding repressors and chromatin modifying enzymes (PMID: 17967884).
- In a human glioblastoma cell line interaction of various cofactors with (Flag-tagged) CTBP1 was studied by immunoprecitipation with the Flag antibody and subsequent proteomic (LC-MS) analysis. This demonstrated reduced interaction in the case of R342W (compared to wt) with Zn-finger transcription factors, histone deacetylases, histone methyltransferases, histone H3-K4 demethylase etc. Western blot analyses also revealed reduced interaction of the R342W with several CTBP cofactors.
- RNA-seq analysis in glioblastoma cell line revealed similar overall transcriptional profiles between wt and R342W though multiple RNA species showed significant differences (eg. genes involved in the biological processes of mitotic nuclear division, DNA repair, transcription and regulation of transcription among those that were most upregulated and genes involved in brain development among the most downregulated).
- Patient fibroblasts under conditions of glucose deprivation exhibited strikingly more cell death compared to control fibroblasts. Study of mRNA levels of pro-apoptotic genes by q-RT-PCR revealed that Noxa expression under glucose deprivation vs under normal glucose was 8 to 10-fold enhanced for control fibroblasts, but more than 30-fold enhanced in the case patient fibroblasts. Western blot analyses were also in line with this.
- Mitochondrial dysfunction (probably secondary) with evidence of decreased complex I (and complex IV) activities in skeletal muscle was the case for 2 individuals among multiple patients who had muscle biopsies.

Animal models:
- Beck et al. discuss previously published mouse models where Ctbp1/2 both play overlapping transcriptional roles during development. Homozygous deletion of Ctbp2 is embryonically lethal (>E10.5). Homozygous deletion of Ctbp1 results in viable mice with reduced size and lifespan (Cited: Hildebrand et al. 2002 - PMID: 12101226)
- As commented on by Sommerville et al., Ctbp1 knockout in mouse embryonic fibroblasts resulted in elongated mitochondria, abnormal mitochondrial cristae, diminished ATP and O2 consumption and mitochondrial membrane potential.

----
CTBP1 is associated with Hypotonia, ataxia, developmental delay, and tooth enamel defect syndrome (617915) in OMIM. It is not associated with any phenotype in G2P.
Some diagnostic laboratories (eg. GeneDx participating in the first study and others) include this gene in panels for intellectual disability.
----

As a result, CTBP1 can be added in the current panel probably as green.
Sources: Literature
Intellectual disability v2.938 TRPM3 Konstantinos Varvagiannis changed review comment from: Dyment et al. (2019 - https://doi.org/10.1038/s41431-019-0462-x) report on 7 unrelated individuals with a recurrent de novo TRPM3 missense variant [NM_020952.4:c.2509G>A - NP_066003.3:p.(Val837Met)] as well as an additional individual with a further de novo missense variant [c.2810C>A or p.(Pro937Gln) - same ref. sequences].

Overlapping features included hypotonia (7/8 - in one case mixed tone abnormality), DD/ID (8/8 - all individuals at appropriate age - degree relevant), EEG-confirmed epilepsy (7/8). Autism-like features were observed in 4 (out of 6 for whom this information was reported). Other features were noted in a minority (or were private to certain) of these individuals.

Different clinical types of seizures were reported incl. absence, generalized-toni-clonic, infantile spasms as well as subclinical ones. Onset was in infancy or early childhood.

In all individuals the variant was found following trio exome sequencing.

The first variant fulfilled ACMG criteria to be classified as pathogenic due to it's de novo occurrence, prevalence in affected individuals (>=6 affected individuals and in the same time) absence from population databases, in silico predictions in favour of pathogenicity (PS2, PS4_Moderate, PM2, PP3).

The Pro937Gln variant is however classified as a VUS. The subject harboring this variant had an additional de novo variant in another gene (DDB1) not associated with any phenotype, to date.

Several other genetic causes had previously been ruled out for most individuals by other investigations : aCGH was normal in all, FMR1 testing in 6 subjects, genes (PHF6, MECP2, MCT8) or smaller panels for ID (the latter in 3 subjects), mtDNA or testing of nuclear genes for mitochondrial disorders, etc.

TRPM3 encodes transient receptor potential (TRP) cation channel, subfamily M, member 3. TRP channels are a superfamily of gated cation channels sensitive to various physical or chemical stimuli (Clapham 2003 - PMID: 14654832 cited) eg. temperature or pain.

The gene is highly expressed in the brain in humans and other vertebrates (Grimm et al. 2003 - PMID : 12672799 and GTEx - https://gtexportal.org/home/gene/TRPM3).

Animal models : In rat brain, expression is initially restricted to neurons but later - as myelination progresses - shifts to oligodendrocytes (cited : Hoffmann et al. 2010 - PMID: 20163522). Most subjects had normal brain MRI appart from one individual with nonspecific white matter hyperintensities and another with possible mild cerebral volume loss. Trpm3 -/- mice show attenuated nocifensive behavior after heat or dermal injection of pregnenolone sulfate. Heat or pain insensitivity was reported only for 2 individuals.

Functional studies were not carried out, although some hypotheses are proposed following in silico modeling of the TRPM3 variants using an available structure for TRPM7.

As discussed by Dyment et al., happloinsufficiency appears to be unlikely given the presence of LoF variants in ExAC/gnomAD (pLI of 0), some intragenic copy number variants in DGV. In addition, pathogenicity of deletions spanning only TRPM3 or additional proximal genes was not evident in 2 cases:
- In the first case a exon 1-9 deletion was found in 2 brothers with Becker muscular dystrophy due to DMD intragenic duplication and autism/cognitive impairment though the TRPM3 deletion was found also in unaffected family members. The deletion was also found in unaffected relatives. A multiple hit hypothesis was hypothesized for this family. [Pagnamenta et al. 2011 - PMID: 21484199]
- Kuniba et al. [2009 - PMID: 19343044] reported a 1.27-Mb deletion spanning TRPM3, KLF9, SMC5 and MAMDC2 in a patient with Kabuki syndrome working diagnosis. Segregation studies were however not possible. At the time, the molecular etiology of Kabuki syndrome (KMT2D/KDM6A) was not known.
-----
TRPM3 is not associated with any phenotype in OMIM or G2P.
This gene is included in panels for ID offered by some diagnostic laboratories (eg. GeneDx participating in the above study).
-----
As a result, TRPM3 seems to fulfill criteria for inclusion in the ID/epilepsy panels probably as green (# of individuals, degree of ID relevant, EEG-confirmed epilepsy) or amber (if further functional evidence would be required).

[Please consider eligibility for inclusion in other possibly relevant panels eg. autism, etc].
Sources: Literature; to: Dyment et al. (2019 - https://doi.org/10.1038/s41431-019-0462-x) report on 7 unrelated individuals with a recurrent de novo TRPM3 missense variant [NM_020952.4:c.2509G>A - NP_066003.3:p.(Val837Met)] as well as an additional individual with a further de novo missense variant [c.2810C>A or p.(Pro937Gln) - same ref. sequences].

Overlapping features included hypotonia (7/8 - in one case mixed tone abnormality), DD/ID (8/8 - all individuals at appropriate age - degree relevant), EEG-confirmed epilepsy (7/8). Autism-like features were observed in 4 (out of 6 for whom this information was reported). Other features were noted in a minority (or were private to certain) of these individuals.

Different clinical types of seizures were reported incl. absence, generalized-toni-clonic, infantile spasms as well as subclinical ones. Onset was in infancy or early childhood.

In all individuals the variant was found following trio exome sequencing.

The first variant fulfilled ACMG criteria to be classified as pathogenic due to it's de novo occurrence, prevalence in affected individuals (>=6 affected individuals and in the same time) absence from population databases, in silico predictions in favour of pathogenicity (PS2, PS4_Moderate, PM2, PP3).

The Pro937Gln variant is however also present once in gnomAD (1/251370 alleles or AF:3.98e-6) and is classified as VUS according to the ACMG criteria. The subject harboring this variant had an additional de novo variant in another gene (DDB1) not associated with any phenotype, to date.

Several other genetic causes had previously been ruled out for most individuals by other investigations : aCGH was normal in all, FMR1 testing in 6 subjects, genes (PHF6, MECP2, MCT8) or smaller panels for ID (the latter in 3 subjects), mtDNA or testing of nuclear genes for mitochondrial disorders, etc.

TRPM3 encodes transient receptor potential (TRP) cation channel, subfamily M, member 3. TRP channels are a superfamily of gated cation channels sensitive to various physical or chemical stimuli (Clapham 2003 - PMID: 14654832 cited) eg. temperature or pain.

The gene is highly expressed in the brain in humans and other vertebrates (Grimm et al. 2003 - PMID : 12672799 and GTEx - https://gtexportal.org/home/gene/TRPM3).

Animal models : In rat brain, expression is initially restricted to neurons but later - as myelination progresses - shifts to oligodendrocytes (cited : Hoffmann et al. 2010 - PMID: 20163522). Most subjects had normal brain MRI appart from one individual with nonspecific white matter hyperintensities and another with possible mild cerebral volume loss. Trpm3 -/- mice show attenuated nocifensive behavior after heat or dermal injection of pregnenolone sulfate. Heat or pain insensitivity was reported only for 2 individuals.

Functional studies were not carried out, although some hypotheses are proposed following in silico modeling of the TRPM3 variants using an available structure for TRPM7.

As discussed by Dyment et al., happloinsufficiency appears to be unlikely given the presence of LoF variants in ExAC/gnomAD (pLI of 0), some intragenic copy number variants in DGV. In addition, pathogenicity of deletions spanning only TRPM3 or additional proximal genes was not evident in 2 cases:
- In the first case a exon 1-9 deletion was found in 2 brothers with Becker muscular dystrophy due to DMD intragenic duplication and autism/cognitive impairment though the TRPM3 deletion was found also in unaffected family members. The deletion was also found in unaffected relatives. A multiple hit hypothesis was hypothesized for this family. [Pagnamenta et al. 2011 - PMID: 21484199]
- Kuniba et al. [2009 - PMID: 19343044] reported a 1.27-Mb deletion spanning TRPM3, KLF9, SMC5 and MAMDC2 in a patient with Kabuki syndrome working diagnosis. Segregation studies were however not possible. At the time, the molecular etiology of Kabuki syndrome (KMT2D/KDM6A) was not known.
-----
TRPM3 is not associated with any phenotype in OMIM or G2P.
This gene is included in panels for ID offered by some diagnostic laboratories (eg. GeneDx participating in the above study).
-----
As a result, TRPM3 seems to fulfill criteria for inclusion in the ID/epilepsy panels probably as green (# of individuals, degree of ID relevant, EEG-confirmed epilepsy) or amber (if further functional evidence would be required).

[Please consider eligibility for inclusion in other possibly relevant panels eg. autism, etc].
Sources: Literature
Intellectual disability v2.938 TRPM3 Konstantinos Varvagiannis gene: TRPM3 was added
gene: TRPM3 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: TRPM3 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: TRPM3 were set to doi.org/10.1038/s41431-019-0462-x
Phenotypes for gene: TRPM3 were set to Generalized hypotonia; Global developmental delay; Intellectual disability; Seizures; Autistic behavior
Penetrance for gene: TRPM3 were set to unknown
Mode of pathogenicity for gene: TRPM3 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: TRPM3 was set to GREEN
gene: TRPM3 was marked as current diagnostic
Added comment: Dyment et al. (2019 - https://doi.org/10.1038/s41431-019-0462-x) report on 7 unrelated individuals with a recurrent de novo TRPM3 missense variant [NM_020952.4:c.2509G>A - NP_066003.3:p.(Val837Met)] as well as an additional individual with a further de novo missense variant [c.2810C>A or p.(Pro937Gln) - same ref. sequences].

Overlapping features included hypotonia (7/8 - in one case mixed tone abnormality), DD/ID (8/8 - all individuals at appropriate age - degree relevant), EEG-confirmed epilepsy (7/8). Autism-like features were observed in 4 (out of 6 for whom this information was reported). Other features were noted in a minority (or were private to certain) of these individuals.

Different clinical types of seizures were reported incl. absence, generalized-toni-clonic, infantile spasms as well as subclinical ones. Onset was in infancy or early childhood.

In all individuals the variant was found following trio exome sequencing.

The first variant fulfilled ACMG criteria to be classified as pathogenic due to it's de novo occurrence, prevalence in affected individuals (>=6 affected individuals and in the same time) absence from population databases, in silico predictions in favour of pathogenicity (PS2, PS4_Moderate, PM2, PP3).

The Pro937Gln variant is however classified as a VUS. The subject harboring this variant had an additional de novo variant in another gene (DDB1) not associated with any phenotype, to date.

Several other genetic causes had previously been ruled out for most individuals by other investigations : aCGH was normal in all, FMR1 testing in 6 subjects, genes (PHF6, MECP2, MCT8) or smaller panels for ID (the latter in 3 subjects), mtDNA or testing of nuclear genes for mitochondrial disorders, etc.

TRPM3 encodes transient receptor potential (TRP) cation channel, subfamily M, member 3. TRP channels are a superfamily of gated cation channels sensitive to various physical or chemical stimuli (Clapham 2003 - PMID: 14654832 cited) eg. temperature or pain.

The gene is highly expressed in the brain in humans and other vertebrates (Grimm et al. 2003 - PMID : 12672799 and GTEx - https://gtexportal.org/home/gene/TRPM3).

Animal models : In rat brain, expression is initially restricted to neurons but later - as myelination progresses - shifts to oligodendrocytes (cited : Hoffmann et al. 2010 - PMID: 20163522). Most subjects had normal brain MRI appart from one individual with nonspecific white matter hyperintensities and another with possible mild cerebral volume loss. Trpm3 -/- mice show attenuated nocifensive behavior after heat or dermal injection of pregnenolone sulfate. Heat or pain insensitivity was reported only for 2 individuals.

Functional studies were not carried out, although some hypotheses are proposed following in silico modeling of the TRPM3 variants using an available structure for TRPM7.

As discussed by Dyment et al., happloinsufficiency appears to be unlikely given the presence of LoF variants in ExAC/gnomAD (pLI of 0), some intragenic copy number variants in DGV. In addition, pathogenicity of deletions spanning only TRPM3 or additional proximal genes was not evident in 2 cases:
- In the first case a exon 1-9 deletion was found in 2 brothers with Becker muscular dystrophy due to DMD intragenic duplication and autism/cognitive impairment though the TRPM3 deletion was found also in unaffected family members. The deletion was also found in unaffected relatives. A multiple hit hypothesis was hypothesized for this family. [Pagnamenta et al. 2011 - PMID: 21484199]
- Kuniba et al. [2009 - PMID: 19343044] reported a 1.27-Mb deletion spanning TRPM3, KLF9, SMC5 and MAMDC2 in a patient with Kabuki syndrome working diagnosis. Segregation studies were however not possible. At the time, the molecular etiology of Kabuki syndrome (KMT2D/KDM6A) was not known.
-----
TRPM3 is not associated with any phenotype in OMIM or G2P.
This gene is included in panels for ID offered by some diagnostic laboratories (eg. GeneDx participating in the above study).
-----
As a result, TRPM3 seems to fulfill criteria for inclusion in the ID/epilepsy panels probably as green (# of individuals, degree of ID relevant, EEG-confirmed epilepsy) or amber (if further functional evidence would be required).

[Please consider eligibility for inclusion in other possibly relevant panels eg. autism, etc].
Sources: Literature
Intellectual disability v2.938 DBT Rebecca Foulger commented on gene: DBT
Intellectual disability v2.938 DBT Rebecca Foulger Publications for gene: DBT were set to
Intellectual disability v2.937 TRAPPC12 Louise Daugherty commented on gene: TRAPPC12: Did not upgrade gene on the Genetic Epilepsy Syndromes panel as there was no phenotype of epilepsy in the third case.
Intellectual disability v2.937 USP7 Rebecca Foulger Phenotypes for gene: USP7 were changed from to Intellectual disability, autism, epilepsy, aggressive behaviour, hypotonia, and hypogonadism
Intellectual disability v2.936 USP7 Rebecca Foulger Classified gene: USP7 as Amber List (moderate evidence)
Intellectual disability v2.936 USP7 Rebecca Foulger Gene: usp7 has been classified as Amber List (Moderate Evidence).
Intellectual disability v2.935 USP7 Rebecca Foulger Classified gene: USP7 as Red List (low evidence)
Intellectual disability v2.935 USP7 Rebecca Foulger Added comment: Comment on list classification: USP7 was rated Green by Konstantinos Varvagiannis. Not currently associated with a disorder in OMIM, but has a 'possible' Disease confidence in Gene2Phenotype for the disorder: Intellectual disability, autism, epilepsy, aggressive behaviour, hypotonia, and hypogonadism (based on PMID:26365382). There is now a 2019 paper in addition to PMID:26365382 (PMID:30679821). In total, 22/23 individuals have an ID/DD phenotype, and 23/23 have speech delay. However, the Tyr143Ter variant described by both PMID:26365382 and PMID:30679821 is a VUS, and the microdeletions in other patients cover additional genes (PMID:26365382, Figure 5). Plus three patients in PMID:30679821 harbour variants in additional genes. Therefore although the phenotype is relevant, I have updated the rating from Red to Amber until there is more evidence that USP7 variants are causative.
Intellectual disability v2.935 USP7 Rebecca Foulger Gene: usp7 has been classified as Red List (Low Evidence).
Intellectual disability v2.934 USP7 Rebecca Foulger Mode of inheritance for gene: USP7 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v2.933 USP7 Rebecca Foulger commented on gene: USP7: PMID:30679821: Fountain et al., 2019 report on the clinical and genetic spectrum of 16 new and 7 previously reported (by PMID:26365382) individuals with USP7 heterozygous de novo variants.
The variants include 2 deletions, 3 nonsense, 3 splice site variants and 8 missense variants. Speech delay was seen in 23/23 patients, and ID/DD was seen in 22/23 patients. Note that Patients 18 and 20 harbor additional variants in TMEM106B and SLC2A1, Patient 19 also has a de novo heterozygous 102.5-kb mosaic loss of uncertain significance at 10q21.1.
Intellectual disability v2.933 USP7 Rebecca Foulger commented on gene: USP7
Intellectual disability v2.933 TRAF7 Rebecca Foulger Classified gene: TRAF7 as Green List (high evidence)
Intellectual disability v2.933 TRAF7 Rebecca Foulger Added comment: Comment on list classification: Updated rating from Amber to Green following advice from the Genomics England clinical team that the combination of motor and speech delay would be regarded by many clinicians as equivalent to global developmental delay.
Intellectual disability v2.933 TRAF7 Rebecca Foulger Gene: traf7 has been classified as Green List (High Evidence).
Intellectual disability v2.932 TRAF7 Rebecca Foulger Publications for gene: TRAF7 were set to 29961569; 27479843; 28135719
Intellectual disability v2.931 PIGC Rebecca Foulger Classified gene: PIGC as Amber List (moderate evidence)
Intellectual disability v2.931 PIGC Rebecca Foulger Added comment: Comment on list classification: Updated rating from Red to Amber following external review by Zornitza Stark. Not yet associated with a disorder in OMIM, and two cases in the current literature (PMID:27694521).
Intellectual disability v2.931 PIGC Rebecca Foulger Gene: pigc has been classified as Amber List (Moderate Evidence).
Intellectual disability v2.930 PIGC Rebecca Foulger commented on gene: PIGC
Intellectual disability v2.930 CACNA1B Louise Daugherty Classified gene: CACNA1B as Green List (high evidence)
Intellectual disability v2.930 CACNA1B Louise Daugherty Added comment: Comment on list classification: New gene added by external expert and reviewed by curation team: appropriate phenotype, sufficient cases and external expert review all support gene-disease association and relevance to this panel to rate gene to Green.
Intellectual disability v2.930 CACNA1B Louise Daugherty Gene: cacna1b has been classified as Green List (High Evidence).
Intellectual disability v2.930 PIGC Rebecca Foulger Phenotypes for gene: PIGC were changed from Glycosylphosphatidylinositol biosynthesis defect 16 to Glycosylphosphatidylinositol biosynthesis defect 16, 617816
Intellectual disability v2.929 CACNA1B Louise Daugherty Added comment: Comment on phenotypes: added Progressive Epilepsy-Dyskinesia from PMID:30982612. gene-phenotype currently not listed in OMIM
Intellectual disability v2.929 CACNA1B Louise Daugherty Phenotypes for gene: CACNA1B were changed from Global developmental delay; Developmental regression; Seizures; Intellectual disability; Abnormality of movement to Global developmental delay; Developmental regression; Seizures; Intellectual disability; Abnormality of movement; Progressive Epilepsy-Dyskinesia
Intellectual disability v2.928 CACNA1B Louise Daugherty Added comment: Comment on publications: added publication to support gene-disease association
Intellectual disability v2.928 CACNA1B Louise Daugherty Publications for gene: CACNA1B were set to
Intellectual disability v2.927 ISCA2 Ivone Leong Classified gene: ISCA2 as Amber List (moderate evidence)
Intellectual disability v2.927 ISCA2 Ivone Leong Added comment: Comment on list classification: After consulting with the Genomics England Clinical team it was decided to only promote this gene to amber as the clinical picture is more of a mitochondrial phenotype and is likely to be investigated that way.
Intellectual disability v2.927 ISCA2 Ivone Leong Gene: isca2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v2.926 CWC27 Ivone Leong Classified gene: CWC27 as Green List (high evidence)
Intellectual disability v2.926 CWC27 Ivone Leong Added comment: Comment on list classification: Promoted from red to green. CWC27 is associated with a phenotype in OMIM and Gene2Phenotype. PMID: 28285769 reported on 7 unrelated families (10 affected individuals) with variants in this gene. 8/10 had neurological problems, which include ID, delayed walking, delayed speech or psychomotor retardation. Two cases (same family) are specified as moderate ID and they have indicated severe psychomotor retardation in others. After consulting the Genomics England Clinical Team, it was decided that there is enough evidence to promote this to green status.
Intellectual disability v2.926 CWC27 Ivone Leong Gene: cwc27 has been classified as Green List (High Evidence).
Intellectual disability v2.925 TRAPPC12 Louise Daugherty changed review comment from: Comment on list classification: Appropriate phenotype, sufficient cases due to on unpublished report all support gene-disease association and relevance to this panel to rate gene to Green.; to: Comment on list classification: Appropriate phenotype, sufficient cases due to an unpublished report that supports gene-disease association and relevance to this panel to rate gene from Red to Green.
Intellectual disability v2.925 SMARCD1 Ivone Leong Publications for gene: SMARCD1 were set to 26350204
Intellectual disability v2.924 TRAPPC12 Louise Daugherty Classified gene: TRAPPC12 as Green List (high evidence)
Intellectual disability v2.924 TRAPPC12 Louise Daugherty Added comment: Comment on list classification: Appropriate phenotype, sufficient cases due to on unpublished report all support gene-disease association and relevance to this panel to rate gene to Green.
Intellectual disability v2.924 TRAPPC12 Louise Daugherty Gene: trappc12 has been classified as Green List (High Evidence).
Intellectual disability v2.923 TRAPPC12 Louise Daugherty Phenotypes for gene: TRAPPC12 were changed from Encephalopathy, progressive, early-onset, with brain atrophy and spasticity, 617669 to Encephalopathy, progressive, early-onset, with brain atrophy and spasticity, 617669; Developmental delay
Intellectual disability v2.922 TRAPPC12 Louise Daugherty Publications for gene: TRAPPC12 were set to 28777934
Intellectual disability v2.922 TRAPPC12 Louise Daugherty Phenotypes for gene: TRAPPC12 were changed from to Encephalopathy, progressive, early-onset, with brain atrophy and spasticity, 617669
Intellectual disability v2.921 TRAPPC12 Louise Daugherty Publications for gene: TRAPPC12 were set to
Intellectual disability v2.921 TRAPPC12 Louise Daugherty Mode of inheritance for gene: TRAPPC12 was changed from to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v2.920 TRAPPC12 Louise Daugherty reviewed gene: TRAPPC12: Rating: GREEN; Mode of pathogenicity: None; Publications: 28777934; Phenotypes: Encephalopathy, progressive, early-onset, with brain atrophy and spasticity, 617669; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v2.920 PPP3CA Ivone Leong Classified gene: PPP3CA as Green List (high evidence)
Intellectual disability v2.920 PPP3CA Ivone Leong Added comment: Comment on list classification: Promoted from red to green. PPP3CA is associated with Epileptic encephalopathy, infantile or early childhood, 1 in OMIM and is probably associated with Severe Neurodevelopmental Disease with Seizures
Page navigation in Gene2Phenotype. PMID: 28942967 reported on 6 unrelated individuals from different ethnic backgrounds who have different PPP3CA variants (missense and nonsense) who have severe ID. Therefore, there is enough evidence to promote this gene to green status.
Intellectual disability v2.920 PPP3CA Ivone Leong Gene: ppp3ca has been classified as Green List (High Evidence).
Intellectual disability v2.919 PPP3CA Ivone Leong Phenotypes for gene: PPP3CA were changed from Epileptic encephalopathy, infantile or early childhood, 1 to Epileptic encephalopathy, infantile or early childhood, 1, 617711
Intellectual disability v2.918 PPP1R15B Ivone Leong Classified gene: PPP1R15B as Green List (high evidence)
Intellectual disability v2.918 PPP1R15B Ivone Leong Added comment: Comment on list classification: Promoted from red to green. PPP1R15B is associated with a phenotype in OMIM and possibly associated with a phenotype in Gene2Phenotype. PMID: 26159176, 26307080 reported on 2 unrelated patients (Canadian, Algerian) who have the same missense variant in the PPP1R15B gene. Both patients have ID. PMID:27640355 reported on another case where the patient was compound heterozygous for 2 different variants (1 frameshift and 1 nonsense). The patient also had ID. Therefore, there is enough evidence to promote this gene to green status.
Intellectual disability v2.918 PPP1R15B Ivone Leong Gene: ppp1r15b has been classified as Green List (High Evidence).
Intellectual disability v2.917 PPP1R15B Ivone Leong Phenotypes for gene: PPP1R15B were changed from Microcephaly, short stature, and impaired glucose metabolism 2 to Microcephaly, short stature, and impaired glucose metabolism 2, 616817
Intellectual disability v2.916 PPP1R15B Ivone Leong Publications for gene: PPP1R15B were set to 26159176, 26307080, 27640355
Intellectual disability v2.915 PIGW Ivone Leong Classified gene: PIGW as Green List (high evidence)
Intellectual disability v2.915 PIGW Ivone Leong Added comment: Comment on list classification: Promoted from red to green, based the expert reviews and the evidence that was provided.
Intellectual disability v2.915 PIGW Ivone Leong Gene: pigw has been classified as Green List (High Evidence).
Intellectual disability v2.914 PIGW Ivone Leong Phenotypes for gene: PIGW were changed from Glycosylphosphatidylinositol biosynthesis defect 11 to Glycosylphosphatidylinositol biosynthesis defect 11, 616025
Intellectual disability v2.913 PIGW Ivone Leong Publications for gene: PIGW were set to 24367057, 27626616, 27626616
Intellectual disability v2.912 NDUFAF5 Ivone Leong Phenotypes for gene: NDUFAF5 were changed from Mitochondrial complex 1 deficiency to Mitochondrial complex 1 deficiency, 618238
Intellectual disability v2.911 MTFMT Ivone Leong Phenotypes for gene: MTFMT were changed from Combined oxidative phosphorylation deficiency 15 to Combined oxidative phosphorylation deficiency 15, 614947
Intellectual disability v2.910 NDUFAF5 Ivone Leong Publications for gene: NDUFAF5 were set to 19542079, 21607760, 18940309
Intellectual disability v2.909 MTFMT Ivone Leong Classified gene: MTFMT as Green List (high evidence)
Intellectual disability v2.909 MTFMT Ivone Leong Added comment: Comment on list classification: Promoted from red to green. MTFMT is associated with a phenotype in OMIM but not in Gene2Phenotype. There are >3 unrelated cases of patients who have different variants in this gene who have ID or developmental delay. Therefore, there is enough evidence to promote this gene to green status.
Intellectual disability v2.909 MTFMT Ivone Leong Gene: mtfmt has been classified as Green List (High Evidence).
Intellectual disability v2.908 MTFMT Ivone Leong Publications for gene: MTFMT were set to 24461907; 23499752
Intellectual disability v2.907 MTFMT Ivone Leong Publications for gene: MTFMT were set to 24461907; 23499752; 24461907
Intellectual disability v2.906 MTFMT Ivone Leong Publications for gene: MTFMT were set to 24461907, 23499752, 24461907
Intellectual disability v2.905 KMT5B Ivone Leong Publications for gene: KMT5B were set to 29276005, 28191889, 25363768
Intellectual disability v2.904 CSNK2B Rebecca Foulger Deleted their comment
Intellectual disability v2.904 KLHL7 Ivone Leong Classified gene: KLHL7 as Green List (high evidence)
Intellectual disability v2.904 KLHL7 Ivone Leong Added comment: Comment on list classification: Promoted from red to green. KLHL7 is associated with Cold-induced sweating syndrome 3 (OMIM: 617055) in OMIM and Gene2Phenotype, but not BOS-like phenotype. There are 7 unrelated cases (PMID: 29074562, 30300710) from 5 unrelated families with affected individuals with BOS-like phenotype, global developmental delay and IUGR, who have different variants (nonsense, splicing and small deletions) in the KLHL7 gene.
There is also several cases (PMID: 30142437, being one reported case) of patients with variants in KLHL7 who have phenotypes that overlap Cold-induced sweating syndrome 3 and BOS-like phenotype. This patient also had global developmental delay and a variant different from those reported in PMID: 29074562, 30300710.

Therefore, there is enough evidence to promote this gene to green status.
Intellectual disability v2.904 KLHL7 Ivone Leong Gene: klhl7 has been classified as Green List (High Evidence).
Intellectual disability v2.903 CSNK2B Rebecca Foulger commented on gene: CSNK2B: PMID:30655572: Nakashima et al, 2019 describe 4 patients with ID, DD and seizures. Two of the patients had variants in CSNK2B: c.533_534insGT, p.(Pro179Tyrfs*49) in Malaysian Patient 3, and c.494A>G, p.(His165Arg) in Japanese Patient 4. Both had seizures within 2 months of age. Both variants occurred de novo. In each patient, only 1 likely candidate variant was proposed. Functional assays suggested that Pro179Tyrfs*49 mutant protein was produced but showed disrupted interaction with CSNK2A1.
Intellectual disability v2.903 CSNK2B Rebecca Foulger Publications for gene: CSNK2B were set to 28585349; 28762608
Intellectual disability v2.902 KLHL7 Ivone Leong Publications for gene: KLHL7 were set to 29074562
Intellectual disability v2.901 TCF20 Eleanor Williams Added comment: Comment on phenotypes: Updated as phenotype added to OMIM in May 2019
Intellectual disability v2.901 TCF20 Eleanor Williams Phenotypes for gene: TCF20 were changed from TCF20 syndrome; Intellectual disability; developmental delay to TCF20 syndrome; Intellectual disability; developmental delay; Developmental delay with variable intellectual impairment and behavioral abnormalities 618430
Intellectual disability v2.900 KIF14 Ivone Leong Classified gene: KIF14 as Green List (high evidence)
Intellectual disability v2.900 KIF14 Ivone Leong Added comment: Comment on list classification: Promoted from red to green. KIF14 is associated with a phenotype in OMIM but not in Gene2Phenotype. PMID: 29343805, 28892560 reported on 7 unrelated families with affected members who have moderate to severe ID and have different variants in KIF14. Therefore, there is enough evidence to promote this gene to green status.
Intellectual disability v2.900 KIF14 Ivone Leong Gene: kif14 has been classified as Green List (High Evidence).
Intellectual disability v2.899 KIF14 Ivone Leong Publications for gene: KIF14 were set to 29343805, 28892560
Intellectual disability v2.898 MAPK8IP3 Eleanor Williams Added comment: Comment on phenotypes: OMIM phenotype recently added to OMIM
Intellectual disability v2.898 MAPK8IP3 Eleanor Williams Phenotypes for gene: MAPK8IP3 were changed from Abnormal muscle tone; Global developmental delay; Intellectual disability; Abnormality of nervous system morphology; No OMIM number to Abnormal muscle tone; Global developmental delay; Intellectual disability; Abnormality of nervous system morphology; Neurodevelopmental disorder with or without variable brain abnormalities, 618443
Intellectual disability v2.897 KIF14 Ivone Leong Phenotypes for gene: KIF14 were changed from Microcephaly 20, primary, autosomal recessive to Microcephaly 20, primary, autosomal recessive, 617914
Intellectual disability v2.896 KCTD3 Ivone Leong Publications for gene: KCTD3 were set to 29406573, 27848944, 25558065
Intellectual disability v2.895 KCTD3 Ivone Leong Phenotypes for gene: KCTD3 were changed from to Epilepsy and global developmental delay
Intellectual disability v2.894 KCTD3 Ivone Leong Classified gene: KCTD3 as Green List (high evidence)
Intellectual disability v2.894 KCTD3 Ivone Leong Added comment: Comment on list classification: Promoted from amber to green. No phenotypes are associated with this gene OMIM or Gene2Phenotype.
One study (PMID: 29406573) reported different variants in KCTD3 for 7 probands from 4 consanguineous families who all have epilepsy and global developmental disability. The families are from the same geographical location. The study did show that the variants segregated with the phenotype. Two other large (PMID: 27848944, 25558065) screening studies reported 2 probands with the same frameshift KCTD3 variant who have epilepsy and global developmental disability. This frameshift variant was also found in one of the probands in PMID: 29406573 article.
Intellectual disability v2.894 KCTD3 Ivone Leong Gene: kctd3 has been classified as Green List (High Evidence).
Intellectual disability v2.893 ISCA2 Ivone Leong Tag founder-effect tag was added to gene: ISCA2.
Intellectual disability v2.893 GEMIN4 Ivone Leong Tag founder-effect tag was added to gene: GEMIN4.
Intellectual disability v2.893 ITPA Ivone Leong Classified gene: ITPA as Green List (high evidence)
Intellectual disability v2.893 ITPA Ivone Leong Added comment: Comment on list classification: Promoted from red to green. ITPA is associated with a phenotype in OMIM but not in Gene2Phenotype. There are 5 unrelated families (PMID: 26224535, 30816001) with affected individuals who have global developmental delay with different variants in ITPA. PMID: 19498443 describes a knockout mouse model of Itpa, which had growth retardation. Therefore, there is enough evidence to promote this gene to green status.
Intellectual disability v2.893 ITPA Ivone Leong Gene: itpa has been classified as Green List (High Evidence).
Intellectual disability v2.892 ITPA Ivone Leong Publications for gene: ITPA were set to 26224535; 30816001
Intellectual disability v2.891 ITPA Ivone Leong Publications for gene: ITPA were set to 26224535; 30816001
Intellectual disability v2.891 ITPA Ivone Leong Publications for gene: ITPA were set to 26224535; 30816001
Intellectual disability v2.891 ITPA Ivone Leong Publications for gene: ITPA were set to 26224535
Intellectual disability v2.890 ITPA Ivone Leong Phenotypes for gene: ITPA were changed from Epileptic encephalopathy, early infantile, 35 to Epileptic encephalopathy, early infantile, 35, 616647
Intellectual disability v2.889 ISCA2 Ivone Leong Publications for gene: ISCA2 were set to 25539947; 29297947; 29359243; 29122497; 28356563
Intellectual disability v2.888 ISCA2 Ivone Leong Publications for gene: ISCA2 were set to 25539947, 29297947, 29359243
Intellectual disability v2.887 GEMIN4 Ivone Leong commented on gene: GEMIN4
Intellectual disability v2.887 ISCA2 Ivone Leong Phenotypes for gene: ISCA2 were changed from Multiple mitochondrial dysfunctions syndrome 4 to Multiple mitochondrial dysfunctions syndrome 4, 616370
Intellectual disability v2.886 GEMIN4 Ivone Leong Phenotypes for gene: GEMIN4 were changed from Neurodevelopmental disorder with microcephaly, cataracts, and renal abnormalities to Neurodevelopmental disorder with microcephaly, cataracts, and renal abnormalities, 617913
Intellectual disability v2.885 CWC27 Ivone Leong Phenotypes for gene: CWC27 were changed from Retinitis pigmentosa with or without skeletal anomalies to Retinitis pigmentosa with or without skeletal anomalies, 250410
Intellectual disability v2.884 CUX2 Sarah Leigh Classified gene: CUX2 as Green List (high evidence)
Intellectual disability v2.884 CUX2 Sarah Leigh Added comment: Comment on list classification: Following personal comunication with Gemma Louise Carvill, the variant was confirmed as de novo in all nine cases mentioned in PMID 29630738.
Intellectual disability v2.884 CUX2 Sarah Leigh Gene: cux2 has been classified as Green List (High Evidence).
Intellectual disability v2.883 CHKB Ivone Leong Classified gene: CHKB as Green List (high evidence)
Intellectual disability v2.883 CHKB Ivone Leong Added comment: Comment on list classification: Promoted from red to green based on expert review. CHKB is associated with a phenotype in OMIM but not in Gene2Phenotype. There are >10 unrelated cases with different variants reported in the literature of patients with congenital muscular dystrophy who also have intellectual disability.
Intellectual disability v2.883 CHKB Ivone Leong Gene: chkb has been classified as Green List (High Evidence).
Intellectual disability v2.882 CHKB Ivone Leong Publications for gene: CHKB were set to 21665002
Intellectual disability v2.881 BRD4 Ivone Leong Classified gene: BRD4 as Green List (high evidence)
Intellectual disability v2.881 BRD4 Ivone Leong Added comment: Comment on list classification: New gene added by external expert and reviewed by curation team. Promoted from red to green based on the evidence provided by Konstantinos Varvagiannis (Other). BRD4 is not associated with a phenotype in OMIM and in Gene2Phenotype it is reported to be probably associated with Cornelia de Lange-like syndrome. Intellectual disability (medium to severe) is a phenotype of Cornelia de Lange-like syndrome.
Intellectual disability v2.881 BRD4 Ivone Leong Gene: brd4 has been classified as Green List (High Evidence).
Intellectual disability v2.880 SETD1B Ivone Leong Classified gene: SETD1B as Green List (high evidence)
Intellectual disability v2.880 SETD1B Ivone Leong Added comment: Comment on list classification: Promoted from amber to green as there is now sufficient evidence to support a gene-disease association, based on submitted reviews.
Intellectual disability v2.880 SETD1B Ivone Leong Gene: setd1b has been classified as Green List (High Evidence).
Intellectual disability v2.879 SETD1B Ivone Leong Publications for gene: SETD1B were set to 29322246; 27106595; 25428890
Intellectual disability v2.878 SETD1B Ivone Leong reviewed gene: SETD1B: Rating: GREEN; Mode of pathogenicity: None; Publications: 31110234; Phenotypes: ; Mode of inheritance: None
Intellectual disability v2.878 COL4A3BP Louise Daugherty commented on gene: COL4A3BP
Intellectual disability v2.878 COL4A3BP Louise Daugherty Tag new-gene-name tag was added to gene: COL4A3BP.
Intellectual disability v2.876 MED12L Eleanor Williams Classified gene: MED12L as Amber List (moderate evidence)
Intellectual disability v2.876 MED12L Eleanor Williams Added comment: Comment on list classification: Rating Amber. CNVs encompass other genes. Two cases with SNVs have moderate/severe ID and one of these also has a VUS in TUBB2B. The other two SNV cases have mild ID.
Intellectual disability v2.876 MED12L Eleanor Williams Gene: med12l has been classified as Amber List (Moderate Evidence).
Intellectual disability v2.875 MED12L Eleanor Williams commented on gene: MED12L
Intellectual disability v2.875 KMT5B Eleanor Williams Deleted their comment
Intellectual disability v2.875 KMT5B Eleanor Williams Deleted their comment
Intellectual disability v2.875 CNOT1 Rebecca Foulger Classified gene: CNOT1 as Green List (high evidence)
Intellectual disability v2.875 CNOT1 Rebecca Foulger Added comment: Comment on list classification: Promoted to green on advice from Helen Brittain (Genomics England Clinical Fellow)- there are 3+ cases with a range of causative variants and a relevant phenotype.
Intellectual disability v2.875 CNOT1 Rebecca Foulger Gene: cnot1 has been classified as Green List (High Evidence).
Intellectual disability v2.874 KMT5B Eleanor Williams Phenotypes for gene: KMT5B were changed from Mental retardation, autosomal dominant 51 to Mental retardation, autosomal dominant 51, 617788
Intellectual disability v2.873 KMT5B Eleanor Williams Classified gene: KMT5B as Green List (high evidence)
Intellectual disability v2.873 KMT5B Eleanor Williams Added comment: Comment on list classification: Sufficient cases of patients with ID to rate green
Intellectual disability v2.873 KMT5B Eleanor Williams Gene: kmt5b has been classified as Green List (High Evidence).
Intellectual disability v2.872 KMT5B Eleanor Williams Classified gene: KMT5B as Green List (high evidence)
Intellectual disability v2.872 KMT5B Eleanor Williams Added comment: Comment on list classification: Sufficient cases of patients with ID to rate green
Intellectual disability v2.872 KMT5B Eleanor Williams Gene: kmt5b has been classified as Green List (High Evidence).
Intellectual disability v2.871 KMT5B Eleanor Williams Classified gene: KMT5B as Green List (high evidence)
Intellectual disability v2.871 KMT5B Eleanor Williams Added comment: Comment on list classification: Sufficient cases of patients with ID to rate green
Intellectual disability v2.871 KMT5B Eleanor Williams Gene: kmt5b has been classified as Green List (High Evidence).
Intellectual disability v2.870 KMT5B Eleanor Williams commented on gene: KMT5B
Intellectual disability v2.870 SEPSECS Ivone Leong Classified gene: SEPSECS as Green List (high evidence)
Intellectual disability v2.870 SEPSECS Ivone Leong Added comment: Comment on list classification: Promoted from red to green based on evidence provided by previous review.
Intellectual disability v2.870 SEPSECS Ivone Leong Gene: sepsecs has been classified as Green List (High Evidence).
Intellectual disability v2.869 SEPSECS Ivone Leong gene: SEPSECS was added
gene: SEPSECS was added to Intellectual disability. Sources: Expert Review
Mode of inheritance for gene: SEPSECS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SEPSECS were set to 26805434; 29464431; 28133863; 26115735; 27576344; 26888482
Phenotypes for gene: SEPSECS were set to Pontocerebellar hypoplasia type 2D, 613811
Review for gene: SEPSECS was set to GREEN
Added comment: Submitted on behalf of Professor Sian Ellard (South West Genomic Laboratory Hub), who has a patient with compound heterozygous SEPSECS variants identified through a gene-agnostic trio analysis of the 100,000 Genome Project data.

SEPSECS is associated with a phenotype in OMIM and Gene2Phenotype and it is a green gene in the Genetic epilepsy syndromes panel (v1.56). There are >3 unrelated cases (PMID: 26805434;29464431;28133863;26115735;26888482) of different missense and frameshift variants in this gene associated with patients who are diagnosed with Pontocerebellar hypoplasia type 2D. All patients have profound intellectual disability and some have developmental delay. PMID: 27576344 is a study that looked at the structural porperties of some of the disease-associated variants and found showed that the variants cause reduced stability and increased propensity towards misfolding of the protein.
Sources: Expert Review
Intellectual disability v2.868 PUF60 Leanne Baxter reviewed gene: PUF60: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Syndromic intellectual disability, prenatal onset growth failure, bifid uvula, retinal atrophy, congenital microcephaly, short stature, long fingers, deviation of toes, short thorax; Mode of inheritance: None
Intellectual disability v2.868 KMT2E Eleanor Williams Phenotypes for gene: KMT2E were changed from to Global developmental delay; Intellectual disability; Autism; Seizures; Abnormality of skull size
Intellectual disability v2.867 KMT2E Eleanor Williams Classified gene: KMT2E as Green List (high evidence)
Intellectual disability v2.867 KMT2E Eleanor Williams Added comment: Comment on list classification: Sufficient cases with ID to rate green.
Intellectual disability v2.867 KMT2E Eleanor Williams Gene: kmt2e has been classified as Green List (High Evidence).
Intellectual disability v2.866 KMT2E Eleanor Williams Publications for gene: KMT2E were set to 31079897
Intellectual disability v2.865 KMT2E Eleanor Williams Publications for gene: KMT2E were set to
Intellectual disability v2.864 KMT2E Eleanor Williams commented on gene: KMT2E
Intellectual disability v2.864 KMT2E Eleanor Williams Mode of inheritance for gene: KMT2E was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v2.863 ALKBH8 Catherine Snow Publications for gene: ALKBH8 were set to
Intellectual disability v2.862 USP7 Rebecca Foulger Publications for gene: USP7 were set to
Intellectual disability v2.861 POLA1 Rebecca Foulger Classified gene: POLA1 as Green List (high evidence)
Intellectual disability v2.861 POLA1 Rebecca Foulger Added comment: Comment on list classification: Updated rating from Red to Green based on additional 2019 paper provided by Konstantinos Varvagiannis. PMID:31006512 (Van Esch et al., 2019) report 9 additional males from 5 families hemizygous for POLA1. ID or DD was a feature in all patients (Table 1) and is seen alongside short stature, microcephaly and hypogonadism. The phenotype was distinct from the previously-reported XLPDR. Although the phenotype spectrum is broad for POLA1 variants, there are sufficient cases of ID/DD (>3 from PMID:31006512 and PMID:27019227, with ID/DD being a consistent phenotype in PMID:31006512 individuals), thereby warranting a Green rating.
Intellectual disability v2.861 POLA1 Rebecca Foulger Gene: pola1 has been classified as Green List (High Evidence).
Intellectual disability v2.860 POLA1 Rebecca Foulger Publications for gene: POLA1 were set to 15844784; 27019227; 19377476
Intellectual disability v2.859 POLA1 Rebecca Foulger Phenotypes for gene: POLA1 were changed from Pigmentary disorder, reticulate, with systemic manifestations, X-linked, 301220; XLPDR to Pigmentary disorder, reticulate, with systemic manifestations, X-linked, 301220; XLPDR; X-Linked Intellectual Disability associated with short stature, microcephaly, and hypogonadism
Intellectual disability v2.858 ASH1L Ellen McDonagh Publications for gene: ASH1L were set to 25961944; 26350204; 29276005; 29753921
Intellectual disability v2.857 MED12L Konstantinos Varvagiannis gene: MED12L was added
gene: MED12L was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: MED12L was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: MED12L were set to 31155615
Phenotypes for gene: MED12L were set to Motor delay; Delayed speech and language development; Intellectual disability; Behavioral abnormality; Abnormality of the abdomen; Seizures; Abnormality of the corpus callosum
Penetrance for gene: MED12L were set to unknown
Review for gene: MED12L was set to AMBER
Added comment: Nizon et al. (2019 - PMID: 31155615) report on 7 unrelated individuals with nucleotide or copy-number variants in MED12L.

Features included motor delay (4/7), speech impairment (7/7) with ID of variable degrees (7/7 - mild to severe). Variable behavioral abnormalities (ASD in 4/7, aggressive behavior, ADHD, etc), functional GI anomalies, corpus callosum abnormalities and seizures were among other features noted in some/few. There was no recognizable facial phenotype.

Nucleotide variants included 1 stopgain, 1 frameshift and 2 splice site variants. 3 CNVs were reported (two 3q25.1 microduplications of 460- and 147-kb respectively and one microdeletion of 291-kb) although all spanned also other genes.

De novo occurrence was shown for 2 CNVs and 2 SNVs, as parental samples were unavailable for 3 of the subjects.

Contribution of other genetic (eg. an inherited 22q11.2 microduplication, VUS in other genes) or environmental factors could not be ruled out for few individuals.

Among the arguments provided:

MED12L encodes a subunit of the kinase module of the mediator complex, a complex required for transcription by RNA polymerase II. Mutations in other subunits of the kinase module (eg. MED12, MED13L, etc) have been implicated in intellectual disability.

The protein is localized in the nucleus. The gene is mainly expressed in the brain.

The functional effect of 2 CNVs was evaluated using the recovery of RNA synthesis assay, an assay reflecting global transcriptional activity. Fibrobast studies from one individual with microdeletion and one further subject with microduplication demonstrated decreased RNA synthesis compared to controls. Decreased RNA synthesis was also observed in cell lines from individuals with mutations in other genes for subunits of the mediator complex (eg. MED12 or MED13L) or from individuals with Cockayne syndrome.

Therefore haploinsufficiency is suggested to underly the transcriptional defect. (MED12L also appears to be intolerant to LoF variation with a pLI score of 1).

Some features appear to be common among the disorders caused by pathogenic variants in MED12L or other subunits of the kinase module (MED12, MED13, MED13L) eg. ID, abnormal behaviour or autistic features.

Animal models are not discussed / (probably not) available (MGI for Med12l : http://www.informatics.jax.org/marker/MGI:2139916).

MED12L is not associated with any phenotype in OMIM or G2P. The gene 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 ID panel, probably as amber (4 variants affecting only MED12L, segregation studies performed for 2, degree of ID reported mild on 2 occasions) pending further reports.
Sources: Literature
Intellectual disability v2.857 BCORL1 Rebecca Foulger Tag watchlist tag was added to gene: BCORL1.
Intellectual disability v2.857 BCORL1 Rebecca Foulger Classified gene: BCORL1 as Amber List (moderate evidence)
Intellectual disability v2.857 BCORL1 Rebecca Foulger Added comment: Comment on list classification: Updated rating from Red to Amber based on external review by Konstantinos Varvagiannis and the new paper Shukla et al., 2019 (PMID:30941876). The original Asn820Ser variant from Schuurs-Hoeijmakers et al., 2013 (PMID:24123876) is still listed as a VUS in OMIM due to a lack of evidence for association with the ID phenotype. Although Shukla et al report 3 cases with 3 new BCORL1 variants (two unrelated males and a further three brothers), patient 2 does not have ID, but instead has typical early motor milestones, and speech delay. ID is also mild in Patient 1. Based on 2 clear cases plus 1 potential case from Shukla et al,. I have rated Amber and added a 'watchlist' tag awaiting further reports.
Intellectual disability v2.857 BCORL1 Rebecca Foulger Gene: bcorl1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v2.856 BCORL1 Rebecca Foulger Publications for gene: BCORL1 were set to 24123876; 24896178; 26350204
Intellectual disability v2.855 BCORL1 Rebecca Foulger Phenotypes for gene: BCORL1 were changed from to Intellectual disability, developmental delay and dysmorphism; Behavioral abnormality
Intellectual disability v2.854 BCORL1 Rebecca Foulger Mode of inheritance for gene: BCORL1 was changed from Unknown to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Intellectual disability v2.853 ALKBH8 Konstantinos Varvagiannis gene: ALKBH8 was added
gene: ALKBH8 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: ALKBH8 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: ALKBH8 were set to Global developmental delay; Intellectual disability; Seizures
Penetrance for gene: ALKBH8 were set to Complete
Review for gene: ALKBH8 was set to AMBER
Added comment: Monies et al. (2019 - PMID: 31079898) report on 7 individuals from 2 different consanguineous Saoudi families, harboring homozygous truncating ALKBH8 pathogenic variants. The same individuals are included in another concurrent publication from the same group (Monies et al. 2019 - PMID: 31130284).

All presented with DD and ID (Fam1 : moderate in the proband, degree not commented on for his 3 sibs / Fam2 : mild in the proband, severe in all his 3 sibs). Epilepsy was reported for 6/7 individuals although the type has not been commented on (onset 9-12 months to 2 years). Variable other features were noted in few.

Affected subjects from the first family were homozygous for a stopgain variant (NM_001301010.1:c.1660C>T or p.Arg554Ter) while individuals from the second family were homozygous for a frameshift one (c.1794delC or p.Trp599Glyfs*19). The variants affected in both cases the last exon of ALKBH8 and RT-PCR confirmed that they escape NMD.

Alternative causes were ruled out, at least for the proband from the second family (chromosomal analysis, SNP-array, metabolic investigations).

Linkage analysis of both families confirmed linkage to the same autozygous interval of chr11q22.3 with a LOD score of 6.

Segregation analyses in both families, confirmed homozygosity for the truncating variants in affected members and heterozygosity in their parents (or several unaffected sibs, none of those studied was homozygous for the ref. allele).

In mouse or human cells, ALKBH8 has previously been shown to be involved in tRNA modifications of the wobble uridines of specific tRNAs (PMIDs cited: 20308323, 20583019, 21653555).

LC-MS/MS analyses of tRNA extracted from LCLs derived from affected individuals, unaffected relatives (UR) and independent controls (IC) revealed that wobble nucleotide modifications were completely absent (or dramatically decreased in the case of mcm5U) in affected individuals but readily detected in UR/IC. As specific modifications were absent, substantial amounts of precursors (eg. cm5U - the precursor of mcm5U) were detected in affected individuals but not in unaffected ones.

Absence of wobble modifications (eg. mchm5U) has equally been observed in Alkbh8 knockout mice. Alkbh8-deficient mice show similar increases in precursors. Alkbh8 KO mice are however phenotypically normal (the authors comment that eventual cognitive defects were not formally evaluated and might have been missed - PMIDs cited: 20123966, 21285950).

As a result, the studies carried out confirmed the loss-of-function effect and were in line with previous functional studies in animal models, although the pathogenesis of ID remains unclear.

The expression profile of ALKBH8 is also unclear (wide profile of expression suggested developmentally, the authors studied LCLs, other studies suggest that embryonic expression is broad but becomes progressively more restricted to specific neuronal cells).

Mutations in other genes involved in tRNA modification (eg. ADAT3, PUS3, PUS7) have been shown underlie disorders affecting the CNS, with ID as a feature.

ALKBH8 is not currently associated with any phenotype in OMIM / G2P.

As a result, this gene can be considered for inclusion in the ID/epilepsy panels as amber pending further evidence.
Sources: Literature
Intellectual disability v2.853 AP2M1 Konstantinos Varvagiannis gene: AP2M1 was added
gene: AP2M1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: AP2M1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: AP2M1 were set to 31104773
Phenotypes for gene: AP2M1 were set to Generalized hypotonia; Global developmental delay; Intellectual disability; Seizures; Ataxia; Autistic behavior
Penetrance for gene: AP2M1 were set to Complete
Review for gene: AP2M1 was set to GREEN
Added comment: Helbig et al. (2019 - PMID: 31104773) report on 4 individuals with developmental and epileptic encephalopathy due to a recurrent de novo AP2M1 missense variant (NM_004068.3:c.508C>T or p.Arg170Trp). Seizure types included atonic, myoclonic-atonic, absence seizures (with or without eyelid myoclonia), tonic-clonic etc. Hypotonia, developmental delay (prior to the onset of seizures at 1y 3m to 4y) and intellectual disability were observed in all four. Other features included ataxia (3/4) or autism spectrum disorder (2/4).

AP2M1 encodes the μ-subunit of the adaptor protein complex 2 (AP-2). AP2M1 is highly expressed in the CNS. The AP-2 complex is involved in clathrin-mediated endocytosis at the plasma mebrane of neurons and non-neuronal cells. This mechanism is important for recycling synaptic vesicle components at mammalian central synapses. Previous evidence suggests regulation of GABA and/or glutamate receptors at the neuronal surface by AP-2 (several references provided by Helbig et al.).

The authors provide evidence for impaired (reduced) clathrin-mediated endocytosis of transferrin in AP-2μ-depleted human HeLa cells upon plasmid-based re-expression of the Arg170Trp variant compaired to re-expression of WT. A similar defect was demonstrated upon comparison of the same process when WT and Arg170Trp re-expression was studied in primary astrocytes from conditional AP-2μ knockout mice.

Expression levels, protein stability, membrane recruitment and localization of the AP-2 complex in clathrin-coated pits were similar for the Arg170Trp variant and WT. As a result, the effect of the specific variant is suggested to be mediated by alteration of the AP-2 complex function (/impaired recognition of cargo membrane proteins) rather than haploinsufficiency.

AP2M1 is highly intolerant to missense / LoF variants with z-score and pLI in ExAC of 5.82 and 0.99 respectively.

As the authors discuss, heterozygous Ap2m1 mutant mice do not have an apparent phenotype. Homozygous mutant mice die before day 3.5 postcoitus, suggesting a critical role in early embryonic development (PMID 16227583 cited)

AP2M1 is currently not associated with any phenotype in OMIM / G2P.

As a result, this gene can be considered for inclusion in the epilepsy and ID panels probably as green (4 individuals with highly similar phenotype of DEE, relevance of phenotype and/or degree of ID, functional studies, etc) rather than amber (single recurrent variant - although this is also the case for other genes rated green).
Sources: Literature
Intellectual disability v2.853 EED Louise Daugherty Added comment: Comment on phenotypes: extended phenotype from new publication
Intellectual disability v2.853 EED Louise Daugherty Phenotypes for gene: EED were changed from Cohen-Gibson syndrome 617561 to Cohen-Gibson syndrome, 617561; Human overgrowth syndrome type; Overgrowth with Intellectual disability
Intellectual disability v2.852 EED Louise Daugherty Publications for gene: EED were set to 25787343; 27193220; 27868325; 28229514
Intellectual disability v2.851 CHD8 Louise Daugherty Phenotypes for gene: CHD8 were changed from AUTISM to Overgrowth with Intellectual disability
Intellectual disability v2.850 DOCK3 Rebecca Foulger Publications for gene: DOCK3 were set to 29130632, 28195318; 30976111
Intellectual disability v2.849 DOCK3 Rebecca Foulger Publications for gene: DOCK3 were set to 29130632, 28195318
Intellectual disability v2.848 DOCK3 Rebecca Foulger Classified gene: DOCK3 as Green List (high evidence)
Intellectual disability v2.848 DOCK3 Rebecca Foulger Added comment: Comment on list classification: Updated rating from Red to Green based on external reviews and curation. Zornitza notes two families in her 2018 review: two siblings from Helbig et al., 2017 (PMID:28195318) plus a boy from Iwata-Otsubo et al. (2018, PMID:29130632). Konstantinos' 2019 review includes an additional 2019 paper with 3 unrelated patients harbouring biallelic DOCK3 variants and global developmental delay. Therefore there are now sufficient cases (5 unrelated) for inclusion on the ID panel as Green.
Intellectual disability v2.848 DOCK3 Rebecca Foulger Gene: dock3 has been classified as Green List (High Evidence).
Intellectual disability v2.847 DOCK3 Rebecca Foulger commented on gene: DOCK3: Helbig et al., 2017 (PMID:28195318) report 2 Ashkenazi and Yemeni Jewish siblings with severe developmental disability amongst phenotypes. WES of the siblings identified a heterozygous maternally-inherited c.382C>G (p.Gln128*) plus a paternally-inherited 458kb heterozygous deletion in 3p21.2 (which includes part of DOCK3).

PMID:30976111 (Wiltrout et al., 2019) report 3 unrelated patients with biallelic DOCK3-related global developmental delay (together with dysmorphic features in 2/3 cases).
Intellectual disability v2.847 DOCK3 Rebecca Foulger commented on gene: DOCK3
Intellectual disability v2.847 DYNC1I2 Konstantinos Varvagiannis gene: DYNC1I2 was added
gene: DYNC1I2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: DYNC1I2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DYNC1I2 were set to 31079899
Phenotypes for gene: DYNC1I2 were set to Microcephaly; Intellectual disability; Abnormality of nervous system morphology; Abnormality of head or neck
Penetrance for gene: DYNC1I2 were set to Complete
Review for gene: DYNC1I2 was set to AMBER
Added comment: Ansar et al. (2019 - PMID: 31079899) report on five individuals from 3 families, with biallelic likely pathogenic DYNC1I2 variants.

The phenotype consisted of microcephaly, intellectual disability, cerebral malformations and suggestive facial features. 2/5 individuals, from different families presented seizures.

Affected individuals from a consanguineous Pakistani family were homozygous for a splicing variant (c.607+1G>A - RNA was unavailable for further studies). One individual from a futher family was compound heterozygous for a missense variant (c.740A>G or p.Tyr247Cys) and a 374 kb deletion encompassing DYNC1I2 as well as 3 other genes (DCAF17, CYBRD1, SLC25A12). Another individual was found to harbor c.740A>G (p.Tyr247Cys) in trans with c.868C>T (p.Gln290*). [NM_001378.2 used as reference].

DYNC1I2 encodes Dynein Cytoplasmic 1 intermediate chain 2, a component of the cytoplasmic dynein 1 complex. This complex is involved in retrograde cargo transport within the cytoplasmic microtubule network. Emerging evidence suggests a critical role of this complex in neurodevelopment and homeostasis (PMIDs cited by the authors: 25374356, 28395088). Mutations in other genes encoding components of the complex (principally DYNC1H1) give rise to neurological disorders, some of which with ID as a principal feature (eg. Mental retardation, autosomal dominant 13 - MIM 614563).

In zebrafish, DYNC1I2 has 2 orthologs - dync1i2a and dync1i2b. The former is suggested to be the functionally relevant DYNC1I2 ortholog as CRISPR-Cas9 dync1i2a disruption and/or suppression with morpholinos resulted in altered craniofacial patterning and reduction in head size (similar to the microcephaly phenotype reported in affected individuals).

In vivo complementation studies suggested a loss of function effect for the p.Tyr247Cys variant, similar to the p.Gln290* one.

Evidence is provided for a role of increased apoptosis, probably secondary to altered cell cycle progression (prolonged mitosis due to abnormal spindle morphology), to explain the reduced head size/microcephaly phenotype.

There is no associated phenotype in OMIM/G2P.

As a result, DYNC1I2 could be considered for inclusion in the ID panel probably as amber (ID reported for 5 individuals from 3 families, severity of ID not specified for all, eg. fam. 2 for whom the deletion was also spanning other genes which might contribute to the phenotype).
Sources: Literature
Intellectual disability v2.847 DOCK3 Rebecca Foulger Phenotypes for gene: DOCK3 were changed from to Neurodevelopmental disorder with impaired intellectual development, hypotonia, and ataxia, 618292
Intellectual disability v2.846 ACTL6B Rebecca Foulger Classified gene: ACTL6B as Green List (high evidence)
Intellectual disability v2.846 ACTL6B Rebecca Foulger Added comment: Comment on list classification: Updated rating from Red to Green based on recent review by Konstantinos Varvagiannis which provides additional recent cases from PMIDs:31031012,30656450,26539891 and 30237576. Sufficient unrelated cases with a consistent ID/global developmental delay phenotype to support inclusion on the panel. Plus functional studies in human and mouse cells in PMIDs:31031012,17920018.
Intellectual disability v2.846 ACTL6B Rebecca Foulger Gene: actl6b has been classified as Green List (High Evidence).
Intellectual disability v2.845 ACTL6B Rebecca Foulger commented on gene: ACTL6B: Karaca et al, 2015 (PMID:26539891) report a homozygous variant (NM_016188: c.G893A; p.R298Q) in two siblings BAB6569 and BAB6570 with severe ID, microcephaly, seizures and some autistic behavioral pattern (BAB6570 appears in the text but not table 1).

Sajan et al., 2017 (PMID:27171548) report a homozygous stoploss variant in ACTL6B: c.1279delT (p.X427D) in an ASD case from the DDD study (PMID:25533962) but no other clinical or EEG data was provided.

Maddirevula et al 2019 (PMID:30237576) searched their database on exomes in search of homozygous variants that could be linked to diseases. They identified the homozygous variant NM_016188.4:c.999T>A:p.(Cys333*) in a 13 year old girl (individual 17-1447) with phenotype global developmental delay, vs hyperekplexia, and basal ganglia abnormalities.
Intellectual disability v2.845 ACTL6B Rebecca Foulger commented on gene: ACTL6B: Bell et al., 2019 (PMID:31031012) identified 11 individuals (from 10 families) with biallelic variants in ACTL6B and global developmental delay, epileptic encephalopathy, and spasticity. They also identified 10 unrelated individuals with de novo heterozygous variants with ID, developmental delay, hypotonia, Rett-like stereotypies (e.g. handwringing), and minor facial dysmorphisms: 9/10 of these individuals had the identical de novo c.1027G>A (p.Gly343Arg) mutation. Engineered knock-out of ACTL6B in wild-type human neurons resulted in profound deficits in dendrite development.
Intellectual disability v2.845 ACTL6B Rebecca Foulger Publications for gene: ACTL6B were set to 26350204
Intellectual disability v2.844 ACTL6B Rebecca Foulger Added comment: Comment on mode of inheritance: Most literature report biallelic ACTL6B variants in individuals with developmental delay/intellectual disability but Bell et al., 2019 (PMID:31031012) identify both biallelic and heterozygous variants. Therefore have set MOI to BOTH monoallelic and biallelic.
Intellectual disability v2.844 ACTL6B Rebecca Foulger Mode of inheritance for gene: ACTL6B was changed from Unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v2.843 ACTL6B Rebecca Foulger Added comment: Comment on mode of pathogenicity: Bell et al., 2019 (PMID:31031012) suggest that biallelic variants are loss-of-function, and heterozygous variants are gain-of-function.
Intellectual disability v2.843 ACTL6B Rebecca Foulger Mode of pathogenicity for gene: ACTL6B was changed from to None
Intellectual disability v2.842 ACTL6B Rebecca Foulger Phenotypes for gene: ACTL6B were changed from to Global developmental delay; Intellectual disability
Intellectual disability v2.841 UFC1 Rebecca Foulger Phenotypes for gene: UFC1 were changed from Neurodevelopmental disorder with spasticity and poor growth, 618076 to Neurodevelopmental disorder with spasticity and poor growth, 618076; global developmental delay with progressive microcephaly
Intellectual disability v2.840 UFC1 Rebecca Foulger Publications for gene: UFC1 were set to 29868776; 27431290
Intellectual disability v2.839 UFC1 Rebecca Foulger commented on gene: UFC1: Maddirevula et al 2019 (PMID:30237576) searched their database on exomes in search of homozygous variants that could be linked to diseases. They identified the NM_016406.3:c.317C>T:p.(Thr106Ile) variant in UFC1 in two cases with global DD and progressive microcephaly (17-3196 and 17-3892). Both of these cases were published in Nahorski et al, 2018 (PMID:29868776, Table 1).
Intellectual disability v2.839 UFM1 Rebecca Foulger Tag watchlist tag was added to gene: UFM1.
Intellectual disability v2.839 UFM1 Rebecca Foulger Phenotypes for gene: UFM1 were changed from Leukodystrophy hypomyelinating 14, 617899; global developmental delay to Leukodystrophy hypomyelinating 14, 617899; global developmental delay with progressive microcephaly
Intellectual disability v2.838 UFM1 Rebecca Foulger Publications for gene: UFM1 were set to 28931644; 29868776
Intellectual disability v2.837 UFM1 Rebecca Foulger Classified gene: UFM1 as Amber List (moderate evidence)
Intellectual disability v2.837 UFM1 Rebecca Foulger Added comment: Comment on list classification: UFM1 was added to the ID panel and rated Green by Konstantinos Varvagiannis. Updated rating from Grey to Amber based on literature evidence. Although 20 patients have been reported so far (16 from a Roma population in PMID:28931644 and 4 from 2 Sudanese families in PMID:29868776), the Sudanese families share a haplotype and the variant is suggested to be a Founder variant. The variant in the Roma population (PMID:28931644) is also suggested to be a Founder variant. Therefore only two distinct cases to date. Have added 'watchlist' tag awaiting a further unrelated case.
Intellectual disability v2.837 UFM1 Rebecca Foulger Gene: ufm1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v2.836 UFM1 Rebecca Foulger commented on gene: UFM1: Maddirevula et al 2019 (PMID:30237576) searched their database on exomes in search of homozygous variants that could be linked to diseases. They identified the NM_016617.3:c.241C>T:p.(Arg81Cys) variant in one case with global DD and progressive microcephaly (10DG0945). This case was published in Nahorski et al, 2018 (PMID:29868776, Table 1) so does not offer an additional case.
Intellectual disability v2.836 UFM1 Rebecca Foulger Added comment: Comment on mode of inheritance: Although the original MOI was set to 'BOTH monoallelic and biallelic', I changed the MOI to 'biallelic only' to match OMIM, literature and Konstantinos Varvagiannis' review.
Intellectual disability v2.836 UFM1 Rebecca Foulger Mode of inheritance for gene: UFM1 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v2.835 UFM1 Rebecca Foulger Phenotypes for gene: UFM1 were changed from Leukodystrophy hypomyelinating 14, 617899 to Leukodystrophy hypomyelinating 14, 617899; global developmental delay
Intellectual disability v2.834 UFM1 Rebecca Foulger commented on gene: UFM1: In 4 patients with profound global developmental delay from 2 Sudanese families, Nahorski et al, 2018 (PMID:29868776) identified a homozygous misense variant in the UFM1 gene (R81C). Functional assays showed the mutated protein had decreased ability to form a complex with UBA5 and UFC1, and suggested that a complete LOF allele would be embryonic lethal. Although the Sudanese families were not known to be related, they originate from the same village in Sudan, and families shared a haplotype, suggesting a founder effect. Nahorski et al, 2018 included a comparison of the phenotypes and UFM1 variants from the Hamilton et al., 2017 (PMID:28931644) in Table 2.
Intellectual disability v2.834 UFM1 Rebecca Foulger commented on gene: UFM1
Intellectual disability v2.834 TSEN15 Rebecca Foulger Added comment: Comment on publications: One of the individuals in family II reported by Breuss et al. (PMID:27392077) was previously included in a study by Alazami et al (PMID:25558065).
Intellectual disability v2.834 TSEN15 Rebecca Foulger Publications for gene: TSEN15 were set to 27392077; 25558065
Intellectual disability v2.833 UFC1 Rebecca Foulger commented on gene: UFC1: Added 'watchlist' tag.
Intellectual disability v2.833 UFC1 Rebecca Foulger Tag watchlist tag was added to gene: UFC1.
Intellectual disability v2.833 UFC1 Rebecca Foulger Classified gene: UFC1 as Amber List (moderate evidence)
Intellectual disability v2.833 UFC1 Rebecca Foulger Added comment: Comment on list classification: UFC1 was added to the ID panel and rated Green by Konstantinos Varvagiannis. Changed rating from Grey to Amber based on literature evidence: PMID:29868776 (Nahorski et al. 2018) identified a homozygous missense variant in the UFC1 gene (T106I) in 7 affected members of 3 consanguineous Saudi families. All members displayed Global Developmental delay. Two of the sisters were previously reported by Anazi et al. (2017, PMID:27431290). Although the Saudi families were said to be unrelated, the families shared a haplotype, suggesting a founder effect. An unrelated Swiss boy was found to have a different homozygous variant in the UFC1 gene (R23Q). There are therefore currently two distinct variants/cases. Based on the Founder effect of the three Saudi families, I have rated as Amber awaiting a further unrelated case.
Intellectual disability v2.833 UFC1 Rebecca Foulger Gene: ufc1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v2.832 UFC1 Rebecca Foulger Publications for gene: UFC1 were set to 29868776
Intellectual disability v2.831 TTI2 Rebecca Foulger commented on gene: TTI2: In 3 siblings (two female and one male) born of first-cousin Algerian parents, Langouet et al. (2013, PMID:23956177) identified a homozygous c.1307T-A transversion in the TTI2 gene (I436N). All patients had severe cognitive impairment with severe speech delay and behavioural disturbances, but no seizures were reported.
Intellectual disability v2.831 TTI2 Rebecca Foulger commented on gene: TTI2
Intellectual disability v2.831 TTI2 Rebecca Foulger Phenotypes for gene: TTI2 were changed from AUTOSOMAL RECESSIVE MENTAL RETARDATION to AUTOSOMAL RECESSIVE MENTAL RETARDATION; Mental retardation, autosomal recessive 39, 615541
Intellectual disability v2.830 TTI2 Rebecca Foulger Publications for gene: TTI2 were set to 21937992
Intellectual disability v2.829 TSEN15 Rebecca Foulger Tag watchlist tag was added to gene: TSEN15.
Intellectual disability v2.829 TSEN15 Rebecca Foulger Phenotypes for gene: TSEN15 were changed from Pontocerebellar hypoplasia, type 2F, 617026 to Pontocerebellar hypoplasia, type 2F, 617026; Intellectual disability; delayed developmental milestones
Intellectual disability v2.828 TSEN15 Rebecca Foulger Classified gene: TSEN15 as Amber List (moderate evidence)
Intellectual disability v2.828 TSEN15 Rebecca Foulger Added comment: Comment on list classification: TSEN15 was added to the ID panel and rated Green by Konstantinos Varvagiannis based on PMID:27392077 (Breuss et al., 2016) who report three homozygous TSEN15 variants in four individuals from three families. Affected individuals showed progressive microcephaly, delayed developmental milestones, variable intellectual disability (and in 2 of 4 cases, epilepsy). Although there are three unrelated cases, I have rated TSEN15 as Amber (borderline) for now because The His116Tyr variant found in the two individuals from Family III had no effect on the level of expression of TSEN15 (but may instead result in destabilization of the complex) and the ID is only mild-moderate in Family III. Added a 'watchlist' tag awaiting further cases.
Intellectual disability v2.828 TSEN15 Rebecca Foulger Gene: tsen15 has been classified as Amber List (Moderate Evidence).
Intellectual disability v2.827 TSEN15 Rebecca Foulger Phenotypes for gene: TSEN15 were changed from Pontocerebellar hypoplasia, type 2F (MIM 617026) to Pontocerebellar hypoplasia, type 2F, 617026
Intellectual disability v2.826 TRMT1 Rebecca Foulger commented on gene: TRMT1: Removed 'watchlist' tag following promotion of gene rating from Amber to Green.
Intellectual disability v2.826 TRMT1 Rebecca Foulger Phenotypes for gene: TRMT1 were changed from autosomal recessive intellectual disorder; ARID to autosomal recessive intellectual disorder; ARID; Mental retardation, autosomal recessive 68, 618302; Global developmental delay; Intellectual disability
Intellectual disability v2.825 TRMT1 Rebecca Foulger Publications for gene: TRMT1 were set to 21937992; 26308914
Intellectual disability v2.824 TRMT1 Rebecca Foulger Classified gene: TRMT1 as Green List (high evidence)
Intellectual disability v2.824 TRMT1 Rebecca Foulger Added comment: Comment on list classification: Updated rating from Amber to Green based on the additional recent publication provided by Konstantinos Varvagiannis. PMID:30289604 (Blaesius et al., 2018) report 4 further patients from 2 unrelated consanguineous Pakistani families with homozygous variants in TRMT1 (a 32 bp deletion, and a G>T transversion predicted to result in abberrant splicing and LOF). All four patients had mild-to -moderate intellectual disability. This brings the total number of unrelated cases to four (the previous two cases coming from PMIDs:21937992 and PMID:26308914) . With functional studies in PMID:28784718 (Dewe et al., 2017), there is now sufficient evidence for a Green (diagnostic-grade) rating.
Intellectual disability v2.824 TRMT1 Rebecca Foulger Gene: trmt1 has been classified as Green List (High Evidence).
Intellectual disability v2.823 TRIM8 Rebecca Foulger Classified gene: TRIM8 as Green List (high evidence)
Intellectual disability v2.823 TRIM8 Rebecca Foulger Gene: trim8 has been classified as Green List (High Evidence).
Intellectual disability v2.822 TRIM8 Rebecca Foulger Classified gene: TRIM8 as No list
Intellectual disability v2.822 TRIM8 Rebecca Foulger Added comment: Comment on list classification: TRIM8 was added to the panel and rated Green by Konstantinos Varvagiannis. Assoum et al, (PMID:30244534) summarises six patients with TRIM8 variants; four new patients plus two previous patients from Sakai et al., 2016 (PMID:27346735) and Epi4K Consortium (PMID:23934111). All six patients had global developmental delay and/or intellectual disability (summarised in Table 1). Therefore sufficient unrelated cases from multiple publications to support a Green (diagnostic) rating on the ID panel.
Intellectual disability v2.822 TRIM8 Rebecca Foulger Gene: trim8 has been removed from the panel.
Intellectual disability v2.821 TRAF7 Rebecca Foulger Tag watchlist tag was added to gene: TRAF7.
Intellectual disability v2.821 TRAF7 Rebecca Foulger Classified gene: TRAF7 as Amber List (moderate evidence)
Intellectual disability v2.821 TRAF7 Rebecca Foulger Added comment: Comment on list classification: TRAF7 was added to the panel and rated Green by Konstantinos Varvagiannis based on PMID:29961569 (Tokita et al, 2018) who report four different heterozygous missense mutations in the TRAF7 gene in 7 unrelated patients with MIM:618164. The variants were de novo in at least six of the patients. Motor and/or speech delay were present to a variable degree in 5 of the 5 subjects for whom this outcome could be assessed (The remaining two subjects were 1 week old and 3 weeks old). After discussion with Louise Daugherty, I have rated TRAF7 as Amber: PMID:29961569 assayed motor delay and speech delay as indicators of developmental delay- the authors don't refer to global DD, and motor/speech delay are not directly linked to ID. Additional evidence comes from an ID cohort study (PMID:27479843, Lelieveld et al, 2016) and the DDD study (PMID:28135719). Rated Amber with a 'watchlist' tag, awaiting further evidence.
Intellectual disability v2.821 TRAF7 Rebecca Foulger Gene: traf7 has been classified as Amber List (Moderate Evidence).
Intellectual disability v2.820 TRAF7 Rebecca Foulger Publications for gene: TRAF7 were set to 29961569; 27479843; 28135719; 25363760; 25961944
Intellectual disability v2.819 TRAF7 Rebecca Foulger Added comment: Comment on publications: PMIDs 25363760 and 25961944 report variants detected in autism patients.
Intellectual disability v2.819 TRAF7 Rebecca Foulger Publications for gene: TRAF7 were set to 29961569; 27479843; 28135719; 25363760; 25961944
Intellectual disability v2.818 TRAF7 Rebecca Foulger commented on gene: TRAF7
Intellectual disability v2.818 BRD4 Catherine Snow Classified gene: BRD4 as Red List (low evidence)
Intellectual disability v2.818 BRD4 Catherine Snow Added comment: Comment on list classification: Addition of gene from reviewer awaiting internal review
Intellectual disability v2.818 BRD4 Catherine Snow Gene: brd4 has been classified as Red List (Low Evidence).
Intellectual disability v2.817 TRAF7 Rebecca Foulger Phenotypes for gene: TRAF7 were changed from Global developmental delay; Abnormal heart morphology; Abnormality of digit; Abnormality of limbs to Cardiac, facial, and digital anomalies with developmental delay, 618164; Global developmental delay; Abnormal heart morphology; Abnormality of digit; Abnormality of limbs
Intellectual disability v2.816 TMEM94 Rebecca Foulger Classified gene: TMEM94 as Green List (high evidence)
Intellectual disability v2.816 TMEM94 Rebecca Foulger Added comment: Comment on list classification: TMEM94 was added to the ID panel by Konstantinos Varvagiannis, and rated Amber. Stephen et al., 2018 (PMID:30526868) identified biallelic (homozygous or compound het) variants in 10 patients from 6 unrelated families of different ethnic origins. All affected individuals manifested with delays in development and dysmorphic facial features. All variants were predicted to be truncating variants. There is a question from Konstantinos over whether the phenotypes fall under the scope of the ID panel since the authors refer to ID in the abstract, and speech delay, motor delay and learning disability in Table 1. Global developmental delay is reported for individual II.1 in Family 1, gross developmental delay is reported in Family 3, mild DD and an IQ of 58 is reported for individual II.2 in Family 5, and developmental delay was reported for Individual II.2 in Family 6. TMEM94 has now also been associated with a disorder in OMIM: Intellectual developmental disorder with cardiac defects and dysmorphic facies, 618316. Therefore on balance and because of sufficient numbers of general DD reported in PMID:30526868, I have included TMEM94 on the ID panel as a Green gene.
Intellectual disability v2.816 TMEM94 Rebecca Foulger Gene: tmem94 has been classified as Green List (High Evidence).
Intellectual disability v2.815 TMEM94 Rebecca Foulger Phenotypes for gene: TMEM94 were changed from Global developmental delay; Intellectual disability; Abnormal heart morphology; Abnormality of head or neck to Intellectual developmental disorder with cardiac defects and dysmorphic facies, 618316; Global developmental delay; Intellectual disability; Abnormal heart morphology; Abnormality of head or neck
Intellectual disability v2.814 TMEM94 Rebecca Foulger Publications for gene: TMEM94 were set to
Intellectual disability v2.813 TELO2 Rebecca Foulger Classified gene: TELO2 as Green List (high evidence)
Intellectual disability v2.813 TELO2 Rebecca Foulger Added comment: Comment on list classification: TELO2 was added to the ID panel by Konstantinos Varvagiannis, and rated Green. Updated rating from Grey to Green based on the evidence Konstantinos provides. In summary, PMID:27132593 (You et al., 2016) report six individuals from 4 families with syndromic ID and compound het variants in TELO2. PMID:28944240 (Moosa et al., 2017) report a family with two sisters harbouring compound het TEL02 variants and with dysmorphic features. The surviving sister had severe ID and global DD in addition to the dysmorphism. Therefore sufficient cases to support association with You-Hoover-Fong syndrome (MIM:616954), which has a spectrum of phenotypes but includes intellectual disability as a consistent feature.
Intellectual disability v2.813 TELO2 Rebecca Foulger Gene: telo2 has been classified as Green List (High Evidence).
Intellectual disability v2.812 TELO2 Rebecca Foulger Phenotypes for gene: TELO2 were changed from You-Hoover-Fong syndrome, MIM 616954 to You-Hoover-Fong syndrome, 616954, syndromic intellectual disability
Intellectual disability v2.811 TCF20 Rebecca Foulger Classified gene: TCF20 as Green List (high evidence)
Intellectual disability v2.811 TCF20 Rebecca Foulger Added comment: Comment on list classification: Updated rating from Amber to Green following recent external review by Konstantinos Varvagiannis (Dec 2018 and Feb 2019). The Torti et al., 2019 article (PMID:30739909) describes 27 individuals from 24 families with novel TCF20 variants. All 27 individuals had developmental delay/intellectual disability (DD/ID). Together with the individual in PMID:30525188 (Snoeijen-Schouwenaars et al 2019, Supplementary Table 2) and the additional evidence listed by Konstantinos Varvagiannis, these papers provide additional cases since the Amber rating in July 2018, and support that ID is a consistent feature amongst TCF20 patients.
Intellectual disability v2.811 TCF20 Rebecca Foulger Gene: tcf20 has been classified as Green List (High Evidence).
Intellectual disability v2.810 TCF20 Rebecca Foulger Phenotypes for gene: TCF20 were changed from TCF20 syndrome; Intellectual disability to TCF20 syndrome; Intellectual disability; developmental delay
Intellectual disability v2.809 TCF20 Rebecca Foulger Publications for gene: TCF20 were set to 27436265; 25533962; 27479843; 28135719
Intellectual disability v2.808 CNOT1 Rebecca Foulger Classified gene: CNOT1 as Amber List (moderate evidence)
Intellectual disability v2.808 CNOT1 Rebecca Foulger Added comment: Comment on list classification: Added to panel as an Amber gene awaiting further evidence/clinical review. PMID:31006513 (De Franco et al., 2019) suggest the CNOT1 phenotype is variant-specific since the DDD project cases had developmental delay but no holoprosencephaly or pancreatic phenotypes. Developmental delay has been reported in the two holoprosencephaly cases from PMID:31006510 (Kruszka et al., 2019) but was not amongst the phenotypes reported in three holoprosencephaly patients from PMID:31006513 (despite carrying the same heterozygous p.Arg535Cys variant).
Intellectual disability v2.808 CNOT1 Rebecca Foulger Gene: cnot1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v2.807 CNOT1 Rebecca Foulger gene: CNOT1 was added
gene: CNOT1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: CNOT1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CNOT1 were set to 31006510; 21679367; 31006513
Phenotypes for gene: CNOT1 were set to global developmental delay
Added comment: Added CNOT1 to the ID panel based on recent (2019) literature evidence: Kruszka et al., 2019 (PMID:31006510) report two unrelated individuals with semilobar holoprosencephaly who have the identical de novo missense variant in the gene CNOT1. (c.1603C>T [p.Arg535Cys]). Both probands had global developmental delay amongst their phenotypes.

De Franco et al., 2019 (PMID:31006513) report that the DDD study has identified de novo CNOT1 variants in three individuals with developmental delay (two missense variants p.Leu2323Phe and p.Arg623Trp, and and a nonsense variant p.Gln33*) not that none of them had holoprosencephaly or diabetes.
Sources: Literature
Intellectual disability v2.806 PHACTR1 Eleanor Williams Phenotypes for gene: PHACTR1 were changed from Global developmental delay; Intellectual disability; Seizures:Epileptic encephalopathy, early infantile, 70 618298; PHACTR1-associated neurodevelopment disorder to Global developmental delay; Intellectual disability; Seizures:Epileptic encephalopathy, early infantile, 70 618298; PHACTR1-associated neurodevelopment disorder
Intellectual disability v2.805 PHACTR1 Eleanor Williams Phenotypes for gene: PHACTR1 were changed from to Global developmental delay; Intellectual disability; Seizures:Epileptic encephalopathy, early infantile, 70 618298; PHACTR1-associated neurodevelopment disorder
Intellectual disability v2.804 PHACTR1 Eleanor Williams Publications for gene: PHACTR1 were set to
Intellectual disability v2.803 PHACTR1 Eleanor Williams Added comment: Comment on mode of pathogenicity: Proposed dominant negative or incomplete penetrance mode of action (PMIDs: 23033978, 28135719)
Intellectual disability v2.803 PHACTR1 Eleanor Williams Mode of pathogenicity for gene: PHACTR1 was changed from to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Intellectual disability v2.802 PHACTR1 Eleanor Williams Mode of inheritance for gene: PHACTR1 was changed from to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v2.801 PHACTR1 Eleanor Williams Classified gene: PHACTR1 as Green List (high evidence)
Intellectual disability v2.801 PHACTR1 Eleanor Williams Added comment: Comment on list classification: 3 cases plus functional evidence (from PMIDs: 23033978, 28135719), supporting a dominant negative mode of action or incomplete penetrance.
Intellectual disability v2.801 PHACTR1 Eleanor Williams Gene: phactr1 has been classified as Green List (High Evidence).
Intellectual disability v2.800 APOPT1 Louise Daugherty Tag new-gene-name tag was added to gene: APOPT1.
Intellectual disability v2.800 APOPT1 Louise Daugherty commented on gene: APOPT1: Added new-gene-name tag, new approved HGNC gene symbol for APOPT1 is COA8
Intellectual disability v2.800 ZNF142 Konstantinos Varvagiannis gene: ZNF142 was added
gene: ZNF142 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: ZNF142 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZNF142 were set to 31036918
Phenotypes for gene: ZNF142 were set to Global developmental delay; Intellectual disability; Seizures; Tremor; Dystonia
Penetrance for gene: ZNF142 were set to unknown
Review for gene: ZNF142 was set to GREEN
Added comment: Khan et al. (2019 - PMID: 31036918) describe the phenotype of 7 females from 4 families, harboring biallelic likely pathogenic ZNF142 variants.

Overlapping features included cognitive impairment (ID in 6/7 from 3 families, borderline intellectual functioning was reported one occasion), speech impairement and motor impairment (7/7), and variably penetrant seizures (5/7), tremor (4/7) and dystonia (3/7). Most individuals (5/7) had experienced at least one episode of seizures (tonic-clonic) though seizures were recurrent in 3 sibs.

Other disorders with ID (eg. Angelman syndrome, Rett syndrome, chromosomal disorders) or movement disorders as a feature were previously ruled out for many subjects.

6 individuals were homozygous or compound heterozygous for LoF (stopgain or frameshift) variants. One individual harbored 2 missense SNVs in the compound heterozygous state. Variants reported include (NM_001105537.2): c. 817_818delAA (p.Lys273Glufs*32), c.1292delG (p.Cys431Leufs*11), c.3175C>T (p.Arg1059*), c.4183delC (p.Leu1395*), c.3698G>T (p.Cys1233Phe), c.4498C>T (p.Arg1500Trp) with the LoF variants predicted to result in NMD. Expression or functional studies were not carried out.

ZNF142 encodes a C2H2 domain-containing transcription factor. Mutations in other zinc finger proteins (ZNF/zfp) have been reported in several neurodevelopmental disorders impacting the CNS (eg. ZBTB20 and ZBTB11 heterozygous and biallelic mutations, respectively) and/or presenting with movement disorders among their manifestations (eg. YY1).

As the authors comment, homozygous ablation of the orthologous (Zfp142) locus in mice results in behavioral and neurological phenotypes [MGI ref.ID: J:211773 cited - http://www.informatics.jax.org/marker/reference/J:211773 (though Zfp142 or its locus do not seem to appear in the list)].

ZNF142 is not - at least commonly - included in gene panels for ID offered by diagnostic laboratories. It is not associated with any phenotype in OMIM, nor in G2P.

As a result, this gene can be considered for inclusion in the current panel as probably as green (individuals from 3 families, appropriate degree of ID for the current panel) or amber (if further evidence would be required).
Sources: Literature
Intellectual disability v2.800 ACTL6B Konstantinos Varvagiannis reviewed gene: ACTL6B: Rating: GREEN; Mode of pathogenicity: None; Publications: 31031012, 30656450, 26539891, 27171548, 30237576; Phenotypes: Global developmental delay, Intellectual disability, Seizures, Spasticity, Global developmental delay, Intellectual disability, Stereotypic behavior, Abnormality of the face; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability v2.800 POLA1 Konstantinos Varvagiannis reviewed gene: POLA1: Rating: GREEN; Mode of pathogenicity: None; Publications: 31006512; Phenotypes: Global developmental delay, Intellectual disability, Microcephaly, Growth abnormality, Hypogonadism; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females; Current diagnostic: yes
Intellectual disability v2.800 SNAP25 Konstantinos Varvagiannis gene: SNAP25 was added
gene: SNAP25 was added to Intellectual disability. Sources: Literature,Radboud University Medical Center, Nijmegen
Mode of inheritance for gene: SNAP25 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SNAP25 were set to 29491473; 28135719; 29100083; 25381298; 25003006
Phenotypes for gene: SNAP25 were set to ?Myasthenic syndrome, congenital 18, 616330
Penetrance for gene: SNAP25 were set to Complete
Review for gene: SNAP25 was set to GREEN
gene: SNAP25 was marked as current diagnostic
Added comment: Probably 9 individuals with heterozygous SNAP25 pathogenic variants have been reported to date, most summarized in the first reference (NM_130811.2 used as reference for all variants below):
- Fukuda et al. (2018 - PMID: 29491473) 2 sibs (~11 and 2.5 y.o) with seizures and cerebellar ataxia but not ID. harboring c.176G>C (p.Arg59Pro) variant which was inherited from a mosaic unaffected parent.
- DDD study (2017 - PMID: 28135719) [also in Heyne et al. 2018 - PMID: 29942082] 3 inividuals (11 m - 7 y of age) with DD and seizures due to c.118A>G (p.Lys40Glu), c.127G>C (p.Gly43Arg) and c.520C>T (p.Gln174*) de novo variants.
- Hamdan et al. (2017 - PMID: 29100083) a 23 y.o. male with epilepsy and ID and c.496G>T (p.Asp166Tyr) de novo variant
- Shen et al. (2014 - PMID: 25381298) a 11 y.o. female with epilepsy and ID and c.200T>A (p.Ile67Asn) de novo variant
- Rohena et al. (2013 - PMID: 25003006) a 15 y.o. female with epilepsy and ID and c.142G>T (p.Val48Phe) de novo variant
- Decipher patient 292139, a male with c.212T>C (p.Met71Thr) with hypotonia, DD, poor coordination and additional features (epilepsy not reported).

Seizures of variable type [absence seizures, generalized tonic-clonic (most), focal clonic, myoclonic, etc] have been reported for most (8/9) of these individuals. DD was a feature in several subjects and intellectual outcome has been specifically commented on for 5 (2 without and 3 with ID - moderate/severe/not further specified).

SNAP25 encodes a (t-)SNARE protein essential for synaptic vesicle exocytosis. Mutations in genes for other components of the SNARE complex (eg. STXBP1) have been associated with epilepsy and/or ID.

SNAP25a and SNAP25b are the 2 major protein isoforms [corresponding transcripts: ENST00000304886 (NM_003081) and ENST00000254976 (NM_130811) respectively]. These isoforms are produced by utilization of alternative exons 5 (5a or 5b) though the amino-acid sequence encoded by these exons appears to be identical except for 9 residues. Most variants reported to date affect both transcripts (and protein isoforms) although 2 were specific for ENST00000254976 (or SNAP25b isoform - Fukuda et al. and Shen et al.).

Mouse Snap25 has also 2 isoforms. Both are predominantly localized in embryonic and adult mouse brains. Snap25a is produced before Snap25b though the latter becomes the major isoform early postnatally (by the second week) [PMIDs cited: 7878010, 21526988].

Based on the phenotype of some individuals with chromosome 20 deletions in Decipher (note: only 3 deletions spanning SNAP25 however appear currently, the phenotype is not specified and 2 of them are >4.5Mb) or the pLI of 0.96 in gnomAD, haploinsufficiency has been proposed as a likely mechanism. A dominant-negative effect was however suggested for the Ile67Asn studied by Shen et al. Functional studies have not been performed for other variants.

Animal models discussed:
- Snap25 null drosophila show complete loss of synaptic transmission upon electroretinogram recordings (PMID cited: 12242238).
- In mice, elimination of Snap25b expression resulted in developmental defects, seizures and impaired short-term synaptic plasticity (PMID cited: 19043548).
- Mice with a 4.6 Mb deletion encompassing 12 genes (incl. Snap25) display seizure predisposition (PMID cited: 23064108).
- Heterozygosity for Ile67Thr in (blind-drunk mutant) mice results in impaired vesicle trafficking, impaired sensorimotor gating and ataxia (PMID cited:17283335).

In OMIM, heterozygous SNAP25 mutations are associated with ?Myasthenic syndrome, congenital, 18 (with intellectual disability and ataxia). SNAP25 is part of the DD panel, associated with "Epilepsy and intellectual disability" (disease confidence: probable).

This gene is included in gene panels for ID offered by some diagnostic laboratories (incl. Radboudumc). SNAP25 is among the genes discussed by Erger et al. (PMID: 30914295) as associated with ID in OMIM/HPO/G2P/SysID but not included in the current panel.

As a result SNAP25 can be considered for inclusion in the ID panel probably as green (3 individuals with ID, role of SNARES in "synaptopathies", supportive animal models) or amber (if functional studies for individual variants would be required).
Sources: Literature, Radboud University Medical Center, Nijmegen
Intellectual disability v2.800 CYP27A1 Philip Dawson reviewed gene: CYP27A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 24442603, 29484516; Phenotypes: Cerebrotendinous Xanthomatosis (CTX), 213700, intellectaul disability including childhood & adult onset; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v2.800 CACNA1B Konstantinos Varvagiannis gene: CACNA1B was added
gene: CACNA1B was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: CACNA1B was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: CACNA1B were set to Global developmental delay; Developmental regression; Seizures; Intellectual disability; Abnormality of movement
Penetrance for gene: CACNA1B were set to Complete
Review for gene: CACNA1B was set to GREEN
Added comment: Gorman et al. (2019 - doi.org/10.1016/j.ajhg.2019.03.005) report on 6 individuals from 3 unrelated families, with biallelic LoF CACNA1B variants. The phenotype corresponds to a developmental epilepic encephalopathy with hyperkinetic movement disorder (ID was a universal feature, DD and/or regression occurred prior to the onset of seizures in several individuals) .

CACNA1B encodes calcium channel, voltage-dependent N type, α-1B subunit (Ca v2.2). As commented by the authors, Ca v2.1 and v2.2 are important for SNARE-mediated release of neurotransmitters through modulation of Ca+2 levels. In addition, Ca v2.2 has been postulated to have a role in synaptic plasticity, synaptogenesis, migration of immature neurons, etc. It is thought to have a crucial role in neurotransmission in the early postnatal period (Ca v2.2 channels are subsequently replaced by Ca v2.1 in mature synapses within the thalamus, cerebellum and auditory brainstem). Knockout mice display neurodevelopmental abnormalities including impaired locomotor activity and memory impairment (all ref. cited within the article).

3 sibs, born to 1st cousin parents, harbored p.Leu1222Argfs*29 (NM_000718.4:c.3665del) in the homozygous state. One additional individual was homozygous for p.Arg383*. Compound heterozygosity for a frameshift and a splicing variant (p,Gly1192Cysfs* and c.4857+1G>C) was identified in 2 sibs from a 3rd family.

Expression/functional studies have not been performed for any of the variants reported.

In OMIM, monoallelic CACNA1B pathogenic variants are associated with ?Dystonia 23 (MIM 614860) based on the identification of a heterozygous missense (R1389H) mutation in members of a Dutch with myoclonus-dystonia syndrome (Groen et al. 2015 - PMID: 25296916).

As a result, this gene can be considered for inclusion in the epilepsy and ID panels as green (or amber).
Sources: Literature
Intellectual disability v2.800 DOCK3 Konstantinos Varvagiannis reviewed gene: DOCK3: Rating: AMBER; Mode of pathogenicity: None; Publications: 30976111, 28195318, 29130632; Phenotypes: Neurodevelopmental disorder with impaired intellectual development, hypotonia, and ataxia, 618292; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability v2.800 BCORL1 Konstantinos Varvagiannis reviewed gene: BCORL1: Rating: AMBER; Mode of pathogenicity: None; Publications: 24123876, 30941876; Phenotypes: Global developmental delay, Intellectual disability, Autism, Behavioral abnormality; 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 v2.800 ISCA-37468-Loss Louise Daugherty Mode of inheritance for Region: ISCA-37468-Loss 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 v2.799 ISCA-37468-Loss Louise Daugherty Mode of inheritance for Region: ISCA-37468-Loss was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Intellectual disability v2.798 P4HTM Konstantinos Varvagiannis gene: P4HTM was added
gene: P4HTM was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: P4HTM was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: P4HTM were set to 30940925; 25078763
Phenotypes for gene: P4HTM were set to Central hypotonia; Muscular hypotonia; Global developmental delay; Intellectual disability; Seizures; Abnormality of the eye; Hypoventilation; Sleep apnea; Dysautonomia
Penetrance for gene: P4HTM were set to Complete
Review for gene: P4HTM was set to GREEN
Added comment: Rahikkala et al. (2019 - PMID: 30940925) report on 13 individuals from 5 families with biallelic pathogenic P4HTM variants. 6 of these individuals from a large consanguineous family from Finland were previously reported by the same group, although studies at the time had revealed a 11.5 Mb region of homozygosity with 3 genes within this interval considered to be candidate for the patients' phenotype (P4HTM, TKT, USP4) [Kaasinen et al. - PMID: 25078763].

Common features included Hypotonia (13/13), DD and ID (the latter present in 12/13 individuals with appropriate age for evaluation) and Eye Abnormalities, reason why the acronym HIDEA is suggested for the disorder. Epilepsy was observed in 10 individuals (10/13). Hypoventilation, sleep apnea and dysautonomia were additional features reported.

Muscle biopsies from 4 individuals had variable findings suggestive of disruption of normal mitochondrial function.

Finnish patients were homozygous for a SNV - possibly a founder variant in this population - predicted to lead to a missense change in the canonical transcript (NM_177938.2:c.1073G>A) but causing an in-frame loss of the complete exon 6 of another transcript (NM_177939.2).

The latter transcript (encoding a 502 aa protein) is the prevalent one in fibroblasts/myoblasts instead of the canonical one (563 aa). It is not known whether the canonical transcript is the prevalent in brain tissue although northern blot analysis in a previous study suggested presence of a 2.3 kb mRNA in brain instead of a 1.8 kb observed in other tissues, a finding which may be suggestive of expression of the canonical transcript. [Reviewer's note: In gnomAD based on the pext values from the GTEx, the noncanonical transcript appears to be prevalent in brain regions - https://gnomad.broadinstitute.org/gene/ENSG00000178467]

All variants reported in affected both transcripts. All 5 variants have been submitted to LOVD ( https://databases.lovd.nl/shared/variants/P4HTM?search_var_status=%3D%22Marked%22%7C%3D%22Public%22 - the first author appearing as the submitter).

Overexpression of wt and 3 mutants (His161Pro, Gln352*and Exon6del) in insect cells followed by analysis with SDS-PAGE and western blot revealed severly reduced/abolished fraction of soluble protein for the 3 studied variants suggesting improper protein folding.

Knockout of the gene in mice leads to retinal defects and/or visual impairment in line with eye abnormalites (nystagmus, strabismus, achromic retinal fundi or cortical blindness) being a prominent feature in affected individuals. Mouse studies suggest that this gene is also important for renal function, although kidney problems were not reported in any affected individual.

Overall loss-of-function is suggested to be the underlying mechanism.

P4HTM is not associated with any phenotype in OMIM, nor in G2P. This gene is not (at least commonly) included in gene panels for ID offered by diagnostic laboratories.

As a result P4HTM can be considered for inclusion in the ID and epilepsy panels probably as green (several affected individuals, degree of ID relevant) or amber.
Sources: Literature
Intellectual disability v2.798 VAMP2 Konstantinos Varvagiannis gene: VAMP2 was added
gene: VAMP2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: VAMP2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: VAMP2 were set to 30929742
Phenotypes for gene: VAMP2 were set to Generalized hypotonia; Global developmental delay; Intellectual disability; Autistic behavior; Stereotypic behavior; Seizures; Abnormality of movement; Cortical visual impairment
Penetrance for gene: VAMP2 were set to unknown
Review for gene: VAMP2 was set to GREEN
gene: VAMP2 was marked as current diagnostic
Added comment: Salpietro et al. (2019 - PMID: 30929742 - DDD study among the co-authors) report on 5 individuals each with private heterozygous de novo variants in VAMP2.

The overlapping phenotype consisted among others of hypotonia with DD, moderate/severe ID and ASD (all in 5/5). Other features included the presence of clinical seizures (3/5 - EEG anomalies observed in all individuals), variable Rett-like stereotypies, hyperkinetic movements, central visual impairment. OFC was normal in all subjects.

VAMP2 encodes the vesicular SNARE protein synaptobrevin-2 which - along with its partners (syntaxin-1A and synaptosomal-associated protein 25) - mediates fusion of synaptic vesicles for the release of neurotransmitters. A number of synaptic proteins involved in Ca+2-regulated neurotransmitter release (eg. Munc18 encoded by STXBP1) regulate the fusion of synaptic vesicles, although SNAREs alone are sufficient for this process.

All variants localized in the v-SNARE domain (aa 31-91 - of 116 total residues - NP_0055047.2) with some phenotypic differences between variants localizing in the C-terminal end of the v-SNARE domain compared to those localizing in its proximal part. The following 3 missense variants and 2 in-frame deletions were reported (using NM_014232 as reference): c.223T>C or p.Ser75Pro - c.233A>C or p.Glu78Ala - c.230T>C or p.Phe77Ser - c.128_130delTGG or p.Val43del and c.135_137delCAT or p.Ile45del.

Functional studies were performed for 2 missense variants and were suggestive of impairment in vesicle fusion for the Ser75Pro variant. The fusion profile for Glu78Ala was however similar to wt. Upon Munc18-activated conditions, wt vesicle fusion was 2-fold increased, in contrast to a >90% loss-of-function effect which was observed for the Ser75Pro variant. Munc18 was however able to activate vesicle fusion mediated by the Glu78Ala variant. When using mixed v-liposomes (50:50 Wildtype:Ser75Pro mutant) the fusion profile was identical to the profile of homogeneous samples containing only the mutant protein which was suggestive of dominant interference of the mutant with wildtype.

In gnomAD, VAMP2 has a (low) Z-score and pLI of 1.41 and 0.89 respectively.

The authors comment that mutations in other genes encoding presynaptic proteins involved in Ca+2-regulated neurotransmitter release (eg SNAP25, STXBP1, etc) have been identified in other neurological disorders (with ID as a feature).

VAMP2 is not associated with any phenotype in OMIM or G2P. This gene is included in gene panels for ID offered by some diagnostic laboratories.

As a result, VAMP2 can be considered for inclusion in the ID panel probably as green (5 individuals, degree of ID relevant) or amber.
Sources: Literature
Intellectual disability v2.798 CDK8 Louise Daugherty Phenotypes for gene: CDK8 were changed from 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 disability v2.797 CDK8 Louise Daugherty Classified gene: CDK8 as Green List (high evidence)
Intellectual disability v2.797 CDK8 Louise Daugherty Added comment: Comment on list classification: Changed from Red to Green. Appropriate phenotype, sufficient cases and external expert review all support gene-disease association and relevance to this panel to rate gene as Green.
Intellectual disability v2.797 CDK8 Louise Daugherty Gene: cdk8 has been classified as Green List (High Evidence).
Intellectual disability v2.796 CDK8 Louise Daugherty Publications for gene: CDK8 were set to 26350204; 24139904
Intellectual disability v2.795 CDK8 Louise Daugherty Mode of inheritance for gene: CDK8 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v2.794 KDM3B Louise Daugherty Classified gene: KDM3B as Amber List (moderate evidence)
Intellectual disability v2.794 KDM3B Louise Daugherty Added comment: Comment on list classification: Rated gene as Amber based on current information in the literature and external expert review there is not enough evidence to support gene-disease association rating of this gene to Green.
Intellectual disability v2.794 KDM3B Louise Daugherty Gene: kdm3b has been classified as Amber List (Moderate Evidence).
Intellectual disability v2.793 KDM3B Louise Daugherty Phenotypes for gene: KDM3B were changed from to Global developmental delay; Intellectual disability; Short stature; Behavioral abnormality; Seizures
Intellectual disability v2.792 KDM3B Louise Daugherty Mode of inheritance for gene: KDM3B was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v2.791 KDM3B Louise Daugherty Publications for gene: KDM3B were set to
Intellectual disability v2.790 ARHGEF6 Louise Daugherty Classified gene: ARHGEF6 as Amber List (moderate evidence)
Intellectual disability v2.790 ARHGEF6 Louise Daugherty Added comment: Comment on list classification: demoted from Green to Amber
Intellectual disability v2.790 ARHGEF6 Louise Daugherty Gene: arhgef6 has been classified as Amber List (Moderate Evidence).
Intellectual disability v2.789 KDM3B Konstantinos Varvagiannis reviewed gene: KDM3B: Rating: AMBER; Mode of pathogenicity: None; Publications: doi.org/10.1016/j.ajhg.2019.02.023; Phenotypes: Global developmental delay, Intellectual disability, Short stature, Behavioral abnormality, Seizures; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v2.789 KDM3B Konstantinos Varvagiannis Deleted their review
Intellectual disability v2.789 KDM3B Konstantinos Varvagiannis Deleted their comment
Intellectual disability v2.789 KDM3B Konstantinos Varvagiannis reviewed gene: KDM3B: Rating: AMBER; Mode of pathogenicity: None; Publications: doi.org/10.1016/j.ajhg.2019.02.023; Phenotypes: Global developmental delay, Intellectual disability, Short stature, Behavioral abnormality, Seizures; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v2.789 RNF135 Louise Daugherty Publications for gene: RNF135 were set to
Intellectual disability v2.788 RNF135 Louise Daugherty Classified gene: RNF135 as Red List (low evidence)
Intellectual disability v2.788 RNF135 Louise Daugherty Added comment: Comment on list classification: Downgraded gene from Amber to Red due to external review highlighting new publication Wright et al. (2019 - PMID: 30665703) that refutes any evidence for developmental disorders (which includes ID)
Intellectual disability v2.788 RNF135 Louise Daugherty Gene: rnf135 has been classified as Red List (Low Evidence).
Intellectual disability v2.787 CDK8 Konstantinos Varvagiannis Deleted their comment
Intellectual disability v2.787 CDK8 Konstantinos Varvagiannis commented on gene: CDK8: Calpena et al. (2019 - PMID: 30905399 - DDD study among the co-authors) report on 12 unrelated individuals with pathogenic CDK8 missense variants.

Common features included hypotonia and DD (universal feature). Older children displayed variable degrees of ID (2 mild, 5 moderate, 2 moderate-severe). Other features included feeding difficulties, behavioral disorders, CHD, epilepsy (2 individuals), impaired vision and hearing problems in few.

CDK8 (alternatively CDK19) serves a one of the four subunits of a kinase module that reversibly binds to the mediator complex to regulate its activity (in turn, regulation of transcription). Mutations in other genes coding for the 3 other subunits of the kinase module (eg. MED12 or MED13L) lead to syndromic neurodevelopmental disorders.

8 missense CDK8 variants were reported in total. Ser62Leu (NM_001260.2:c.185C>T) was recurrent, observed in 5 subjects. The variants had occurred as de novo events in all cases (10 individuals) where parental samples were available.

All variants clustered in the kinase domain (residues 21-335 - of 464 total) around the ATP binding pocket. A thermal stability assay did not reveal gross protein instability in the presence or absence of ATP while the ability to bind ATP was retained for most/all variants. Study of STAT1 phosphorylation was suggestive of attenuated kinase activity for all variants, though to a lesser degree for 2 of them. Given the type of variants (all missense) and the pLI of 0.38 haploinsufficiency appears to be unlikely. A dominant-negative mechanism is favoured.

CDK8 is not associated with any phenotype in G2P.

As a result, CDK8 can be considered for upgrade to green or amber (if the degree of ID is relevant for the current panel).
Intellectual disability v2.787 CDK8 Konstantinos Varvagiannis reviewed gene: CDK8: 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: 30905399; Phenotypes: Generalized hypotonia, Feeding difficulties, Global developmental delay, Intellectual disability, Behavioral abnormality, Abnormality of cardiovascular system morphology, Hearing impairment, Abnormality of vision, Anorectal anomaly, Seizures; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v2.787 ARHGEF6 Richard Scott commented on gene: ARHGEF6: Literature review identifies lack of clarity about published data on this gene. As per note in OMIM entry:

ARHGEF6, IVS1AS, T-C, -11 (rs140322310)
RCV000012185
This variant, formerly titled MENTAL RETARDATION, X-LINKED 46, has been reclassified based on a review of the ExAC database by Hamosh (2018).
In affected males in a large Dutch family with nonspecific X-linked mental retardation (MRX46; 300436), Kutsche et al. (2000) identified a mutation in the ARHGEF6 gene. The base change IVS1-11T-C had a marginal effect on the predicted splicing efficiency but was not detected in 170 control chromosomes. In affected males, RT-PCR amplification demonstrated products of 2 different sizes: a larger amplicon corresponding to the wildtype fragment, and a smaller amplicon in which exon 1 was spliced to exon 3. Thus, all mentally retarded males in the MRX46 family exhibited enhanced skipping of exon 2.
Hamosh (2018) found that the IVS1-11T-C variant (rs140322310) was present in 53 hemizygotes in the ExAC database (November 21, 2018), suggesting that the variant is not pathogenic
Intellectual disability v2.787 ARHGEF6 Richard Scott reviewed gene: ARHGEF6: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: 300436; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v2.787 NBEA Ivone Leong Classified gene: NBEA as Green List (high evidence)
Intellectual disability v2.787 NBEA Ivone Leong Added comment: Comment on list classification: New gene added by external expert and reviewed by curation team: After discussion with the Genomics England Clinical team, there is sufficient evidence has been provided by the external expert review for this gene to be rated green. NBEA is not associated with any phenotypes on OMIM and Gene2Phenotype.
Intellectual disability v2.787 NBEA Ivone Leong Gene: nbea has been classified as Green List (High Evidence).
Intellectual disability v2.786 NFIB Ivone Leong Classified gene: NFIB as Amber List (moderate evidence)
Intellectual disability v2.786 NFIB Ivone Leong Added comment: Comment on list classification: New gene added by external expert and reviewed by curation team: After discussion with the Genomics England Clinical team, it was decided to give NFIB an amber gene rating. Although ID was reported the severity is mild-moderate and on this basis, not considered appropriate for green status on the ID panel. NFIB is associated with a phenotype in OMIM and is probably associated with a phenotype on Gene2Phenotypes. The "Autism Spectrum Disorder" and "watchlist" tags have also been added.
Intellectual disability v2.786 NFIB Ivone Leong Gene: nfib has been classified as Amber List (Moderate Evidence).
Intellectual disability v2.785 NFIB Ivone Leong Tag watchlist tag was added to gene: NFIB.
Tag Autism Spectrum Disorder tag was added to gene: NFIB.
Intellectual disability v2.785 NR4A2 Ivone Leong Tag watchlist tag was added to gene: NR4A2.
Tag Autism Spectrum Disorder tag was added to gene: NR4A2.
Intellectual disability v2.785 NR4A2 Ivone Leong Classified gene: NR4A2 as Amber List (moderate evidence)
Intellectual disability v2.785 NR4A2 Ivone Leong Added comment: Comment on list classification: New gene added by external expert and reviewed by curation team: After discussion with the Genomics England Clinical team, it was decided to give NR4A2 an amber gene rating. Although ID was reported the severity is mild-moderate and on this basis, not considered appropriate for green status on the ID panel. The "Autism Spectrum Disorder" tag has also been added.
Intellectual disability v2.785 NR4A2 Ivone Leong Gene: nr4a2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v2.784 KMT2E Konstantinos Varvagiannis reviewed gene: KMT2E: Rating: GREEN; Mode of pathogenicity: None; Publications: https://doi.org/10.1101/56609; Phenotypes: Global developmental delay, Intellectual disability, Autism, Seizures, Abnormality of skull size; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Intellectual disability v2.784 FARS2 Konstantinos Varvagiannis gene: FARS2 was added
gene: FARS2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: FARS2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FARS2 were set to 30869852
Phenotypes for gene: FARS2 were set to Combined oxidative phosphorylation deficiency 14, 614946; Spastic paraplegia 77, autosomal recessive, 617046
Penetrance for gene: FARS2 were set to Complete
Review for gene: FARS2 was set to GREEN
gene: FARS2 was marked as current diagnostic
Added comment: PMID: 30869852 (Almannai et al, 2019) is a review on FARS2 deficiency.

DD/ID and seizures are observed in both infantile- and later-onset forms of the disorder (FARS2-related infantile-onset epileptic mitochondrial encephalopathy and FARS2-related later-onset spastic paraplegia respectively). The phenotype of 26 individuals (from 19 families) and 11 individuals (from 6 families) with infantile and later-onset FARS2 deficiency is summarized in table 2. As commented by the authors, pathogenic variants may include missense, nonsense, splice-site variants, small indels as well as larger deletions/duplications (table 1 and footnote).

The relevant OMIM entries are the following: Combined oxidative phosphorylation deficiency 14 (MIM 614946) and Spastic paraplegia 77, autosomal recessive (MIM 617046).

FARS2 is included in the DD panel of G2P, associated with Neurometabolic disorder due to FARS2 deficiency (disease confidence: confirmed).

This gene is included in gene panels for ID offered by some diagnostic laboratories.

As a result, FARS2 can be considered for inclusion in the ID panel as green (or amber)
Sources: Literature
Intellectual disability v2.784 BRSK2 Konstantinos Varvagiannis gene: BRSK2 was added
gene: BRSK2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: BRSK2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: BRSK2 were set to https://doi.org/10.1016/j.ajhg.2019.02.002
Phenotypes for gene: BRSK2 were set to Global developmental delay; Intellectual disability; Autism; Behavioral abnormality
Penetrance for gene: BRSK2 were set to unknown
Review for gene: BRSK2 was set to GREEN
gene: BRSK2 was marked as current diagnostic
Added comment: Hiatt et al. (2019 - https://doi.org/10.1016/j.ajhg.2019.02.002) report on 9 individuals, each with private heterozygous BRSK2 variant.

Features included among others speech or motor delay, ID (8/9), ASD and variable behavioral anomalies.

6 variants predicted LoF (stopgain, frameshift or affecting splice-site) while 3 additional ones were missense (2 in the protein kinase domain and 1 in the kinase-associated 1 domain). In 6 individuals the variant had occurred as a de novo event while for 3 others parental samples were unavailable. Given the unknown inheritance, a single variant did not meet sufficient ACMG criteria to be classified as P/LP.

All variants had in silico predictions supporting a deleterious effect and were absent from bravo database and gnomAD, where the gene appears to be relatively intolerant to protein-altering variation.

As the authors note BRSK2 encodes a serine/threonine protein kinase involved in axonogenesis and polarization of cortical neurons. Although Brsk2- (or Brsk1-) knockout mice appear to be healthy and fertile, double knockouts for these genes resulted in pups with decreased spontaneous movement, poor response to tactile stimulation that died shortly after birth. In mice Brsk2 (and Brsk1) expression is restricted to the nervous system (PMID cited by the authors: 15705853) while in humans this gene is most highly expressed in brain (PMID cited: 23715323 - GTEx project).

BRSK2 has been shown to interact with other neurodevelopmental genes eg. TSC2, PTEN, WDR45.

Within the cohort of individuals studied, there was statistically significant enrichment for de novo BRSK2 variants when compared to the estimated backround mutation rate.

Two further BRSK2 de novo protein-altering variants were previously reported in individuals with neurodevelopmental disorders (Iossifov et al. - PMID: 25363768 and DDD study - PMID: 28135719) although the missense variant in the latter study is also present in gnomAD database.

BRSK2 is not associated with any phenotype in OMIM, nor in G2P.
The gene is included in gene panels for ID offered by some diagnostic laboratories (eg. among those participating in the study).

As a result, this gene can be considered for inclusion in the ID panel as green (or amber).
Sources: Literature
Intellectual disability v2.784 SMARCD1 Konstantinos Varvagiannis reviewed gene: SMARCD1: Rating: GREEN; Mode of pathogenicity: None; Publications: https://doi.org/10.1016/j.ajhg.2019.02.001; Phenotypes: Generalized hypotonia, Feeding difficulties, Global developmental delay, Intellectual disability, Abnormality of the hand, Abnormality of the foot; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v2.784 ATN1 Konstantinos Varvagiannis reviewed gene: ATN1: 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: 30827498; Phenotypes: Generalized hypotonia, Global developmental delay, Intellectual disability, Seizures, Feeding difficulties, Abnormality of the cardiovascular system, Cleft palate, Abnormality of the kidney; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Intellectual disability v2.784 ATAD3A Louise Daugherty Publications for gene: ATAD3A were set to 27640307
Intellectual disability v2.783 TRRAP Konstantinos Varvagiannis gene: TRRAP was added
gene: TRRAP was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: TRRAP was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: TRRAP were set to 30827496
Phenotypes for gene: TRRAP were set to Global developmental delay; Intellectual disability; Autism; Microcephaly; Abnormal heart morphology; Abnormality of the urinary system; Seizures
Penetrance for gene: TRRAP were set to unknown
Mode of pathogenicity for gene: TRRAP 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: TRRAP was set to GREEN
gene: TRRAP was marked as current diagnostic
Added comment: Cogné et al. (DDD study among the co-authors - PMID: 30827496) report on 24 individuals with pathogenic TRRAP variants.

17 different variants were reported. All variants were missense SNVs and on most occasions had occurred as de novo or apparently de novo events (paternity and maternity not checked). On one occasion, a parent was not unavailable although the respective grand-parents were not found to harbor the variant. Parental germline mosaicism explained the occurence of a variant in 2 sibs.

The authors suggest a strong genotype-phenotype correlation. Individuals whose variant localized within the residues 1031-1159 (NM_001244580.1) presented with a syndromic form of ID with additional malformations. ID was a universal feature in this group (for those subjects evaluated). For variants outside this cluster of residues the phenotype was rather that of ASD without ID or isolated ID with or without ASD, albeit with some exceptions (eg. F860L also associated with a syndromic presentation). ID was a feature in the majority of individuals belonging to the latter group (67% - all with DD) or overall irrespective of the variant localization (85% for those evaluated - all with DD).

Epilepsy was a feature in 4 individuals (4/24) belonging to either group.

All 17 variants were absent from gnomAD with CADD scores supporting a deleterious effect (SIFT/PolyPhen2 (both) predicted a tolerated/benign effect for some eg. Ala1043Thr). A few variants were recurrent, namely Ala1043Thr (5 individuals), Glu1106Lys (2), Gly1883Arg (2), Pro1932Leu (in 2 sibs).

6 further subjects (individuals 25-30, reported separately in the supplement) harbored 6 additional variants with lesser evidence for pathogenicity.

TRRAP is among the 5 most intolerant genes to missense mutations (z-score of 10.1 in ExAC) while it is also intolerant to LoF variants (pLI of 1). No deletions have been reported in DECIPHER and no LoF were identified in the study. Given type of variants and their clustering rather a gain-of-function effect or dominant-negative effect is suggested. As the authors note a LoF effect of non-clustering variants, associated with a milder phenotype cannot excluded. [Mode of pathogenicity to change if thought to be useful].

TRRAP encodes a protein involved in the recruitment to chromatin of histone acetyltransferases. The latter control the process of acetylation of lysine residues in histones and other DNA-binding proteins thus playing a major role in regulation of gene expression. In line with this, RNA sequencing analysis in skin fibroblasts from affected subjects demonstrated dysregulation of expression for several genes implicated in neuronal function and ion transport.

As summarized by the authors: In mice, Trapp knockout is embryonically lethal. Brain-specific knockout leads to premature differentiation of neural progenitors and abnormal brain development. Brain atrophy and microcephaly are observed (microcephaly was a feature in some affected individuals as well, primarily those with variants affecting residues 1031-1159). [PMIDs cited: 11544477, 24792116].

De novo TRRAP variants have been reported also in individuals with neuropsychiatric disorders (PMIDs: 21822266, 23042115, 28392909, 30424743) while TRRAP has been classified among the prenatally-biased genes relevant to its brain expression (PMID:23042115).

A de novo missense variant (c.11270G>A or p.R3757Q) was also previously reported in a study of 264 individuals with epileptic encephalopathy (Epi4K Consortium - PMID: 23934111 - indiv. ND29352).
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TRRAP is not associated with any phenotype in OMIM, nor in G2P.
The gene is included in gene panels for ID offered by some diagnostic laboratories (eg. GeneDx participating in the current study).
-----------
As a result, this gene can be considered for inclusion in the ID panel as green (or amber).
Sources: Literature
Intellectual disability v2.783 Richard Scott 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
Intellectual disability v2.782 CARS Konstantinos Varvagiannis gene: CARS was added
gene: CARS was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: CARS was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: CARS were set to Microcephaly; Neurodevelopmental delay; Brittle hair; Fragile nails
Penetrance for gene: CARS were set to Complete
Review for gene: CARS was set to GREEN
Added comment: Kuo et al. (2019 - doi.org/10.1016/j.ajhg.2019.01.006) report on 4 individuals from 3 families with biallelic pathogenic CARS variants.

Common features included microcephaly, DD, brittle hair and nails. All 4 were adults and presented with motor, language and cognitive disabilities.

Reported genotypes (and variants) included [NM_001751.5 and NP_001742.1]:
- c.1138C>T (p.Gln380*) and c.1022G>A (p.Arg341His) (1 individual)
- c.1076C>T (p.Ser359Leu) and c.1199T>A (p.Leu400Gln) (2 sibs)
- c.2061dup (p.Ser688Glnfs ∗2) in homozygous state (1 individual - no reported consanguinity)

Segregation studies confirmed the in trans occurrence of the variants in affected individuals and carrier state in unaffected parents or other family members.

CARS encodes Cysteinyl-tRNA synthetase an aminoacyl-tRNA synthetase (ARS). ARSs are a group of enzymes responsible for ligating amino acids to cognate tRNA molecules. CARS responsible for charging cysteine to tRNA molecules in the cytoplasm (CARS2 is responsible for charging cysteine to tRNA molecules in mitochondria).

Mutations in several ARSs have been linked to disorders with features overlapping to CARS-related phenotype.

Studies included:
- Western blot (pat. fibroblasts) confirmed expression of stable truncated p.Ser688Glnfs ∗2 but absence of the predicted truncating p.Gln380*. Expression in fibroblasts from the individual with compound heteroz. for the missense variants was similar to controls.
- Subcellular localization did not appear to be affected.
- Aminocacylation was significantly reduced (~40-80%) using protein lysates from affected individual fibroblasts (all families) supporting a LoF effect.
- A yeast complementation assay suggested LoF/hypomorphic effect with no or reduced yeast cell growth depending on the variant tested (hypomorphic variants: Arg341His and Ser359Leu). Aminoacylation assays (in yeast) showed reduced activity (by 50% and 84% respectively) for the 2 hypomorphic variants (compatible with the observations in patient fibroblasts).
- Conservation and the presumed effect of individual variants (in catalytic domain, truncation upstream of anticodon-binding domain or in a region affecting binding specificity of CARS and tRNA-cys) also supported pathogenicity.

All individuals demonstrated strikingly similar hair-shaft anomalies upon polarized light microscopy (eg. trichorrhexis/tiger-tail patterns/abnormal shaft diameter) in line with macroscopical observations of fine brittle hair suggesting a common underlying genetic cause (presumably explained by high cysteine content of keratins).
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CARS is not associatated with any phenotype in OMIM, nor in G2P.
The gene is not - at least 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 as green (or amber).
Sources: Literature
Intellectual disability v2.782 FUK Louise Daugherty commented on gene: FUK
Intellectual disability v2.782 FUK Louise Daugherty Tag new-gene-name tag was added to gene: FUK.
Intellectual disability v2.782 NUS1 Eleanor Williams Added comment: Comment on mode of inheritance: Only single family with a biallelic pattern is reported so assigning only monoallelic inheritance until more evidence is gathered for biallelic inheritance.
Intellectual disability v2.782 NUS1 Eleanor Williams Mode of inheritance for gene: NUS1 was changed from BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v2.781 NUS1 Eleanor Williams Classified gene: NUS1 as Red List (low evidence)
Intellectual disability v2.781 NUS1 Eleanor Williams Added comment: Comment on list classification: Following review by the Genomics England clinical team it was decided to rate this gene red on the Intellectual disabilities panel at this time.

Further cases advised to confirm MOI and delineate potential ID phenotype aside from that associated with an epileptic encephalopathy.

It will be added as Amber to the Genetic epilepsy syndromes panel.
Intellectual disability v2.781 NUS1 Eleanor Williams Gene: nus1 has been classified as Red List (Low Evidence).
Intellectual disability v2.780 KDM5B Ivone Leong Added comment: Comment on mode of inheritance: Changed mode of inheritance from Monoallelic to Both monoallelic and biallelic based on evidence provided by expert review.
Intellectual disability v2.780 KDM5B Ivone Leong Mode of inheritance for gene: KDM5B was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v2.779 KDM5B Ivone Leong Added comment: Comment on publications: PMID: 30217758 reports on 2 de novo splice variants found in 3 patients from 2 unrelated families who have ID and ASD. One variant was found in a boy with mild ID and autism traits. In vitro studies found that this variant reduced KDM5B mRNA production. The sister of this affected patient did not have carry this splice variant but she also presented with mild ID and epilepsy. The authors suggest that a variant in another gene may be linked to these phenotypes and that KDM5B haploinsufficiency cannot explain the ID/ASD phenotype.

The other variant was found in a pair of monozygotic twins who both presented with global developmental delay, poor language and ASD. In vitro studies of this second variant showed that it causes the production of an abnormal transcript which is degraded by nonsense-mediated decay.
Intellectual disability v2.779 KDM5B Ivone Leong Publications for gene: KDM5B were set to 25363768; 24307393; 29276005; 30409806; 25529582
Intellectual disability v2.778 NBEA Ivone Leong Classified gene: NBEA as No list
Intellectual disability v2.778 NBEA Ivone Leong Gene: nbea has been removed from the panel.
Intellectual disability v2.777 NBEA Ivone Leong Deleted their review
Intellectual disability v2.777 NBEA Ivone Leong Deleted their comment
Intellectual disability v2.777 NFIB Ivone Leong Classified gene: NFIB as No list
Intellectual disability v2.777 NFIB Ivone Leong Gene: nfib has been removed from the panel.
Intellectual disability v2.776 NFIB Ivone Leong Deleted their review
Intellectual disability v2.776 NFIB Ivone Leong Deleted their comment
Intellectual disability v2.776 NR4A2 Ivone Leong Publications for gene: NR4A2 were set to 29770430; 30504930; 28544326; 27569545; 23554088; 28135719; 27479843; 25363768
Intellectual disability v2.775 ITCH Ivone Leong Classified gene: ITCH as Red List (low evidence)
Intellectual disability v2.775 ITCH Ivone Leong Added comment: Comment on list classification: There is evidence that shows that ITCH is relevant to this panel; however, as there is only 1 case it has been given a red gene rating.
Intellectual disability v2.775 ITCH Ivone Leong Gene: itch has been classified as Red List (Low Evidence).
Intellectual disability v2.774 TBC1D7 Rebecca Foulger commented on gene: TBC1D7: Added watchlist tag.
Intellectual disability v2.774 TBC1D7 Rebecca Foulger Tag watchlist tag was added to gene: TBC1D7.
Intellectual disability v2.774 TBC1D7 Rebecca Foulger Classified gene: TBC1D7 as Amber List (moderate evidence)
Intellectual disability v2.774 TBC1D7 Rebecca Foulger Added comment: Comment on list classification: Updated rating from Grey to Amber. Gene added to panel and reviewed Amber by Konstantinos Varvagiannis. Currently only 2 unrelated ID cases from 2 publications (PMID:23687350 Capo-Chichi et al 2013 and PMID:24515783 Alfaiz et al 2014). TBC1D7 is not currently associated with a phenotype in DD-Gene2Phenotype. Therefore rated Amber awaiting further cases.
Intellectual disability v2.774 TBC1D7 Rebecca Foulger Gene: tbc1d7 has been classified as Amber List (Moderate Evidence).
Intellectual disability v2.773 TBC1D20 Rebecca Foulger Classified gene: TBC1D20 as Green List (high evidence)
Intellectual disability v2.773 TBC1D20 Rebecca Foulger Added comment: Comment on list classification: Updated rating from Grey to Green. Gene added to panel and reviewed Green by Konstantinos Varvagiannis. 5 unrelated families (7 individuals) reported in PMID:24239381 (Liegel et al, 2013) with 5 different homozygous TBC1D20 loss of function variants, and all with profound or severe mental retardation and developmental delay (Supplementary table S4).
Intellectual disability v2.773 TBC1D20 Rebecca Foulger Gene: tbc1d20 has been classified as Green List (High Evidence).
Intellectual disability v2.772 TBC1D20 Rebecca Foulger Added comment: Comment on mode of inheritance: Biallelic MOI supported by OMIM and PMID:24239381.
Intellectual disability v2.772 TBC1D20 Rebecca Foulger Mode of inheritance for gene: TBC1D20 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v2.771 TBC1D20 Rebecca Foulger Added comment: Comment on publications: PMID:26063829 demonstrates biochemically that TBC1D20 is a regulator of RAB18 (associated with Warburg micro syndrome 3, 614222).
Intellectual disability v2.771 TBC1D20 Rebecca Foulger Publications for gene: TBC1D20 were set to 24239381; 26063829
Intellectual disability v2.770 TBC1D20 Rebecca Foulger Phenotypes for gene: TBC1D20 were changed from Warburg Micro syndrome 4 (MIM 615663) to Warburg micro syndrome 4, 615663; mental retardation; developmental delay
Intellectual disability v2.769 STAG2 Rebecca Foulger Classified gene: STAG2 as Green List (high evidence)
Intellectual disability v2.769 STAG2 Rebecca Foulger Added comment: Comment on list classification: Updated rating from Grey to Green. STAG2 gene added to panel and reviewed Green by Konstantinos Varvagiannis. Confirmed DD-G2P rating for ''STAG2-related developmental delay with microcephaly and congenital anomalies' (note that DD-G2P has monoallelic (not X-linked) inheritance listed). Sufficient cases of STAG2 variants from the literature supporting causation for ID/DD (1 girl from PMID:28296084, 5 males from one family in PMID:29263825, one male in PMID:30447054, plus PMID:30158690).
Intellectual disability v2.769 STAG2 Rebecca Foulger Gene: stag2 has been classified as Green List (High Evidence).
Intellectual disability v2.768 STAG2 Rebecca Foulger Added comment: Comment on mode of inheritance: PMID:29263825 report syndromic mental retardation in an X-linked recessive pattern (with two healthy female carriers) wheras PMID:28296084 report an 8 year old girl with a heterozygous variant and ID phenotype. Therefore have selected XLD inheritance in PanelApp to catch all cases.
Intellectual disability v2.768 STAG2 Rebecca Foulger Mode of inheritance for gene: STAG2 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 v2.767 STAG2 Rebecca Foulger Phenotypes for gene: STAG2 were changed from STAG2-related developmental delay with microcephaly and congenital anomalies; Global developmental delay; Intellectual disability; Abnormality of head or neck; Microcephaly; Growth delay; Hearing impairment; Abnormal heart morphology to STAG2-related developmental delay with microcephaly and congenital anomalies; STAG2-related X-linked Intellectual Deficiency; cohesinopathy; Global developmental delay; Intellectual disability; Abnormality of head or neck; Microcephaly; Growth delay; Hearing impairment; Abnormal heart morphology
Intellectual disability v2.766 STAG2 Rebecca Foulger commented on gene: STAG2: PMID:30447054 (Mullegama et al, 2018) report a 4 year old male with DD, failure to thrive, short stature and polydactyly with a likely pathogenic STAG2 de novo hemizygous variant c.3027A>T, p.Lys1009Asn.
Intellectual disability v2.766 STAG2 Rebecca Foulger commented on gene: STAG2: PMID:29263825 (Soardi et al., 2017) report 5 individuals from a pedigree with a STAG2 p.Ser327Asn (c.980 G > A) variant that perfectly cosegregates with a phenotype of syndromic mental retardation in a characteristic X-linked recessive pattern- heterozygous female carriers of the variant (aunt and mother of the proband) were healthy. Other healthy relatives did not have the c.980 G>A variant.
Intellectual disability v2.766 STAG2 Rebecca Foulger commented on gene: STAG2
Intellectual disability v2.766 STAG2 Rebecca Foulger Phenotypes for gene: STAG2 were changed from Global developmental delay; Intellectual disability; Abnormality of head or neck; Microcephaly; Growth delay; Hearing impairment; Abnormal heart morphology to STAG2-related developmental delay with microcephaly and congenital anomalies; Global developmental delay; Intellectual disability; Abnormality of head or neck; Microcephaly; Growth delay; Hearing impairment; Abnormal heart morphology
Intellectual disability v2.765 CWF19L1 Louise Daugherty Classified gene: CWF19L1 as Green List (high evidence)
Intellectual disability v2.765 CWF19L1 Louise Daugherty Added comment: Comment on list classification: New gene added by external expert and reviewed by curation team: appropriate phenotype, sufficient cases and external expert review all support gene-disease association and relevance to this panel to rate gene to Green.
Intellectual disability v2.765 CWF19L1 Louise Daugherty Gene: cwf19l1 has been classified as Green List (High Evidence).
Intellectual disability v2.764 CWF19L1 Louise Daugherty Phenotypes for gene: CWF19L1 were changed from Spinocerebellar ataxia, autosomal recessive 17, 616127; intellectual disability to Spinocerebellar ataxia, autosomal recessive 17, 616127; intellectual disability, developmental delay
Intellectual disability v2.763 CWF19L1 Louise Daugherty Added comment: Comment on publications: Added PMID:30167849 Novel candidate genes and variants underlying autosomal recessive neurodevelopmental disorders with intellectual disability Santos-Cortez et.el, (2018)
Intellectual disability v2.763 CWF19L1 Louise Daugherty Publications for gene: CWF19L1 were set to 25361784; 15981765; 26197978; 27016154
Intellectual disability v2.762 SOX4 Rebecca Foulger Classified gene: SOX4 as Green List (high evidence)
Intellectual disability v2.762 SOX4 Rebecca Foulger Added comment: Comment on list classification: Updated rating from Grey to Green: Gene added and reviewed by Konstantinos Varvagiannis based on a recent publication (PMID:30661772, Zawerton et al 2019) which provides 4 unrelated cases of patients with ID and DD, and a heterozygous variant in SOX4. Therefore sufficient cases for diagnostic rating on this panel.
Intellectual disability v2.762 SOX4 Rebecca Foulger Gene: sox4 has been classified as Green List (High Evidence).
Intellectual disability v2.761 SOX4 Rebecca Foulger commented on gene: SOX4
Intellectual disability v2.761 SOX4 Rebecca Foulger Phenotypes for gene: SOX4 were changed from Global developmental delay; Intellectual disability; Growth delay; Clinodactyly of the 5th finger; Abnormality of head or neck to Syndromic intellectual disability; Global developmental delay; Intellectual disability; Growth delay; Clinodactyly of the 5th finger; facial dysmorphism
Intellectual disability v2.760 CWF19L1 Louise Daugherty Phenotypes for gene: CWF19L1 were changed from Spinocerebellar ataxia, autosomal recessive 17, 616127 to Spinocerebellar ataxia, autosomal recessive 17, 616127; intellectual disability
Intellectual disability v2.759 SOX4 Rebecca Foulger Publications for gene: SOX4 were set to
Intellectual disability v2.758 CTNNA2 Louise Daugherty Classified gene: CTNNA2 as Green List (high evidence)
Intellectual disability v2.758 CTNNA2 Louise Daugherty Added comment: Comment on list classification: New gene added by external expert and reviewed by curation team: appropriate phenotype, sufficient cases and external expert review all support gene-disease association and relevance to this panel to rate gene to Green.
Intellectual disability v2.758 CTNNA2 Louise Daugherty Gene: ctnna2 has been classified as Green List (High Evidence).
Intellectual disability v2.757 CTNNA2 Louise Daugherty commented on gene: CTNNA2
Intellectual disability v2.757 CTNNA2 Louise Daugherty Phenotypes for gene: CTNNA2 were changed from Cortical dysplasia, complex, with other brain malformations 9, 618174 to Cortical dysplasia, complex, with other brain malformations 9, 618174; intellectual disability; global developmental delay
Intellectual disability v2.756 CTNNA2 Louise Daugherty Phenotypes for gene: CTNNA2 were changed from Cortical dysplasia, complex, with other brain malformations 9 (MIM 618174) to Cortical dysplasia, complex, with other brain malformations 9, 618174
Intellectual disability v2.755 NBEA Ivone Leong Classified gene: NBEA as Green List (high evidence)
Intellectual disability v2.755 NBEA Ivone Leong Added comment: Comment on list classification: New gene added by external expert and reviewed by curation team: Sufficient evidence has been provided by the external expert review for this gene to be rated green.
Intellectual disability v2.755 NBEA Ivone Leong Gene: nbea has been classified as Green List (High Evidence).
Intellectual disability v2.754 COG6 Louise Daugherty Classified gene: COG6 as Green List (high evidence)
Intellectual disability v2.754 COG6 Louise Daugherty Added comment: Comment on list classification: New gene added by external expert and reviewed by curation team: appropriate phenotype, sufficient cases and external expert review all support gene-disease association and relevance to this panel to rate gene to Green.
Intellectual disability v2.754 COG6 Louise Daugherty Gene: cog6 has been classified as Green List (High Evidence).
Intellectual disability v2.753 CHD3 Louise Daugherty Classified gene: CHD3 as Green List (high evidence)
Intellectual disability v2.753 CHD3 Louise Daugherty Added comment: Comment on list classification: New gene added by external expert and reviewed by curation team: appropriate phenotype, sufficient cases and external expert review all support gene-disease association and relevance to this panel to rate gene to Green.
Intellectual disability v2.753 CHD3 Louise Daugherty Gene: chd3 has been classified as Green List (High Evidence).
Intellectual disability v2.752 SMARCC2 Rebecca Foulger Classified gene: SMARCC2 as Green List (high evidence)
Intellectual disability v2.752 SMARCC2 Rebecca Foulger Added comment: Comment on list classification: Updated rating from Red to Green following review from Konstantinos Varvagiannis and recent paper: PMID:30580808 (Machol et al., 2019) report on 15 unrelated individuals with varying degrees of neurodevelopmental delay in all 15 cases, harbouring one of 13 heterozygous pathogenic SMARCC2 variants. Therefore sufficient unrelated cases in this paper to support causation. Konstantinos Varvagiannis notes that SMARCC2 is not yet associated with a phenotype in OMIM or Gene2Phenotype, but this is most likely because the 2019 paper PMID:30580808 has not yet been curated in these databases.
Intellectual disability v2.752 SMARCC2 Rebecca Foulger Gene: smarcc2 has been classified as Green List (High Evidence).
Intellectual disability v2.751 SMARCC2 Rebecca Foulger Phenotypes for gene: SMARCC2 were changed from to Global developmental delay; Intellectual disability; neurodevelopmental delay and growth retardation; prominent speech impairment, hypotonia, feeding difficulties, behavioral abnormalities, and dysmorphic features
Intellectual disability v2.750 SMARCC2 Rebecca Foulger Publications for gene: SMARCC2 were set to 26350204; 27392482
Intellectual disability v2.749 CHD3 Louise Daugherty Added comment: Comment on publications: added publication to support gene-disease association
Intellectual disability v2.749 CHD3 Louise Daugherty Publications for gene: CHD3 were set to 30397230
Intellectual disability v2.748 SMARCC2 Rebecca Foulger Added comment: Comment on publications: PMID:27392482 (Tuoc et al., 2017, demonstrating a mouse model of learning and memory as included in the review by Konstantinos Varvagiannis) use BAF170 nomenclature; BAF170 is a synonym of SMARCC2.
Intellectual disability v2.748 SMARCC2 Rebecca Foulger Publications for gene: SMARCC2 were set to 26350204
Intellectual disability v2.747 SMARCC2 Rebecca Foulger Added comment: Comment on mode of inheritance: Monoallelic MOI supported by PMID:30580808.
Intellectual disability v2.747 SMARCC2 Rebecca Foulger Mode of inheritance for gene: SMARCC2 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v2.746 CHD3 Louise Daugherty Added comment: Comment on phenotypes: added MIMid from OMIM
Intellectual disability v2.746 CHD3 Louise Daugherty Phenotypes for gene: CHD3 were changed from Global developmental delay; Intellectual disability; Macrocephaly to Global developmental delay; Intellectual disability; Macrocephaly; Snijders Blok-Campeau syndrome, 618205
Intellectual disability v2.745 NBEA Ivone Leong Phenotypes for gene: NBEA were changed from Global developmental delay; Intellectual disability; Seizures to Global developmental delay; Intellectual disability; Seizures; No OMIM number
Intellectual disability v2.744 MSL3 Ivone Leong Classified gene: MSL3 as Green List (high evidence)
Intellectual disability v2.744 MSL3 Ivone Leong Added comment: Comment on list classification: Promoted from amber to green based on the new evidence provided by Konstantinos Varvagiannis. MSL3 is not associated with any phenotypes in OMIM; however, it has been confirmed to be associated with a phenotype in Gene2Phenotype with intellectual disability listed as one of the phenotypes.
Intellectual disability v2.744 MSL3 Ivone Leong Gene: msl3 has been classified as Green List (High Evidence).
Intellectual disability v2.743 MAST1 Ivone Leong Classified gene: MAST1 as Green List (high evidence)
Intellectual disability v2.743 MAST1 Ivone Leong Added comment: Comment on list classification: MAST1 has been given a green gene rating based on the evidence provided by Konstantinos Varvagiannis.
Intellectual disability v2.743 MAST1 Ivone Leong Gene: mast1 has been classified as Green List (High Evidence).
Intellectual disability v2.742 PUS7 Konstantinos Varvagiannis edited their review of gene: PUS7: Added comment: PMID: 30778726 (2019 - Shaheen et al.) reports 3 additional individuals from 2 consanguineous families. ID was a feature in all three. Variants reported: NM_019042.3 c.1507G>T or p.(Asp503Tyr) and c.329_332delCTGA or p.(Thr110Argfs*4), each found in homozygous state in affected individuals. As a result, PUS7 can be considered for inclusion in the ID panel as green. (The PMID for the article by de Brouwer et al. was added).; Changed publications: 30526862, 30778726
Intellectual disability v2.742 HK1 Konstantinos Varvagiannis reviewed gene: HK1: Rating: GREEN; Mode of pathogenicity: None; Publications: 30778173, 28135719; Phenotypes: Abnormal muscle tone, Global developmental delay, Intellectual disability, Visual impairment, Neurological speech impairment, Ataxia; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Intellectual disability v2.742 WARS2 Konstantinos Varvagiannis gene: WARS2 was added
gene: WARS2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: WARS2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: WARS2 were set to 28236339; 28650581; 28905505; 29783990; 29120065
Phenotypes for gene: WARS2 were set to Neurodevelopmental disorder, mitochondrial, with abnormal movements and lactic acidosis, with or without seizures, 617710
Penetrance for gene: WARS2 were set to unknown
Review for gene: WARS2 was set to GREEN
gene: WARS2 was marked as current diagnostic
Added comment: Several individuals with biallelic pathogenic WARS2 variants have been published to date. DD and ID have been reported among others in most of the affected individuals (only the respective features are commented on below):

PMID: 28236339 (Musante et al. 2017) : 2 sibs compound heterozygous for NM_201263.2:c.325delA (p.Ser109Alafs*159) and c.37T>G (p.Trp13Gly). DD with ID were features in both.

PMID: 28650581 (Theisen et al. 2017) : The authors report on 1 individual with DD, ID and seizures was found to harbor in the compound heterozygous state NM_0158360.3:c.938A>T (p.K313M) and c.298_300delCTT (p.L100del).

PMID: 28905505 (Wortmann et al. 2017) : Details on 6 individuals from 5 unrelated families are provided. DD and ID were observed in 5 of these individuals (Fam 2-5). Severe, neonatal presentation was the case for an additional subject. Confirmed occurrence of epilepsy was reported for 3 individuals from 2 families (and suspected in a further one). Using NM_0158360.3 variants were the following :
Fam1 : c.91-8725_348+27113del36096 (p.Lys31_Glndel116) in trans with c.1045G>C (p.Val349Leu)
Fam2 : c.797del (p.Pro266Argfs*10) in trans with c.938A>T (p.Lys313met) [in 2 individuals]
Fam3 : c.231C>G (p.His77Gln) in trans with c.1054G>A (p.Glu352Lys)
Fam4 : c.532G>C (p.Val178Leu) in homozygous state
Fam5 : c.134G>T (p.Gly45Val) in trans with c.938A>T (p.Lys313Met)

PMID: 29783990 (Vantroys et al. 2018) : The authors report on 1 individual with DD, ID and seizures (among other features), compound heterozygous for c.797del (p.Pro266Argfs*10) and c.938A>T (p.Lys313met), similar to subjects from family 2 in PMID: 28905505.

PMID: 29120065 (Burke et al. 2018) : One 17-year-old boy with infantile-onset Parkinsonism but not DD/ID is described in this study. This individuals was found to harbor in the following variants in the compound heterozygous state: NM_015836.3: c.37T>G (p.Trp13Gly) and c.683C>G (p.Ser228Trp).

Probably 7 missense variants, 3 frameshift ones and an intragenic deletion have been reported in individuals with DD/ID (overview in fig 4. - in PMID: 29783990).
- p.Pro266Argfs*10 is located in the last exon of the gene (NM_015836.3).
- p.Trp13Gly (c.37T>G using either NM_201263.2 or NM_015836.3 as ref) has been commented to be a functional polymorphism 'uncovered' by the presence of a LoF allele in trans in affected individuals (AF : 0.003265 and 6 homozygotes in gnomAD)
- p.Lys313Met is possibly the most frequently reported variant as discussed by Vantroys et al.

WARS2 encodes mitochondrial tryptophanyl-tRNA synthetase (a cytoplasmic form is encoded by WARS). As commented in most of the articles, aminoacyl-tRNA synthetases (ARS) are a group of enzymes responsible for ligating amino acids to cognate tRNA molecules. Mutations in mitochondrial ARSs lead to impaired intramitochondrial translation affecting OXPHOS complexes (with mitochondrial-encoded subunits). Mutations in all 19 mitochondrial ARSs have been linked to disorders affecting different organ systems with variable severity and phenotypic presentation (summarized by Vantroys et al.).

Several lines of evidence have been provided to support a role for specific variants (eg. reduced WARS2 amounts upon Western blot, or impaired mitochondrial localization depending on the different variants and their effect) or WARS2 (expression in brain, impaired aminoacylation, abnormalities in OXPHOS enzymes/biosynthesis , etc).

Alternative causes (disorders of the differential diagnosis) have been ruled out on most - if not all - occasions.

As commented by Wortmann et al. the clinical spectrum appears to be broad as for the age of onset, features and clinical course (as happens to be the case for some other disorders due deficiencies of other ARSs). The same authors state that apart from elevated lactate which is suggestive of mitochondrial dysfunction, no specific metabolite was found to be altered in affected individuals.

Phenotypic variability even between individuals with the same genotype has been reported. Eg. severe neonatal presentation with lactic acidosis/hypoglycaemia was the case for 2 sibs in family 2 from Wortmann et al. but the clinical course was different for the subject reported by Vantroys et al. (DD/ID with seizure onset at the age of 6 yrs).

As a result, investigations (and selection of gene panel) may not be straightforward.

In addition consideration of this gene in the epilepsy panel seems to be relevant given that seizures were noted in at least 5 individuals (from 4 families - 28650581, 28905505, 29783990) and severe adverse effects of valproate administration occurred in the subject reported by Vantroys et al.
-----------
The associated phenotype in OMIM is Neurodevelopmental disorder, mitochondrial, with abnormal movements and lactic acidosis, with or without seizures (# 617710). WARS2 is not associated with any disorder in G2P.
This gene is included in panels for ID offered by some diagnostic laboratories.
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As a result, WARS2 can be considered for inclusion in the ID and epilepsy panels as green (or amber).
Sources: Literature
Intellectual disability v2.742 KDM5B Ivone Leong Phenotypes for gene: KDM5B were changed from neurodevelopment delay and autism spectrum disorder to neurodevelopment delay and autism spectrum disorder; Mental retardation, autosomal recessive 65, 618109
Intellectual disability v2.741 KDM5B Ivone Leong Publications for gene: KDM5B were set to http://www.nature.com/nature/journal/v515/n7526/pdf/nature13908.pdf; 24307393
Intellectual disability v2.740 ITCH Ivone Leong Added comment: Comment on publications: PMID: 20170897 describes a large Amish family with 10 affected individuals from 8 consanguineous and related families with multisystem autoimmune disease with facial dysmorphism. The affected individuals have organomegaly, failure to thrive, developmental delay, dysmorphic features, and autoimmune inflammatory cell infiltration of the lungs, liver, and gut.
Intellectual disability v2.740 ITCH Ivone Leong Publications for gene: ITCH were set to
Intellectual disability v2.739 ITCH Ivone Leong Phenotypes for gene: ITCH were changed from to Autoimmune disease, multisystem, with facial dysmorphism, 613385
Intellectual disability v2.738 ITCH Ivone Leong Mode of inheritance for gene: ITCH was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v2.737 NUDT2 Ivone Leong Classified gene: NUDT2 as Amber List (moderate evidence)
Intellectual disability v2.737 NUDT2 Ivone Leong Added comment: Comment on list classification: NUDT2 has been given an amber gene rating based on the evidence provided by Konstantinos Varvagiannis.
Intellectual disability v2.737 NUDT2 Ivone Leong Gene: nudt2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v2.736 HEPACAM Ivone Leong Classified gene: HEPACAM as Green List (high evidence)
Intellectual disability v2.736 HEPACAM Ivone Leong Added comment: Comment on list classification: Promoted from red to green, based on the evidence provided by Konstantinos Varvagiannis (Other) and Zornitza Stark (Australian Genomics).
Intellectual disability v2.736 HEPACAM Ivone Leong Gene: hepacam has been classified as Green List (High Evidence).
Intellectual disability v2.735 HEPACAM Ivone Leong Phenotypes for gene: HEPACAM were changed from Megalencephalic leukoencephalopathy with subcortical cysts 2B, remitting, with or without mental retardation (AD); Megalencephalic leukoencephalopathy with subcortical cysts 2A (AR) to Megalencephalic leukoencephalopathy with subcortical cysts 2B, remitting, with or without mental retardation (AD), 613926; Megalencephalic leukoencephalopathy with subcortical cysts 2A (AR), 613925
Intellectual disability v2.734 NUDT2 Ivone Leong Tag founder-effect tag was added to gene: NUDT2.
Intellectual disability v2.734 NUDT2 Ivone Leong Phenotypes for gene: NUDT2 were changed from Muscular hypotonia; Global developmental delay; Intellectual disability to Muscular hypotonia; Global developmental delay; Intellectual disability; no OMIM number
Intellectual disability v2.733 NTRK2 Ivone Leong Classified gene: NTRK2 as Green List (high evidence)
Intellectual disability v2.733 NTRK2 Ivone Leong Added comment: Comment on list classification: NTRK2 has been given a green gene rating based on the expert review provided by Konstantinos Varvagiannis.
Intellectual disability v2.733 NTRK2 Ivone Leong Gene: ntrk2 has been classified as Green List (High Evidence).
Intellectual disability v2.732 NTRK2 Ivone Leong Phenotypes for gene: NTRK2 were changed from Epileptic encephalopathy, early infantile, 58 (MIM 617830); Obesity, hyperphagia, and developmental delay (MIM 613886) to Epileptic encephalopathy, early infantile, 58, 617830; Obesity, hyperphagia, and developmental delay, 613886
Intellectual disability v2.731 NSD2 Ivone Leong Classified gene: NSD2 as Green List (high evidence)
Intellectual disability v2.731 NSD2 Ivone Leong Added comment: Comment on list classification: NSD2 has been given a green gene rating based on the evidence provided by Konstantinos Varvagiannis. NSD2 is not associated with any phenotypes on OMIM or Gene2Phenotypes.
Intellectual disability v2.731 NSD2 Ivone Leong Gene: nsd2 has been classified as Green List (High Evidence).
Intellectual disability v2.730 NSD2 Ivone Leong Phenotypes for gene: NSD2 were changed from Intrauterine growth retardation; Growth delay; Microcephaly; Muscular hypotonia; Neurodevelopmental delay; Intellectual disability to Intrauterine growth retardation; Growth delay; Microcephaly; Muscular hypotonia; Neurodevelopmental delay; Intellectual disability; No OMIM number
Intellectual disability v2.729 NR4A2 Ivone Leong Phenotypes for gene: NR4A2 were changed from Language impairment; Intellectual disability; Autism; Behavioral abnormality to Language impairment; Intellectual disability; Autism; Behavioral abnormality; No OMIM number
Intellectual disability v2.728 FRMPD4 Louise Daugherty Phenotypes for gene: FRMPD4 were changed from Mental retardation, X-linked 104, 300983 to Mental retardation, X-linked 104, 300983; global developmental delay; intellectual disability
Intellectual disability v2.727 FRMPD4 Louise Daugherty Added comment: Comment on publications: Added PMID: 29267967 from external review, to support this gene being upgraded to Green
Intellectual disability v2.727 FRMPD4 Louise Daugherty Publications for gene: FRMPD4 were set to 26350204; 24896178; 25644381; 20613765; 23871722
Intellectual disability v2.726 FRMPD4 Louise Daugherty Phenotypes for gene: FRMPD4 were changed from Mental retardation, X-linked 104 300983 to Mental retardation, X-linked 104, 300983
Intellectual disability v2.725 FRMPD4 Louise Daugherty Added comment: Comment on mode of inheritance: reviewed MOI in view of external review
Intellectual disability v2.725 FRMPD4 Louise Daugherty Mode of inheritance for gene: FRMPD4 was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Intellectual disability v2.724 DOCK6 Louise Daugherty edited their review of gene: DOCK6: Added comment: Changed from Amber to Green. Appropriate phenotype, sufficient cases, external review comment and internal clinical review all support gene-disease association.; Changed rating: GREEN
Intellectual disability v2.724 DOCK6 Louise Daugherty Classified gene: DOCK6 as Green List (high evidence)
Intellectual disability v2.724 DOCK6 Louise Daugherty Added comment: Comment on list classification: Changed from Amber to Green. Appropriate phenotype, sufficient cases, external review comment and internal clinical review all support gene-disease association.
Intellectual disability v2.724 DOCK6 Louise Daugherty Gene: dock6 has been classified as Green List (High Evidence).
Intellectual disability v2.723 DOCK6 Louise Daugherty Phenotypes for gene: DOCK6 were changed from Adams-Oliver syndrome 2 614219 to Adams-Oliver syndrome 2, 614219; intellectual disability, developmental delay
Intellectual disability v2.722 DOCK6 Louise Daugherty Tag watchlist was removed from gene: DOCK6.
Intellectual disability v2.722 CDK10 Louise Daugherty Classified gene: CDK10 as Green List (high evidence)
Intellectual disability v2.722 CDK10 Louise Daugherty Added comment: Comment on list classification: Changed from Red to Green. Appropriate phenotype, sufficient cases and external expert review all support gene-disease association and relevance to this panel to rate gene as Green.
Intellectual disability v2.722 CDK10 Louise Daugherty Gene: cdk10 has been classified as Green List (High Evidence).
Intellectual disability v2.721 CDK10 Louise Daugherty Mode of inheritance for gene: CDK10 was changed from to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v2.720 CDK10 Louise Daugherty Added comment: Comment on publications: Added publication suggested by external reviewer to support gene-disease association, and upgrading of the gene to Green
Intellectual disability v2.720 CDK10 Louise Daugherty Publications for gene: CDK10 were set to
Intellectual disability v2.719 CDK10 Louise Daugherty Phenotypes for gene: CDK10 were changed from to Al Kaissi syndrome, 617694; intellectual disability
Intellectual disability v2.718 CCDC47 Louise Daugherty Classified gene: CCDC47 as Green List (high evidence)
Intellectual disability v2.718 CCDC47 Louise Daugherty Added comment: Comment on list classification: New gene added by external expert and reviewed by curation team: appropriate phenotype, sufficient cases and external expert review all support gene-disease association and relevance to this panel to rate gene to Green.
Intellectual disability v2.718 CCDC47 Louise Daugherty Gene: ccdc47 has been classified as Green List (High Evidence).
Intellectual disability v2.717 CCDC47 Louise Daugherty commented on gene: CCDC47: Trichohepatoneurodevelopmental syndrome is a complex multisystem disorder characterized by woolly or coarse hair, liver dysfunction, pruritus, dysmorphic features, hypotonia, and severe global developmental delay (Morimoto el al., 2018)
Intellectual disability v2.717 CCDC47 Louise Daugherty Added comment: Comment on phenotypes: Added OMIM phenotype and MIMid
Intellectual disability v2.717 CCDC47 Louise Daugherty Phenotypes for gene: CCDC47 were changed from Woolly hair; Abnormality of the liver; Global developmental delay; Intellectual disability to Woolly hair; Abnormality of the liver; Global developmental delay; Intellectual disability; Trichohepatoneurodevelopmental syndrome, 618268
Intellectual disability v2.716 CACNA1E Louise Daugherty Classified gene: CACNA1E as Green List (high evidence)
Intellectual disability v2.716 CACNA1E Louise Daugherty Added comment: Comment on list classification: New gene added by external expert and reviewed by curation team, appropriate phenotype, sufficient cases and external expert review all support gene-disease association and relevance to this panel to rate gene to Green.
Intellectual disability v2.716 CACNA1E Louise Daugherty Gene: cacna1e has been classified as Green List (High Evidence).
Intellectual disability v2.715 CACNA1E Louise Daugherty Added comment: Comment on publications: added Helbig et al. publication that supports the gene-disease association, and upgrading of the gene to Green
Intellectual disability v2.715 CACNA1E Louise Daugherty Publications for gene: CACNA1E were set to 29942082
Intellectual disability v2.714 CACNA1E Louise Daugherty Added comment: Comment on phenotypes: added phenotype info from OMIM and MIMid
Intellectual disability v2.714 CACNA1E Louise Daugherty Phenotypes for gene: CACNA1E were changed from Global developmental delay; Intellectual disability; Seizures; Dystonia; Congenital contracture; Macrocephaly to Global developmental delay; Intellectual disability; Seizures; Dystonia; Congenital contracture; Macrocephaly; Epileptic encephalopathy, early infantile, 69, 618285
Intellectual disability v2.713 BCL11B Louise Daugherty Classified gene: BCL11B as Green List (high evidence)
Intellectual disability v2.713 BCL11B Louise Daugherty Added comment: Comment on list classification: New gene added by external expert and reviewed by curation team, appropriate phenotype, sufficient cases and external expert review all support gene-disease association and relevance to this panel to rate gene to Green.
Intellectual disability v2.713 BCL11B Louise Daugherty Gene: bcl11b has been classified as Green List (High Evidence).
Intellectual disability v2.712 BCL11B Louise Daugherty Added comment: Comment on phenotypes: Added phenotypes from OMIM and MIMid that indicate relevance to inclusion on the intellectual disability panel
Intellectual disability v2.712 BCL11B Louise Daugherty Phenotypes for gene: BCL11B were changed from Intellectual disability to Intellectual disability; Intellectual developmental disorder with dysmorphic facies, speech delay, and T-cell abnormalities, 618092
Intellectual disability v2.711 ATP8A2 Louise Daugherty Classified gene: ATP8A2 as Green List (high evidence)
Intellectual disability v2.711 ATP8A2 Louise Daugherty Added comment: Comment on list classification: Changed from Amber to Green. Appropriate phenotype, sufficient cases, and external review comment all support gene-disease association.
Intellectual disability v2.711 ATP8A2 Louise Daugherty Gene: atp8a2 has been classified as Green List (High Evidence).
Intellectual disability v2.710 ATP8A2 Louise Daugherty Phenotypes for gene: ATP8A2 were changed from ?Cerebellar ataxia, mental retardation, and dysequilibrium syndrome 4 615268 to ?Cerebellar ataxia, mental retardation, and dysequilibrium syndrome 4 615268; intellectual disability
Intellectual disability v2.709 ATP8A2 Louise Daugherty Phenotypes for gene: ATP8A2 were changed from ?Cerebellar ataxia, mental retardation, and dysequilibrium syndrome 4 615268 to ?Cerebellar ataxia, mental retardation, and dysequilibrium syndrome 4 615268
Intellectual disability v2.708 ATP8A2 Louise Daugherty Added comment: Comment on publications: Added publications suggested from external expert review to support upgrading of the gene to Green
Intellectual disability v2.708 ATP8A2 Louise Daugherty Publications for gene: ATP8A2 were set to 22892528
Intellectual disability v2.707 ASNS Louise Daugherty Publications for gene: ASNS were set to 24139043; 25227173; 30234940; 27743885; 29375865
Intellectual disability v2.706 ASNS Louise Daugherty Classified gene: ASNS as Green List (high evidence)
Intellectual disability v2.706 ASNS Louise Daugherty Added comment: Comment on list classification: New gene added by external expert and reviewed by curation team, enough evidence to support gene-disease association and relevance to this panel to rate this gene Green. From PMID: 29375865 (2018) A. Abhyankar et al. summarised Ruzzo et al. (PMID:24139043) studied nine children from four families presenting with similar phenotypes and reported two missense mutations‐c.1084T>G (p.F362V; NM_183356) and c.1648C>T (p.R550C; NM_183356) in the asparagine synthetase domain that dramatically reduce ASNS protein abundance. The authors concluded that accumulation of aspartate/glutamate secondary to ASNS depletion in the brain resulted in the neurologic impairment. One of the two mutations reported in that study, c.1084T>G (p.F362V; NM_183356), is four residues upstream of NP_001664.3:p.Gly366Glu seen in our patient. HEK293 cells expressing c.1084T>G (p.F362V; NM_183356) mutant allele showed dramatic reduction in protein abundance. Additionally, Ruzzo et al. reported a hypomorphic ASNS mouse knockout with structural brain abnormalities and deficits in learning/memory. Subsequently, eight more cases of ASNSD have been reported in the literature PMID: 2566342,27422383, 27469131, 27743885.
Intellectual disability v2.706 ASNS Louise Daugherty Gene: asns has been classified as Green List (High Evidence).
Intellectual disability v2.705 ASNS Louise Daugherty commented on gene: ASNS: Comment on publications: Added GeneReview PMID: 30234940 (2018) for Asparagine Synthetase Deficiency and PMID:27743885 (2017) first two cases (related) Japanese patients with ASNS deficiency with developmental delay and PMID: 29375865 (2017) reports two novel compound heterozygous missense variants in asparagine synthetase gene as the likely cause of fatal asparagine synthetase deficiency in a single neonate case.
Intellectual disability v2.705 ASNS Louise Daugherty Phenotypes for gene: ASNS were changed from Asparagine synthetase deficiency, 615574; congenital microcephaly, severe developmental delay, and axial hypotonia followed by spastic quadriplegia to Asparagine synthetase deficiency, 615574; congenital microcephaly, intellectual disability, progressive cerebral atrophy, intractable seizures
Intellectual disability v2.704 ASNS Louise Daugherty Added comment: Comment on publications: Added GeneReview PMID: 30234940 (2018) for Asparagine Synthetase Deficiency and PMID:27743885 (2017) first two cases (related) Japanese patients with ASNS deficiency with developmental delay
Intellectual disability v2.704 ASNS Louise Daugherty Publications for gene: ASNS were set to 24139043; 25227173
Intellectual disability v2.703 ASNS Louise Daugherty Added comment: Comment on phenotypes: added phenotypes to indicate relevance to panel
Intellectual disability v2.703 ASNS Louise Daugherty Phenotypes for gene: ASNS were changed from Asparagine synthetase deficiency, 615574 to Asparagine synthetase deficiency, 615574; congenital microcephaly, severe developmental delay, and axial hypotonia followed by spastic quadriplegia
Intellectual disability v2.702 ARL13B Louise Daugherty Added comment: Comment on phenotypes: Added
Intellectual disability v2.702 ARL13B Louise Daugherty Phenotypes for gene: ARL13B were changed from Joubert syndrome 8 612291 to Joubert syndrome 8, 612291; Intellectual disability
Intellectual disability v2.701 ARL13B Louise Daugherty Added comment: Comment on publications: Added publications suggested from external expert review to support Green rating
Intellectual disability v2.701 ARL13B Louise Daugherty Publications for gene: ARL13B were set to 18674751; 25138100
Intellectual disability v2.700 AIMP2 Louise Daugherty Phenotypes for gene: AIMP2 were changed from Leukodystrophy, hypomyelinating, 17, 618006; neurodevelopmental disorder with microcephaly, seizures, and spastic quadriparesis to Leukodystrophy, hypomyelinating, 17, 618006; neurodevelopmental disorder with microcephaly, seizures, and spastic quadriparesis
Intellectual disability v2.699 AIMP2 Louise Daugherty Classified gene: AIMP2 as Amber List (moderate evidence)
Intellectual disability v2.699 AIMP2 Louise Daugherty Added comment: Comment on list classification: New gene added by external expert and reviewed by curation team, enough evidence to support gene-disease association and relevance to this panel to rate this gene currently as Amber
Intellectual disability v2.699 AIMP2 Louise Daugherty Gene: aimp2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v2.698 AIMP2 Louise Daugherty Phenotypes for gene: AIMP2 were changed from Leukodystrophy, hypomyelinating, 17 (MIM 618006) to Leukodystrophy, hypomyelinating, 17, 618006; neurodevelopmental disorder with microcephaly, seizures, and spastic quadriparesis
Intellectual disability v2.697 AGO1 Louise Daugherty Classified gene: AGO1 as Amber List (moderate evidence)
Intellectual disability v2.697 AGO1 Louise Daugherty Added comment: Comment on list classification: Changed rating of gene from Red to Amber based on current information in the literature and external expert review. There is not enough evidence to support gene-disease association rating of this gene to Green.
Intellectual disability v2.697 AGO1 Louise Daugherty Gene: ago1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v2.696 AGO1 Louise Daugherty Tag missense tag was added to gene: AGO1.
Intellectual disability v2.696 AGO1 Louise Daugherty Added comment: Comment on phenotypes: Added phenotypes suggested from expert review that indicate relevance to inclusion on the ID panel
Intellectual disability v2.696 AGO1 Louise Daugherty Phenotypes for gene: AGO1 were changed from to Generalized hypotonia; Global developmental delay; Intellectual disability; Autism
Intellectual disability v2.695 AGO1 Louise Daugherty Added comment: Comment on publications: Added publications suggested from external expert review to support upgrading of the gene. Also added PMID: 29726122 (2018) that reports a novel 2.3 Mb, de novo, 1p34.3p34.2 deletion in a patient with who has a history of global developmental delay, mild intellectual disability, delayed bone age, bilateral vesicoureteral reflux, vocal cord paralysis, right aberrant subclavian artery, kyphoscoliosis, bilateral metatarsus adductus, and valgus knee deformity. This adds to the evolving genetic literature that haploinsufficiency of this region and genes other than AGO1, AGO3, GRIK3, SLC2A1, and RIMS3 may lead to the neurocognitive delays
Intellectual disability v2.695 AGO1 Louise Daugherty Publications for gene: AGO1 were set to 26350204
Intellectual disability v2.694 NFIB Ivone Leong Classified gene: NFIB as Green List (high evidence)
Intellectual disability v2.694 NFIB Ivone Leong Added comment: Comment on list classification: NFIB has been given a green gene status based on the evidence provided by Konstantinos Varvagiannis. NFIB is associated with phenotypes in OMIM and Gene2Phenotype.
Intellectual disability v2.694 NFIB Ivone Leong Gene: nfib has been classified as Green List (High Evidence).
Intellectual disability v2.693 AGO1 Louise Daugherty commented on gene: AGO1: AGO1 previous HGNC gene symbol was EIF2C1.
Intellectual disability v2.693 AGO1 Louise Daugherty Added comment: Comment on mode of inheritance: changed MOI- agreed with external reviwer that x linked is not appropriate for this gene and was an error
Intellectual disability v2.693 AGO1 Louise Daugherty Mode of inheritance for gene: AGO1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v2.692 ADAT3 Louise Daugherty Classified gene: ADAT3 as Green List (high evidence)
Intellectual disability v2.692 ADAT3 Louise Daugherty Added comment: Comment on list classification: New gene added by external expert and reviewed by curation team, enough evidence to support gene-disease association and relevance to this panel to rate this gene Green
Intellectual disability v2.692 ADAT3 Louise Daugherty Gene: adat3 has been classified as Green List (High Evidence).
Intellectual disability v2.691 ADAT3 Louise Daugherty Phenotypes for gene: ADAT3 were changed from # 615286. MENTAL RETARDATION, AUTOSOMAL RECESSIVE 36; MRT36 to Mental retardation, autosomal recessive 36, 615286; MRT36
Intellectual disability v2.690 NFIB Ivone Leong Phenotypes for gene: NFIB were changed from Global developmental delay; Intellectual disability; Macrocephaly to Global developmental delay; Intellectual disability; Macrocephaly; Macrocephaly, acquired, with impaired intellectual development, 618286
Intellectual disability v2.689 NECAP1 Ivone Leong Classified gene: NECAP1 as Amber List (moderate evidence)
Intellectual disability v2.689 NECAP1 Ivone Leong Added comment: Comment on list classification: NECAP1 has been given an amber gene rating based on the evidence provided by Konstantinos Varvagiannis. As patients from the cases described in PMID: 24399846, 30525121 are from Saudi Arabia and have the same variant, these are counted as a single piece of evidence. Therefore, there are not enough evidence to promote this gene to a green rating at this stage.
Intellectual disability v2.689 NECAP1 Ivone Leong Gene: necap1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v2.688 ABAT Louise Daugherty Phenotypes for gene: ABAT were changed from GABA-transaminase deficiency, 613163 to GABA-transaminase deficiency, 613163; developmental delay
Intellectual disability v2.687 ABAT Louise Daugherty Classified gene: ABAT as Amber List (moderate evidence)
Intellectual disability v2.687 ABAT Louise Daugherty Added comment: Comment on list classification: Rated gene as Amber based on current information in the literature and external expert review there is not enough evidence to support gene-disease association rating of this gene to Green.
Intellectual disability v2.687 ABAT Louise Daugherty Gene: abat has been classified as Amber List (Moderate Evidence).
Intellectual disability v2.686 ABAT Louise Daugherty Publications for gene: ABAT were set to 27596361; 28411234
Intellectual disability v2.685 ABAT Louise Daugherty Added comment: Comment on publications: Added publications suggested from external expert review to support upgrading of the gene to Green
Intellectual disability v2.685 ABAT Louise Daugherty Publications for gene: ABAT were set to 27596361
Intellectual disability v2.684 MSL3 Ivone Leong Phenotypes for gene: MSL3 were changed from to Muscular hypotonia; Feeding difficulties; Neurodevelopmental delay; Intellectual disability; no OMIM number
Intellectual disability v2.683 MSL3 Ivone Leong Publications for gene: MSL3 were set to 26350204; 19377476; 28135719; 25529582
Intellectual disability v2.682 METTL23 Ivone Leong Classified gene: METTL23 as Green List (high evidence)
Intellectual disability v2.682 METTL23 Ivone Leong Added comment: Comment on list classification: METTL23 has been given a green gene rating based on the evidence provided by Konstantinos Varvagiannis (Other). There is enough evidence to support a gene-disease link.
Intellectual disability v2.682 METTL23 Ivone Leong Gene: mettl23 has been classified as Green List (High Evidence).
Intellectual disability v2.681 METTL23 Ivone Leong Phenotypes for gene: METTL23 were changed from Mental retardation, autosomal recessive 44 (MIM 615942) to Mental retardation, autosomal recessive 44, 615942
Intellectual disability v2.680 MEIS2 Ivone Leong Publications for gene: MEIS2 were set to 27225850, 24678003, 25712757; 30291340; 30055086
Intellectual disability v2.679 NBEA Ivone Leong Publications for gene: NBEA were set to
Intellectual disability v2.678 MEIS2 Ivone Leong Classified gene: MEIS2 as Green List (high evidence)
Intellectual disability v2.678 MEIS2 Ivone Leong Added comment: Comment on list classification: Promoted from red to green based on the additional evidence provided by Konstantinos Varvagiannis (Other). MEIS2 is associated with a phenotype in OMIM but not in Gene2Phenotype.
Intellectual disability v2.678 MEIS2 Ivone Leong Gene: meis2 has been classified as Green List (High Evidence).
Intellectual disability v2.677 MEIS2 Ivone Leong Phenotypes for gene: MEIS2 were changed from Cleft palate, cardiac defects, and mental retardation to Cleft palate, cardiac defects, and mental retardation; Oral cleft; Abnormal heart morphology; Intellectual disability; Cleft palate, cardiac defects, and mental retardation, 600987
Intellectual disability v2.676 MEIS2 Ivone Leong Publications for gene: MEIS2 were set to 27225850, 24678003, 25712757
Intellectual disability v2.675 MCM3AP Ivone Leong Classified gene: MCM3AP as Green List (high evidence)
Intellectual disability v2.675 MCM3AP Ivone Leong Added comment: Comment on list classification: MCM3AP has been given a green gene rating, based on the evidence provided by Konstantinos Varvagiannis (Other) and that there are >3 cases of unrelated patients with variants in MCM3AP who have ID. The gene is associated with a phenotype on OMIM but not Gene2Phenotype.
Intellectual disability v2.675 MCM3AP Ivone Leong Gene: mcm3ap has been classified as Green List (High Evidence).
Intellectual disability v2.674 SLC35A1 Rebecca Foulger commented on gene: SLC35A1: Removed watchlist tag following promotion of SLC35A1 to Green.
Intellectual disability v2.674 SLC35A1 Rebecca Foulger Tag watchlist was removed from gene: SLC35A1.
Intellectual disability v2.674 SLC35A1 Rebecca Foulger Classified gene: SLC35A1 as Green List (high evidence)
Intellectual disability v2.674 SLC35A1 Rebecca Foulger Added comment: Comment on list classification: Updated rating from Amber to Green following clinical agreement from Helen Brittain: Green review by Konstantinos Varvagiannis, and currently 3 SLC35A1 cases with ID and seizures (PMIDs: 23873973, 28856833, 30115659).
Intellectual disability v2.674 SLC35A1 Rebecca Foulger Gene: slc35a1 has been classified as Green List (High Evidence).
Intellectual disability v2.673 SLC35A1 Rebecca Foulger Publications for gene: SLC35A1 were set to 23873973, 15576474, 28856833; 30115659
Intellectual disability v2.672 SLC35A1 Rebecca Foulger Phenotypes for gene: SLC35A1 were changed from Congenital disorder of glycosylation, type Iif, 603585; intellectual disability, ataxia, seizures, bleeding diathesis and proteinuria to Congenital disorder of glycosylation, type IIf, 603585; intellectual disability, ataxia, seizures, bleeding diathesis and proteinuria
Intellectual disability v2.671 SLC35A1 Rebecca Foulger Publications for gene: SLC35A1 were set to 23873973, 15576474, 28856833
Intellectual disability v2.670 SLC35A1 Rebecca Foulger edited their review of gene: SLC35A1: Added comment: Summary of evidence: There are 2 existing cases of ID and SLC35A1 variants (a Turkish patient in PMID:23873973, and a German patient in PMID:28856833). There is a further paper linking SLC35A1 to a glycosylation disorder (PMID:15576474) but without an ID or epilepsy phenotype. As noted by Konstantinos Varvagiannis, a 2018 paper (PMID:30115659) now reports 2 siblings with a haematological phenotype and a homozygous p.Ser147Pro variant in SLC35A1. The authors say that the siblings' phenotypes included delayed psychomotor development, epilepsy, ataxia, microcephaly, choreiform movements, and macrothrombocytopenia.; Changed phenotypes: Congenital disorder of glycosylation, type Iif, 603585, intellectual disability, ataxia, seizures, bleeding diathesis and proteinuria
Intellectual disability v2.670 MCM3AP Ivone Leong Phenotypes for gene: MCM3AP were changed from Peripheral neuropathy, autosomal recessive, with or without impaired intellectual development (MIM 618124) to Peripheral neuropathy, autosomal recessive, with or without impaired intellectual development, 618124
Intellectual disability v2.669 MAST1 Ivone Leong Phenotypes for gene: MAST1 were changed from Global developmental delay, Intellectual disability, Abnormality of the corpus callosum, Cerebellar hypoplasia, Abnormality of the cerebral cortex, Seizures; Global developmental delay, Intellectual disability, Microcephaly, Autism, Seizures to Global developmental delay, Intellectual disability, Abnormality of the corpus callosum, Cerebellar hypoplasia, Abnormality of the cerebral cortex, Seizures; Global developmental delay, Intellectual disability, Microcephaly, Autism, Seizures; Mega-corpus-callosum syndrome with cerebellar hypoplasia and cortical malformations, 618273
Intellectual disability v2.668 MAPK8IP3 Ivone Leong Classified gene: MAPK8IP3 as Green List (high evidence)
Intellectual disability v2.668 MAPK8IP3 Ivone Leong Added comment: Comment on list classification: MAPK8IP3 has been given a green gene rating based on the evidence provided by the expert review. This gene is not associated with any phenotype on OMIM or Gene2Phenotype.
Intellectual disability v2.668 MAPK8IP3 Ivone Leong Gene: mapk8ip3 has been classified as Green List (High Evidence).
Intellectual disability v2.667 MAPK8IP3 Ivone Leong Phenotypes for gene: MAPK8IP3 were changed from 25363768; 28213671; 28135719 to Abnormal muscle tone; Global developmental delay; Intellectual disability; Abnormality of nervous system morphology; No OMIM number
Intellectual disability v2.666 MAPK8IP3 Ivone Leong Publications for gene: MAPK8IP3 were set to
Intellectual disability v2.665 MAP1B Ivone Leong Classified gene: MAP1B as Amber List (moderate evidence)
Intellectual disability v2.665 MAP1B Ivone Leong Added comment: Comment on list classification: MAP1B has been given an amber gene rating based on the evidence provided by the expert review. It is not associated with any phenotype on OMIM or Gene2Phenotype.
Intellectual disability v2.665 MAP1B Ivone Leong Gene: map1b has been classified as Amber List (Moderate Evidence).
Intellectual disability v2.664 MAP1B Ivone Leong Phenotypes for gene: MAP1B were changed from Intellectual disability to Intellectual disability; No OMIM number
Intellectual disability v2.663 MACF1 Ivone Leong Classified gene: MACF1 as Green List (high evidence)
Intellectual disability v2.663 MACF1 Ivone Leong Added comment: Comment on list classification: MACF1 has been given a green gene rating based on the evidence provided by the expert review. The gene is associated with a phenotype on OMIM but not on Gene2Phenotype.
Intellectual disability v2.663 MACF1 Ivone Leong Gene: macf1 has been classified as Green List (High Evidence).
Intellectual disability v2.662 MACF1 Ivone Leong Publications for gene: MACF1 were set to 30471716
Intellectual disability v2.661 MACF1 Ivone Leong Publications for gene: MACF1 were set to
Intellectual disability v2.660 MACF1 Ivone Leong Phenotypes for gene: MACF1 were changed from Intellectual disability; Seizures; Lissencephaly; Brainstem dysplasia to Intellectual disability; Seizures; Lissencephaly; Brainstem dysplasia; Lissencephaly 9 with complex brainstem malformation, 618325
Intellectual disability v2.659 MAB21L1 Ivone Leong Classified gene: MAB21L1 as Green List (high evidence)
Intellectual disability v2.659 MAB21L1 Ivone Leong Added comment: Comment on list classification: MAB21L1 has been given a green gene rating based on the evidence provided by the expert review. It is not associated with any phenotypes on OMIM or Gene2Phenotype.
Intellectual disability v2.659 MAB21L1 Ivone Leong Gene: mab21l1 has been classified as Green List (High Evidence).
Intellectual disability v2.658 MAB21L1 Ivone Leong Publications for gene: MAB21L1 were set to 27103078
Intellectual disability v2.657 MAB21L1 Ivone Leong Phenotypes for gene: MAB21L1 were changed from Global developmental delay; Intellectual disability; Cerebellar hypoplasia; Abnormality of the eye; Abnormality of the genital system to Global developmental delay; Intellectual disability; Cerebellar hypoplasia; Abnormality of the eye; Abnormality of the genital system; No OMIM number
Intellectual disability v2.656 LNPK Ivone Leong Classified gene: LNPK as Amber List (moderate evidence)
Intellectual disability v2.656 LNPK Ivone Leong Added comment: Comment on list classification: LNPK is associated with a phenotype in OMIM but not on Gene2Phenotype. It has been given an amber gene rating based on expert review. A watchlist tag has also been added.
Intellectual disability v2.656 LNPK Ivone Leong Gene: lnpk has been classified as Amber List (Moderate Evidence).
Intellectual disability v2.655 LNPK Ivone Leong Tag watchlist tag was added to gene: LNPK.
Intellectual disability v2.655 LNPK Ivone Leong Phenotypes for gene: LNPK were changed from Generalized hypotonia; Global developmental delay; Intellectual disability; Seizures; Hypoplasia of the corpus callosum; Abnormality of the cerebellum to Generalized hypotonia; Global developmental delay; Intellectual disability; Seizures; Hypoplasia of the corpus callosum; Abnormality of the cerebellum; Neurodevelopmental disorder with epilepsy and hypoplasia of the corpus callosum, 618090
Intellectual disability v2.654 CUX1 Konstantinos Varvagiannis gene: CUX1 was added
gene: CUX1 was added to Intellectual disability. Sources: Literature,Radboud University Medical Center, Nijmegen
Mode of inheritance for gene: CUX1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CUX1 were set to 30014507; 20510857; 25059644
Phenotypes for gene: CUX1 were set to Global developmental delay with or without impaired intellectual development, 618330
Penetrance for gene: CUX1 were set to unknown
Review for gene: CUX1 was set to GREEN
gene: CUX1 was marked as current diagnostic
Added comment: Heterozygous pathogenic variants in CUX1 cause Global developmental delay with or without impaired intellectual development (MIM 618330).

Platzer et al. (2018 - PMID: 30014507) report on 9 individuals from 7 families with heterozygous null-allele variants in CUX1.

All individuals displayed DD (speech delay 9/9 - motor delay 7/9 - hypotonia 3/7 for whom this information was available). Mild/moderate ID was a feature in 5/8. Catch up was observed in 3/8 individuals who - despite a history of previous significant DD - displayed a normal age-related intelligence. For 1/9 individual (Decipher 338131) information on eventual ID was unavailable. Overall the phenotype was compatible with non-syndromic DD with possible ID.

CUX1 encodes Cut homebox-1 transcription factor.

5 LoF variants (Gln21*, Gln800Argfs*19, Gln873*, Ala1067Cysfs*3, Leu1262Argfs*10) and 2 intragenic deletions (deletion of exons 9-24 in one subject and 3-24 in another) are reported.

In 6/9 individuals the variant (SNV/CNV) had occurred as a de novo event. Mosaic de novo intragenic deletion was reported for the subject from Decipher. In one family 2 sibs with mild ID had inherited a LoF variant from their affected mother with moderate ID (origin of the variant unknown in her case).

Leu1262Argfs*10 lies in the penultimate exon (NM_001202543.1 used as ref.) and is presumed to escape NMD.

Expression studies (or functional studies) are not performed for any of the variants.

As Gln800Argfs*19, found in one subject with mild ID in the present study, has been reported once in gnomAD, and given the presence of 12 individuals overall with LoF variants in the specific database, plausible explanations are discussed (among others : mild phenotype, incomplete penetrance, somatic mosaicism, exclusion of individuals with severe early-onset disorders in gnomAD, etc).

Given the reported variants, the probability of LoF intolerance (pLI:1.00), and the haploinsufficiency score (% HI) of 7.19, haploinsufficiency is thought to be the underlying mechanism. CUX1 however appears to be intolerant also to missense SNVs (z-score : 5.05).

Mouse models suggest a role for Cux1 in brain development and signaling. As the authors note, Cux1 (similar to its paralog, Cux2) is selectively expressed in layer II to IV cortical neurons. In Cux1-deficient mice, dendrites display a simpler morphology with decrease in dendritic length and number of branches (PMIDs cited: 20510857, 25059644). (MGI db for Cux1 - http://www.informatics.jax.org/marker/MGI:88568 : "Homozygotes for a targeted null mutation exhibit delayed lung development and neonatal mortality. Survivors show growth retardation and hair defects. Homozygotes for a partially deleted protein have curly hair, and females tend to lose their litters").

Finally, heterozygous mutations in CUX2, encoding cut-like homeobox-2 transcription factor, cause Epileptic encephalopathy, early infantile, 67 (MIM 618141 - in all cases reported to date due to a recurrent missense variant. Gene rated green in the current panel).
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CUX1 is not associated with any phenotype in G2P.
This gene is included in panels for ID offered by diagnostic laboratories (incl. Radboudumc).
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As a result, CUX1 can be considered for inclusion in the ID panel as green (or amber).
Sources: Literature, Radboud University Medical Center, Nijmegen
Intellectual disability v2.654 LINS1 Ivone Leong Phenotypes for gene: LINS1 were changed from AUTOSOMAL RECESSIVE MENTAL RETARDATION to AUTOSOMAL RECESSIVE MENTAL RETARDATION; Mental retardation, autosomal recessive 27, 614340
Intellectual disability v2.653 LINS1 Ivone Leong Publications for gene: LINS1 were set to
Intellectual disability v2.652 LINGO1 Ivone Leong Classified gene: LINGO1 as Amber List (moderate evidence)
Intellectual disability v2.652 LINGO1 Ivone Leong Added comment: Comment on list classification: Gave LINO1 amber gene rating based on review by Konstantinos Varvagiannis (Other). Have so added the 'watchilist' tag.
Intellectual disability v2.652 LINGO1 Ivone Leong Gene: lingo1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v2.651 LINGO1 Ivone Leong Tag watchlist tag was added to gene: LINGO1.
Intellectual disability v2.651 PHACTR1 Eleanor Williams commented on gene: PHACTR1
Intellectual disability v2.651 TCF20 Konstantinos Varvagiannis edited their review of gene: TCF20: Added comment: PMID: 30739909 (Torti et al. 2019) provides information on 27 new individuals and compares with the phenotype of 17 previously reported individuals. DD/ID was an almost universal feature (27/27 or 43/44 when considering all previously published cases).; Changed publications: 30739909, 27436265, 25228304, 28135719, 27479843, 28333917, 28554332, 30525188
Intellectual disability v2.651 SLC35A3 Rebecca Foulger Tag watchlist tag was added to gene: SLC35A3.
Intellectual disability v2.651 SLC35A3 Rebecca Foulger commented on gene: SLC35A3: Added watchlist tag.
Intellectual disability v2.651 SLC35A3 Rebecca Foulger Classified gene: SLC35A3 as Amber List (moderate evidence)
Intellectual disability v2.651 SLC35A3 Rebecca Foulger Added comment: Comment on list classification: Updated rating from Grey to Amber. Gene was added to panel and rated Green by Konstantinos Varvagiannis. 1 case (multiple individuals from Ashkenazi Jewish kindred) in PMID:24031089. A second case comes from PMID:28328131 (Marini et al. 2017). ID is not recorded in the SLC35A3‐related skeletal dysplasia patient from PMID:28777481 who died at 21days. ClinVar submissions weren't included as additional cases as individual phenotypes were not recorded. Therefore rated Amber awaiting further published or clinical cases.
Intellectual disability v2.651 SLC35A3 Rebecca Foulger Gene: slc35a3 has been classified as Amber List (Moderate Evidence).
Intellectual disability v2.650 KCNQ3 Ivone Leong Classified gene: KCNQ3 as Green List (high evidence)
Intellectual disability v2.650 KCNQ3 Ivone Leong Added comment: Comment on list classification: Promoted from amber to green, based on the expert reviews already provided. There are also >3 unrelated cases of patients with different variants in the KCNQ3 gene who have the described phenotype.
Intellectual disability v2.650 KCNQ3 Ivone Leong Gene: kcnq3 has been classified as Green List (High Evidence).
Intellectual disability v2.649 SLC35A3 Rebecca Foulger commented on gene: SLC35A3: The 2013 and 2016 ClinVar submissions SCV000699337.1 and SCV000108589.2 reported in the review by Konstantinos Varvagiannis link to the same publication: Edvardson et al. (2013, PMID:24031089).
Intellectual disability v2.649 PBX1 Eleanor Williams Publications for gene: PBX1 were set to 28566479, 29036646
Intellectual disability v2.648 PBX1 Eleanor Williams Classified gene: PBX1 as Green List (high evidence)
Intellectual disability v2.648 PBX1 Eleanor Williams Added comment: Comment on list classification: More than 3 cases where patients show developmental delay as part of the phenotype.
Intellectual disability v2.648 PBX1 Eleanor Williams Gene: pbx1 has been classified as Green List (High Evidence).
Intellectual disability v2.647 SLC35A3 Rebecca Foulger commented on gene: SLC35A3: Marini et al. 2017 (PMID: 28328131) provide a second case. They report a non-consanguineous Italian family with two siblings manifesting a severe EE. Both siblings exhibited infantile spasms associated with focal and tonic seizures from early infancy. In addition, both had quadriplegia, acquired microcephaly and severe ID. WGS identified novel compound het variants in SLC35A3 in both children.
Intellectual disability v2.647 SLC35A3 Rebecca Foulger commented on gene: SLC35A3
Intellectual disability v2.647 PBX1 Eleanor Williams commented on gene: PBX1
Intellectual disability v2.647 PAK1 Eleanor Williams Classified gene: PAK1 as Amber List (moderate evidence)
Intellectual disability v2.647 PAK1 Eleanor Williams Added comment: Comment on list classification: Changing rating from grey to amber. 2 cases to date. Appears to be gain of function
Intellectual disability v2.647 PAK1 Eleanor Williams Gene: pak1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v2.646 PAK1 Eleanor Williams commented on gene: PAK1
Intellectual disability v2.646 KCNK4 Ivone Leong Classified gene: KCNK4 as Amber List (moderate evidence)
Intellectual disability v2.646 KCNK4 Ivone Leong Added comment: Comment on list classification: Given an amber rating as there is currently only one report detailing 3 unrelated patients (2 Italian and 1 of European ancestry) who have variants (2 patients have the same missense variant and the third patient has a different missense variant). The paper also describe some in vitro cell studies.
Intellectual disability v2.646 KCNK4 Ivone Leong Gene: kcnk4 has been classified as Amber List (Moderate Evidence).
Intellectual disability v2.645 ODC1 Eleanor Williams Classified gene: ODC1 as Green List (high evidence)
Intellectual disability v2.645 ODC1 Eleanor Williams Added comment: Comment on list classification: Changing rating from grey to green. 5 unrelated cases with likely disease causing variants. All de novo.
Intellectual disability v2.645 ODC1 Eleanor Williams Gene: odc1 has been classified as Green List (High Evidence).
Intellectual disability v2.644 ODC1 Eleanor Williams commented on gene: ODC1
Intellectual disability v2.644 KARS Ivone Leong Classified gene: KARS as Green List (high evidence)
Intellectual disability v2.644 KARS Ivone Leong Added comment: Comment on list classification: Promoted from amber to green based on the evidence provided by Zornitza Stark (Australian Genomics) and Konstantinos Varvagiannis (Other).
Intellectual disability v2.644 KARS Ivone Leong Gene: kars has been classified as Green List (High Evidence).
Intellectual disability v2.643 KARS Ivone Leong Phenotypes for gene: KARS were changed from ?Charcot-Marie-Tooth disease, recessive intermediate, B, 613641; Deafness, autosomal recessive 89, 613916 to Global developmental delay; Intellectual disability; Seizures; ?Charcot-Marie-Tooth disease, recessive intermediate, B, 613641; Deafness, autosomal recessive 89, 613916
Intellectual disability v2.642 NUS1 Eleanor Williams commented on gene: NUS1
Intellectual disability v2.642 SLC1A2 Rebecca Foulger Classified gene: SLC1A2 as Green List (high evidence)
Intellectual disability v2.642 SLC1A2 Rebecca Foulger Added comment: Comment on list classification: Updated rating from Grey to Green. Added to panel and reviewed Green by Konstantinos Varvagiannis. As noted by Konstantinos Varvagiannis, 4 unrelated individuals reported (PMIDs:27476654, 28777935) all with profound/severe ID as a feature. Therefore sufficient cases to support a Green (diagnostic-grade) rating.
Intellectual disability v2.642 SLC1A2 Rebecca Foulger Gene: slc1a2 has been classified as Green List (High Evidence).
Intellectual disability v2.641 SLC1A2 Rebecca Foulger commented on gene: SLC1A2
Intellectual disability v2.641 SLC1A2 Rebecca Foulger Phenotypes for gene: SLC1A2 were changed from Epileptic encephalopathy, early infantile, 41, 617105 to Epileptic encephalopathy, early infantile, 41, 617105; Intellectual disability
Intellectual disability v2.640 KARS Ivone Leong Publications for gene: KARS were set to 29615062; 30252186; 28496994; 28887846, 25330800
Intellectual disability v2.639 KARS Ivone Leong Publications for gene: KARS were set to
Intellectual disability v2.638 INTS1 Ivone Leong Classified gene: INTS1 as Green List (high evidence)
Intellectual disability v2.638 INTS1 Ivone Leong Added comment: Comment on list classification: Promoted from red to green based on the new evidence provided by Konstantinos Varvagiannis (Other).
Intellectual disability v2.638 INTS1 Ivone Leong Gene: ints1 has been classified as Green List (High Evidence).
Intellectual disability v2.637 INTS1 Ivone Leong Phenotypes for gene: INTS1 were changed from Hypotonia; Global developmental delay; Cataract; Abnormality of the skeletal system to Hypotonia; Global developmental delay; Cataract; Abnormality of the skeletal system
Intellectual disability v2.636 INTS1 Ivone Leong Phenotypes for gene: INTS1 were changed from to Hypotonia; Global developmental delay; Cataract; Abnormality of the skeletal system
Intellectual disability v2.635 INTS1 Ivone Leong Publications for gene: INTS1 were set to 28542170
Intellectual disability v2.634 SET Rebecca Foulger Classified gene: SET as Green List (high evidence)
Intellectual disability v2.634 SET Rebecca Foulger Added comment: Comment on list classification: Updated rating from Amber to Green: Sufficient (>3) cases to support ID causation as noted in the review by Konstantinos Varvagiannis: 5 families (6 individuals) reported in PMID:29688601 (Stevens et al., 2018), plus 3 ID patients in the DDD study (PMID:28135719), including the variant found in the mother and son in PMID:29688601. Plus the large scale PMID:25356899 (Hamdan et al 2014) study.
Intellectual disability v2.634 SET Rebecca Foulger Gene: set has been classified as Green List (High Evidence).
Intellectual disability v2.633 SET Rebecca Foulger Phenotypes for gene: SET were changed from Intellectual disability; SET syndrome to Intellectual disability; SET syndrome; Mental retardation, autosomal dominant 58, 618106
Intellectual disability v2.632 LSS Konstantinos Varvagiannis gene: LSS was added
gene: LSS was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: LSS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LSS were set to 30723320; 30401459
Phenotypes for gene: LSS were set to Alopecia; Abnormality of the skin; Hypotonia; Global developmental delay; Intellectual disability; Seizures; Abnormality of the genital system; Microcephaly
Penetrance for gene: LSS were set to Complete
Review for gene: LSS was set to GREEN
Added comment: DD and ID seem to be among the features observed in some individuals with biallelic LSS mutations, although the clinical presentation appears to be highly variable.

PMID: 30723320 [Besnrard et al, 2019] reports on 10 individuals from 6 unrelated families with biallelic LSS variants. One additional subject from a seventh family was found to harbor only a missense SNV (in the maternal allele) while the transcript corresponding to the other (/paternal) allele was less expressed upon RNA studies from patient fibroblasts. The allelic imbalance and the phenotypic overlap with the other individuals of the study were thought to be explained by an LSS defect.

The phenotype consisted of total alopecia (11/11) with additional dermatological features in most (9/11), hypotonia (7/11), DD with variable degrees of ID (11/11 both), epilepsy (8/11), microcephaly and genital anomalies in few. Cataracts were not noted in any individuals. The authors suggest that the phenotype corresponds to that observed in a neuroectodermal syndrome previously known as APMR (alopecia with mental retardation - other genes or loci earlier proposed).

Variants included: 7 missense SNVs, 1 nonsense, 1 frameshift, 2 splice variants (c.1109+2T>C / c.1194+5G>A - using NM_002340.5).

Using a minigene assay the latter variants were confirmhed (both) to affect splicing, at least to some important extent. However the splicing defect for one SNV (c.1194+5G>A - skipping of exon 12) was not confirmed upon RNA studies from blood samples of the respective individuals but an allelic balance in favor of the other allele instead (due to presumed utilisation of an alternative splice site, introduction of a premature stop codon and NMD).

Allelic imbalance is discussed for the individual with the single LSS variant but not shown.

Variants did not show clustering (also upon 3D modelling).

Lanosterol synthase converts (S)-2,3-oxidosqualene to lanosterol in the cholesterol biosynthesis pathway. Quantification of cholesterol and its precursors in affected individuals did not however reveal any important imbalance.

As most individuals harbored an allele with missense variant, and mice homozygous for an allele with absent LSS activity show variable lethality, residual LSS activity is suggested for the individuals studied.

Several other disorders affecting cholesterol biosynthesis present overlapping features eg. DD/ID in Lathosterolosis, Desmosterolosis, Smith-Lemli-Opitz syndrome (in this case also genital anomalies), etc or cutaneous anomalies in others.

A neurodevelopmental phenotype in animal models for LSS deficiency is not commented.
-----
Based on the discussion of the current article (and OMIM):

Earlier studies [PMIDs : 26200341, 29016354 - Zhao et al 2015 and Chen and Liu 2017 respectively] found biallelic missense in individuals with congenital cataracts. DD/ID were not commented/observed. The subject reported by Chen had baldness and genital defects. Shumiya cataract rats due to mutation in Lss gene recapitulate the specific human phenotype [PMID: 16440058 and OMIM]. Cataract was not a feature in any of the individuals of the present study. The corresponding entry for this phenotype in OMIM is Cataract 44 (#616509).

PMID: 30401459 [Romano et al, 2018] reported biallelic LSS mutations in 3 unrelated families with hypotrichosis. Intellectual disability was a feature in 2 sibs from 1 non-consanguineous family (among the three). ID was considered to be coincidental by the authors. The respective entry in OMIM is Hypotrichosis 14 (#618275).
-----
LSS is not included in the DD panel of G2P, nor in gene panels for ID offered by diagnostic laboratories.
-----
As a result this gene can be considered for inclusion in this panel as green (or amber).
Sources: Literature
Intellectual disability v2.632 PHF21A Alistair Pagnamenta reviewed gene: PHF21A: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 30487643, 22770980, 27124303, 28127865, 26333423; Phenotypes: intellectual disability, craniofacial anomalies, epilepsy, ASD, overgrowth; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v2.632 Louise Daugherty removed gene:ZNF970P from the panel
Intellectual disability v2.631 Louise Daugherty removed gene:ZNF8 from the panel
Intellectual disability v2.630 Louise Daugherty removed gene:ZNF965P from the panel
Intellectual disability v2.629 ZNF965P Louise Daugherty gene: ZNF965P was added
gene: ZNF965P was added to Intellectual disability. Sources: Other
Mode of inheritance for gene: ZNF965P was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: ZNF965P were set to test 4
Added comment: test 4
Sources: Other
Intellectual disability v2.628 ZNF970P Louise Daugherty gene: ZNF970P was added
gene: ZNF970P was added to Intellectual disability. Sources: Other
Mode of inheritance for gene: ZNF970P was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: ZNF970P were set to test 3
Added comment: test
Sources: Other
Intellectual disability v2.628 ZNF970P Louise Daugherty gene: ZNF970P was added
gene: ZNF970P was added to Intellectual disability. Sources: Other
Mode of inheritance for gene: ZNF970P was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: ZNF970P were set to test 3
Added comment: test
Sources: Other
Intellectual disability v2.627 ZNF8 Louise Daugherty gene: ZNF8 was added
gene: ZNF8 was added to Intellectual disability. Sources: Other
Mode of inheritance for gene: ZNF8 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: ZNF8 were set to test 2
Added comment: test
Sources: Other
Intellectual disability v2.626 LZTR1 Ellen McDonagh Classified gene: LZTR1 as Green List (high evidence)
Intellectual disability v2.626 LZTR1 Ellen McDonagh Added comment: Comment on list classification: This gene is Green on the RASopathies gene panel version 1.27. Clinical input from Ellen Thomas (Genomics England Clinical Team) suggested this should also be added to the Intellectual disability panel.
Intellectual disability v2.626 LZTR1 Ellen McDonagh Gene: lztr1 has been classified as Green List (High Evidence).
Intellectual disability v2.625 LZTR1 Ellen McDonagh gene: LZTR1 was added
gene: LZTR1 was added to Intellectual disability. Sources: Other
Mode of inheritance for gene: LZTR1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: LZTR1 were set to 25795793; 29469822
Phenotypes for gene: LZTR1 were set to Noonan syndrome 10; Prenatal hydrops; increased nuchal translucency; cardiac findings
Intellectual disability v2.624 SOS2 Ellen McDonagh Classified gene: SOS2 as Green List (high evidence)
Intellectual disability v2.624 SOS2 Ellen McDonagh Gene: sos2 has been classified as Green List (High Evidence).
Intellectual disability v2.623 SOS2 Ellen McDonagh Classified gene: SOS2 as Green List (high evidence)
Intellectual disability v2.623 SOS2 Ellen McDonagh Gene: sos2 has been classified as Green List (High Evidence).
Intellectual disability v2.622 SOS2 Ellen McDonagh gene: SOS2 was added
gene: SOS2 was added to Intellectual disability. Sources: Other
Mode of inheritance for gene: SOS2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SOS2 were set to 25795793; 26173643
Phenotypes for gene: SOS2 were set to Noonan syndrome 9
Added comment: This gene is Green on the RASopathies gene panel version 1.27. Clinical input from Ellen Thomas (Genomics England Clinical Team) suggested this should also be added to the Intellectual disability panel.
Sources: Other
Intellectual disability v2.621 NECAP1 Konstantinos Varvagiannis gene: NECAP1 was added
gene: NECAP1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: NECAP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NECAP1 were set to 24399846; 30525121; 30626896
Phenotypes for gene: NECAP1 were set to ?Epileptic encephalopathy, early infantile 21, 615833
Penetrance for gene: NECAP1 were set to Complete
Review for gene: NECAP1 was set to GREEN
gene: NECAP1 was marked as current diagnostic
Added comment: Biallelic pathogenic variants in NECAP1 cause ?Epileptic encephalopathy, early infantile, 21 (MIM 615833).
----
PMID: 24399846 (Alazami et al. 2014) report on 6 individuals from an multigenerational family from Saudi Arabia with biallelic NECAP1 nonsense variant. The common phenotype consisted of hypotonia, profound global developmental delay preceding the onset of intractable seizures (fragmented multifocal clonic and tonic) in early infancy. Initial workup excluded metabolic causes.

4 of these individuals were born to first cousins once removed, while 2 additional affected subjects from the broader pedigree were born to seemingly unrelated parents from the same region. All affected individuals shared a single autozygous 4.78-Mb interval on chromosome 12p. Linkage analysis confirmed involvement of this locus (LOD score : 5.0447). Exome sequencing demonstrated homozygosity for a nonsense variant (NM_015509.3:c.142C>T - p.R48*). mRNA levels in lymphoblast cell lines from affected subjects were significantly reduced when compared to controls, probably due to NMD.

Necap1 was shown to be strongly expressed in the developing (E14.5) mouse brain and spinal cord, upon immunohistochemical analysis (part of the current study).

NECAP1 has been previously shown to have a functional role in Clathrin-mediated encocytocis (CME), a process which plays a critical role at the site of synapsis (in synaptic vesicle recycling).
----
PMID: 30525121 (Alsahli et al. 2018) report on a 41-month-old girl with hypotonia, profound global developmental delay and onset of seizures at the age of 3 months (generalized tonic and clonic / flexor hemispasms). Initial workup was negative for an eventual metabolic origin. The girl was born to consanguineous Saudi parents and was found to harbor the p.R48* variant in the homozygous state, following trio-WES.
----
PMID: 30626896 (Mizuguchi et al. 2019) report on a 16-month-old boy, born to consanguineous parents from Malaysia. This individual presented with axial hypotonia and profound developmental delay and developed generalized tonic-clonic and clonic seizures at the (corrected) age of 3 months. EEG demonstrated a burst suppression pattern and a clinical diagnosis of Ohtahara syndrome was retained. Metabolic workup was normal.

Homozygosity for a splice-site NECAP1 variant (NM_015509.3:c.301+1G>A) was demonstrated following exome sequencing. The variant was shown to result in inclusion of a 44-bp intron, resulting in frameshift and introduction of a premature termination codon (p.Gly101Aspfs*45). The level of abnormal transcript was 2-fold increased in lymphoblast cells trated with cycloheximide when compared to cells treated with DMSO, suggesting involvement of NMD.

As also in PMID: 30525121, the present study suggests similarities with the DNM1-related phenotype (Epileptic encephalopathy, early infantile, 31 - #616346 - DNM1 is rated green in the ID panel) as DNM1 also participates in vesicle recycling. The authors of the present study also note that mutations in CLTC (encoding clathrin heavy chain) cause hypotonia with DD/ID with or without epilepsy (Mental retardation, autosomal dominant 56 - #617854 - CLTC is rated green in the ID panel).
----
NECAP1 is not associated with any phenotype in G2P.
This gene is included in gene panels for ID offered by some diagnostic laboratories.
----
As a result this gene can be considered for inclusion in this panel as green (or amber).
Sources: Literature
Intellectual disability v2.621 PUS3 Konstantinos Varvagiannis edited their review of gene: PUS3: Added comment: PMID: 30697592 reports 2 additional individuals with intellectual disability, leukoencephalopathy and adult onset nephropathy. These individuals harbored 2 missense variants in the compound heterozygous state (c.497G>A - p.Arg166Gln and c.1097T>C - p.Leu366Pro - Ref. sequence not mentioned).

As a result amber/green rating could be considered.; Changed publications: 27055666, 30308082, 30697592
Intellectual disability v2.621 PUS3 Konstantinos Varvagiannis Deleted their comment
Intellectual disability v2.621 PUS3 Konstantinos Varvagiannis edited their review of gene: PUS3: Added comment: PMID: 30697592 reports 2 additional individuals with intellectual disability, leukoencephalopathy and adult onset nephropathy. These individuals harbored 2 missense variants in the compound heterozygous state (c.497G>A - p.Arg166Gln and c.1097T>C - p.Leu366Pro - Ref. sequence not mentioned).

As a result amber/green rating could be considered.; Changed publications: 30697592
Intellectual disability v2.620 RNF135 Konstantinos Varvagiannis reviewed gene: RNF135: Rating: RED; Mode of pathogenicity: None; Publications: 30665703, 17632510, 26368817; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v2.620 MTR Eleanor Williams Phenotypes for gene: MTR were changed from Homocystinuria-megaloblastic anemia, cblG complementation type, 250940{Neural tube defects, folate-sensitive, susceptibility to}, 601634; METHYLCOBALAMIN DEFICIENCY TYPE G (CBLG) to Homocystinuria-megaloblastic anemia, cblG complementation type, 250940; {Neural tube defects, folate-sensitive, susceptibility to}, 601634; METHYLCOBALAMIN DEFICIENCY TYPE G (CBLG)
Intellectual disability v2.619 MED23 Louise Daugherty Classified gene: MED23 as Green List (high evidence)
Intellectual disability v2.619 MED23 Louise Daugherty Added comment: Comment on list classification: Removed Watchlist tag. Changed from Amber to Green. Appropriate phenotype, sufficient cases, and external review comment all support gene-disease association
Intellectual disability v2.619 MED23 Louise Daugherty Gene: med23 has been classified as Green List (High Evidence).
Intellectual disability v2.618 MED23 Louise Daugherty Tag watchlist was removed from gene: MED23.
Intellectual disability v2.618 MED23 Louise Daugherty Added comment: Comment on publications: Added publications suggested from external expert review to support upgrading of the gene to Green
Intellectual disability v2.618 MED23 Louise Daugherty Publications for gene: MED23 were set to 21868677; 25845469; 25527630; 22129135
Intellectual disability v2.617 FRMPD4 Konstantinos Varvagiannis reviewed gene: FRMPD4: Rating: GREEN; Mode of pathogenicity: None; Publications: 29267967, 25644381; Phenotypes: Mental retardation, X-linked 104, 300983; 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 v2.615 ISCA-37494-Gain Louise Daugherty Haploinsufficiency Score for ISCA-37494-Gain was changed from 3 to None.
Rating Changed from Green List (high evidence) to Green List (high evidence)
Intellectual disability v2.614 INTS1 Konstantinos Varvagiannis reviewed gene: INTS1: Rating: GREEN; Mode of pathogenicity: None; Publications: 28542170, 30622326, 17544522; Phenotypes: Hypotonia, Global developmental delay, Cataract, Abnormality of the skeletal system; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability v2.614 ISPD Louise Daugherty commented on gene: ISPD
Intellectual disability v2.614 ISPD Louise Daugherty Tag new-gene-name tag was added to gene: ISPD.
Intellectual disability v2.613 ISCA-37494-Loss Louise Daugherty Triplosensitivity Score for ISCA-37494-Loss was changed from 3 to None.
Rating Changed from Green List (high evidence) to Green List (high evidence)
Intellectual disability v2.612 ISCA-37501-Loss Louise Daugherty Triplosensitivity Score for ISCA-37501-Loss was changed from 2 to None.
Rating Changed from Green List (high evidence) to Green List (high evidence)
Intellectual disability v2.611 USP7 Konstantinos Varvagiannis reviewed gene: USP7: Rating: GREEN; Mode of pathogenicity: None; Publications: 26365382, 19946331; Phenotypes: Global developmental delay, Delayed speech and language development, Intellectual disability, Behavioral abnormality, Seizures, Abnormality of brain morphology, Hypogonadism; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Intellectual disability v2.611 CYFIP2 Konstantinos Varvagiannis gene: CYFIP2 was added
gene: CYFIP2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: CYFIP2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CYFIP2 were set to 29534297; 29667327; 30664714; 25432536; 27524794; 12818175; 20537992
Phenotypes for gene: CYFIP2 were set to Epileptic encephalopathy, early infantile 65, 618008
Penetrance for gene: CYFIP2 were set to unknown
Review for gene: CYFIP2 was set to GREEN
gene: CYFIP2 was marked as current diagnostic
Added comment: Heterozygous pathogenic variants in CYFIP2 cause Epileptic encephalopathy, early infantile, 65 (MIM 618008)
--------------
[Apologies for any eventual mistakes esp.as for the functional evidence]:

Nakashima et al. (2018 - PMID: 29534297) report on 4 unrelated individuals with early-onset epileptic encephalopathy due to de novo missense CYFIP2 variants.

The phenotype consisted of early-onset intractable seizures (diagnosis of West syndrome in 2, Ohtahara syndrome in further individuals) with hypotonia (3/4), DD/ID (4/4) and microcephaly (3/4).

All variants affected Arg87 residue (NM_001037333.2:c.259C>T or p.Arg87Cys in 2 individuals, the 2 other subjects harbored Arg87Leu and Arg87Pro respectively).

CYFIP2 encodes the cytoplasmic FMRP interacting protein 2. CYFIP2 (similar to CYFIP1) is a component of the WAVE regulatory complex (WRC) which has been shown to play a role in actin remodeling, axon elongation, dendritic morphogenesis and synaptic plasticity (several PMIDs cited).

In the inactive state of the WRC complex, CYFIP2 binds to the VCA domain of WAVE. GTP-bound Rac1 (GTPase) leads to release of the VCA domain from CYFIP2 which allows binding of this domain to the Arp2/3 complex (active WRC state) and in turn stimulates actin polymerization and lamellipodia formation.

Using lymphoblastoid cell lines from affected individuals and healthy controls and CYFIP2 expression was evaluated by Western Blot and was found to be similar between the 2 groups.

Additional studies suggested weaker binding of the WAVE1 VCA domain to mutant CYFIP2 compared to WT CYFIP2 (upon transfection of HEK293T cells). This could possibly favor activation of WRC (/the WAVE signalling pathway).

As a result a gain-of-function effect on the WAVE signalling pathway is suggested as a possible mechanism.

Using B16F1 mouse melanoma cells lamellipodia formation (process in which CYFIP2 has previously been implicated) was not shown to be impaired in the case of mutant CYFIP2. However aberrant accumulation of F-actin (and co-localization with mutant CYFIP2) was observed in the present study.

Only large 5q deletions spanning CYFIP2 (and several other genes) have been described to date.

Cyfip2 heterozygous knockout in mice results in abnormal behavior and memory loss. WAVE activity was enhanced (despite reduced WAVE protein production). Homozygous Cyfip2 loss is lethal (PMIDs cited by the authors: 25432536, 27524794). Impaired axonal growth, guidance and branching is noted in Drosophila mutants (CYFIP1/2 ortholog) (PMID cited: 12818175). The authors comment that Cyfip2 (nev) mutant zebrafish show a similar phenotype to mutant flies (PMID cited: 20537992).
--------------
Peng et al. (2018 - PMID: 29667327) in a study of 56 Chinese families with West Syndrome (epileptic/infantile spasms, hypsarrhytmia and ID) identified 1 individual with the Arg87Cys CYFIP2 variant as a de novo occurrence.
--------------
Zweier et al. (2019 - DDD study among the co-authors - PMID: 30664714) report on 12 unrelated subjects with heterozygous pathogenic de novo CYFIP2 variants.

The common phenotype consisted of tone abnormalities (12/12), DD/ID (12/12) and seizures (12/12 though a single individual had experienced a single episode of febrile seizure). Absolute or relative microcephaly and/or additional features were also noted in several individuals.

7 missense variants (4 occurrences of the Arg87Cys variant) as well as splice variant (shown to lead to exon skipping) are reported, as de novo events in these individuals. The splice variant was expected to escape NMD producing a truncating protein.

Although the variants are distantly located in the primary structure, spatial clustering (in the tertiary structure) is suggested by in silico modelling (all in proximity at the CYFIP2-WAVE1 interface).

CYFIP2 appears to be intolerant to both missense and LoF variants (Z-score of 6.15 and pLI of 1 respectively in ExAC).

The authors comment that haploinsufficiency as a mechanism is rather unlikely given the absence of small CNVs or variants predicted to lead to NMD. Again, a gain-of-function effect of these variants on WAVE activation (partial-loss-of function in terms of WRC stabilization and/or conformation of the VCA region in the inactive state) is proposed.
--------------
CYFIP2 is not associated with any phenotype in G2P.
The gene is included in gene panels for intellectual disability offered by some diagnostic laboratories (eg. participants in these studies).
--------------
As a result this gene could be considered for inclusion in this panel as green.
Sources: Literature
Intellectual disability v2.610 ISCA-37396-Loss Louise Daugherty Triplosensitivity Score for ISCA-37396-Loss was changed from 1 to None.
Rating Changed from Green List (high evidence) to Green List (high evidence)
Intellectual disability v2.609 ISCA-46299-Gain Louise Daugherty Haploinsufficiency Score for ISCA-46299-Gain was changed from 0 to None.
Rating Changed from Green List (high evidence) to Green List (high evidence)
Intellectual disability v2.608 ISCA-37494-Loss Louise Daugherty Classified Region: ISCA-37494-Loss as Green List (high evidence)
Intellectual disability v2.608 ISCA-37494-Loss Louise Daugherty Region: isca-37494-loss has been classified as Green List (High Evidence).
Intellectual disability v2.607 ISCA-37494-Gain Louise Daugherty Classified Region: ISCA-37494-Gain as Green List (high evidence)
Intellectual disability v2.607 ISCA-37494-Gain Louise Daugherty Region: isca-37494-gain has been classified as Green List (High Evidence).
Intellectual disability v2.606 ISCA-46299-Gain Louise Daugherty Classified Region: ISCA-46299-Gain as Green List (high evidence)
Intellectual disability v2.606 ISCA-46299-Gain Louise Daugherty Region: isca-46299-gain has been classified as Green List (High Evidence).
Intellectual disability v2.605 ISCA-37501-Loss Louise Daugherty Classified Region: ISCA-37501-Loss as Green List (high evidence)
Intellectual disability v2.605 ISCA-37501-Loss Louise Daugherty Region: isca-37501-loss has been classified as Green List (High Evidence).
Intellectual disability v2.604 ISCA-37396-Loss Louise Daugherty Classified Region: ISCA-37396-Loss as Green List (high evidence)
Intellectual disability v2.604 ISCA-37396-Loss Louise Daugherty Region: isca-37396-loss has been classified as Green List (High Evidence).
Intellectual disability v2.603 ISCA-37396-Loss Louise Daugherty Marked Region: ISCA-37396-Loss as ready
Intellectual disability v2.603 ISCA-37396-Loss Louise Daugherty Region: isca-37396-loss has been classified as Red List (Low Evidence).
Intellectual disability v2.603 SCO2 Rebecca Foulger Phenotypes for gene: SCO2 were changed from Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 1, 604377Myopia 6, 608908; FATAL INFANTILE CARDIOENCEPHALOMYOPATHY DUE TO CYTOCHROME C OXIDASE DEFICIENCY to Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 1, 604377; Myopia 6, 608908; FATAL INFANTILE CARDIOENCEPHALOMYOPATHY DUE TO CYTOCHROME C OXIDASE DEFICIENCY
Intellectual disability v2.602 ISCA-37494-Gain Louise Daugherty Region: ISCA-37494-Gain was added
Region: ISCA-37494-Gain was added to Intellectual disability. Sources: Expert list
Mode of inheritance for Region: ISCA-37494-Gain was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Publications for Region: ISCA-37494-Gain were set to 25927380; 21984752; 24357492
Phenotypes for Region: ISCA-37494-Gain were set to Chromosome Xq28 duplication syndrome, 300815; X linked intellectual disability (XLID); PMID: 25927380 cognitive impairment, behavioral problems, distinctive facial features; duplication affects males with a recognizable syndrome, females exhibiting milder phenotypes; PMID:21984752 behavioural abnormalities (hyperactivity and aggressiveness), characteristic facial features (high forehead, upper eyelid fullness, broad nasal bridge and thick lower lip); PMID:24357492 Cognitive impairment in male patients
Review for Region: ISCA-37494-Gain was set to GREEN
Added comment: Sources: Expert list
Intellectual disability v2.601 ISCA-37494-Loss Louise Daugherty Region: ISCA-37494-Loss was added
Region: ISCA-37494-Loss was added to Intellectual disability. Sources: Expert list
Mode of inheritance for Region: ISCA-37494-Loss was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Publications for Region: ISCA-37494-Loss were set to 25927380; 21984752
Phenotypes for Region: ISCA-37494-Loss were set to PMID: 25927380 cognitive impairment, behavioral problems, distinctive facial features; deletion results in skewed chromosome X inactivation and no clinical phenotype in females; PMID: 21984752 in utero male lethality with deletions
Review for Region: ISCA-37494-Loss was set to GREEN
Added comment: Sources: Expert list
Intellectual disability v2.600 ISCA-46299-Gain Louise Daugherty Region: ISCA-46299-Gain was added
Region: ISCA-46299-Gain was added to Intellectual disability. Sources: Expert list
Mode of inheritance for Region: ISCA-46299-Gain was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Publications for Region: ISCA-46299-Gain were set to 22840365; 20655035; 26692240
Phenotypes for Region: ISCA-46299-Gain were set to X linked intellectual disability (XLID); PMID: 26692240 Mild‐profound intellectual disability, speech delay, failure to thrive, hand abnormalities, motor delay, abnormal palate; PMID:22840365 Mild intellectual disability; PMID:26692240 Region 2 (53,160,114–53,713,154 bp Within Chromosome Xp11.22)
Review for Region: ISCA-46299-Gain was set to GREEN
Added comment: Sources: Expert list
Intellectual disability v2.599 ISCA-37501-Loss Louise Daugherty Region: ISCA-37501-Loss was added
Region: ISCA-37501-Loss was added to Intellectual disability. Sources: Expert list
Mode of inheritance for Region: ISCA-37501-Loss was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for Region: ISCA-37501-Loss were set to 20206336; 22052739
Phenotypes for Region: ISCA-37501-Loss were set to Chromosome 17q23.1-q23.2 deletion syndrome, 613355; PMID:20206336 mild to moderate developmental delay (particularly speech delay), microcephaly, postnatal growth retardation, heart defects, hand, foot and limb abnormalities; PMID: 22052739 Developmental delay, heart defects, microcephaly, postnatal growth retardation, hand, foot and limb abnormalities, sensorineural hearing loss
Review for Region: ISCA-37501-Loss was set to GREEN
Added comment: Sources: Expert list
Intellectual disability v2.598 ISCA-37396-Loss Louise Daugherty Region: ISCA-37396-Loss was added
Region: ISCA-37396-Loss was added to Intellectual disability. Sources: Expert list
Mode of inheritance for Region: ISCA-37396-Loss was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for Region: ISCA-37396-Loss were set to 22180641; 19557438; 19233321
Phenotypes for Region: ISCA-37396-Loss were set to Chromosome 15q24 deletion syndrome, 613406; PMID: 22180641 intellectual disability, growth retardation, unusual facial morphology; developmental delay, severe speech problems; PMID:19557438 Developmental delay, short stature, hypotonia, digital abnormalities, joint laxity, genital abnormalities, characteristic facial features; PMID:614294 Developmental delay, loose connective tissue, digital and genital anomalies, distinct facial gestalt, congenital diaphragmatic hernia
Review for Region: ISCA-37396-Loss was set to GREEN
Added comment: Sources: Expert list
Intellectual disability v2.597 PLEKHG2 Konstantinos Varvagiannis gene: PLEKHG2 was added
gene: PLEKHG2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: PLEKHG2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: PLEKHG2 were set to 26539891; 26573021; 24001768
Phenotypes for gene: PLEKHG2 were set to Leukodystrophy and acquired microcephaly with or without dystonia, 616763
Penetrance for gene: PLEKHG2 were set to unknown
Review for gene: PLEKHG2 was set to AMBER
gene: PLEKHG2 was marked as current diagnostic
Added comment: Karaca et al. (2015 - PMID: 26539891) in a study of 128 - mostly consanguineous - families with neurogenetic disorders and brain malformations, identified an individual homozygous for a PLEKHG2 missense variant (NM_022835.2:c.1708G>A or p.Gly570Arg). This individual (BAB4830) had a similarly affected sib. Features included hypotonia, intellectual disability, microcephaly, cerebellar atrophy and nystagmus (description provided in supplement - Table S1). This variant has been submitted in ClinVar as likely pathogenic by the corresponding laboratory (SCV000537940.1).
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Edvardson et al. (2016 - PMID: 26573021) reported on 5 individuals from 2 unrelated consanguineous Palestinian families, harboring a missense variant in the homozygous state (NM_022835.2:c.610C>T or p.Arg204Trp - 1/5 was unavailable for testing).
Unaffected relatives here either heterozygous for this variant or homozygous for the reference allele.

Common features included hypotonia (5/5), DD/ID (5/5), postnatal microcephaly (5/5), dystonia (3/5), nystagmus (2/5) or seizures (1/5) [many of these similar to those reported by Karaca et al]. Brain MRI images were consistent with leukodystrophy and prolonged relaxation of dorsal tegmental tracts (similar findings were not commented by Karaca et al).

PLEKHG2 encodes a Rho guanine exchange factor (RhoGEF). RhoGEFs activate RhoGTPases through release of GDP and binding of GTP. Mutations in other RhoGEFs have been associated with neurodevelopmental disorders.

PLEKHG2 activity was shown to be significantly decreased in HEK293A cells transfected with R204W-PLEKHG2 when compared to tranfection with wt. Western blotting suggested that this was not the result of defective expression.

Using lymphoblastoid cell lines from peripheral B lymphocytes from individuals homozygous for R204W and controls, similar levels of expression were shown between the 2 groups.

As the authors note, PLEKHG2 is required for Rac- and Cdc42-stimulated actin polymerization in leukocytes (PMID cited: 24001768).

SDF1a-stimulated actin polymerization was studied in patient cells and was shown to be significantly impaired. In line with this actin polymerization was also impaired upon siRNA-mediated downregulation of PLEKHG2 expression in control cells.
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A subsequent submission of the Gly570Arg variant in ClinVar (2017 - SCV000609979.1 - same variant as the one reported by Karaca et al) reports this as a VUS.
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PLEKHG2 is associated with Leukodystrophy and acquired microcephaly with or without dystonia (616763) in OMIM.
This gene is not associated with any phenotype in G2P.
PLEKHG2 is included in gene panels for ID offered by some diagnostic laboratories.
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As a result, this gene could be considered for inclusion in this panel probably as amber (or green if the current evidence is considered to be sufficient).
Sources: Literature
Intellectual disability v2.597 DHPS Konstantinos Varvagiannis gene: DHPS was added
gene: DHPS was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: DHPS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DHPS were set to 21389784; 21850436
Phenotypes for gene: DHPS were set to Abnormal muscle tone; Global developmental delay; Intellectual disability; Seizures; EEG abnormality; Behavioral abnormality; Abnormality of head or neck
Penetrance for gene: DHPS were set to Complete
Review for gene: DHPS was set to GREEN
Added comment: Ganapathi et al. (doi.org/10.1016/j.ajhg.2018.12.017 - PMID : NA) report on 5 individuals from 4 unrelated families with biallelic pathogenic variants in DHPS.

The phenotype consisted of DD/ID (5/5), tone abnormalities (hypotonia/hypertonia/spasticity - 5/5), seizures (5/5 - in one case though unclear staring spells) with EEG abnormalities (5/5). Additionally most individuals displayed behavioral issues, or some common facial features.

Several other disorders had been ruled prior to the diagnosis, in all cases by exome sequencing.

All individuals harbored a specific missense variant (c.518A>G or p.Asn173Ser) in trans with various other variants incl. a splice site mutation (c.1014+1G>A), an in-frame deletion of 2 amino acids (c.912_917delTTACAT or p.Tyr305_Ile306del) or a variant abolishing the translation initiation codon (c.1A>G or p.Met1?) [All variants using NM_001930.3 as a reference].

Deoxyhypusine synthase (encoded by DHPS) is an enzyme participating in the first step of hypusine synthesis, an amino-acid which is specific to eukaryotic initiation factor 5A (eIF5A) and its homolog (eIF5A2).

eIF5A, its hypusinated form and DHPS have all been previously implicated in cellular proliferation/differentiation. eIF5A has also been proposed to be a mRNA translation elongation factor. A role of eIF5A in neuronal growth and survival has been proposed previously (all ref. in present article).

Neither eIF5A, nor DHPS or DOHH (an enzyme required for the second step of hypusination) have been associated to any disorders previously. Mutations in genes encoding other eukaryotic elongator factors (eg. EEF1A2, EEF2) have been associated with neurodevelopmental disorders.

Concerning the DHPS variants reported:

cDNA studies suggested that the c.1014+1G>A variant is translated but results in aberrant splicing and truncation of the protein before its active site.

The in-frame deletion as well as the missense variant were shown to have absent or partial (20%) enzyme activity in vitro respectively compared to wild-type (following expression in E.coli BL21(DE3) cells).

In line with this, reduced hypusination of eIF5A was observed for these 2 variants when compared to wild-type DHPS, upon co-transfection of constructs overexpressing DHPS (wt or mut.) and eIF5A in HEK293T cells.

Absence of homozygous DHPS LoF variants in population databases might suggest that complete deficiency is incompatible with normal embryonic development. Mice heterozygous for Dhps deletion do not demonstrate severe phenotypes, though homozygosity is embryonically lethal (PMIDs: 21389784, 21850436).
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DHPS is not associated with any phenotype in G2P, nor in OMIM.
This gene is not - at least commonly - included in gene panels for ID offered by diagnostic laboratories.
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As a result, DHPS can be considered for inclusion in this panel as green (or amber).
Sources: Literature
Intellectual disability v2.597 SOX4 Konstantinos Varvagiannis gene: SOX4 was added
gene: SOX4 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: SOX4 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: SOX4 were set to Global developmental delay; Intellectual disability; Growth delay; Clinodactyly of the 5th finger; Abnormality of head or neck
Penetrance for gene: SOX4 were set to unknown
Review for gene: SOX4 was set to GREEN
Added comment: Zawerton et al. (DDD study among the co-authors - doi.org/10.1016/j.ajhg.2018.12.014 - PMID:NA) report on 4 unrelated individuals with de novo SOX4 pathogenic variants. The common phenotype consisted of DD/ID (4/4 - very mild to severe), overlapping facial features as well as digital anomalies (5th finger clinodactyly in 4/4).

SOX4 is a member of the SOX family of transcription factors, all presenting at least 50% identity with SRY (the first identified member of this family) in the HMG (DNA-binding) domain. Most SOX genes have important roles in cell fate / differentiation. Mutations in other genes of this family (eg. SRY, SOX9, SOX10, SOX5) are associated with severe human syndromes.

SOX4 is highly expressed in human brain during gestation - particularly in areas of active neurogenesis - with progressive decrease thereafter until the 3rd - 4th decade of life.

Knockdown of the SOX4 ortholog in Xenopus laevis embryos resulted in smaller head size, microphthalmia, shorter body length and underdevelopment of fore- and mid-brain. (Growth deficiency was a common feature in affected individuals, and microcephaly in 2/4).

Sox4-null mice die in utero due to heart septation defects, while such abnormalities were not reported in heterozygous mice. One affected subject had a VSD. Sox4 inactivation in mice results in impaired skeletal growth (similarly to the patients).

All 4 different missense variants clustered in the HMG domain (aa 58-133) which appears relatively (more) depleted in missense variants (only 12 missense HMG-domain variants in gnomAD). [Overall the Z-score for missense variants is 3.72. pLI = 0.38. %HI in DECIPHER : 24.67%].

The 4 missense variants presented impaired DNA binding and transcription activation in COS-1 transfected cells which appeared to distinguish them from the 12 gnomAD ones. Synthesis, stability and nuclear translocation appeared to be similar to wt.

Other parameters eg. residue conservation in the SOX family, presence of "equivalent" known disease causing mutations in other SOX genes or in silico analyses suggesting structural consequences were supportive of a deleterious effect for the 4 variants (but also for some of the 12 gnomAD ones).

SOX4 and SOX11 have almost identical DNA-binding domains, while the mechanism of mutations reported and the phenotypes appear to be relatively similar, as commented by the authors.
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SOX4 is not associated with any phenotype in G2P, nor in OMIM.
This gene is not - at least commonly - included in gene panels for ID offered by diagnostic laboratories.
--------------
As a result SOX4 can be considered for inclusion in the ID panel as green (or amber).
Sources: Literature
Intellectual disability v2.597 SLC1A2 Louise Daugherty Added comment: Comment on phenotypes: amended formatting of MIM phenotype
Intellectual disability v2.597 SLC1A2 Louise Daugherty Phenotypes for gene: SLC1A2 were changed from Epileptic encephalopathy, early infantile, 41 (MIM 617105) to Epileptic encephalopathy, early infantile, 41, 617105
Intellectual disability v2.596 PPP1R21 Louise Daugherty Deleted their comment
Intellectual disability v2.596 PPP1R21 Louise Daugherty commented on gene: PPP1R21: this is a test comment
Intellectual disability v2.596 PPP1R21 Louise Daugherty Added comment: Comment on publications: added publications recommended by external reviews
Intellectual disability v2.596 PPP1R21 Louise Daugherty Publications for gene: PPP1R21 were set to 29808498; 28940097
Intellectual disability v2.595 NUS1 Konstantinos Varvagiannis gene: NUS1 was added
gene: NUS1 was added to Intellectual disability. Sources: Literature,Radboud University Medical Center, Nijmegen
Mode of inheritance for gene: NUS1 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Publications for gene: NUS1 were set to 25066056; 29100083; 24824130; 30348779
Phenotypes for gene: NUS1 were set to #617082 - ?Congenital disorder of glycosylation, type 1aa; #617831 - Mental retardation, autosomal dominant 55, with seizures; Abnormality of extrapyramidal motor function
Penetrance for gene: NUS1 were set to unknown
Review for gene: NUS1 was set to AMBER
gene: NUS1 was marked as current diagnostic
Added comment: Mutations in NUS1 have been implicated in recessive as well as dominant forms of ID (1 and 3 unrelated individuals respectively). The latter individuals presented with a developmental and epileptic encephalopathy with ID. At least 2 of these individuals had tremor and other movement disorders. A recent study proposes that NUS1 variants contribute to Parkinson's disease (1 individual with de novo variant affecting the canonical splice site, 26 additional individuals with missense variants - for which segregation studies where not however performed). ID is not commented on for these individuals.

NUS1 is included in the DD panel of G2P, associated with "Epilepsy and intellectual disability". (Monoallelic LoF variants / Disease confidence : probable). This gene is included in gene panels for ID offered by diagnostic laboratories (incl. Radboudumc). Associated phenotypes in OMIM and others discussed in the literature are summarized below (to my understanding).

As a result, NUS1 can be considered for inclusion in the ID panel probably as amber.
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Recessive - [MIM #617082 - ?Congenital disorder of glycosylation, type 1aa] :

Park et al. (2014 - PMID: 25066056) report on an individual homozygous for a NUS1 missense variant (R290H) and suggest that biallelic variants cause a congenital disorder of glycosylation.

The authors based in studies in yeast, mice and man provide evidence that NUS1 encodes the Nogo-B receptor (NgBR), a subunit of cis-prenyltransferase (cis-PTase), important for its activation. cis-PTase catalyzes one of the reactions for dolichol biosynthesis. Dolichol, in turn, is a carrier of glycans for N-linked glycosylation, O-mannosylation and GPI anchor biosynthesis.

Genetic defects in the dolichol biosynthetic pathway have been linked to other forms of CDG and/or other recessive or dominant neurodevelopmental disorders (eg. SRD5A3- and DHDDS-related disorders).

Similarities are provided at the cellular level between different organisms. Heterozygous knockout mice appear normal. Homozygosity is associated with embryonic lethality before E6.5. Conditional knockout in mouse embryonic fibroblasts led to accumulation of free cholesterol, decreased cis-PTase activity, and mannose incorporation in protein (the first & third rescued by transduction with lentiviral human NgBR).

In patient fibroblasts protein levels appeared similar to controls. Interaction with Nogo-B (and hCIT - the product of DHDDS) was not affected. As in mice, accumulation of free cholesterol was observed in cells, with decreased cis-PTase activity and mannose incorporation. LAMP-1 and ICAM-1 were hypoglycosylated in patient fibroblasts. Altered dolichol profiles in serum and urine were observed in carriers of the NUS1 variant, similarly to what described in individuals with DHDDS LoF variants.
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Dominant - [MIM #617831 - Mental retardation, autosomal dominant 55, with seizures].

Hamdan et al. (2017 - PMID: 29100083) report on 3 unrelated individuals with developmental and epileptic encephalopathy (onset: 10m - 2.5y) and ID. Two individuals harbored de novo LoF variants while a third subject had a deletion of exon 2. Movement disorders were noted in all 3 and included tremor (2 subjects) or ataxia (1 additional subject).

The authors cite a previous study on 6q22.1 deletions the critical region of which encompassed only NUS1 and the promoter of SLC35F1 (Szafranski et al. - PMID: 24824130). Haploinsufficiency is discussed as a possible mechanism (pLI of 0.87). A more severe phenotype due to dramatic reduction of NUS1 activity is proposed for the previously reported patient with CDG.
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Other:
Guo et al. (2018 - PMID: 30348779) suggest that NUS1 pathogenic variants contribute to Parkinson's disease. By performing WES in 39 individuals with early onset Parkinson's disease and their unaffected patients (and sibs) the authors identified 1 individual with de novo insertion affecting a NUS1 canonical splice site. RT-PCR demonstrated increased mRNA levels compared with controls. Skipping of 91 bp of exon 3 was demonstrated.

Study in 2 large sporadic PD-patient (N=1852+3237)/control cohorts (N=1565+2858) suggested association between NUS1 non-synonymous variants and PD (P=1.01e-5, OR:11.3). Other genetic causes of PD were excluded in 26 additional individuals with NUS1 missense variants.

Phenotypes of all 27 individuals are provided in Dataset_S04.

NUS1 has been found to be differentially expressed in PD mouse models.

RNAi-mediated knockdown of Tango14 (the Drosophila NUS1) resulted in impaired climbing activity, reduction in brain dopamine levels and abnormal apoptotic signals in brain.
Sources: Literature, Radboud University Medical Center, Nijmegen
Intellectual disability v2.595 STAG2 Konstantinos Varvagiannis gene: STAG2 was added
gene: STAG2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: STAG2 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: STAG2 were set to 29263825; 28296084; 30158690; 30447054; 19449417; 26443594; 25677961; 23637084; 25450604
Phenotypes for gene: STAG2 were set to Global developmental delay; Intellectual disability; Abnormality of head or neck; Microcephaly; Growth delay; Hearing impairment; Abnormal heart morphology
Penetrance for gene: STAG2 were set to unknown
Review for gene: STAG2 was set to GREEN
gene: STAG2 was marked as current diagnostic
Added comment: Several affected individuals (from at least 8 unrelated) families have been reported in the literature. The phenotype consists - among others - of DD/ID. STAG2 is located on long arm of chromosome X (Xq25). Based on these reports, both males and females can be affected.

Soardi et al. (2017 - PMID: 29263825) report an affected male belonging to a large pedigree with 4 other similarly affected males. The disorder in this pedigree followed a typical X-linked inheritance pattern. All affected males were hemizygous for a missense variant (NM_001042749.1:c.980G>A or p.Ser327Asn). Common phenotype consisted of moderate ID, short stature, sensory hearing loss and some similar facial features. Unaffected males did not harbor the variant. Heterozygous females were not affected. Co-segragation of the variant with the affected status under an X-linked model, appeared unlikely to have occurred by chance (probability of 1/131,072 - logarithm of odds score of 5.12).

Mullegama et al. (2017 - PMID: 28296084) report on an 8-year-old girl harboring a de novo nonsense variant in STAG2 (NM_001042749.1:c.205C>T or p.Arg69Ter). This individual presented - among others with - DD, microcephaly, growth delay, digit anomalies, particular facial features, and anomalies of other systems (eg. hearing loss, cardiac defect, etc). The authors summarize the features of 2 subjects from the DDD study as available in DECIPHER, without additional details. [Variants of these individuals NM_001042749.1:c.1913_1922del10 or p.(A638Vfs*10) / NM_001042749.1:c.1811G>A p.(R604Q)].

Yuan et al. (2018 - PMID: 30158690) report on 4 females with de novo LoF STAG2 variants as well as 1 male subject with a de novo missense one. DD (5/5) and ID (4/4) were features in all individuals for whom this information was available. One additional female had an intragenic STAG2 deletion, although this subject was not reported to have DD or ID (table S6 : microcephaly, seizures and facial phenotype). It is not known whether the deletion was inherited or had occurred as a de novo event. All variants from this study have been submitted in ClinVar (phenotype : STAG2-related disorder).

Mullegama et al. (2018 - PMID: 30447054) report on a 4-year-old male with DD, microcephaly, growth delay, digit anomalies due to a de novo missense STAG2 variant (c.3027A>T or p.Lys1009Asn). As discussed by the authors at the time of the study 33 males with Xq25 duplications and ID had been reported (PMIDs cited: 19449417, 26443594, 25677961, 23637084, 25450604).

Discussed in these articles :

STAG2 (or STAG1) is one of the 4 core proteins of the cohesin complex, the other 3 being SMC1A, SMC3 and RAD21. Mutations in genes encoding these proteins or their interactors (eg. NIBPL, HDAC8, ESCO2, etc) have been associated cohesinopathies, a group of multisystem developmental disorders (eg. Cornelia de Lange syndrome, Roberts/SC phocomelia, etc).

It has been commented that the phenotype of STAG2-related disorder presents overlap with other cohesinopathies (eg. DD, microcephaly and growth retardation, craniofacial features, anomalies of the digits, etc).

Decreased proportion of nuclei with premature sister chromatid separation compared to controls was found on one occasion (suggestive of tighter sister chromatid cohesion) [Mullegama-A]. Sister chromatid cohesion was not affected in another report [Soardi et al.].

Western blot demonstrated significant reduction of STAG2 levels for a nonsense variant [Mullegama-A]. Levels were not perturbed for a missense variant [Soardi et al.].

Upon immunofluorescence STAG2 presented normal (nuclear) localization for a missense variant for which this was studied [Soardi et al.].

Perturbation of the cell cycle profile (higher percentage of G2/M cells) was demonstrated for patient fibroblasts compared to controls on one occasion where this was studied. [Soardi et al.].

Microarray expression studies in patient fibroblasts demonstrated altered transcription (upregulation) of genes implicated in cell division, mitosis and DNA replication upon comparison with normal fibroblasts [Soardi et al.].

The effect of a missense variant on STAG2 binding to other cohesin subunits (SCC1, SMC1 and SMC3) and regulators was studied. Binding was found to be reduced in vivo (in HeLa cells) for SCC1 (its direct binding partner) as well as SMC1, SMC3 (possibly indirectly). Reduced STAG2 binding to cohesin regulators was also shown in vivo. However, in vitro studies were not suggestive of impaired binding of STAG2 to SCC1 (a finding difficult to explain) [Soardi et al.].

STAG2 appears to be intolerant to LoF variants (pLI of 1 in ExAC). Z-Score for missense variants is 5.11.

Mullegama et al. (B) comment that Xq25 duplications in males may be associated with milder phenotypes compared to intragenic variants. They further hypothesize that males are able to survive less damaging variants while females are able to survive more deleterious (eg. LoF) ones though with more severe phenotypes (similarity to the MECP2 model is discussed).
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STAG2 is not associated with any phenotype in OMIM.
In G2P this gene is associated with STAG2-related developmental delay with microcephaly and congenital anomalies (disease confidence : confirmed / Both DD and ID among the phenotypes assigned to this entry).
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STAG2 is included in gene panels for ID offered by some diagnostic laboratories.
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As a result, this gene can be considered for inclusion in the ID panel as green (or amber).
Sources: Literature
Intellectual disability v2.595 NR4A2 Konstantinos Varvagiannis commented on gene: NR4A2: In a study of 457 autism families (Feliciano et al. - doi.org/10.1101/516625) the authors provide phenotypic information on a further individual with ASD and ID. This subject (SP0041645 - SPARK cohort) harbored a de novo frameshift variant (p.G231fs using ENST00000409572.1 as reference). Table 2 includes also the individual previously reported by Iossifov et al. who also presented with ASD and ID (11172.p1 - SSC cohort - PMID and details discussed below).
Intellectual disability v2.595 ZMIZ1 Konstantinos Varvagiannis gene: ZMIZ1 was added
gene: ZMIZ1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: ZMIZ1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ZMIZ1 were set to 29754769; 18053775; 17967885; 26163108; 27479843
Phenotypes for gene: ZMIZ1 were set to Global developmental delay; Intellectual disability; Feeding difficulties; Growth abnormality; Microcephaly; Abnormality of the skeletal system; Abnormality of the urinary system; Abnormality of the cardiovascular system; Abnormality of head or neck
Penetrance for gene: ZMIZ1 were set to unknown
Review for gene: ZMIZ1 was set to GREEN
gene: ZMIZ1 was marked as current diagnostic
Added comment: Carapito et al. (doi.org/10.1016/j.ajhg.2018.12.007 - PMID to add) report on 19 individuals with variants affecting ZMIZ1 (alternative symbols RAI17/KIAA1224/ZIMP10).

Features included DD/ID (19/19), feeding difficulties, growth failure, microcephaly and variable congenital malformations. Seizures were noted in 3 unrelated individuals (with different variants).

Variants included 6 missense SNVs, 5 frameshift variants, 1 splice site variant, 1 synonymous variant with probable impact on splicing (not studied) and 2 translocations.

In all individuals for whom parental studies were possible (n=16), the variants had occurred as de novo events while for 3 sibs harboring a frameshift variant parental samples were unavailable. These subjects however harbored the same variant as a DDD study participant included in the current report.

One translocation disrupted only ZMIZ1 while a second [t(X;10)] did not disrupt the coding sequence of any gene but only a distal enhancer 276 kb upstream of ZMIZ1. A previous study had found recurrent SNVs of the same region in ASD subjects and suggested possible interaction with the ZMIZ1 promoter (Liu et al. - PMID: 29754769).

The deleterious effect of both translocations was confirmed by quantitative RT-PCR. For 4 missense SNVs as well as a splice variant mRNA levels were similar to controls. The splice site (-2) variant was shown to produce 2 new splicing isoforms from utilization of alternative splice site acceptors.

ZMIZ1 belongs to the PIAS-like family of transcriptional coregulators.

Five missense variants were located in an alanine rich domain (aa 280-305). Seven other variants were predicted to shorten or remove the C-terminal transactivation domain.

This gene enhances - among others - the transcriptional activity of androgen receptor (AR). In vitro studies using HEK293T cell lines supported impaired coactivation of the AR for 3 variants studied. In utero electroporation of pathogenic variants in mouse embryos (E14.5) led to impaired neuronal positioning of the electroporated neurons and disruption of the morphology/polarization.

As the authors note previous studies have shown expression of Zimp10 in the developing mouse brain, craniofacial tissue as well as the interdigital region of limbs (PMIDs cited : 18053775 and 17967885) in line with ID, facial phenotype and syndactyly observed in some patients.

Finally the authors cite a previous report on an individual with ID due to a translocation [t(10;19)] disrupting both ZMIZ1 and PRR12 (Córdova-Fletes al. - PMID: 26163108). Although disruption of ZMIZ1 is discussed as a cause, PRR12 has recently been proposed as (also) an ID gene (Leduc et al. - PMID: 29556724). [For details see PRR12 in the current panel].
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One of the variants found in 2 unrelated individuals in the aforementioned study [NM_020338.3:c.899C>T or p.(T300M)] has been reported in a further individual investigated for ID in the context of a bigger cohort (Lelieveld et al. - PMID: 27479843).
[ Details in the denovo-db : http://denovo-db.gs.washington.edu/denovo-db/QueryVariantServlet?searchBy=Gene&target=ZMIZ1 ]
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ZMIZ1 is not associated with any phenotype in OMIM, nor in G2P.
This gene has been included in gene panels for intellectual disability offered by some diagnostic laboratories.
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As a result, ZMIZ1 can be considered for inclusion in the ID panel as green.
Sources: Literature
Intellectual disability v2.595 LMBRD1 Louise Daugherty Phenotypes for gene: LMBRD1 were changed from Gene2Phenotype confirmed gene with ID HPO to Gene2Phenotype confirmed gene with ID HPO; Methylmalonic aciduria and homocystinuria, cblF type, 277380
Intellectual disability v2.594 CWF19L1 Louise Daugherty Publications for gene: CWF19L1 were set to 25361784
Intellectual disability v2.593 CWF19L1 Louise Daugherty Phenotypes for gene: CWF19L1 were changed from Spinocerebellar ataxia, autosomal recessive 17 (MIM 616127) to Spinocerebellar ataxia, autosomal recessive 17, 616127
Intellectual disability v2.592 HEXA Louise Daugherty Phenotypes for gene: HEXA were changed from Tay-Sachs disease, 272800GM2-gangliosidosis, several forms, 272800[Hex A pseudodeficiency], 272800; GM2-GANGLIOSIDOSIS TYPE 1 (GM2G1) to Tay-Sachs disease, 272800; GM2-gangliosidosis, several forms, 272800; GM2-GANGLIOSIDOSIS TYPE 1 (GM2G1)
Intellectual disability v2.591 WDR73 Louise Daugherty Phenotypes for gene: WDR73 were changed from GALLOWAY-MOWAT SYNDROME: MICROCEPHALY AND STEROID-RESISTANT NEPHROTIC SYNDROME to GALLOWAY-MOWAT SYNDROME: MICROCEPHALY AND STEROID-RESISTANT NEPHROTIC SYNDROME; Galloway-Mowat syndrome 1, 251300
Intellectual disability v2.590 GRIN2D Louise Daugherty Phenotypes for gene: GRIN2D were changed from Epileptic encephalopathy, early infantile, 46 (MIM 617162) to Epileptic encephalopathy, early infantile, 46, 617162; intellectual disability
Intellectual disability v2.589 GRIN2D Louise Daugherty Classified gene: GRIN2D as Green List (high evidence)
Intellectual disability v2.589 GRIN2D Louise Daugherty Added comment: Comment on list classification: New gene added by external expert and reviewed by curation team, enough evidence to support gene-disease association and relevance to this panel to rate this gene Green
Intellectual disability v2.589 GRIN2D Louise Daugherty Gene: grin2d has been classified as Green List (High Evidence).
Intellectual disability v2.588 LINS1 Konstantinos Varvagiannis reviewed gene: LINS1: Rating: GREEN; Mode of pathogenicity: None; Publications: 21937992, 23773660, 28181389, 30090841; Phenotypes: Mental retardation, autosomal recessive 27 (MIM 614340); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability v2.588 MAPK8IP3 Konstantinos Varvagiannis reviewed gene: MAPK8IP3: Rating: GREEN; Mode of pathogenicity: None; Publications: 25363768, 28213671, 28135719; Phenotypes: Abnormal muscle tone, Global developmental delay, Intellectual disability, Abnormality of nervous system morphology; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v2.588 MAPK8IP3 Konstantinos Varvagiannis Deleted their review
Intellectual disability v2.588 MAPK8IP3 Konstantinos Varvagiannis gene: MAPK8IP3 was added
gene: MAPK8IP3 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: MAPK8IP3 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: MAPK8IP3 were set to 25363768; 28213671; 28135719
Penetrance for gene: MAPK8IP3 were set to unknown
Review for gene: MAPK8IP3 was set to GREEN
Added comment: Platzer et al. (doi.org/10.1016/j.ajhg.2018.12.008) report on 13 unrelated individuals with de novo pathogenic variants in MAPK8IP3.

The phenotype consisted - among others - of DD with ID (13/13) as well as variable brain anomalies (incl. cerebral or cerebellar atrophy, corpus callosum anomalies, perisylvian polymicrogyria, etc). Microcephaly, seizures, ataxia, ASD were features seen in fewer individuals.

The variants reported included 2 nonsense, 1 frameshift as well as 6 missense mutations (3 missense variants were found - each - in 2 or more individuals).

All three LoF variants were located in the first exon. (mRNA levels were not studied for these variants although NMD is presumed). The brain anomalies were more consistent for missense variants.

MAPK8IP3 appears intolerant to LoF variants (pLI of 1) with constraint also for missense variants (Z-score of 4.06).

In silico structural modeling was possible for 4 missense variants based on available crystal structures and different mechanisms were presumed (disruption of contacts between Leu444 of adjacent subunits, altered interaction between proximal residues at positions 461 and 466, or disruption of protein protein interactions).

The C.elegans MAPK8IP3 ortholog is encoded by the unc-16 gene. Impaired clearance and accumulation of organelles (incl. lysosomes) in axons is observed in unc-16 mutants (recessive phenotype).

For 6 variants, also conserved in C.elegans, mutants were engineered using CRISPR genome editing. The observed mutant phenotypes (increased axonal lysosomal density compared to controls for 2 variants, sluggish locomotion with lower swimming cycle rate for 1 nonsense and 4 missense variants) were rescued upon CRISPR reverse engineering of each mutant allele back to its wild-type sequence.

The authors cite 3 previous studies, in which individuals investigated for neurodevelopmental disorders where found to harbor de novo MAPK8IP3 variants, namely:
- PMID 25363768 (Iossifov et al.) : p.Tyr94Cys [ASD without ID]
- PMID 28213671 (Berger et al.) : p.Glu461Gly [Smith-Magenis-like phenotype)
- PMID 28135719 (DDD study) p.Arg1146Cys [This variant was found in 3 individuals in the study by Platzer et al.]
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A few additional individuals with neurodevelopmental disorders appear in the denovo-db after filtering for coding variants:
http://denovo-db.gs.washington.edu/denovo-db/QueryVariantServlet?searchBy=Gene&target=MAPK8IP3
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NM_015133.4:c.111C>G (p.Tyr37Ter) has been submitted in ClinVar by the Undiagnosed Diseases Network (NIH) as likely pathogenic, associated with MAPK8IP3-related disorder (hypotonia, DD, EEG anomalies among the phenotypes). It is not clear whether this subject corresponds to individual #3 reported by the previous study (possibly not the case).
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MAPK8IP3 is not associated with any phenotype in OMIM, nor in G2P.
This gene is not commonly included in gene panels for ID.
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As a result, MAPK8IP3 can be considered for inclusion in this panel as green (rather than amber).
Sources: Literature
Intellectual disability v2.588 ZNF462 Konstantinos Varvagiannis gene: ZNF462 was added
gene: ZNF462 was added to Intellectual disability. Sources: Literature,Radboud University Medical Center, Nijmegen
Mode of inheritance for gene: ZNF462 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ZNF462 were set to 28513610; 29427787; 14564155; 12825074
Phenotypes for gene: ZNF462 were set to Ptosis; Prominent metopic ridge; Craniosynostosis; Global developmental delay; Intellectual disability; Autistic behavior
Penetrance for gene: ZNF462 were set to unknown
Review for gene: ZNF462 was set to AMBER
gene: ZNF462 was marked as current diagnostic
Added comment: Weiss et al. (PMID: 28513610) report on 8 individuals (from 6 unrelated families) with heterozygous pathogenic variants affecting ZNF462.

Frequent features included ptosis metopic ridging, craniosynostosis, dysgenesis of corpus callosum. DD (with or without ASD) was a feature in 4 (4/8), one of whom was reported to present mild ID.

4 LoF mutations as well as 2 9q31.2 deletions spanning also other genes are reported [NM_021224.4]:
Fam. 1 - c.3787C>T p.(Arg1263*) (familial) - Normal development in all 3 family members
Fam. 2 - c.2979_2980delinsA p.(Val994Trpfs*147) (de novo) - DD
Fam. 3 - c.4263delA p.(Glu1422Serfs*6) (de novo) - DD
Fam. 4 - Chr9:g.(108940763-110561397)del (hg19) (de novo) - Normal development
Fam. 5- Chr9:g(108464368-110362345)del (hg19) (de novo) - DD with mild ID
Fam. 6 - c.5145delC p.(Tyr1716Thrfs*28) (de novo) - DD

There were no expression/functional studies performed although haploinsufficiency can be presumed based on these variants (ZNF462 has a pLI of 1 in ExAC).
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Cosemans et al. (PMID: 29427787) report on an individual investigated - among others - for mild ID and ASD. This individual harbored a de novo (complex) translocation disrupting ZNF462 and KLF12.

As this subject presented similar features to those reported by Weiss et al. (eg. craniofacial anomalies, abn. development, ASD) and given that KLF12 is not associated with any disorder, the phenotype of this individual was thought to be secondary to disruption of ZNF462.

Details on this patient - before delineation of the translocation breakpoints - were provided previously by Fryns and Hendrickx ( PMID:9297446).
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Cited by the previous article, a further case of ZNF462 disruption due to translocation was previously published in the literature (same individual - Talisetti et al. PMID: 14564155 / Ramocki et al. PMID: 12825074). Profound ID was among the features of this individual although the translocation disrupted also a further ID gene (ASXL2).
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In ClinVar 8 variants have been submitted as pathogenic/likely pathogenic although a phenotype is provided only for 3 variants published by Weiss et al.(submitting lab participating in PMID: 28513610 / SCV000494060.1 corresp. to Fam.1 / SCV000494061.1 - Fam.2 / SCV000494062.1 - Fam. 3).
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Several individuals with de novo coding variants in ZNF462 have been reported in the context of larger cohorts (some with ID as a principal feature).
http://denovo-db.gs.washington.edu/denovo-db/QueryVariantServlet?searchBy=Gene&target=ZNF462
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In Decipher apart from the DDD study participants DDD4K.03663 and DDD4K.03792 (appearing in the denovo-db) with LoF and abnormality of the nervous system, several further individuals have been submitted.

2 of these subjects, harbored a de novo LoF (submitted as pathogenic) and had ID as a feature.
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ZNF462 is included in the DD panel of G2P, associated with Craniofacial anomalies, corpus callosum dysgenesis, ptosis, and developmental delay [Disease confidence: probable / Global DD (but not ID) among the phenotypes assigned to this entry].

This gene is not associated with any phenotype in OMIM.
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ZNF462 is included in gene panels for ID offered by diagnostic laboratories (incl. Radboudumc).
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As a result this gene can be considered for inclusion in the ID panel probably as amber (or green if the current evidence is thought to be sufficient).
Sources: Literature, Radboud University Medical Center, Nijmegen
Intellectual disability v2.588 TBC1D20 Konstantinos Varvagiannis gene: TBC1D20 was added
gene: TBC1D20 was added to Intellectual disability. Sources: Literature,Radboud University Medical Center, Nijmegen
Mode of inheritance for gene: TBC1D20 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TBC1D20 were set to 24239381; 26063829
Phenotypes for gene: TBC1D20 were set to Warburg Micro syndrome 4 (MIM 615663)
Penetrance for gene: TBC1D20 were set to Complete
Review for gene: TBC1D20 was set to GREEN
gene: TBC1D20 was marked as current diagnostic
Added comment: Biallelic pathogenic variants in TBC1D20 cause Warburg Micro syndrome 4 (MIM 615663).
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Liegel et al. (PMID: 24239381) report on 7 individuals from 5 unrelated families. ID was a universal feature along with opthalmological, endocrine and other neurological features of the disorder. Seizures were noted in 4 individuals from 2 families. Table S4 of this article provides clinical details on each subject.

All affected individuals were homozygous for LoF variants, private to each family. 3 nonsense variants, 1 frameshift one as well as an intragenic deletion (exons 2-8) were identified.

These subjects belonged to a cohort of 77 individuals with suspected Warburg Micro syndrome (WMS) or disorders of the same spectrum (eg. Martsof syndrome).

Screening for TBC1D20 mutations in these individuals was performed after identification of a homozygous LoF Tbc1d20 mutation in blind sterile mice, presenting a phenotype somewhat similar to WMS (congenital cataracts and testicular anomalies).

Alternative causes of WM (eg. pathogenic variants in RAB3GAP1, RAB3GAP2 and RAB18) had previously been excluded in this cohort.

The authors demonstrated aberrant lipid droplet formation in embryonic fibroblasts from blind sterile mice as well as in fibroblasts from individuals with a diagnosis of WMS due to mutations in either of TBC1D20, RAB18 and RAB3GAP1.
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TBC1D20 is included in the DD panel of G2P, associated with Warburg micro syndrome 4 (Disease confidence: probable / ID among the phenotypes assigned to this entry).

This gene is included in gene panels for ID offered by different diagnostic laboratories (incl. Radboudumc).
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As a result, TBC1D20 can be considered for inclusion in the ID panel as green (or amber).
Sources: Literature, Radboud University Medical Center, Nijmegen
Intellectual disability v2.588 CWF19L1 Konstantinos Varvagiannis reviewed gene: CWF19L1: Rating: GREEN; Mode of pathogenicity: None; Publications: 25361784, 15981765, 26197978, 27016154; Phenotypes: Spinocerebellar ataxia, autosomal recessive 17 (MIM 616127); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability v2.588 CWF19L1 Konstantinos Varvagiannis Deleted their review
Intellectual disability v2.588 CWF19L1 Konstantinos Varvagiannis gene: CWF19L1 was added
gene: CWF19L1 was added to Intellectual disability. Sources: Literature,Radboud University Medical Center, Nijmegen
Mode of inheritance for gene: CWF19L1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CWF19L1 were set to 25361784
Phenotypes for gene: CWF19L1 were set to Spinocerebellar ataxia, autosomal recessive 17 (MIM 616127)
Penetrance for gene: CWF19L1 were set to Complete
Review for gene: CWF19L1 was set to GREEN
gene: CWF19L1 was marked as current diagnostic
Added comment: Biallelic pathogenic variants in CWF19L1 cause Spinocerebellar ataxia, autosomal recessive 17 (MIM 616127).
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Burns et al. (2014 - PMID: 25361784) report on 2 sibs born to consanguineous parents, homozygous for a splice site variant (NM_018294.5:c.964+1G>A). Congenital ataxia with hypoplasia of vermis and cerebellar hemispheres and ID were features reported in both in this study.

Clinical details on this family were published previously (Yapici and Eraksoy - PMID: 15981765) where ID appeared to be a feature for one of the sibs (FSIQ of 68) but not the other (IQ of 90) [the sibs seem to correspond to patients 5 and 6 from the third family of the original report].

Expression in patient lymphoblastoid cell lines was reduced using expression micro-arrays and quantitative reverse-transcription PCR.

The variant was shown to lead to skipping of exon 9. Introduction of an out-of-frame stop codon (thus NMD) may explain mRNA levels.

Western blot using epitope spanning exons 5-7 demonstrated absence (in patient but not in control LCLs) of the 2 protein bands expected based on this epitope. [A shorter isoform due to downstream alternative start site would not be detectable].

Using commercial normal tissue brain lysates revealed only the canonical protein band suggesting that this is the isoform present in brain.

Morpholino knockdown of cwf91l1 in zebrafish resulted in altered cerebellar staining (/structure) and abnormal motor behavior.
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Nguyen et al. (2016 - PMID: 26197978) report on a further individual with ID, ataxia and abnormal cerebellum (extensive discussions whether this represents hypoplasia/atrophy) compound heterozygous for a missense (NM_018294.4:c.37G>C / p.Asp13His) and a nonsense variant (c.946A>T / p.Lys316*).

mRNA expression in patient fibroblasts was similar to control while cDNA sequence analysis was suggestive of lower levels for the r.946A>U transcript (compared to r.37G>C) possibly due to NMD.
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Evers et al. (2016 - PMID: 27016154) report on a further individual, born to consanguineous parents, homozygous a frameshift variant (NM_018294.5:c.467delC or p.Pro156Hisfs). This individual presented with ID, ataxia and similar cerebellar anomalies.

cDNA of 3 different regions of CWF19L1 suggested tht mRNA was not entirely degraded by NMD. Western blot demonstrated absence of a band corresponding to the longest isoform in patient LCL cells. [All isoforms discussed in Fig3].

A subsequent pregnancy of the same couple was terminated due to presence of additional fetal anomalies possibly not explained by homozygosity (only) for this variant which was confirmed (cerebellar measurements were in the the low-normal range and morphology reportedly normal).
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In ClinVar additional variants have been submitted as pathogenic/likely pathogenic (although a phenotype is not specified for all).
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CWF19L1 is not associated with any phenotype in G2P.
This gene is included in gene panels for ID offered by diagnostic laboratories (incl. Radboudumc).
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As a result CWF19L1 can be considered for inclusion in this panel probably as green (rather than amber).
Sources: Literature, Radboud University Medical Center, Nijmegen
Intellectual disability v2.588 RNF13 Konstantinos Varvagiannis gene: RNF13 was added
gene: RNF13 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: RNF13 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: RNF13 were set to Congenital microcephaly; Feeding difficulties; Failure to thrive; Abnormal muscle tone; Global developmental delay; Intellectual disability; Seizures; Cortical visual impairment; Sensorineural hearing impairment
Penetrance for gene: RNF13 were set to unknown
Mode of pathogenicity for gene: RNF13 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: RNF13 was set to GREEN
Added comment: Edvardson et al. (doi.org/10.1016/j.ajhg.2018.11.018) report on 3 unrelated individuals with heterozygous de novo missense RNF13 variants.

Features included (rather borderline) congenital microcephaly, feeding difficulties, tone abnormalities, DD/ID (3/3), seizures (3/3), hearing loss and cortical visual impairment.

One individual harbored the p.Leu311Ser variant while 2 others the p.Leu312Pro.

RNF13 encodes a protein known to interact and activate IRE1a, an endoplasmatic reticulum (ER) stress sensor.

The 2 variants are predicted in silico not to affect the tertiary structure of the protein. Further to this, RNF13 is tolerant to LoF variants (pLI of 0 in ExAC). Therefore a gain-of-function mechanism was hypothesized for the 2 missense variants and demonstrated for the Leu311Ser:
- Protein levels were similar to controls upon Western blotting in patient fibroblasts.
- Enhanced IRE1a activation was demonstrated in patient cells when compared to controls, confirming gain-of-function.
- Increased activation (/ER stress), in turn, resulted in abnormally increased apoptosis similarly to what is observed in other neurological disorders.

Fibroblast/lymphoblast cells were not available from individuals with the Leu312Pro variant although a similar mechanism is presumed.

Although neurodegeneration is suggested by the above pathophysiologic mechanism, this is manifested by failure to achieve milestones (rather than eg. regression after a normal period of postnatal development / loss of milestones).
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RNF13 is not associated with any phenotype in OMIM, nor in G2P.
This gene is not commonly included in gene panels for ID offered by diagnostic laboratories.
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As a result, RNF13 can be considered for inclusion in this panel possibly as green (or amber).
Sources: Literature
Intellectual disability v2.588 PPP2CA Konstantinos Varvagiannis gene: PPP2CA was added
gene: PPP2CA was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: PPP2CA was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: PPP2CA were set to 29274472; 30030003
Phenotypes for gene: PPP2CA were set to Feeding difficulties; Muscular hypotonia; Global developmental delay; Intellectual disability; Language impairment; Seizures; Abnormality of nervous system morphology
Penetrance for gene: PPP2CA were set to unknown
Review for gene: PPP2CA was set to GREEN
Added comment: Reynhout et al. (doi.org/10.1016/j.ajhg.2018.12.002 - PMID not available) report on 16 individuals with heterozygous pathogenic PPP2CA variants.

Frequent features included feeding difficulties, hypotonia, developmental delay (16/16) with intellectual disability (probably 15/16 - a single individual developped cognitive dysfunction following a psychotic episode), language impairment, behavioral problems, seizures (10/16), brain abnormalities and variable other features.

The variants reported included 3 nonsense mutations, 1 frameshift, 1 duplication of one amino acid, 9 missense variants (of which one was observed twice and 2 affected Asp223) as well as a partial gene deletion (spanning also CDKL3).

Various mechanisms seemed to explain the effect of the different variants - among others - haploinsufficiency for some or a dominant negative effect for others, etc.

Type 2A protein phosphatases (PP2As) comprise 3 subunits, a catalytic C-type subunit (PPP2CA encodes the Cα subunit), a scaffolding A-type subunit as well as a regulatory B-type subunit important for their function. Impairment of PP2A-B56δ (encoded by PPP2R5D) binding/functionality was suggested for most of the variants. Similar dysfunction has been observed - among others - upon loss of one functional allele of PPP2R1A.

The effect of 2 variants affecting Asp223 (Asp223Val and Asp233His) was unclear as they largely behaved similar to wild-type in various functional assays. The authors argue that contribution of mutations in other genes could not be ruled out for the individuals harboring these variants, as could also be the case for the subject with disruption of (also) CDKL3.

The authors note overlapping phenotype with PPP2R1A and PPP2R5D-related ID (MIM 616362 and 616355 respectively - genes rated green in this panel).

Brain-specific Ppp2ca knockout in mice (PMID: 29274472) resulted in morphological and behavioral abnormalities partly overlapping with features observed in individuals with PPP2CA mutations. However mice heterozygous for null mutations have not been phenotypically examined (PMID: 30030003).
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PPP2CA is not associated with any phenotype in OMIM, nor in G2P.
This gene is not commonly included in gene panels for ID offered by diagnostic laboratories.
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As a result, PPP2CA can be considered for inclusion in this panel as green.
Sources: Literature
Intellectual disability v2.588 CTNNA2 Konstantinos Varvagiannis gene: CTNNA2 was added
gene: CTNNA2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: CTNNA2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CTNNA2 were set to 30013181
Phenotypes for gene: CTNNA2 were set to Cortical dysplasia, complex, with other brain malformations 9 (MIM 618174)
Penetrance for gene: CTNNA2 were set to Complete
Review for gene: CTNNA2 was set to AMBER
Added comment: Biallelic loss-of-function mutations in CTNNA2 cause cortical dysplasia, complex, with other brain malformations 9 (MIM 618174).
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Schaffer et al. (PMID: 30013181) report on 7 individuals from 3 unrelated consanguineous families. All individuals presented with profoundly impaired motor and cognitive development (severe ID in 6/7 for whom this information was available, all 6 from 2 families - a further individual from the 3rd family was non-ambulatory with absent speech at the age of 28 months), with acquired microcephaly and intractable seizures (7/7 - onset: 6m-3y - atonic/myoclonic/infantile spasms). Pachygyria without posterior-anterior gradient or focal dysplasias was common to all.

CTNNA2 encodes αN-catenin. It is expressed in human fetal brain, mainly in regions expressing migration markers DCX and TUJ1. Reduced migration was shown for iPSC-derived neural progenitor cells from an affected individual, compared to controls. The protein contains a putative actin-binding domain (ABD) at its C terminus. Several lines of evidence are provided that this domain is critical for the process of neuronal migration.
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CTNNA2 is included in the DD panel of G2P associated with disordered cortical neuronal migration (Disease confidence: probable / ID and seizures among the phenotypes assigned to this entry).

This gene is not commonly included in gene panels for intellectual disability.
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As a result CTNNA2 could be considered for inclusion in this panel as amber or possibly green.
Sources: Literature
Intellectual disability v2.588 TSEN15 Konstantinos Varvagiannis gene: TSEN15 was added
gene: TSEN15 was added to Intellectual disability. Sources: Literature,Radboud University Medical Center, Nijmegen
Mode of inheritance for gene: TSEN15 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TSEN15 were set to 27392077; 25558065
Phenotypes for gene: TSEN15 were set to Pontocerebellar hypoplasia, type 2F (MIM 617026)
Penetrance for gene: TSEN15 were set to Complete
Review for gene: TSEN15 was set to GREEN
gene: TSEN15 was marked as current diagnostic
Added comment: Biallelic pathogenic variants in TSEN15 cause Pontocerebellar hypoplasia, type 2F (MIM 617026).

Four individuals with molecular confirmation of the diagnosis, from 3 unrelated consanguineous families have been reported by Breuss et al. (PMID: 27392077). One of these individuals was previously included in a study of neurogenetic disorders in consanguineous families (Alazami et al. - PMID: 25558065). A similarly affected sib (possibly not tested) was reported for one patient.

DD with variable degrees of ID (mild to severe), progressive microcephaly were common to all. Seizures were noted in 2 individuals. MRI images (for the feature of pontocerebellar hypoplasia - PCH) were only available for 2 families.

Affected subjects were homozygous for missense variants private to each family, namely:
- NM_052965.3:c.226T>G (p.Trp76Gly)
- NM_052965.3:c.346C>T (p.His116Tyr)
- NM_052965.3:c.455A>G (p.Tyr152Cys)

Trp76Gly and Tyr152Cys resulted in reduced protein abundance while His116Tyr did not have an effect on TSEN15 expression levels.

TSEN15 is part of the tRNA splicing endonuclease complex, the 3 other components of which (TSEN2, TSEN34, TSEN54) have already been associated with PCH. The complex interacts with an RNA kinase encoded by CLP1.

All 3 variants resulted in altered stoichiometry (/relative abundance) of the 3 other subunits of the complex as well as the relative levels of CLP1.

Almost complete loss of in vitro tRNA cleavage activity was the case for purified complexes from all 3 mutants.
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TSEN15 is included in the DD panel of G2P associated with Pontocerebellar Hypoplasia and Progressive Microcephaly (Disease confidence: probable). ID is among the assigned phenotypes.

This gene is included in gene panels for ID offered by diagnostic laboratories (incl. Radboudumc).
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As a result, TSEN15 could be considered for inclusion in this panel as green (or amber).
Sources: Literature, Radboud University Medical Center, Nijmegen
Intellectual disability v2.588 RAB11A Konstantinos Varvagiannis gene: RAB11A was added
gene: RAB11A was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: RAB11A was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: RAB11A were set to 29100083
Phenotypes for gene: RAB11A were set to Global developmental delay; Intellectual disability
Penetrance for gene: RAB11A were set to unknown
Review for gene: RAB11A was set to AMBER
gene: RAB11A was marked as current diagnostic
Added comment: PMID: 29100083 (by Hamdan et al.) is a study on de novo mutations in individuals with developmental and epileptic encephalopathies (DEE).

One subject from this study was found to harbor a de novo missense RAB11A variant [NM_004663.4:c.244C>T or p.(Arg82Cys)]. This individual presented with epilepsy, developmental regression and severe ID.

In their cohort the authors also identified an additional individual with a de novo missense variant [(c.71A>G or p.(Lys24Arg)] who had moderate ID and abnormal EEG albeit without seizures.

De novo variants in RAB11A had previously been identified in 3 DDD study participants with ID.

The authors obtained clinical details on the 2 individuals with the p.(Ser154Leu) variant [NM_004663.4:c.461C>T]. One of them had moderate ID without seizures while the other had moderate global DD at the age of 4 years, also without seizures.

A third DDD study participant harbored another missense variant p.(Lys13Asn) [NM_004663.4:c.39A>C] as a de novo occurence. The authors did not manage to obtain clinical details although this patient was reported to have abnormalities of the nervous system in Decipher.

The features of all 4 individuals for whom clinical details were available are summarized in table 7.

Previous studies suggest that RAB11A has a role in NTRK2 and AMPA receptor recycling at the post-synaptic membrane of neurons and - as a result - in regulation of synaptic plasticity.
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RAB11A is not associated with any phenotype in OMIM.

This gene is included in the DD panel of G2P, associated with epilepsy and intellectual disability (disease confidence: probable).

It is also included in gene panels for ID offered by some diagnostic laboratories.
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As a result, it can be considered for inclusion in this panel as amber or possibly green (3 unrelated individuals with ID, 1 further with DD at a young age).
Sources: Literature
Intellectual disability v2.588 SLC35A3 Konstantinos Varvagiannis gene: SLC35A3 was added
gene: SLC35A3 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: SLC35A3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC35A3 were set to 24031089; 28328131; 28777481; 16344554
Phenotypes for gene: SLC35A3 were set to ?Arthrogryposis, mental retardation, and seizures (MIM 615553)
Penetrance for gene: SLC35A3 were set to Complete
Review for gene: SLC35A3 was set to GREEN
gene: SLC35A3 was marked as current diagnostic
Added comment: Biallelic pathogenic variants in SLC35A3 cause Arthrogryposis, mental retardation, and seizures (MIM 615553).
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Edvardson et al. (PMID: 24031089) report on 8 affected individuals from 3 nuclear Ashkenazi Jewish families. All harbored a nonsense [NM_012243.1:c.514C>T / p.(Gln172*)] as well as a missense variant [NM_012243.1:c.886A>G / p.(Ser296Gly)] in the compound heterozygous state. Most of the parents, who were heterozygous for the one or the other variant, were distantly related.

Common features included ASD (8/8), arthrogryposis (8/8), seizures (6/8) and intellectual disability (6/8 - variable degrees).

Upon cDNA studies, the (predicted) missense variant led to skipping of exon 8 and there was no normal size transcript (as would be expected for a variant of this type). Introduction of a premature stop codon due to this variant as well instability of the mRNA from the Gln172Ter allele was presumed to lead to absence of functional SLC35A3 protein.

Testing of 2045 Ashkenazi Jewish individuals revealed a carrier frequency of 1/205 for the missense variant in this community (with no occurrence of the nonsense variant).

SLC35A3 is a nucleotide sugar transporter that transports (uniquely) UDP-N-acetylglucosamine (UDP-GlcNAc) from the cytoplasm where it is synthesized to its site of use in the Golgi. Proper function of such transporters is essential for biosynthesis of glycoproteins, glycolipids and proteoglycans.

Although the transport of UDP-GlcNAc is mediated also by other less specific transporters, members of the SLC35 family, reduced transport was shown in patient fibroblasts compared to controls. In addition an abnormal N-glycan profile was shown in patient fibroblasts (but was not the case in serum).

Biallelic SLC35A3 mutations in cattle were previously shown to cause a Complex Vertebral Malformation (CVM) syndrome characterized by abnormal growth, vertebral and heart malformations as well as arthrogryposis (Thomsen et al. - PMID: 16344554). Arthrogryposis as well as some skeletal features observed in patients were similar to those of the animal model.
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Marini et al. (PMID: 28328131) report on 2 sibs compound heterozygous for a missense and a frameshift variant [NM_012243.2:c.73C>T or p.(Arg25Cys) and c.899_900delTTinsA or p.(Leu300Glnfs*6)]. Hypotonia, DD with ID, early-onset seizures and arthrogryposis were features in both. Severe scoliosis was also noted in the younger sib.
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Edmondson et al. (PMID: 28777481) report on a neonate (follow-up till the 21st day of life) with extensive vertebral anomalies (butterfly vertebrae, hemibertebrae, sagittal clefts, scoliosis), heart defects (PFO, PDA) and arthrogryposis. Presence of hypotonia or other neurologic features (eg. seizures) is not commented on. Conventional caryotype and SNP-array analysis were normal apart from the presence of ROH regions due to parental consanguinity. Exome sequencing revealed only a homozygous missense SNV [c.74G>T or p.(Arg25Leu) - NP_036375.1] which was supported by an abnormal N-glycan profile. As proposed for the bovine model (PMID: 16344554) and discussed in this article, similarity of the skeletal/congenital heart defects with those observed in Alagille syndrome might be due to some of the Notch functions being dependent upon N-acetylglucosamine modification.
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In ClinVar :

There is a further submission of p.Ser296Gly as pathogenic (SCV000699337.1 - 2016) apart from the submission by OMIM (SCV000108589.2 - 2013). The associated condition is Arthrogryposis, mental retardation, and seizures.

A frameshift variant [NM_012243.2(SLC35A3):c.680dup (p.Asp227Glufs)- SCV000826704.1 - April 2018] as well as an intragenic deletion [NC_000001.10:g.(?_100472570)_(100477109_?)del (GRCh37) - SCV000837123.1 - June 2018] have both been submitted as pathogenic, associated with Arthrogryposis, mental retardation, and seizures. (Note: due to the different submission dates, one can presume that these variants were found in different individuals).
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SLC35A3 is not associated with any phenotype in OMIM.
It is included in gene panels for ID offered by some diagnostic laboratories.
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As a result, this gene can be considered for inclusion in the ID panel probably as green (or amber)
[Consider upgrade of this gene to green in other panels (eg. CDGs, arthrogryposis, IEMs) and/or inclusion in other possibly relevant panels.]
Sources: Literature
Intellectual disability v2.588 SLC35A1 Konstantinos Varvagiannis reviewed gene: SLC35A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 30115659, 23873973, 28856833; Phenotypes: Congenital disorder of glycosylation, type IIf (MIM 603585); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability v2.588 PTRH2 Konstantinos Varvagiannis gene: PTRH2 was added
gene: PTRH2 was added to Intellectual disability. Sources: Literature,Radboud University Medical Center, Nijmegen
Mode of inheritance for gene: PTRH2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PTRH2 were set to 25574476; 27129381; 25558065; 28328138; 28175314
Phenotypes for gene: PTRH2 were set to Infantile-onset multisystem neurologic, endocrine, and pancreatic disease (MIM 616263)
Penetrance for gene: PTRH2 were set to Complete
Review for gene: PTRH2 was set to GREEN
gene: PTRH2 was marked as current diagnostic
Added comment: Biallelic pathogenic variants in PTRH2 cause Infantile-onset multisystem neurologic, endocrine, and pancreatic disease (MIM 616263).

Several affected individuals have been reported to date. ID was a feature in the majority.

Hu et al. (2014 - PMID:25574476) reported on 2 sibs born to consanguineous Yazidian-Turkish family, homozygous for a frameshift variant [NM_016077.4(PTRH2):c.269_270delCT (p.Ala90Glyfs)].

In PMID: 27129381 (2016) the same group reported on 5 additional individuals, from 2 unrelated consanguineous (Tunesian / Saudi-Arabian) pedigrees. These subjects were homozygous for a missense variant [NM_016077.4(PTRH2):c.254A>C (p.Gln85Pro)].

A summary of the features observed in all 7 cases is provided in table 1 of the latter article. ID was a feature in all 6 individuals for whom this information was available (6/7). Phenotypic variability even among individuals with the same variant is underscored.

mRNA studies for both variants have shown similar levels compared to controls, with reduced protein upon Western blot (for both). In Ptrh2-null mouse model a similar to the human phenotype is observed (muscle weakness and wasting, ataxia, cerebelar atrophy, etc.) (PMIDs:25574476 and 28175314).

Alazami et al. (PMID: 25558065 - 2015) report on an additional individual homozygous for the p.Gln85Pro variant. This boy presented with intellectual disability (clinical details provided in the supplement).

Sharkia et al. (PMID: 28328138) describe 3 sibs homozygous for the p.Gln85Pro variant. The index patient was reported to have normal intelligence upon formal testing which also appeared to be the case for her 2 sisters.

Apart from the 2 variants observed in the published patients, 2 further variants have been submitted in ClinVar as likely pathogenic, namely : NM_016077.4(PTRH2):c.253C>T (p.Gln85Ter) and NM_001015509.2(PTRH2):c.114dup (p.Gly39Trpfs).

PTRH2 is not associated with any phenotype in G2P.

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

As a result it can be considered for inclusion in the ID panel as green (or amber).

[As several individuals presented with ataxia, demyelinating sensorimotor neuropathy, sensorineural hearing loss and other possibly relevant phenotypes, consider inclusion in the respective gene panels].
Sources: Literature, Radboud University Medical Center, Nijmegen
Intellectual disability v2.588 KARS Zornitza Stark Deleted their comment
Intellectual disability v2.588 KARS Zornitza Stark Deleted their comment
Intellectual disability v2.588 KARS Zornitza Stark Deleted their comment
Intellectual disability v2.588 KARS Zornitza Stark Deleted their comment
Intellectual disability v2.588 KARS Zornitza Stark commented on gene: KARS: At least 6 individuals reported with a childhood-onset disorder characterised by intellectual disability, seizures, leucoencephalopathy, microcephaly and bi-allelic variants in this gene.
Intellectual disability v2.588 KARS Zornitza Stark commented on gene: KARS: At least 6 individuals reported with childhood-onset intellectual disability, seizures, leucoencephalopathy, microcephaly.
Intellectual disability v2.588 KARS Zornitza Stark commented on gene: KARS: At least 6 patients reported with a childhood-onset disorder, characterised by intellectual disability, seizures, leucoencephalopathy, and microcephaly.
Intellectual disability v2.588 KARS Zornitza Stark commented on gene: KARS: At least 6 individuals reported with childhood-onset intellectual disability, seizures, leucoencephalopathy, microcephaly.
Intellectual disability v2.588 KARS Zornitza Stark reviewed gene: KARS: Rating: GREEN; Mode of pathogenicity: None; Publications: 28887846, 25330800, 29615062, 30252186, 28496994; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability v2.588 FAH Konstantinos Varvagiannis reviewed gene: FAH: Rating: AMBER; Mode of pathogenicity: None; Publications: 28377889; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v2.588 HEPACAM Konstantinos Varvagiannis reviewed gene: HEPACAM: Rating: GREEN; Mode of pathogenicity: None; Publications: 21419380; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability v2.588 ABAT Konstantinos Varvagiannis reviewed gene: ABAT: Rating: GREEN; Mode of pathogenicity: None; Publications: 28411234; Phenotypes: GABA-transaminase deficiency (MIM 613163); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability v2.588 ABAT Konstantinos Varvagiannis Deleted their review
Intellectual disability v2.588 ABAT Konstantinos Varvagiannis reviewed gene: ABAT: Rating: AMBER; Mode of pathogenicity: None; Publications: 28411234; Phenotypes: GABA-transaminase deficiency (MIM 613163); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability v2.588 SMARCC2 Konstantinos Varvagiannis reviewed gene: SMARCC2: Rating: GREEN; Mode of pathogenicity: None; Publications: 27392482; Phenotypes: Hypotonia, Feeding difficulties, Global developmental delay, Intellectual disability, Behavioral abnormality, Abnormality of head or neck; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Intellectual disability v2.588 CSTB_CCCCGCCCCGCG Louise Daugherty GRCh38 position for CSTB_CCCCGCCCCGCG was changed from 43776447-43776470 to 43776429-43776470.
Intellectual disability v2.587 CDK10 Konstantinos Varvagiannis reviewed gene: CDK10: Rating: GREEN; Mode of pathogenicity: None; Publications: 28886341; Phenotypes: Al Kaissi syndrome (MIM 617694); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability v2.587 COLEC10 Konstantinos Varvagiannis reviewed gene: COLEC10: Rating: RED; Mode of pathogenicity: None; Publications: 28301481; Phenotypes: 3MC syndrome 3 (MIM 248340); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v2.587 SETD1B Konstantinos Varvagiannis reviewed gene: SETD1B: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None; Current diagnostic: yes
Intellectual disability v2.587 EPB41L1 Konstantinos Varvagiannis reviewed gene: EPB41L1: Rating: AMBER; Mode of pathogenicity: None; Publications: 21376300, 19503082, 11050113, 26539891, 25961944; Phenotypes: ; Mode of inheritance: None; Current diagnostic: yes
Intellectual disability v2.587 FRRS1L Konstantinos Varvagiannis gene: FRRS1L was added
gene: FRRS1L was added to Intellectual disability. Sources: Literature,Radboud University Medical Center, Nijmegen
Mode of inheritance for gene: FRRS1L was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FRRS1L were set to 27236917; 27239025; 21147040; 29276473
Phenotypes for gene: FRRS1L were set to Epileptic encephalopathy, early infantile, 37 (MIM 616981)
Penetrance for gene: FRRS1L were set to Complete
Review for gene: FRRS1L was set to GREEN
gene: FRRS1L was marked as current diagnostic
Added comment: Biallelic pathogenic variants in FRRS1L cause Epileptic encephalopathy, early infantile, 37 (EIEE37 - MIM 616981).

Several individuals homozygous for LoF variants have been reported by Madeo et al. (PMID:27236917) and Shaheen et al. (PMID:27239025 - 2 individuals of this family previously published in 21147040). DD and choreoathetotic movement disorder may precede onset of seizures and subsequent regression. Intellectual disability was a universal feature.

Both articles and the respective phenotype are summarized in OMIM.

Extensive functional studies have been performed in the article by Madeo et al. as well as in PMID: 29276473 (Han et al.) and suggest a role in glutamatergic transmission.

FRRS1L is included in the DD panel of G2P, associated with Epileptic encephalopathy with continuous spike-and-wave during sleep.

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

As a result, this gene can be considered for inclusion in the ID panel as green, if the phenotype of EIEE is thought to be relevant.
Sources: Literature, Radboud University Medical Center, Nijmegen
Intellectual disability v2.587 GTF3C3 Konstantinos Varvagiannis reviewed gene: GTF3C3: Rating: AMBER; Mode of pathogenicity: None; Publications: 30552426, 28940097, 28097321; Phenotypes: Global developmental delay, Intellectual disability, Seizures; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v2.587 TCF20 Konstantinos Varvagiannis edited their review of gene: TCF20: Added comment: One further individual investigated for mild ID and focal epilepsy was found to harbor a de novo frameshift variant [NM_005650.3:c.5430dup or p.(Ala1811Serfs*4)] in PMID: 30525188.; Changed publications: 27436265, 25228304, 28135719, 27479843, 28333917, 28554332, 30525188
Intellectual disability v2.587 DONSON Konstantinos Varvagiannis gene: DONSON was added
gene: DONSON was added to Intellectual disability. Sources: Literature,Radboud University Medical Center, Nijmegen
Mode of inheritance for gene: DONSON was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DONSON were set to 28630177; 28191891
Phenotypes for gene: DONSON were set to Microcephaly, short stature, and limb abnormalities (MIM 617604); Microcephaly-micromelia syndrome (MIM 251230)
Penetrance for gene: DONSON were set to unknown
Review for gene: DONSON was set to AMBER
gene: DONSON was marked as current diagnostic
Added comment: It seems that the phenotypes related to DONSON biallelic mutations (PMIDs: 28630177, 28191891) can be extremely variable with pre-/perinatally lethal cases to variable degrees of microcephaly (-2.4 to -10.7 SD), short stature (several individuals with height within the normal percentiles), limb anomalies (many without such anomalies, or at least significant). Similarly, DD and more specifically ID has been observed in some patients (when it happened to be the case it was most commonly mild).

This is most evident in the supplementary information of PMID: 28191891, specifically the following table:
https://media.nature.com/original/nature-assets/ng/journal/v49/n4/extref/ng.3790-S2.xlsx

Clinical synopses for the DONSON-related phenotypes:
https://www.omim.org/clinicalSynopsis/table?mimNumber=617604,251230

The gene is not associated with any phenotype in G2P.

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

As a result, gene could be considered for inclusion in the ID panel probably as amber (or green) following further review and/or if the phenotype is though to be relevant.

[Consider also inclusion in other relevant panels apart from microcephaly, eg. limb disorders etc.]
Sources: Literature, Radboud University Medical Center, Nijmegen
Intellectual disability v2.587 KCNQ3 Konstantinos Varvagiannis reviewed gene: KCNQ3: Rating: GREEN; Mode of pathogenicity: None; Publications: 24851285, 24375629, 25524373, 23934111, 28135719; Phenotypes: ; Mode of inheritance: None; Current diagnostic: yes
Intellectual disability v2.587 STAT1 Konstantinos Varvagiannis reviewed gene: STAT1: Rating: AMBER; Mode of pathogenicity: None; Publications: 27114460; Phenotypes: ; Mode of inheritance: None
Intellectual disability v2.587 TCF20 Konstantinos Varvagiannis reviewed gene: TCF20: Rating: GREEN; Mode of pathogenicity: None; Publications: 27436265, 25228304, 28135719, 27479843, 28333917, 28554332; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Intellectual disability v2.587 MED23 Konstantinos Varvagiannis reviewed gene: MED23: Rating: GREEN; Mode of pathogenicity: None; Publications: 21868677, 25845469, 27311965; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability v2.587 MED23 Konstantinos Varvagiannis Deleted their review
Intellectual disability v2.587 MED23 Konstantinos Varvagiannis reviewed gene: MED23: Rating: GREEN; Mode of pathogenicity: None; Publications: 21868677, 25845469, 27311965; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v2.587 Louise Daugherty 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; GMS R29 to Coarse facial features including Coffin-Siris-like disorders; ID; Moderate; severe or profound intellectual disability; Schizophrenia plus additional features; Intellectual disability – microarray; fragile X and sequencing
Intellectual disability v2.584 ATP8B1 Konstantinos Varvagiannis Deleted their comment
Intellectual disability v2.584 ATP8B1 Konstantinos Varvagiannis commented on gene: ATP8B1: I could not find any evidence that ATP8B1 deficiency is associated with DD/ID.

Kinsley et al. (2014 - PMID: 20301474) review the spectrum of the disorder. DD/ID is not among the features and not mentioned among extrahepatic manifestations. The only possibly relevant complication is vitamin E deficiency which can lead to neurologic manifestations (but not of this type).

Bull and Thompson (2018 - PMID: 30266155) also provide a review. DD/ID is not a feature, nor is it included in extrahepatic manifestations.

This was similarly the case in a previous review on PFIC1 by Paulusma et al. (2010 - PMID: 20422494).

The only potentially relevant article (Li et al. - PMID: 26382629) comments on the possibility of congenital hypothyroidism which seemed to be the case for 3 of 13 patients with ATP8B1 deficiency (2 further out of 13 had sub-clinical hypothyroidism). For the 3 individuals with primary hypothyroidism TSH and free thyroxine measurements were available at the ages of 2, 0 and 3 months. Among these patients however, one did not show biparental inheritance of the ATP8B1 variants as expected (both of maternal origin). For the 2 patients with subclinical hypothyroidism TSH was measured at the ages of 3 and 16 months. The authors suggest that congenital hypoparathyroidism - which in turn may affect cognitive development - may be a manifestation of ATP8B1 deficiency and as a result thyroid function should be monitored in these patients. [However testing for congenital hypothyroidism is commonly part of the newborn screening].

The ATP8B1-related phenotypes in OMIM include the following:
- Cholestasis, benign recurrent intrahepatic, MIM 243300 (AR)
- Cholestasis, intrahepatic, of pregnancy, 1, MIM 147480 (AD)
- Cholestasis, progressive familial intrahepatic 1, MIM 211600 (AR)

In G2P this gene is included in the DD panel, associated with ATP8B1-Related intrahepatic cholestasis.

ATP8B1 is not commonly included in gene panels for intellectual disability although this seems to be the case for few laboratories.

As a result, this gene could possibly be demoted to red.
Intellectual disability v2.584 ATP8B1 Konstantinos Varvagiannis reviewed gene: ATP8B1: Rating: RED; Mode of pathogenicity: None; Publications: 20301474, 30266155, 20422494, 26382629; Phenotypes: ; Mode of inheritance: None; Current diagnostic: yes
Intellectual disability v2.584 ACAN Konstantinos Varvagiannis reviewed gene: ACAN: Rating: RED; Mode of pathogenicity: None; Publications: 27353333, 29464738, 27870580, 19110214, 11389160; Phenotypes: ; Mode of inheritance: None
Intellectual disability v2.584 ZBTB11 Konstantinos Varvagiannis gene: ZBTB11 was added
gene: ZBTB11 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: ZBTB11 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZBTB11 were set to 29893856; 28382966
Phenotypes for gene: ZBTB11 were set to Intellectual disability
Penetrance for gene: ZBTB11 were set to Complete
Review for gene: ZBTB11 was set to AMBER
Added comment: Fattahi et al. (PMID: 29893856) report on 9 individuals from 2 broader consanguineous pedigrees with biallelic ZBTB11 mutations.

Features in the first family (from Iran) consisted of moderate ID, microcephaly, ataxic gait, and spasticity with MRI findings of cerebellar atrophy and ventriculomegaly.

Individuals from the second family (from Pakistan) presented with moderate ID and variable features.

Homozygosity for missense ZBTB11 variants, private to each family was shown (NM_014415.3:c.2185C>T / p.H729Y and c.2640T>G / p.H880Q for the first and second family respectively).

As the authors note, ZBTB11 is predicted to be a zinc finger transcriptional regulator and one of the hypotheses emitted suggests possible disruption of DNA binding.

Functional studies performed demonstrated that the mutant proteins were excluded from the nucleolus where the (wt) protein localizes.

Previous zebrafish models (PMID: 28382966) suggested CNS degeneration among other phenotypes in Zbtb11 mutants.

Knockdown of the drosophila ZBTB11-ortholog (CkIIα-i1) resulted in recognizable shrinking of the mushroom body with significant reduction in the number of neurons compared to controls.

Other Zinc Finger and BTB Domain-Containing proteins cause disorders with ID as a prominent feature (eg. ZBTB16, ZBTB20, etc.).

ZBTB11 is not associated with any phenotype in OMIM nor in G2P.

As a result, this gene can be considered for inclusion in this panel probably as amber (2 pedigrees only) or green (given the supportive functional studies).
Sources: Literature
Intellectual disability v2.584 NR4A2 Konstantinos Varvagiannis gene: NR4A2 was added
gene: NR4A2 was added to Intellectual disability. Sources: Literature,Radboud University Medical Center, Nijmegen
Mode of inheritance for gene: NR4A2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: NR4A2 were set to 29770430; 30504930; 28544326; 27569545; 23554088; 28135719; 27479843; 25363768
Phenotypes for gene: NR4A2 were set to Language impairment; Intellectual disability; Autism; Behavioral abnormality
Penetrance for gene: NR4A2 were set to unknown
Review for gene: NR4A2 was set to GREEN
gene: NR4A2 was marked as current diagnostic
Added comment: Recent publications provide several lines of evidence that pathogenic NR4A2 variants cause DD/ID and/or autism spectrum disorder (ASD).

Lévy et al. (PMID: 29770430) summarize the phenotype of 2q24.1 microdeletions spanning either only NR4A2 [2 new patients as well as an individual reported by Reuter et al (PMID: 28544326)] or both NR4A2 and GPD2 (1 patient from this study as well as 2 further from Leppa et al. (PMID: 27569545) and Barge-Schaapveld et al. (PMID: 23554088)]. All these CNVs had occurred as de novo events. Common features included - among others - language impairment (6/6), ID (6/6), ASD (3/4) or abnormal behaviour (4/4).

As the authors note, NR4A2 belongs to a subfamily of highly conserved transcription factors. The gene is involved in several developmental processes, among others in neuronal development. Previous studies have also shown high expression in human fetal brain as well as a role in the development of language-related brain regions.

The absence of CNVs in general population encompassing NR4A2 (and presence of such CNVs spanning GDP2) as well as the minimal deletions confined to NR4A2 suggest that happloinsufficiency of NR4A2 is responsible for the DD/ID/ASD phenotypes. This is also supported by the HI index of 1.28 as well as pLI of 0.99.

Guo et al. (PMID: 30504930) report on a patient with de novo frameshift variant (p.P201Rfs*82) and provide a summary of individuals with de novo missense variants reported in larger DD/ID/ASD cohorts, namely :

- The DDD study (PMID: 28135719) : subjects DDD4K.00386 (R312Q - https://decipher.sanger.ac.uk/ddd/research-variant/1e7622c3a0ba1b506c5808ccea46e759#overview) and DDD4K.04161 (R289P - https://decipher.sanger.ac.uk/ddd/research-variant/673e8e570d28dd0c5797ddafb22e53eb#overview)

- By Lelieveld et al. (PMID: 27479843) : patient with ID and V307G

- By Iossifov et al. (PMID: 25363768) : subject with ASD and Y275H.

[All these appear to cluster in a region of missense constraint : https://decipher.sanger.ac.uk/gene/NR4A2#overview/protein-info].

NR4A2 is not associated with any phenotype in OMIM, nor in G2P.

The gene is included in gene panels for intellectual disability offered by diagnostic laboratories (incl. Radboudumc).

As a result, it could be considered for inclusion in this panel possibly as green (or amber).
Sources: Literature, Radboud University Medical Center, Nijmegen
Intellectual disability v2.584 ELN Konstantinos Varvagiannis reviewed gene: ELN: Rating: RED; Mode of pathogenicity: None; Publications: 20301427, 14556246, 11701637; Phenotypes: ; Mode of inheritance: None; Current diagnostic: yes
Intellectual disability v2.584 ELN Konstantinos Varvagiannis Deleted their review
Intellectual disability v2.584 ELN Konstantinos Varvagiannis reviewed gene: ELN: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: 20301427, 14556246, 11701637; Mode of inheritance: None; Current diagnostic: yes
Intellectual disability v2.584 TRPS1 Konstantinos Varvagiannis reviewed gene: TRPS1: Rating: AMBER; Mode of pathogenicity: None; Publications: 28426188, 25792522, 28256045, 11112658, 17689056, 22127049, 14560312, 17854380; Phenotypes: Trichorhinophalangeal syndrome, type I (MIM 190350), Trichorhinophalangeal syndrome, type III (MIM 190351); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Intellectual disability v2.584 GUCY2C Konstantinos Varvagiannis reviewed gene: GUCY2C: Rating: RED; Mode of pathogenicity: None; Publications: 22436048; Phenotypes: ; Mode of inheritance: None
Intellectual disability v2.584 RASA1 Konstantinos Varvagiannis reviewed gene: RASA1: Rating: RED; Mode of pathogenicity: None; Publications: 29891884, 21348050, 21626678; Phenotypes: ; Mode of inheritance: None
Intellectual disability v2.584 AIMP2 Konstantinos Varvagiannis gene: AIMP2 was added
gene: AIMP2 was added to Intellectual disability. Sources: Literature,Radboud University Medical Center, Nijmegen
Mode of inheritance for gene: AIMP2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AIMP2 were set to 29215095
Phenotypes for gene: AIMP2 were set to Leukodystrophy, hypomyelinating, 17 (MIM 618006)
Penetrance for gene: AIMP2 were set to Complete
Review for gene: AIMP2 was set to AMBER
gene: AIMP2 was marked as current diagnostic
Added comment: Biallelic pathogenic variants in AIMP2 cause Leukodystrophy, hypomyelinating, 17 (MIM 618006).

3 individuals from 2 unrelated consanguineous families, of Indian origin have been reported (all in PMID: 29215095).

The phenotype consisted of feeding difficulties, lack of development with intellectual disability and seizures as well as brain MRI abnormalities (cerebral and cerebellar atrophy, hypo-intensities of the basal ganglia on T2w sequences). Severe microcephaly was observed in 2 patients for whom this information was available (birth measurements not specified).

All patients described to date were homozygous for a nonsense variant [NM_006303.3:c.105C>A or p.(Tyr35Ter)] which appears to be a founder mutation in this population.

Quantitative reverse transcription PCR demonstrated reduced mRNA levels in peripheral lymphocytes, but this decrease was not significant compared to controls (the authors presume low level of NMD).

Previous mouse models provide some - but not substantial - support.

The authors note marked similarity with the phenotype associated with AIMP1 (Leukodystrophy, hypomyelinating, 3 - MIM 260600), another auxiliary protein of the macromolecular multienzyme multi-tRNA synthetase complex. AIMP1 is listed in the current panel as green.

AIMP2 is not associated with any phenotype in G2P.

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

As a result, AIMP2 can be considered for inclusion in this panel probably as amber.
Sources: Literature, Radboud University Medical Center, Nijmegen
Intellectual disability v2.584 VPS11 Konstantinos Varvagiannis gene: VPS11 was added
gene: VPS11 was added to Intellectual disability. Sources: Literature,Radboud University Medical Center, Nijmegen
Mode of inheritance for gene: VPS11 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: VPS11 were set to 27120463; 26307567; 27473128
Phenotypes for gene: VPS11 were set to Leukodystrophy, hypomyelinating, 12 (MIM 616683)
Penetrance for gene: VPS11 were set to Complete
Review for gene: VPS11 was set to GREEN
gene: VPS11 was marked as current diagnostic
Added comment: Biallelic mutations in VPS11 cause Leukodystrophy, hypomyelinating, 12 (MIM 616683).

PMIDs: 27120463, 26307567, 27473128 all report on this disorder.

The phenotype consists of global DD, ID, (variable) acquired microcephaly with hypomyelination upon brain MRI. Seizures appear to be a feature in several individuals.

Almost all individuals appear to be of Ashkenazi Jewish descent, homozygous for a founder mutation (NM_021729.5:c.2536T>G or p.Cys846Gly). PMIDs: 27120463 and 26307567 report on 13 individuals from 7 Ashkenazi families.

A second variant (p.Leu387_Gly395del) was however found in the homozygous state in 2 sibs born to consanguineous parents.

Pathogenicity is supported by extensive functional studies in all relevant articles.

VPS11 is not associated with any phenotype in G2P.

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

As a result, this gene can be considered for inclusion in this panel as green.

[Please consider inclusion in the lysosomal disorders panel as well as in the undiagnosed metabolic disorders panel].
Sources: Literature, Radboud University Medical Center, Nijmegen
Intellectual disability v2.584 PITRM1 Konstantinos Varvagiannis gene: PITRM1 was added
gene: PITRM1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: PITRM1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PITRM1 were set to 26697887; 29764912; 29383861
Phenotypes for gene: PITRM1 were set to Intellectual disability; Ataxia
Penetrance for gene: PITRM1 were set to Complete
Review for gene: PITRM1 was set to GREEN
gene: PITRM1 was marked as current diagnostic
Added comment: Biallelic pathogenic variants in PITRM1 seem to be associated with a phenotype of DD/ID and spinocerebellar ataxia.

6 individuals from 3 unrelated families have been reported.

PMID: 26697887 reports on 2 individuals from a consanguineous Norwegian family homozygous for a missense variant (NM_014889.2:c.548G> or p.Arg183Gln).

PMID: 29764912 reports on 2 consanguineous Palestinian families each with 2 affected boys. All affected individuals for both families were homozygous for a further missense variant (p.Thr931Met).

The boys from one Palestinian family appeared to be more severely affected - compared to the sibs from the other family with the same variant - due to a concurrent X-chromosome rearrangement.

Pathogenicity is supported by extensive functional studies performed in both articles as well as an additional one (PMID: 29383861) on Arg183Gln.

PITRM1 is included in gene panels for ID offered by (few) diagnostic laboratories.

The gene is not associated with any phenotype in OMIM nor in G2P.

As a result, PITRM1 can be considered for inclusion in the ID panel as green (or amber).
Sources: Literature
Intellectual disability v2.584 LINGO1 Konstantinos Varvagiannis gene: LINGO1 was added
gene: LINGO1 was added to Intellectual disability. Sources: Literature,Radboud University Medical Center, Nijmegen
Mode of inheritance for gene: LINGO1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LINGO1 were set to 28837161
Phenotypes for gene: LINGO1 were set to Mental retardation, autosomal recessive 64 (MIM 618103)
Penetrance for gene: LINGO1 were set to Complete
Review for gene: LINGO1 was set to AMBER
gene: LINGO1 was marked as current diagnostic
Added comment: Biallelic pathogenic variants in LINGO1 cause Mental retardation, autosomal recessive 64 (MIM 618103).

Ansar et al. (PMID: 28837161) report on 5 individuals from 2 consanguineous Pakistani families.

Affected individuals from both families presented with similar phenotype consisting of global developmental delay (5/5), intellectual disability (5/5), microcephaly (4/5) as well as abnormal behavior (5/5).

Subjects from both families were homozygous for missense variants (private to each family) affecting proximal residues (290 and 288) of the protein (NM_032808.6:c.869G>A or p.Arg290His and c.863A>G or p.Tyr288Cys).

All variants were absent in an ethnically matched control cohort (201 individuals) as well as the relevant subpopulation in gnomAD.

Functional studies were not performed.

LINGO1 is a transmembrane protein predominantly expressed in the CNS. Previous studies suggest that this protein has an important role in myelination, neuronal survival and CNS repair.

LINGO1 is rather intolerant to both missense and LoF variants (Z-score of 4 and pLI of 0.95). According to the authors these variants may be hypomorphic, which might in turn suggest that monoallelic heterozygous LoF mutations could cause ID (although this remains an assumption).

This gene is not associated with any phenotype in G2P but is included in panels for ID offered by diagnostic laboratories (incl. Radboudumc).

As a result, LINGO1 can be considered for inclusion in this panel probably as amber (2 families, no functional studies).
Sources: Literature, Radboud University Medical Center, Nijmegen
Intellectual disability v2.584 SLC1A2 Konstantinos Varvagiannis reviewed gene: SLC1A2: Rating: GREEN; Mode of pathogenicity: None; Publications: 27476654, 28777935; Phenotypes: Epileptic encephalopathy, early infantile, 41 (MIM 617105); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Intellectual disability v2.584 ABCC6 Konstantinos Varvagiannis reviewed gene: ABCC6: Rating: AMBER; Mode of pathogenicity: None; Publications: 20301292, 25392903, 22209248; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v2.584 ABCB11 Konstantinos Varvagiannis reviewed gene: ABCB11: Rating: RED; Mode of pathogenicity: None; Publications: 30236549, 20232290; Phenotypes: ; Mode of inheritance: None
Intellectual disability v2.584 PAK1 Konstantinos Varvagiannis gene: PAK1 was added
gene: PAK1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: PAK1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: PAK1 were set to 30290153
Phenotypes for gene: PAK1 were set to Intellectual developmental disorder with macrocephaly, seizures, and speech delay (MIM 618158)
Penetrance for gene: PAK1 were set to unknown
Mode of pathogenicity for gene: PAK1 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: PAK1 was set to AMBER
Added comment: Heterozygous pathogenic PAK1 variants cause Intellectual developmental disorder with macrocephaly, seizures, and speech delay (MIM 618158).

Harms et al. (PMID: 30290153) report on two unrelated individuals with de novo missense mutations in PAK1. Common features included developmental delay with associated intellectual disability, seizures, ataxic gait. Postnatal-onset microcephaly as well as some facial features were also common to both subjects.

Each patient was found to harbour a (private) de novo missense variant [NM_001128620.1:c.392A>G or p.(Tyr131Cys) - c.1286A>G or p.(Tyr429Cys)]. Expression studies demonstrated similar levels for the mutant and wt transcript and Western blot confirmed similar amounts of protein in patient fibroblasts when compared to controls. Functional studies suggest that gain-of-function is the underlying mechanism for both variants.

PAK1 is not associated with any phenotype in G2P.

As a result, this gene can be considered for inclusion in this panel as amber.
Sources: Literature
Intellectual disability v2.584 FUK Konstantinos Varvagiannis gene: FUK was added
gene: FUK was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: FUK was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FUK were set to 30503518
Phenotypes for gene: FUK were set to Feeding difficulties; Generalized hypotonia; Global developmental delay; Intellectual disability; Seizures
Penetrance for gene: FUK were set to Complete
Review for gene: FUK was set to AMBER
Added comment: Ng et al. (PMID: 30503518) report on 2 unrelated individuals with biallelic pathogenic variants in FUK. The common features consisted of feeding difficulties, hypotonia, global developmental delay with severe intellectual disability, seizures as well as visual impairment.

The first patient was compound heterozygous for 2 missense variants (Ser223Pro and Arg683Cys) while the second - born to consanguineous parents - was homozygous for Lys994Gln.

Significant reduction in the FUK protein amount was demonstrated upon Western blot for the first individual for whom fibroblast and lymphoblast cell lines were available.

Fucokinase (FUK) is an enzyme of the fucose salvage pathway, one of the mechanisms (the other and main contributor being the de novo pathway) for synthesis of GDP-fucose. GDP-fucose is a donor substrate for fucosylation, a form of glycosylation. Significant decrease of fucokinase activity was shown for this individual when compared to controls.

Cell lines from the second individual were not available for expression/functional studies.

Overall the authors suggest loss-of-function variants cause a congenital disorder of glycosylation with ID and seizures.

There are no further cases published in the literature.

FUK is not associated with any phenotype in OMIM nor in G2P.

As a result this gene can be considered for inclusion in this panel as amber.

[You might consider inclusion of this gene also in the CDG gene panel].
Sources: Literature
Intellectual disability v2.584 SLC1A2 Konstantinos Varvagiannis Deleted their review
Intellectual disability v2.584 SLC1A2 Konstantinos Varvagiannis gene: SLC1A2 was added
gene: SLC1A2 was added to Intellectual disability. Sources: Literature,Radboud University Medical Center, Nijmegen
Mode of inheritance for gene: SLC1A2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SLC1A2 were set to 27476654; 28777935
Phenotypes for gene: SLC1A2 were set to Epileptic encephalopathy, early infantile, 41 (MIM 617105)
Penetrance for gene: SLC1A2 were set to Complete
Review for gene: SLC1A2 was set to AMBER
gene: SLC1A2 was marked as current diagnostic
Added comment: Pathogenic variants in SLC1A2 cause Epileptic encephalopathy, early infantile, 41 (EIEE41 - MIM 617105).

At least 4 unrelated patients each with (private) de novo variants have been reported. ID is a universal feature.

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

SLC1A2 is a probable DD gene in G2P associated with Epileptic encephalopathy.

As a result this gene could possibly be included in this panel as amber or green if the phenotype is thought to be relevant (5 more EIEEs in this panel - all rated green).
Sources: Literature, Radboud University Medical Center, Nijmegen
Intellectual disability v2.584 PTRHD1 Konstantinos Varvagiannis gene: PTRHD1 was added
gene: PTRHD1 was added to Intellectual disability. Sources: Literature,Radboud University Medical Center, Nijmegen
Mode of inheritance for gene: PTRHD1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PTRHD1 were set to 30398675; 27134041; 29143421; 27753167
Phenotypes for gene: PTRHD1 were set to Parkinsonism; Intellectual disability
Penetrance for gene: PTRHD1 were set to Complete
Review for gene: PTRHD1 was set to AMBER
gene: PTRHD1 was marked as current diagnostic
Added comment: 7 individuals with biallelic PTRHD1 mutations from 3 pedigrees have been reported. The phenotype in all consisted of early-onset Parkinsonism with intellectual disability (overview in Table 1 - PMID: 30398675).

Jaberi et al. (PMID: 27134041) first reported on 2 sibs born to consanguineous Iranian parents. Both presented with parkinsonism with ID. After homozygosity mapping and exome sequencing, one variant in PTRHD1 (NM_001013663.1:c.155G>A or p.Cys52Tyr) as well as another variant in ADORA1 were the only candidates for the patients phenotype. At the time, the authors favored ADORA1 as the causative gene for their patients' phenotype but could not exclude pathogenicity of PTRHD1.

Khodadadi et al. (PMID: 27753167) published on 2 additional sibs from Iran with a similar phenotype. These individuals - born to consanguineous parents - were homozygous for a further PTRHD1 missense variant (p.His53Tyr) which is proximal to the variant reported by Jaberi et al.

This led the authors of the first publication to acknowledge that PTRHD1 was probably responsible for their patients' phenotype (PMID: 29143421). [A recent study of exome sequencing data of a Parkinson disease 1214-patient cohort failed to find any case explained by biallelic ADORA1 mutations - PMID: 27987235].

The variants reported in these 2 publications are classified as VUS in OMIM (last update : 02/23/2017).

Kuipers et al. (PMID: 30398675) report on 3 additional individuals of African origin with identical phenotype. These individuals, whose parents originated from an isolated african community, were homozygous for a frameshift PTRHD1 deletion (c.169_196del or p.Ala57Argfs*26). This variant is rare in gnomAD (MAF of 0.018% overall or 0.15% in the African subpopulation). Alternative causes of PD / parkinsonism were previously excluded.

The phenotype of all reported individuals is summarized in Table 1 of this article.

PTRHD1 is not assocated with any phenotype in OMIM nor in G2P.

This gene is included in the gene panel for ID, offered by Radboudumc.

Therefore, this gene can be considered for inclusion in this panel as amber or green.

[Please consider inclusion of this gene in the Parkinson Disease and Complex Parkinsonism gene panel].
Sources: Literature, Radboud University Medical Center, Nijmegen
Intellectual disability v2.583 CCDC47 Konstantinos Varvagiannis gene: CCDC47 was added
gene: CCDC47 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: CCDC47 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CCDC47 were set to 30401460
Phenotypes for gene: CCDC47 were set to Woolly hair; Abnormality of the liver; Global developmental delay; Intellectual disability
Penetrance for gene: CCDC47 were set to Complete
Review for gene: CCDC47 was set to GREEN
Added comment: Morimoto el al. (PMID: 30401460) report on 4 individuals from 4 unrelated families with biallelic LoF variants in CCDC47. The phenotype consisted of abnormal (woolly) hair, liver dysfunction, common facial features as well as DD/ID.

The patients were found to harbor the variants in compound heterozygous or more commonly in homozygous state (due to consanguinity and/or common ancestry). 4 loss-of-function variants are reported in total (using NM_020198.2 as a reference):
- c.811C>T or p.(Arg271*) [consanguineous family of Turkish origin]
- c.1145delT or p.(Leu382Argfs*2) [probably a founder mutation in Amish]
- c.1165delT or p.(Ser389Leufs*25)
- c.1189C>T or p.(Arg397*)

Decreased mRNA levels in fibroblasts/lymphoblastoid cells were shown as well as absence of the protein upon Western blot using antibodies recognizing the N and C terminus (thus suggesting NMD).

Localization of CCDC47 in the ER was demonstrated with perturbed Ca+2 homeostasis and signalling in the ER.

Ccdc47-knockout mice present features similar to the human phenotypes eg. growth, neurological as well as heart anomalies. In mice embryonic/neonatal lethality was noted in some cases which might be associated with recurrent miscarriages reported in 3 patient families.

CCDC47 is not associated with any phenotype in G2P or OMIM.

As a result, this gene can be considered for inclusion in this panel as green (or amber).
Sources: Literature
Intellectual disability v2.583 DHDDS Rebecca Foulger Classified gene: DHDDS as Green List (high evidence)
Intellectual disability v2.583 DHDDS Rebecca Foulger Added comment: Comment on list classification: Added DHDDS to panel and rated Green: Probable DD-G2P gene for 'Epilepsy and intellectual disability' and sufficient unrelated (>3) cases of ID phenotype associated with heterozygous DHDDS variants from PMID:29100083. Plus compound het case of patient with glycosylation disorder and complex developmental phenotypes from PMID:27343064.
Intellectual disability v2.583 DHDDS Rebecca Foulger Gene: dhdds has been classified as Green List (High Evidence).
Intellectual disability v2.582 DHDDS Rebecca Foulger Phenotypes for gene: DHDDS were changed from Developmental delay and seizures with or without movement abnormalities, 617836 to Developmental delay and seizures with or without movement abnormalities, 617836; ?Congenital disorder of glycosylation, type 1bb, 613861
Intellectual disability v2.581 DHDDS Rebecca Foulger Added comment: Comment on mode of inheritance: Sabry et al (PMID:27343064) report a patient with DHDDS deficiency. The patient died at 8 months during a status epilepticus. The patient was compound heterozygous for variants in the DHDDS gene. The patient is also homozygous for the c.911 T>C (p.F304S) ALG6 variant that occurs in about one third of the population and does not cause CDG (but is a disease modifier to exacerbate symptoms in patients with glycosylation pathway defects). During his short life, the boy made little psychomotor acquisitions, had no eye contact, poor sucking with frequent regurgitations and failure to thrive. I have selected both monoallelic and biallelic MOI to cover MIM:617836 (AD) and future cases where ID presents as a symptom of a recessive glycosylation disorder.
Intellectual disability v2.581 DHDDS Rebecca Foulger Mode of inheritance for gene: DHDDS was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v2.580 DHDDS Rebecca Foulger gene: DHDDS was added
gene: DHDDS was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: DHDDS was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: DHDDS were set to 29100083; 27343064
Phenotypes for gene: DHDDS were set to Developmental delay and seizures with or without movement abnormalities, 617836
Review for gene: DHDDS was set to GREEN
Added comment: In 5 unrelated patients with developmental delay and seizures with or without movement abnormalities (DEDSM; 617836), Hamdan et al. (2017, PMID:29100083) identified 2 different de novo heterozygous missense mutations in the DHDDS gene (R37H and R211Q). The ID phenotype of patients covers severe/moderate-to-severe ID and global developmental delay.
Sources: Literature
Intellectual disability v2.579 NTRK2 Konstantinos Varvagiannis gene: NTRK2 was added
gene: NTRK2 was added to Intellectual disability. Sources: Literature,Radboud University Medical Center, Nijmegen
Mode of inheritance for gene: NTRK2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: NTRK2 were set to 29100083; 28135719; 15494731; 27884935
Phenotypes for gene: NTRK2 were set to Epileptic encephalopathy, early infantile, 58 (MIM 617830); Obesity, hyperphagia, and developmental delay (MIM 613886)
Penetrance for gene: NTRK2 were set to unknown
Review for gene: NTRK2 was set to GREEN
gene: NTRK2 was marked as current diagnostic
Added comment: Heterozygous pathogenic variants in NTRK2 cause Epileptic encephalopathy, early infantile, 58 (EIEE58 - MIM 617830) or Obesity, hyperphagia, and developmental delay (MIM 613886).

DD/ID are among the observed features.

Seizures can be noted in individuals falling into either diagnosis [eg. observed in the individuals with obesity and hyperphagia as in PMIDs: 15494731 and 29100083 (individual with Thr720Ile who presented also with moderate to severe ID)].

Concerning EIEE58 Tyr434Cys appears to be a recurrent variant that has been observed in 4 unrelated individuals (summary in table 2 from PMID: 29100083).

A de novo missense variant (Gly344Cys) was observed in DDD study participant DDD4K.02136 (PMID: 28135719).

NTRK2 is a probable DD gene in G2P associated with epilepsy and ID.

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

As a result, this gene can be considered for inclusion in this panel as green (rather than amber).
Sources: Literature, Radboud University Medical Center, Nijmegen
Intellectual disability v2.579 TMEM94 Konstantinos Varvagiannis gene: TMEM94 was added
gene: TMEM94 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: TMEM94 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: TMEM94 were set to Global developmental delay; Intellectual disability; Abnormal heart morphology; Abnormality of head or neck
Penetrance for gene: TMEM94 were set to Complete
Review for gene: TMEM94 was set to AMBER
Added comment: Stephen et al. (https://doi.org/10.1016/j.ajhg.2018.11.001) report on 10 individuals from 6 unrelated families with bi-allelic truncating TMEM94 variants. The common phenotype consisted of global DD/ID, similar facial features as well as the presence of congenital heart defects (in all but one).

Speech as well as motor delay and learning difficulties were universal features. ID is mentioned in the abstract, explicitly specified for one individual and implied for some of the rest.

Overall 6 different LoF variants are reported. Reduced expression was demonstrated while gene expression microarray and RNA sequencing expression studies demonstrated dysregulation of several essential genes. Using a CRISPR/Cas9 mouse model loss of Tmem94 was shown to be embryonically lethal with craniofacial, cardiac anomalies as well as abnormal neuronal migration pattern observed in homozygous mutant mice embryos.

TMEM94 is not associated with any phenotype in G2P nor in OMIM.

As a result this gene can be considered for inclusion in this panel probably as amber (or green).
Sources: Literature
Intellectual disability v2.579 PUS3 Konstantinos Varvagiannis reviewed gene: PUS3: Rating: AMBER; Mode of pathogenicity: None; Publications: 27055666, 30308082; Phenotypes: ?Mental retardation, autosomal recessive 55 (MIM 617051); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability v2.579 PUS3 Konstantinos Varvagiannis Deleted their review
Intellectual disability v2.579 PUS3 Konstantinos Varvagiannis gene: PUS3 was added
gene: PUS3 was added to Intellectual disability. Sources: Literature,Radboud University Medical Center, Nijmegen
Mode of inheritance for gene: PUS3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PUS3 were set to 27055666; 30308082
Phenotypes for gene: PUS3 were set to Global developmental delay; Intellectual disability; Microcephaly
Penetrance for gene: PUS3 were set to Complete
Review for gene: PUS3 was set to AMBER
gene: PUS3 was marked as current diagnostic
Added comment: PUS3 (Pseudouridylate synthase 3) is proposed as a gene related to ID in a recent publication on PUS7.

Biallelic mutations in this gene are associated in OMIM with ?Mental retardation, autosomal recessive 55 (MIM 617051).

PMID: 27055666 reports on 3 sisters from a consanguineous Saudi Arabian family with failure to thrive, DD/ID, microcephaly and some common (coarse) facial features. These individuals were homozygous for a stopgain mutation in the last exon of the gene. Pseudouridylation appeared to be defective (as has also been the case with other genes related to ID, eg. PUS7).

PMID: 30308082 describes 1 individual born to consanguineous Palestinian parents, homozygous for a further LoF variant. Despite the localisation of this variant (again in the last exon of the gene) qPCR analyses were suggestive of degradation of the abnormal transcript possibly by NMD. The phenotype consisted of DD/ID and microcephaly.

In a further publication (http://dx.doi.org/10.7124/bc.0008D6) Gulkovskyi et al. report on 2 siblings with ID, born to non-consanguineous Ukranian parents. Pathogenicity of the variant is disputed. [NM_031307.4:c.212A>G or p.(Tyr71Cys) is found in an apparent homozygous state in the sibs but was only found in their father. De novo occurence in the maternal allele is proposed although the possibility of microdeletion missed by aCGH or other plausible mechanisms are not considered. This variant has maximum pathogenicity scores in silico (not discussed) and has an allele frequency of 0.00006717 in gnomAD. The authors did not perform studies of pseudouridylation but examined for the presence of hypoproteinemia, observed in some disorders affecting this process).

PUS3 is not associated with any phenotype in G2P but is associated with disease in OMIM.

The gene is included in gene panels for ID offered by various diagnostic laboratories (including Radboudumc). PUS1 is included in the current panel as green and PUS7 has been suggested for inclusion.

As a result, these gene can be considered for inclusion as amber (2 families) or green (given the supportive functional studies and/or the proposed role for the gene).
Sources: Literature, Radboud University Medical Center, Nijmegen
Intellectual disability v2.579 PBX1 Konstantinos Varvagiannis reviewed gene: PBX1: Rating: GREEN; Mode of pathogenicity: None; Publications: 28270404, 28566479, 29036646; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Intellectual disability v2.579 PBX1 Konstantinos Varvagiannis Deleted their review
Intellectual disability v2.579 PBX1 Konstantinos Varvagiannis reviewed gene: PBX1: Rating: GREEN; Mode of pathogenicity: None; Publications: 28270404, 28566479, 29036646; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Intellectual disability v2.579 PPP1R21 Zornitza Stark reviewed gene: PPP1R21: Rating: GREEN; Mode of pathogenicity: None; Publications: 30520571, 29808498, 2894097; Phenotypes: severe intellectual disability, hypotonia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability v2.579 METTL23 Konstantinos Varvagiannis gene: METTL23 was added
gene: METTL23 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: METTL23 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: METTL23 were set to 24501276; 24626631
Phenotypes for gene: METTL23 were set to Mental retardation, autosomal recessive 44 (MIM 615942)
Penetrance for gene: METTL23 were set to Complete
Review for gene: METTL23 was set to GREEN
gene: METTL23 was marked as current diagnostic
Added comment: Biallelic pathogenic variants in METTL23 cause Mental retardation, autosomal recessive 44 (MIM 615942).

Reiff et al. (PMID: 24501276) report on a consanguineous pedigree of Yemeni origin with 7 individuals presenting intellectual disability. Clinical details are provided for 3 subjects from one branch of the family. Findings included moderate (2/3) or severe (1/3) ID, seizures (2/3) and some common facial features. Seizures were not observed in individuals from other branch of the family. The affected individuals were homozygous for a 4-bp deletion.

Bernkopf et al. (PMID: 24626631) report on a consanguineous family from Pakistan with 2 affected sibs as well as a non-consanguineous family from Austria with 4 affected sibs. The parents in the latter family originated from a small - geographically isolated - village. Individuals from the Pakistani family were homozygous for a nonsense variant, while the sibs from the Austrian family for a frameshift variant. Mild ID was noted in all.

In total 3 different LoF variants have been reported. Extensive functional studies have been performed in both articles.

METTL23 (methyltransferase like 23) is expressed at low-to-moderate levels in the developping human brain. Bernkopf et al. suggest that METTL23 is indeed a methyltransferase.

The gene has 7 transcripts of which one is non-coding. 3 transcripts encode isoform 1 and 3 other encode isoform 2.

The variant reported by Reiff et al. affects the coding region of 3 (of the 6 coding) transcripts (corresponding to isoform 1) and the 5'-UTR of the other 3 transcripts. It is however shown that this first coding exon (specific to isoform 1) is expressed in the developing human brain, though at lower levels than downstream exons common to both isoforms. In addition, only isoform 1 appears to be conserved in most other species.

The variants described by Bernkopf et al. affect all 6 coding trancripts and as a result both isoforms. [However, the individuals reported by Bernkopf et al. were less severely affected compared to those reported by Reiff et al.]

Nonsense-mediated decay appeared unlikely since mRNA levels for both isoforms in lymphoblasts from affected individuals were similar to controls (upon qRT-PCR) [The specific nonsense variant tested would be expected to be subject to NMD given its localization].

METTL23 is not associated with any phenotype in G2P.

This gene is included in gene panels for intellectual disability offered by various diagnostic laboratories.

As a result, METTL23 can be considered for inclusion in the ID panel as green (or amber).
Sources: Literature
Intellectual disability v2.579 MAST1 Konstantinos Varvagiannis gene: MAST1 was added
gene: MAST1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: MAST1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: MAST1 were set to 30449657; 28135719; 25666757; 27479843
Phenotypes for gene: MAST1 were set to Global developmental delay, Intellectual disability, Abnormality of the corpus callosum, Cerebellar hypoplasia, Abnormality of the cerebral cortex, Seizures; Global developmental delay, Intellectual disability, Microcephaly, Autism, Seizures
Penetrance for gene: MAST1 were set to unknown
Review for gene: MAST1 was set to GREEN
gene: MAST1 was marked as current diagnostic
Added comment: PMID: 30449657 reports on 6 unrelated individuals with de novo mutations in MAST1. All these 6 individuals were investigated for a strikingly similar phenotype of enlarged corpus callosum (CC), cerebellar hypoplasia, cortical malformation with associated DD/ID. Seizures were a feature in 2/6 (one further had EEG anomalies without clinical seizures).

Three of them harbored an in-frame deletion of 1 amino-acid (3 different indels reported - all in a specific domain) while 3 others had a missense variant (NM_014975.2:c.1549G>A or p.Gly517Ser).

Mast1 has embryonic expression in murine models with postnatal decrease. Similarly qPCR of human fetal brain cDNA demonstrated expression at 13 and 22 gestational weeks. A murine model for L278del recapitulated the brain (incl. CC) and cerebellar phenotype while Mast1 knockout mice do not present similar morphological defects. While Western blot in murine brain lysates demonstrated absence of Mast1 in knockout and reduction in the L278del, Mast1 transcript levels for L278del were similar to wildtype. Other Mast proteins (Mast1 & Mast2) were significantly reduced upon western blot while this was not reflected in their mRNA levels, suggesting a dominant-negative effect, at least for the L278del.

4 additional individuals with somewhat different phenotype consisting DD/ID and microcephaly/autism are described in the supplement. All 4 had de novo missense variants but did not display the CC-cerebral and cerebellar anomalies. Four different (additional to Gly517Ser) missense SNVs were observed.

Several additional individuals exist in the denovo-db (among others DDD participant DDD4K.02310 published in 28135719, 25666757 - McMichael et al. commented in the article, 27479843, etc.). [http://denovo-db.gs.washington.edu/denovo-db/QueryVariantServlet?searchBy=Gene&target=Mast1]

Epilepsy was a feature in 4/10 individuals (with an additional one with EEG anomalies without clinical seizures). One further individual from PMID:23934111 (in denovo-db) had seizures.

As the authors comment (and as evident from the 6+4 reported patients) the related neurodevelopmental phenotype may be more complex.

MAST1 is not related to any phenotype in G2P, nor in OMIM.

The gene is included in gene panels for ID offered by different diagnostic laboratories.

As a result, this gene can be considered for inclusion in this panel as green.
Sources: Literature
Intellectual disability v2.579 RPIA Konstantinos Varvagiannis gene: RPIA was added
gene: RPIA was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: RPIA was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RPIA were set to 14988808; 20499043; 28801340; 30088433
Phenotypes for gene: RPIA were set to Ribose 5-phosphate isomerase deficiency, MIM 608611.
Penetrance for gene: RPIA were set to unknown
Review for gene: RPIA was set to GREEN
gene: RPIA was marked as current diagnostic
Added comment: Biallelic pathogenic variants in RPIA cause Ribose 5-phosphate isomerase deficiency, MIM 608611.

PMID: 14988808 is the first report on the disorder with molecular (incl. genetic) confirmation of the diagnosis. A patient initially investigated for early developmental delay, leukoencephalopathy, seizures with onset at 4 years, with subsequent neurologic regression and peripheral neuropathy at the age of 7, was suspected to have a disorder of the pentose phosphate pathway on the basis of highly elevated polyols on brain MRS and body fluid analysis. Reduced ribose 5-phosphate isomerase activity was shown in fibroblasts. Genetic testing demonstrated the presence of a missense (NM_144563.2:c.404C>T / NP_653164.2:p.Ala135Val - previously referred to as A61V) as well as a frameshift variant (NM_144563.2:c.762delG / NP_653164.2:p.Asn255Ilefs). Additional extensive supportive functional studies were published a few years later (PMID: 20499043). [This patient was initially described in PMID: 10589548].

PMID: 28801340 is a report on a second patient. This individual presented with delayed early development (independent walking and speech achieved at 2 and 5 years respectively), seizures and regression at the age of 7 with MRI white matter abnormalities. Review of magnetic resonance spectroscopy (MRS) was suggestive of elevated polyols (arabitol and ribitol). In line with this, genetic testing revealed a homozygous missense variant in RPIA (NM_144563.2:c.592T>C or p.Phe198Leu). Urine analysis confirmed elevated excretion of polyols, thus confirming the diagnosis.

PMID: 30088433 reports on a boy with neonatal onset leukoencephalopathy and developmental delay having undergone early metabolic testing and aCGH (the latter at the age of 16 months). Persistance of his delay motivated exome sequencing at the age of approx. 4.5 years which demonstrated 2 RPIA variants (NM_144563.2:c.253G>A or p.Ala85Thr and NM_144563.2:c.347-1G>A). Measurement of ribitol and arabitol in urine demonstrated significant elevations (>20x) consistent with this diagnosis.

RPIA is included in gene panels for intellectual disability offered by various diagnostic laboratories.

As a result this gene can be considered for inclusion in this panel as green (or amber).
Sources: Literature
Intellectual disability v2.579 PUS7 Konstantinos Varvagiannis reviewed gene: PUS7: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Intellectual disability, Microcephaly, Short stature, Behavioral abnormality; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability v2.579 PUS7 Konstantinos Varvagiannis Deleted their review
Intellectual disability v2.579 PUS7 Konstantinos Varvagiannis gene: PUS7 was added
gene: PUS7 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: PUS7 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: PUS7 were set to Intellectual disability; Microcephaly; Short stature; Behavioral abnormality
Penetrance for gene: PUS7 were set to Complete
Review for gene: PUS7 was set to GREEN
gene: PUS7 was marked as current diagnostic
Added comment: de Brouwer et al. (https://doi.org/10.1016/j.ajhg.2018.10.026) report on 6 individuals from 3 unrelated families homozygous for truncating variants in PUS7.

The common phenotype consisted of ID with speech delay, microcephaly, short stature as well as aggressive behavior.

One frameshift, one nonsense and one intragenic deletion affecting the penultimate exon of PUS7 were private respectively to each family. qPCR demonstrated reduction of mRNA levels for the two first variants, with absence of the normally sized protein upon Western blot for the first one.

The deletion, not identified due to its small size by aCGH, was found in the exome analysis and confirmed by MAQ. RT-PCR demonstrated the absence of the respective exon in mRNA. The deletion resulted in introduction of a stop codon in the last exon and mRNA expression levels were shown to be normal. Western blot demonstrated absence of a normally sized protein. (As a result, truncating mutations in the last exon may also be deleterious).

Functional studies demonstrated defective tRNA and mRNA pseudouridylation. Drosophila knockouts recapitulated the behavioral phenotype.

Biallelic mutations in PUS1 and PUS3 have been reported in individuals with intellectual disability (as well as some other features noted in PUS7-related disorder).

PUS7 is included in the gene panel for ID offered by Radboud UMC (among the principal authors of the study).

Therefore this gene can be considered for inclusion in this panel as green (rather than amber).
Sources: Literature
Intellectual disability v2.579 ATXN10_ATTCT Louise Daugherty Phenotypes for STR: ATXN10_ATTCT were changed from Spinocerebellar ataxia 603516 to Spinocerebellar ataxia 10 603516
Intellectual disability v2.578 ATXN10_ATTCT Louise Daugherty Phenotypes for STR: ATXN10_ATTCT were changed from Spinocerebellar ataxia , 603516 to Spinocerebellar ataxia 603516
Intellectual disability v2.577 ATXN7_CAG Louise Daugherty Classified STR: ATXN7_CAG as No list
Intellectual disability v2.577 ATXN7_CAG Louise Daugherty Added comment: Comment on list classification: Removed STR from Panel. This STR was not listed on the recent GMC STRs document supplied by Arianna Tucci.
Intellectual disability v2.577 ATXN7_CAG Louise Daugherty Str: atxn7_cag has been removed from the panel.
Intellectual disability v2.576 PPP1R21 Konstantinos Varvagiannis gene: PPP1R21 was added
gene: PPP1R21 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: PPP1R21 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PPP1R21 were set to 29808498; 28940097
Phenotypes for gene: PPP1R21 were set to Generalized hypotonia; Feeding difficulties; Profound global developmental delay; Abnormality of the face; Abnormality of vision; Abnormal heart morphology; Abnormality of the respiratory system; Hepatosplenomegaly
Penetrance for gene: PPP1R21 were set to Complete
Review for gene: PPP1R21 was set to GREEN
Added comment: Biallelic pathogenic variants in PPP1R21 have been reported so far in 9 individuals from 7 unrelated families. All (7 different) variants reported to date are truncating.

PMID: 29808498 is the first detailed clinical description on the related phenotype. 3 individuals from 3 families are reported. One of these individuals was previously included in a larger patient cohort (in PMID: 28940097).

In a subsequent further publication, Rehman et al. (https://doi.org/10.1002/humu.23694) describe 6 additional patients from 4 unrelated consanguineous families. Again, these individuals were homozygous for truncating mutations. The authors summarize the findings in their patients as well as the previously reported ones.

Common features included feeding difficulties, hypotonia with severe global DD and mildly coarsened facial features (all were observed in 9/9), visual anomalies (8/9), respiratory problems (7/9), cardiac anomalies (4/9) and hepato-/splenomegaly (3/7). Brain MRI anomalies were observed in the majority. DD was severe in all and ID (which is not explicitly mentioned) was evident from the clinical description of several individuals (eg. in PMID: 29808498).

In total 7 loss-of-function variants have been reported. The authors in the first article, underscore the possibility of less severe phenotypes associated to biallelic missense variants (although none has been reported so far).

Functional studies have shown great reduction (but not complete absence) of PPP1R21 mRNA levels in patient fibroblasts compared to controls. A role of PPP1R21 in the endosomal-lysosomal function is demonstrated in line with the presence of myelin figures in patient fibroblasts as well as some phenotypic similarities to neurometabolic/lysosomal storage disorders.

Most variants reported in the most recent publication except one (NM_001135629.2:c.1607dupT) seem to affect all 3 PPP1R21 isoforms (which also seems to be the case for previously published variants). c.1607dupT appears to be the single truncating variant affecting 2 (of 3) isoforms. This variant was however shown to have severely reduced expression in fibroblasts upon qPCR, absent protein staining, and increase in myelin figures.

The protein is expressed in embryonic mouse cortex.

Overall, this gene can be considered for inclusion in this panel as green (or amber).
Sources: Literature
Intellectual disability v2.576 GRIN2D Konstantinos Varvagiannis gene: GRIN2D was added
gene: GRIN2D was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: GRIN2D was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: GRIN2D were set to 27616483; 30280376
Phenotypes for gene: GRIN2D were set to Epileptic encephalopathy, early infantile, 46 (MIM 617162)
Penetrance for gene: GRIN2D were set to unknown
Review for gene: GRIN2D was set to GREEN
gene: GRIN2D was marked as current diagnostic
Added comment: Heterozygous pathogenic variants in GRIN2D cause Epileptic encephalopathy, early infantile, 46 (MIM 617162).

As commented in the previous review, PMID: 27616483 is the first report on 2 unrelated individuals with severe epileptic encephalopathy (onset of seizures at the age of 2 and 4 months). Severe DD with ID was noted in both.

Each of these individuals were heterozygous for the same missense variant (NM_000836.2:c.1999G>A p.Val667Ile) as a de novo event. Functional studies demonstrated a gain-of-function effect.

GRIN2D encodes for an NMDA receptor subunit, and the gain-of-function effect shown for this variant suggests that NMDAR antagonists might be useful as adjuvant therapy (some improvement noted in both individuals).

[The mode of pathogenicity selected here may be modified as more evidence on further variants becomes available. GRIN2D appears to be intolerant also to LoF mutations with a pLI of 1. Both LoF and GoF mutations have been described for genes encoding other NMDAR subunits].

PMID: 30280376 reports on 3 additional unrelated patients with developmental and epileptic encephalopathy and pathogenic or likely pathogenic missense variants in GRIN2D.

Three additional missense variants are reported (Met681Ile, Ser694Arg, Asp449Asn). Parental studies were possible only for the patient with Met681Ile (de novo) as well as for the individual with Ser694Arg (only one parent available though).

Significant developmental delay was evident in all prior to the onset of seizures (1m/2y/3y respectively) and subsequent developmental stagnation/regression with ID.

The phenotype of these 3 individuals as well as of the 2 previously described is summarized in table 1 of the latter article.

GRIN2D is a probable DD gene in G2P and is included in gene panels for ID offered by diagnostic laboratories.

Several other genes for NMDA receptor subunits (eg. GRIN2A, GRIN2B, GRIN1) and relevant/similar phenotypes are included in this panel as green.

As a result, this gene can be considered for inclusion in the ID panel as green (or amber).
Sources: Literature
Intellectual disability v2.575 C9orf72_GGGGCC Louise Daugherty Pathogenic Number of Repeats for C9orf72_GGGGCC was changed from 60 to 30.
Intellectual disability v2.574 MCM3AP Konstantinos Varvagiannis gene: MCM3AP was added
gene: MCM3AP was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: MCM3AP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MCM3AP were set to 24123876; 28633435; 28969388; 29982295
Phenotypes for gene: MCM3AP were set to Peripheral neuropathy, autosomal recessive, with or without impaired intellectual development (MIM 618124)
Penetrance for gene: MCM3AP were set to Complete
Review for gene: MCM3AP was set to AMBER
gene: MCM3AP was marked as current diagnostic
Added comment: Biallelic mutations in MCM3AP cause Peripheral neuropathy, autosomal recessive, with or without impaired intellectual development (MIM 618124).

All relevant publications [PMIDs: 24123876, 28633435 (first detailed description of a series of patients with functional studies), 28969388, 29982295) are summarized in OMIM.

Overall more than 18 patients from 10 families and at least 8 pathogenic variants have been reported.

Apart from abnormal motor development which may be associated with the sensorimotor neuropathy, intellectual disability was a feature in several individuals (although not a universal one).

Some patients were initially evaluated for their ID while investigations for the neuropathy may be conducted late (as evident in PMID: 28633435).

MCM3AP is included in gene panels for intellectual disability offered by diagnostic laboratories.

As a result, this gene can be considered for inclusion in the ID panel as amber or green (depending on its relevance to the specific panel).
Sources: Literature
Intellectual disability v2.574 SET Konstantinos Varvagiannis reviewed gene: SET: Rating: GREEN; Mode of pathogenicity: None; Publications: 29688601, 25356899, 28135719; Phenotypes: Mental retardation, autosomal dominant 58 (MIM 618106); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Intellectual disability v2.574 PPP2R2B_CAG Louise Daugherty Classified STR: PPP2R2B_CAG as No list
Intellectual disability v2.574 PPP2R2B_CAG Louise Daugherty Added comment: Comment on list classification: Removed STR from Panel. This STR was not listed on the recent GMC STRs document supplied by Arianna Tucci.
Intellectual disability v2.574 PPP2R2B_CAG Louise Daugherty Str: ppp2r2b_cag has been removed from the panel.
Intellectual disability v2.573 FXN_GAA Louise Daugherty Classified STR: FXN_GAA as No list
Intellectual disability v2.573 FXN_GAA Louise Daugherty Added comment: Comment on list classification: Removed STR from Panel. This STR was not listed on the recent GMC STRs document supplied by Arianna Tucci.
Intellectual disability v2.573 FXN_GAA Louise Daugherty Str: fxn_gaa has been removed from the panel.
Intellectual disability v2.572 FXN_GAA Louise Daugherty Normal Number of Repeats for FXN_GAA was changed from 33 to 44.
Intellectual disability v2.571 CSTB_CCCCGCCCCGCG Louise Daugherty Classified STR: CSTB_CCCCGCCCCGCG as No list
Intellectual disability v2.571 CSTB_CCCCGCCCCGCG Louise Daugherty Added comment: Comment on list classification: Removed STR from Panel. This STR was not listed on the recent GMC STRs document supplied by Arianna Tucci.
Intellectual disability v2.571 CSTB_CCCCGCCCCGCG Louise Daugherty Str: cstb_ccccgccccgcg has been removed from the panel.
Intellectual disability v2.570 C9orf72_GGGGCC Louise Daugherty Classified STR: C9orf72_GGGGCC as No list
Intellectual disability v2.570 C9orf72_GGGGCC Louise Daugherty Added comment: Comment on list classification: Removed STR from Panel. This STR was not listed on the recent GMC STRs document supplied by Arianna Tucci.
Intellectual disability v2.570 C9orf72_GGGGCC Louise Daugherty Str: c9orf72_ggggcc has been removed from the panel.
Intellectual disability v2.569 ATXN3_CAG Louise Daugherty Classified STR: ATXN3_CAG as No list
Intellectual disability v2.569 ATXN3_CAG Louise Daugherty Added comment: Comment on list classification: Removed STR from Panel. This STR was not listed on the recent GMC STRs document supplied by Arianna Tucci.
Intellectual disability v2.569 ATXN3_CAG Louise Daugherty Str: atxn3_cag has been removed from the panel.
Intellectual disability v2.568 ATXN2_CAG Louise Daugherty Classified STR: ATXN2_CAG as No list
Intellectual disability v2.568 ATXN2_CAG Louise Daugherty Added comment: Comment on list classification: Removed STR from Panel. This STR was not listed on the recent GMC STRs document supplied by Arianna Tucci.
Intellectual disability v2.568 ATXN2_CAG Louise Daugherty Str: atxn2_cag has been removed from the panel.
Intellectual disability v2.567 ATXN10_ATTCT Louise Daugherty Classified STR: ATXN10_ATTCT as No list
Intellectual disability v2.567 ATXN10_ATTCT Louise Daugherty Added comment: Comment on list classification: Removed STR from Panel. This STR was not listed on the recent GMC STRs document supplied by Arianna Tucci.
Intellectual disability v2.567 ATXN10_ATTCT Louise Daugherty Str: atxn10_attct has been removed from the panel.
Intellectual disability v2.566 ATXN1_CAG Louise Daugherty Pathogenic Number of Repeats for ATXN1_CAG was changed from 39 to 44.
Intellectual disability v2.565 ATXN1_CAG Louise Daugherty Classified STR: ATXN1_CAG as No list
Intellectual disability v2.565 ATXN1_CAG Louise Daugherty Added comment: Comment on list classification: Removed STR from Panel. This STR was not listed on the recent GMC STRs document supplied by Arianna Tucci
Intellectual disability v2.565 ATXN1_CAG Louise Daugherty Str: atxn1_cag has been removed from the panel.
Intellectual disability v2.564 TRMT1 Konstantinos Varvagiannis reviewed gene: TRMT1: Rating: GREEN; Mode of pathogenicity: None; Publications: 30289604, 21937992, 26308914, 28784718; Phenotypes: Global developmental delay, Intellectual disability, Seizures, Microcephaly; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability v2.564 PRR12 Konstantinos Varvagiannis reviewed gene: PRR12: Rating: GREEN; Mode of pathogenicity: None; Publications: 29556724, 26163108, 28135719; Phenotypes: Global developmental delay, Intellectual disability, Abnormality of the iris, Abnormality of vision, Behavioral abnormality; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Intellectual disability v2.564 PRR12 Konstantinos Varvagiannis Deleted their review
Intellectual disability v2.564 PRR12 Konstantinos Varvagiannis gene: PRR12 was added
gene: PRR12 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: PRR12 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: PRR12 were set to 29556724; 26163108
Phenotypes for gene: PRR12 were set to Global developmental delay; Intellectual disability; Abnormality of the iris; Abnormality of vision; Behavioral abnormality
Penetrance for gene: PRR12 were set to unknown
Review for gene: PRR12 was set to GREEN
gene: PRR12 was marked as current diagnostic
Added comment: PMID: 29556724 (Leduc et al. 2018) reports on 3 unrelated individuals with de novo pathogenic variants in PRR12. The common phenotype consisted of DD/ID (3/3), iris anomalies (colobomas in 2/3 with stellate iris patern in all) as well as additional vision problems and behavioral anomalies.

3 different loss-of-function variants are reported. These variants affected the longer transcript (Ensembl ENST00000418929.6 or NM_020719 - short : ENST00000615927.1) with a single one affecting both.

PRR12 appears to be intolerant to loss-of-function muatations (pLI of 1). Some LoF variants exist in ExAC/gnomAD although the majority appear to be low-quality variants.

As commented by the authors 2 individuals with de novo variants exist in Decipher (1 in-frame deletion and a missense SNV - both variants appear in fig.2 of the article) [a few more DDD study participants in the denovo-db all from PMID: 28135719 : http://denovo-db.gs.washington.edu/denovo-db/QueryVariantServlet?searchBy=Gene&target=PRR12].

Alternative explanations for the phenotype (eg. CHARGE syndrome, etc) were ruled out in many individuals in the article.

Functional studies have not been performed. //

PMID: 26163108 (Córdova-Fletes al. 2015) is a previous report cited by Leduc et al. One individual with balanced translocation [t(10;19)] with disruption of PRR12 is described. This individual presented with ID and behavioral anomalies (without details on eventual coloboma or other iris anomalies).

The translocation was balanced and led to fusion of PRR12 with LMIZ1. The breakpoint was located within intron 11 (PRR12 is a 14-exon gene) with fusion of PRR12 exon 11 with ZMIZ1 exon 8 upon RT-PCR. Both PRR12/ZMIZ1 products were predicted to be truncated due to frameshift and introduction of premature stop codon.

[Surprisingly qPCR and Western blot in patient LCLs were suggestive of increased PRR12 expression compared to controls suggesting either a compensation mechanism or longer half-life/accumulation of the aberrant PRR12].

Expression of wt PRR12 was highest during embryonic development in mouse/rat brain cells suggesting a role in early CNS development. The transcript studied (corresponding to the longest human transcript) was exclusively located in the nucleus compared to a shorter one located primary in the nucleus but also outside suggesting that PRR12 might be involved in regulation of transcription.

In line with this several genes linked to neurodevelopmental processes/neuronal communication appeared be dysregulated in lymphoblastoid cell lines (LCLs) from the translocation patient.

A role for ZMIZ1 is similarly discussed. //

PRR12 is included in gene panels for ID offered by diagnostic laboratories. //

As a result, this gene can be considered for inclusion in this panel as green (or amber).
Sources: Literature
Intellectual disability v2.564 DMPK_CTG Arianna Tucci Classified STR: DMPK_CTG as Green List (high evidence)
Intellectual disability v2.564 DMPK_CTG Arianna Tucci Str: dmpk_ctg has been classified as Green List (High Evidence).
Intellectual disability v2.563 DMPK_CTG Arianna Tucci Marked STR: DMPK_CTG as ready
Intellectual disability v2.563 DMPK_CTG Arianna Tucci Added comment: Comment when marking as ready: Marked as ready following the Webex discussion with experts from the GMCs (6/09/2018) about feeding back STR results
Intellectual disability v2.563 DMPK_CTG Arianna Tucci Str: dmpk_ctg has been classified as Red List (Low Evidence).
Intellectual disability v2.563 DMPK_CTG Arianna Tucci Normal Number of Repeats for DMPK_CTG was changed from 34 to 38.
Intellectual disability v2.562 CAD Konstantinos Varvagiannis gene: CAD was added
gene: CAD was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: CAD was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CAD were set to 25678555; 28007989
Phenotypes for gene: CAD were set to Epileptic encephalopathy, early infantile, 50 - MIM 616457
Penetrance for gene: CAD were set to Complete
Review for gene: CAD was set to AMBER
gene: CAD was marked as current diagnostic
Added comment: Biallelic pathogenic variants in CAD cause Epileptic encephalopathy, early infantile, 50 - MIM 616457.

Overall 5 individuals from 4 unrelated families have been reported in detail in PMIDs 25678555 and 28007989 (table 1 in this article provides a summary).

The phenotype consisted of developmental delay which preceded the onset of seizures (6 months to 2 years) and hematologic anomalies (anemia and anisopoikilocytosis). The patients presented developmental stagnation/regression, which in most cases occurred several months following the seizure onset.

CAD is a tri-functional protein catalyzing the first 3 steps of the de novo pyrimidine biosynthesis.

In total, 5 variants have been reported (2 missense, 1 nonsense and 2 splice-site SNVs) with functional studies (cDNA, metabolites) supporting pathogenicity and disruption of this pathway.

CAD mutations have previously been studied in other model organisms.

Mutations in enzymes catalyzing downstream steps of the same pathway are associated with other syndromes.

The disorder appears to be amenable to dietary intervention (uridine supplementation).

CAD is included in gene panels for intellectual disability offered by different diagnostic laboratories.

As a result, this gene can be considered for inclusion in the ID panel as amber or green.
Sources: Literature
Intellectual disability v2.562 PHF21A Konstantinos Varvagiannis reviewed gene: PHF21A: Rating: GREEN; Mode of pathogenicity: None; Publications: 22770980, 30487643; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Intellectual disability v2.562 RALA Konstantinos Varvagiannis gene: RALA was added
gene: RALA was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: RALA was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: RALA were set to Global developmental delay; Intellectual disability; Seizures; Abnormality of nervous system morphology
Penetrance for gene: RALA were set to unknown
Mode of pathogenicity for gene: RALA 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: RALA was set to GREEN
Added comment: Hiatt et al. (doi.org/10.1371/journal.pgen.1007671) report on 11 individuals (incl. a pair of monozygotic twins) from 10 unrelated families, most (10/11) with de novo mutations in RALA.

DD/ID was a prominent feature (the authors note that ID was specifically noted in 8 but could not be excluded in 3 further individuals who appear to be very young in the table). Structural brain anomalies (9/11), seizures (6/11) and common facial features were also noted.

RALA belongs to the RAS superfamily of small GTPases.

5 different de novo missense variants and 1 in-frame deletion, all within a GTP/GDP binding region of RALA (although appart in the protein primary structure) were observed. 7 occurrences of missense variants concerned Val25 and Lys128 (V25M, V25L, K128R), one Asp130 (D130G) and a further one Ser157 (S157A). The in-frame deletion concerned Ala158.

Missense variants in corresponding positions of RAS proteins (HRAS/KRAS/NRAS) have been reported in RASopathies, while the authors observed some phenotypic overlap with the latter group of disorders (DD/ID, growth delay, macrocephaly, high forehead and position of ears).

Functional studies demonstrated reduction in GTPase activity (for all variants) and altered RALA effector binding (for most reduction - in the case of S157A, increase).

Several lines of evidence are provided to show that alteration of the GTP/GTP-binding rather than a dosage effect is considered the likely mechanism. RALA is depleted in missense mutations in its GTP/GDP binding domain.

For these reasons and others (segregation studies not possible, variant observed 2x in Bravo database, phenotypic differences compared to the rest of the cohort, ROH suggesting parental consanguinity in the specific individual) the single nonsense variant (R176X) reported in the study is considered a VUS.

As a result, this gene can be considered for inclusion in this panel as green.
Sources: Literature
Intellectual disability v2.562 RORB Louise Daugherty gene: RORB was added
gene: RORB was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: RORB was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RORB were set to 27352968; 24355400
Phenotypes for gene: RORB were set to generalized epilepsies with predominant absence seizures, intellectual disability
Review for gene: RORB was set to RED
Added comment: PMID 27352968 identified a patient with intellectual disability and a balanced translocation where one breakpoint truncates RORB and also found two de novo deletions in patients with behavioral and cognitive impairment and epilepsy: a 52-kb microdeletion involving exons 5-10 of RORB and a larger 9q21-microdeletion.
Sources: Literature
Intellectual disability v2.561 MAB21L1 Konstantinos Varvagiannis gene: MAB21L1 was added
gene: MAB21L1 was added to Intellectual disability. Sources: Literature,Expert Review
Mode of inheritance for gene: MAB21L1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MAB21L1 were set to 27103078
Phenotypes for gene: MAB21L1 were set to Global developmental delay; Intellectual disability; Cerebellar hypoplasia; Abnormality of the eye; Abnormality of the genital system
Penetrance for gene: MAB21L1 were set to Complete
Review for gene: MAB21L1 was set to GREEN
gene: MAB21L1 was marked as current diagnostic
Added comment: Bruel et al. (PMID: 27103078) report on a boy, born to consanguineous Algerian parents, homozygous for a frameshift MAB21L1 variant.

Rad et al. (http://dx.doi.org/10.1136/jmedgenet-2018-105623) describe 10 additional individuals from 5 unrelated consanguineous families (from Iran, Lebanon and Turkey). These subjects were homozygous for truncating variants appart from a patient with a missense one [NM_005584.4:c.698A>C or p.(Gln233Pro)].

All 11 individuals presented with a common phenotype consisting of DD/ID (in 9/11 for whom this information was available), cerebellar, ocular and genital anomalies as well as similar facial features.

In total 6 different variants (5 truncating and 1 missense SNV) have been reported. There are no functional studies performed appart from in silico visualisation for the missense variant and protein interaction network analysis for MAB21L1. Previous studies in Mab21l1 knockout mice suggest ocular as well as preputial gland anomalies.

ID appears to be a feature for biallelic mutations in MAB21L2, another member of the male abnormal 21 (MAB21)-like proteins (gene rated green in this panel - associated phenotype : Microphthalmia/coloboma and skeletal dysplasia syndrome, MIM 615877).

MAB21L1 is included in gene panels for intellectual disability offered by some diagnostic laboratoires.

As a result, this gene can be considered for inclusion in this panel as green (or amber)
Sources: Literature, Expert Review
Intellectual disability v2.561 COASY Louise Daugherty Phenotypes for gene: COASY were changed from NEURODEGENERATION WITH BRAIN IRON ACCUMULATION to Neurodegeneration with brain iron accumulation 6, 615643
Intellectual disability v2.560 SCAPER Louise Daugherty Classified gene: SCAPER as Green List (high evidence)
Intellectual disability v2.560 SCAPER Louise Daugherty Added comment: Comment on list classification: Changed from Red to Green. Appropriate phenotypes, sufficient cases, and external review comment all support gene-disease association in view of new publication Tatour et al. (2017) PMID: 28794130
Intellectual disability v2.560 SCAPER Louise Daugherty Gene: scaper has been classified as Green List (High Evidence).
Intellectual disability v2.559 SCAPER Louise Daugherty edited their review of gene: SCAPER: Changed rating: GREEN
Intellectual disability v2.559 SCAPER Louise Daugherty Publications for gene: SCAPER were set to 21937992; 28794130
Intellectual disability v2.558 FMR1_CGG Ellen McDonagh Tag currently-ngs-unreportable tag was added to STR: FMR1_CGG.
Intellectual disability v2.558 DOCK6 Konstantinos Varvagiannis reviewed gene: DOCK6: Rating: GREEN; Mode of pathogenicity: None; Publications: 25824905, 27077170; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability v2.558 KMT2B Konstantinos Varvagiannis reviewed gene: KMT2B: Rating: GREEN; Mode of pathogenicity: None; Publications: 29697234; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Intellectual disability v2.558 ODC1 Konstantinos Varvagiannis gene: ODC1 was added
gene: ODC1 was added to Intellectual disability. Sources: Literature,Expert Review
Mode of inheritance for gene: ODC1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ODC1 were set to 30239107; 30475435
Phenotypes for gene: ODC1 were set to Global developmental delay; Intellectual disability; Macrocephaly; Alopecia; Ectodermal dysplasia
Penetrance for gene: ODC1 were set to unknown
Review for gene: ODC1 was set to GREEN
Added comment: PMIDs 30239107 and 30475435 report on 5 cases of de novo truncating ODC1 variants in unrelated families. One concerned a stillborn male. The 4 remaining individuals presented with a similar phenotype consisting of alopecia and other ectodermal anomalies, DD/ID, relative or absolute macrocephaly and common facial features. DD/ID was severe in some instances and many of these individuals had extensive prior testing for other disorders (Fragile-X, PTEN, SLC2A1, chromosomal disorders, etc).

ODC1 (ornithine decarboxylase 1) converts enzymatically ornithine to putrescine. All variants reported to date are truncating but lead to gain-of-function. Specifically they affect a 37 amino acid c-terminal destabilization region critical for the degradation of ODC1 and - as a result - lead to increased levels of ODC1 as well as putrescine.

A mouse model with identical phenotype has been described several years ago.

The role of ODC inhibitors is extensively discussed in both publications.

As a result, ODC1 can be considered for inclusion in the ID panel as green (or amber).
Sources: Literature, Expert Review
Intellectual disability v2.558 FBXL3 Konstantinos Varvagiannis gene: FBXL3 was added
gene: FBXL3 was added to Intellectual disability. Sources: Literature,Expert Review
Mode of inheritance for gene: FBXL3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FBXL3 were set to 30481285
Phenotypes for gene: FBXL3 were set to Intellectual disability; Short stature
Penetrance for gene: FBXL3 were set to Complete
Review for gene: FBXL3 was set to GREEN
Added comment: Ansar et al. (PMID: 30481285) report on 8 individuals from 3 consanguineous families, all homozygous for FBXL3 variants.

The phenotype consisted of mild to severe intellectual disability (8/8), short stature (8/8) with a few common facial features.

In the first family - from Pakistan - all affected individuals were homozygous for a frameshift variant. The 2 sibs from the second family (from Lebanon) were homozygous for a nonsense variant. A further patient, born to distantly related parents from Italy, was found to harbor a missense variant [NM_012158.2:c.1072T>C or p.(Cys358Arg)] in the homozygous state.

FBXL3 is part of an ubiquitin ligase complex that binds the central clock protein cryptochromes (CRY1/2) mediating their degradation. Cys358Arg concerns the same codon as a similar - previously studied - variant (Cys358Ser) reported to affect the mouse circadian rhythm. Disturbance of circadian rhythm was observed in the patient with the Cys358Arg variant.

As previously demonstrated for mutations of the same codon and in line with a pathogenic role for this variant, in silico studies predict impaired interaction of FBXL3 with CRY2. It is proposed that the nonsense and frameshift variants lead to a similar effect due to severe truncation of the protein (upstream of leucine-rich domains important for this interaction).

The authors note that other F-box proteins are implicated in intellectual disability (as in the case of FBXO11 and FBXL4, both rated green in this panel).

As a result, FBXL3 can be considered for inclusion in this panel as green (or amber).
Sources: Literature, Expert Review
Intellectual disability v2.558 FUCA1 Louise Daugherty Phenotypes for gene: FUCA1 were changed from Fucosidosis, 230000; FUCOSIDOSIS (FUCA1D) to Fucosidosis, 230000; FUCOSIDOSIS (FUCA1D); intellectual disability
Intellectual disability v2.557 FUCA1 Louise Daugherty Publications for gene: FUCA1 were set to
Intellectual disability v2.556 DDX59 Konstantinos Varvagiannis gene: DDX59 was added
gene: DDX59 was added to Intellectual disability. Sources: Literature,Expert Review
Mode of inheritance for gene: DDX59 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DDX59 were set to 23972372; 28711741; 29127725
Phenotypes for gene: DDX59 were set to Orofaciodigital syndrome V, 174300
Penetrance for gene: DDX59 were set to Complete
Review for gene: DDX59 was set to GREEN
Added comment: Biallelic mutations in DDX59 cause Orofaciodigital syndrome V, 174300.

PMID: 23972372 reports on 6 individuals from 2 consanguineous Arab families. All 6 presented with palatal anomalies (cleft palate or bifid uvula), lobulated tongue, facial anomalies (frontal bossing and hypertelorism) as well as intellectual disability.

Individuals from the first family were homozygous for the Val367Gly (NM_001031725.4:c.1100T>G) variant while those from the second were homozygous for Gly534Arg (NM_001031725.4:c.1600G>A), both predicted to be pathogenic in silico. Immunoblot demonstrated reduced levels of the Val367Gly variant in patient fibroblasts (the other variant was probably not tested). Ddx59 was shown to be expressed in lips, palatal shelves and developing limb buds of mouse embryos.

PMID: 28711741 describes 3 further patients (from two consanguineous Pakistani families), presenting the cardinal features of orofaciodigital syndrome (though polydactyly was only reported in one of the three). Developmental delay was reported in all (in the first family one of the sibs had more severe delay with no speech at the age of 7 years, in the patient from the other family speech was limited to 2 words at school age). Affected individuals from both families were found to harbor a SNV leading to loss of a stop codon, thus extending the reading frame by 21 codons.

PMID: 29127725 reports on two sibs with a diagnosis of orofaciodigital syndrome born to non-consanguineous parents. ID was a feature in both. These individuals were homozygous for a frameshift variant. Reverse transcription PCR/semiquantitative PCR demonstrated reduction of the mutant transcript compared to the levels in wt controls (suggestive of incomplete NMD). Functional studies showed possible perturbation of the Sonic Hedgehog pathway. DDX59 expression in CNS from control post-mortem human brains was confirmed to be high (based on data generated in a previous study). Studies in Drosophila suggest reduced lifespan and neuronal defects secondary to mutations in mahe (the Drosophila homolog of DDX59).

As a result this gene can be considered for inclusion in the ID panel as green.
Sources: Literature, Expert Review
Intellectual disability v2.556 DPH1 Konstantinos Varvagiannis gene: DPH1 was added
gene: DPH1 was added to Intellectual disability. Sources: Literature,Expert Review
Mode of inheritance for gene: DPH1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DPH1 were set to 25558065; 26220823; 29362492; 29410513
Phenotypes for gene: DPH1 were set to Developmental delay with short stature, dysmorphic features, and sparse hair, 616901
Penetrance for gene: DPH1 were set to Complete
Review for gene: DPH1 was set to GREEN
gene: DPH1 was marked as current diagnostic
Added comment: Biallelic mutations in DPH1 cause Developmental delay with short stature, dysmorphic features, and sparse hair, MIM 616901.

Overall 11 patients from 6 different families have probably been reported in detail. DD/ID is a universal feature.

In PMID 25558065, Alazami et al. identified 1 patient from the same consanguineous Saudi Arabian family (of 8 total similarly affected individuals) homozygous for the Leu234Pro (NM_001383.3:c.701T>C) variant. This individual was part of a large cohort of patients with neurogenetic disorders from consanguineous families. The phenotype is not described in detail.

In PMID 26220823 Louks et al. report on 4 patients from 3 families belonging to the same genetic isolate from North America and provide details on 4 of the individuals identified by Alazami et al.

The individuals identified in this study were homozygous for Met6Lys which was however predicted to be benign and tolerated (by PolyPhen2 and SIFT respectively) in silico.

DD/ID, unusual skull shape, ectodermal anomalies were universal (8/8) with additional features including short stature (7/8), renal (4/6) or cardiac anomalies (3/8). Some facial features appeared to be common, too.

Functional studies were not performed. However Dph1 pathogenic variants in mice result in restricted growth, craniofacial and developmental defects similar to the human phenotypes (PMIDs 14744934 and 24895408 are cited).

PMIDs 29362492 and 29410513 report on 3 further patients with similar (as well as some additional) features including DD/ID. The individual in the first article was compound heterozygous for a missense (Leu164Pro) and a frameshift variant (c.289delG) while 2 sibs born to consanguineous parents in the second article were homozygous for a frameshift variant (c.1227delG).

The phenotype appears to be consistent among all the published patients.

DPH1 is included in gene panels for intellectual disability offered by different diagnostic laboratories.

As a result, this gene can be considered for inclusion in this panel as green.
Sources: Literature, Expert Review
Intellectual disability v2.556 RARS2 Sarah Leigh Publications for gene: RARS2 were set to
Intellectual disability v2.555 COG6 Konstantinos Varvagiannis gene: COG6 was added
gene: COG6 was added to Intellectual disability. Sources: Literature,Expert Review
Mode of inheritance for gene: COG6 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COG6 were set to 26260076; 20605848; 23430903; 23606727; 28139241; 28742265; 29445937; 29709711
Phenotypes for gene: COG6 were set to Congenital disorder of glycosylation, type IIl, 614576; Shaheen syndrome, 615328
Penetrance for gene: COG6 were set to Complete
Review for gene: COG6 was set to GREEN
gene: COG6 was marked as current diagnostic
Added comment: DD/ID is an almost universal feature of individuals with biallelic COG6 mutations, whether this is associated with a type II transferrin IEF pattern (as in Congenital disorder of glycosylation, type IIl, 614576) or not (as in Shaheen syndrome, 615328).

More than 15 patients from several different families have been reported to date.

PMID: 26260076 is a collaborative study reporting on new patients as well as on individuals previously described up to 2015 by Lubbehusen et al. (2010 - PMID: 20605848), Huybrechts et al. (2012 - PMID: 23430903) as well as Shaheen et al. (2013 - PMID: 23606727).

As summarized in table 1 of this article, developmental disability was a feature in 8/10, although for a further 2/10 this was probably not relevant (both deceased too early).

The following articles are additional reports although there might be some overlap (applicable for the Saudi patients) : PMIDs: 28139241 (individuals with diagnosis of CDG from Spain), 28742265 (cohort of CDG patients from Saudi Arabia), 29445937 (case report of Saudi subject), 29709711 (Chinese individual with COG6-CDG).

All types of variants have been observed including missense, stopgain and frameshift ones, as well as variants leading to aberrant splicing [eg. positions -2, -9, -24]. The deep intronic variant (position -24) in the individuals reported by Shaheen and others is considered a founder mutation in the Saudi population.

Individuals homozygous for the latter variant have detectable levels of the normal transcript, although 75% of the produced transcript (upon RT-PCR analysis) correspond to retention of 37 intronic nucleotides leading to frameshift and introduction of a premature stop codon. This was also confirmed with Western blot.

Given the detectable levels of the normal transcript, it has been proposed that Shaheen syndrome represents the mildest end of the spectrum COG6-related disorders.

COG6 is included in gene panels for intellectual disability offered by different diagnostic laboratories.

As a result this gene can be considered for inclusion in this panel as green.
Sources: Literature, Expert Review
Intellectual disability v2.555 TELO2 Konstantinos Varvagiannis gene: TELO2 was added
gene: TELO2 was added to Intellectual disability. Sources: Literature,Expert Review
Mode of inheritance for gene: TELO2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TELO2 were set to 27132593; 28944240
Phenotypes for gene: TELO2 were set to You-Hoover-Fong syndrome, MIM 616954
Penetrance for gene: TELO2 were set to Complete
Review for gene: TELO2 was set to GREEN
gene: TELO2 was marked as current diagnostic
Added comment: Biallelic mutations in TELO2 cause You-Hoover-Fong syndrome (MIM 616954). //

PMID: 27132593 reports on 6 patients (from 4 non-consanguineous families) with biallelic TELO2 variants and a similar phenotype.

Intellectual disability and microcephaly were universal features (6/6). Abnormal hearing (3/6), cortical visual impairment (3/6), abnormality of the cardiovascular system (3/6), behavioral problems (laughter outbursts in 3/6) and abnormal balance and movement disorder (6/6) were part of the phenotype. One individual had seizures.

5 missense variants and a complex allele with a stopgain variant localized in cis with a splice-site variant (NM_016111.3:c.514C>T or p.Gln172* in cis with c.2034+1G>A) are reported.

As a result heterozygosity for the complex variant may be confounded with compound heterozygous state until segregation studies are performed.

Functional studies support pathogenicity of the missense variants (reduced protein steady-state levels of TELO2 as well as TTI1 and TTI2 - the 2 other members of the TTT complex) suggesting loss of function.

PMID: 28944240 reports on 2 sisters born to non-consanguineous parents. Both were compound heterozygous for 2 novel variants, a missense and a frameshift one. Severe microcephaly (-8.5 SD and -10.7 SD) and seizures were noted in both. The first sister passed away at the age of 2 months due to a respiratory infection. The other sister demonstrated a compatible, though much more severe phenotype (of ID, dwarfism, retinitis pigmentosa, etc) compared to previously reported patients. //

Biallelic mutations in TTI2 (of the same complex) lead to similar phenotypes (gene rated green in the ID panel). //

TELO2 is included in gene panels for intellectual disability offered by different diagnostic laboratories. //

As a result this gene can be considered for inclusion in this panel as green.
Sources: Literature, Expert Review
Intellectual disability v2.555 TTI2 Konstantinos Varvagiannis Deleted their review
Intellectual disability v2.555 TTI2 Konstantinos Varvagiannis reviewed gene: TTI2: Rating: GREEN; Mode of pathogenicity: None; Publications: 23956177; Phenotypes: ; Mode of inheritance: None
Intellectual disability v2.555 BRD4 Konstantinos Varvagiannis gene: BRD4 was added
gene: BRD4 was added to Intellectual disability. Sources: Literature,Expert Review
Mode of inheritance for gene: BRD4 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: BRD4 were set to 29379197; 30055032; 30302754
Phenotypes for gene: BRD4 were set to Intellectual disability; Microcephaly; Abnormal heart morphology; Abnormality of the face
Penetrance for gene: BRD4 were set to unknown
Review for gene: BRD4 was set to GREEN
gene: BRD4 was marked as current diagnostic
Added comment: PMID: 29379197 reports on 3 unrelated individuals with de novo mutations in BRD4 and a Cornelia de Lange-like phenotype. One of these individuals was a DDD study participant (DDD4K.04273). A further (fourth) individual had a 1.04 Mb deletion encompassing BRD4 (and 28 other genes) and presented with a similar phenotype.

Appart from intellectual disability which was a universal feature common features included a CdLS-like appearance (3/4), microcephaly (3/4) and cardiac malformations (VSD in 2/4).

Review of published patients with multigenic deletions spanning also BRD4 support a CdLS-like phenotype as well as haploinsufficiency as the underlying mechanism.

As the authors note, mice heterozygous for loss-of-function mutations in BRD4 show CdLS like features.
Functional studies performed demonstrated association of BRD4 with NIPBL with colocalization (/shared binding) to super-enhancers and co-regulation of gene expression.

The variants reported in this study included a missense as well as 2 frameshift mutations.

PMIDs: 30055032 and 30302754 report further patients with deletions spanning BRD4 and review the previously published patients.

BRD4 is included in gene panels for intellectual disability offered by different diagnostic laboratories.

As a result this gene can be considered for inclusion in this panel as green.
Sources: Literature, Expert Review
Intellectual disability v2.555 ATP8A2 Konstantinos Varvagiannis reviewed gene: ATP8A2: Rating: GREEN; Mode of pathogenicity: None; Publications: 22892528, 27679995, 30012219, 29531481; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability v2.555 MACF1 Konstantinos Varvagiannis gene: MACF1 was added
gene: MACF1 was added to Intellectual disability. Sources: Literature,Expert Review
Mode of inheritance for gene: MACF1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: MACF1 were set to Intellectual disability; Seizures; Lissencephaly; Brainstem dysplasia
Penetrance for gene: MACF1 were set to unknown
Mode of pathogenicity for gene: MACF1 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: MACF1 was set to GREEN
Added comment: Dobyns et al. (doi.org/10.1016/j.ajhg.2018.10.019) report on 9 individuals (all unrelated appart from a pair of monozygotic twins) with de novo variants in MACF1.

All patients presented lissencephaly and brainstem hypoplasia with associated intellectual disability (9/9) and seizures (9/9).

Seven of these individuals had de novo missense variants within the GAR domain and an eighth had a deletion of several exons also spanning this domain and leading to an in-frame deletion. A further ninth patient had a de novo missense variant in the spectrin repeat domain and was found to have similar features although the brainstem dysplasia was rather subtle.

5 missense variants (4 of which in the GAR domain) and an intragenic deletion are reported in total.

The variants in the GAR domain were predicted to have important effect in the zinc-binding pocket. The spectrin repeat (SR4) is thought to have an important role for the function of MACF1 and further to neuronal migration.

Knockdown of Macf1 in mice has been shown to result in developmental defects similar to the human malformation.

The authors note that several high-confidence loss-of-function mutations are listed in ExAC and as a result this type of variants could be non-pathogenic (or lead to neurodevelopmental disorders with reduced penetrance). Still MACF1 has a pLI of 1.0.

As for the missense variants, the authors suggest either a gain-of-function or dominant negative mechanism.

Caution should be taken when interpreting variants as the ENST00000372915.7 (or MACF1-204) transcript is used for the predicted protein changes, although ENST00000361689.6 or MACF1-203 (corresponding to NM_012090.5) has also been used in some tables or figures.

As a result, this gene can be considered for inclusion in this panel probably as green.
Sources: Literature, Expert Review
Intellectual disability v2.555 GABRB2 Louise Daugherty commented on gene: GABRB2: New gene added by external expert and reviewed by curation team. Appropriate phenotype, sufficient cases, and external review comment all support gene-disease association and to rate this gene as Green
Intellectual disability v2.555 GABRB2 Louise Daugherty Deleted their comment
Intellectual disability v2.555 GABRB2 Louise Daugherty Classified gene: GABRB2 as Green List (high evidence)
Intellectual disability v2.555 GABRB2 Louise Daugherty Added comment: Comment on list classification: New gene added by external expert and reviewed by curation team, enough evidence to support gene-disease association and relevance to this panel to rate this gene Green.
Intellectual disability v2.555 GABRB2 Louise Daugherty Gene: gabrb2 has been classified as Green List (High Evidence).
Intellectual disability v2.554 PHACTR1 Konstantinos Varvagiannis reviewed gene: PHACTR1: Rating: GREEN; Mode of pathogenicity: None; Publications: 30256902, 23033978, 28135719; Phenotypes: Global developmental delay, Intellectual disability, Seizures; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v2.554 GABRB2 Louise Daugherty Added comment: Comment on phenotypes: Added phenotypes suggested from expert review that indicate relevance to inclusion on the Intellectual disability panel
Intellectual disability v2.554 GABRB2 Louise Daugherty Phenotypes for gene: GABRB2 were changed from intellectual disability to Epileptic encephalopathy, infantile or early childhood, 2, 617829; intellectual disability
Intellectual disability v2.553 SCAPER Louise Daugherty Added comment: Comment on publications: Added publications to support upgrading of the gene to Green
Intellectual disability v2.553 SCAPER Louise Daugherty Publications for gene: SCAPER were set to 21937992
Intellectual disability v2.552 SCAPER Louise Daugherty edited their review of gene: SCAPER: Changed rating: AMBER
Intellectual disability v2.552 SCAPER Louise Daugherty Added comment: Comment on phenotypes: added phenotype and MIM from OMIM : Tatour et al. (2017) PMID: 28794130 describes 4 patients from 3 unrelated families with intellectual disability disorder and retinitis pigmentosa and identified homozygosity or compound heterozygosity for mutations in the SCAPER gene. Noting that the retinal phenotype associated with null SCAPER mutations is not congenital but presents around the second decade of life, the authors suggested that in the retina, SCAPER does not play a developmental role, but rather is important for photoreceptor function and/or maintenance.
Intellectual disability v2.552 SCAPER Louise Daugherty Phenotypes for gene: SCAPER were changed from AUTOSOMAL RECESSIVE MENTAL RETARDATION to AUTOSOMAL RECESSIVE MENTAL RETARDATION; Intellectual developmental disorder and retinitis pigmentosa, 618195
Intellectual disability v2.551 NUDT2 Konstantinos Varvagiannis gene: NUDT2 was added
gene: NUDT2 was added to Intellectual disability. Sources: Literature,Expert Review
Mode of inheritance for gene: NUDT2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NUDT2 were set to 27431290; 30059600
Phenotypes for gene: NUDT2 were set to Muscular hypotonia; Global developmental delay; Intellectual disability
Penetrance for gene: NUDT2 were set to Complete
Review for gene: NUDT2 was set to AMBER
Added comment: PMID: 27431290 reports briefly on 2 sibs from a consanguineous Saudi family, as part of a cohort of 337 patients investigated for intellectual disability. Both were homozygous for a nonsense NUDT2 mutation [NM_001161.4:c.34C>T or p.Arg12Ter / rs148119952]. The common features included hypotonia, global developmental delay (first words at 2.5 years, sitting at 2-2.5 years,walking achieved by 4 years - valid for both sibs) and intellectual disability. No other candidate variants were found in the exome.

PMID: 30059600 is a further report on 5 individuals from 3 consanguineous families from Saudi Arabia. All presented with low birth weight and height, poor suck, hypotonia, motor and language delay and borderline intelligence. All patients were homozygous for the same nonsense variant (Arg12Ter) which seems to be a founder mutation in Saudi Arabia.

As truncating NUDT2 variants have a combined allele frequency of 0.02% in gnomAD (no homozygotes in the database) the authors comment that most of the other LoF variants observed are in the second - and last - exon of the gene (thus probably escaping NMD) and downstream of its catalytic domain.

As a result this gene can be considered for inclusion in the ID panel probably as amber (single founder mutation - the degree of intellectual disability appears to be more severe in the first report but borderline in the subsequent) or green.
Sources: Literature, Expert Review
Intellectual disability v2.551 GFAP Louise Daugherty Publications for gene: GFAP were set to
Intellectual disability v2.550 UFM1 Konstantinos Varvagiannis reviewed gene: UFM1: Rating: GREEN; Mode of pathogenicity: None; Publications: 28931644, 29868776; Phenotypes: Leukodystrophy hypomyelinating 14, 617899; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v2.550 UFM1 Konstantinos Varvagiannis Deleted their review
Intellectual disability v2.550 UFM1 Konstantinos Varvagiannis gene: UFM1 was added
gene: UFM1 was added to Intellectual disability. Sources: Literature,Expert Review
Mode of inheritance for gene: UFM1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: UFM1 were set to 28931644; 29868776
Phenotypes for gene: UFM1 were set to Leukodystrophy hypomyelinating 14, 617899
Penetrance for gene: UFM1 were set to Complete
Review for gene: UFM1 was set to GREEN
Added comment: Biallelic UFM1 mutations cause Leukodystrophy hypomyelinating 14, MIM 617899.

PMID: 28931644 is the first report on 16 individuals from 14 families with shared Roma ethnic background. All subjects were found to harbor a UFM1 promoter 3 basepair deletion in the homozygous state.

All patients demonstrated a severe phenotype including lack of development and severe epileptic encephalopathy while their MRI images demonstrated hypomyelination with atrophy of the basal ganglia and the cerebellum.

The promoter deletion was detected by exome sequencing. Previously a 0.8 Mb homozygous region was identified to be shared by all the patients in whom a SNP array was performed. Alternative causes, notably TUBB4A mutations and deletions/duplications were excluded. 3 individuals had Sanger sequencing of all coding regions within the homozygous interval to rule out other - eventually missed - variants.

PMID: 29868776 reports 4 additional individuals from 2 consanguineous families (one from Ethiopia, for the other this was not specified). All 4 patients were homozygous for the c.241C>T (NM_016617.3) or p.(Arg81Cys) variant which was shown to be hypomorphic upon functional studies.

The phenotype consisted of developmental delay (4/4 or 20/20 including the patients from the previous report with which comparison is made in table 2 of the article) with microcephaly (4/4 or 20/20) and seizures (4/4 or 16/20) as well as MRI abnormalities. Failure to thrive and/or short stature were also among the most common features.

UFM1 (as well as UFC1 also discussed in the same article) participate in ufmylation, with mutations in other enzymes of the same process (notably UBA5 - gene rated Green in the ID and epilepsy panels) having already been described in neurodevelopmental disorders.

As a result, this gene can be considered for inclusion in this panel as green (or amber).
Sources: Literature, Expert Review
Intellectual disability v2.550 GLB1 Louise Daugherty Publications for gene: GLB1 were set to
Intellectual disability v2.549 CSNK2B Rebecca Foulger Phenotypes for gene: CSNK2B were changed from to Intellectual disability with or without myoclonic epilepsy
Intellectual disability v2.548 CSNK2B Rebecca Foulger Publications for gene: CSNK2B were set to 28585349, 28762608
Intellectual disability v2.547 CSNK2B Rebecca Foulger Classified gene: CSNK2B as Green List (high evidence)
Intellectual disability v2.547 CSNK2B Rebecca Foulger Added comment: Comment on list classification: Updated rating from Red to Green: As summarised by Zornitza, three unrelated patients reported in the literature (one in PMID:28762608 and two in PMID:28585349) with intellectual disability and de novo variants in CSNK2B (splice variant and a frameshift truncating variant). Two of the patients also had monoclonic epilepsy.
Intellectual disability v2.547 CSNK2B Rebecca Foulger Gene: csnk2b has been classified as Green List (High Evidence).
Intellectual disability v2.546 CSNK2B Rebecca Foulger Mode of inheritance for gene: CSNK2B was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v2.545 UFC1 Konstantinos Varvagiannis gene: UFC1 was added
gene: UFC1 was added to Intellectual disability. Sources: Literature,Expert Review
Mode of inheritance for gene: UFC1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: UFC1 were set to 29868776
Phenotypes for gene: UFC1 were set to Neurodevelopmental disorder with spasticity and poor growth, 618076
Penetrance for gene: UFC1 were set to Complete
Review for gene: UFC1 was set to GREEN
Added comment: Biallelic UFC1 mutations cause Neurodevelopmental disorder with spasticity and poor growth, MIM 618076.

PMID: 29868776 describes 7 individuals (most) born to consanguineous Saudi families (in one case the parents were not consanguineous but originated from the same tribe) as well as a further individual born to distantly related Swiss parents. One of these patients was previously briefly published by the same authors (PMID: 27431290).

The phenotype consisted of developmental delay (8/8 - usually profound), failure to thrive (8/8), short stature and microcephaly (both observed in 7/8), seizures (4/8) and variable brain MRI anomalies in some of these subjects.

Overall, two UFC1 missense variants are reported [NM_016406.3:c.317C>T or p.(Thr106Ile) and c.68G>A or p.(Arg23Gln) the former in the Saudi individuals]. Functional studies demonstrated the hypomorphic nature of the variants.

UFC1 (as well as UFM1 also discussed in the same article) participate in ufmylation, with mutations in other enzymes of the same process (notably UBA5 - gene rated Green in the ID and epilepsy panels) having already been described in neurodevelopmental disorders.

As a result this gene can be considered for inclusion in the ID panel as green (or amber).
Sources: Literature, Expert Review
Intellectual disability v2.545 CCDC88A Konstantinos Varvagiannis reviewed gene: CCDC88A: Rating: AMBER; Mode of pathogenicity: None; Publications: 26917597, 30392057; Phenotypes: ?PEHO syndrome-like, 617507; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v2.545 EIF3F Louise Daugherty Classified gene: EIF3F as Green List (high evidence)
Intellectual disability v2.545 EIF3F Louise Daugherty Added comment: Comment on list classification: New gene added by external expert and reviewed by curation team, enough evidence to support gene-disease association and relevance to this panel to rate this gene Green
Intellectual disability v2.545 EIF3F Louise Daugherty Gene: eif3f has been classified as Green List (High Evidence).
Intellectual disability v2.544 RHOBTB2 Louise Daugherty Classified gene: RHOBTB2 as Green List (high evidence)
Intellectual disability v2.544 RHOBTB2 Louise Daugherty Added comment: Comment on list classification: New gene added by external expert and reviewed by curation team, enough evidence to support gene-disease association and relevance to this panel to rate this gene Green
Intellectual disability v2.544 RHOBTB2 Louise Daugherty Gene: rhobtb2 has been classified as Green List (High Evidence).
Intellectual disability v2.543 RHOBTB2 Louise Daugherty Added comment: Comment on phenotypes: Added phenotypes suggested from expert review that indicate relevance to inclusion on the Intellectual disability panel
Intellectual disability v2.543 RHOBTB2 Louise Daugherty Phenotypes for gene: RHOBTB2 were changed from Global developmental delay; Intellectual disability; Seizures; Postnatal microcephaly to Epileptic encephalopathy, early infantile, 64, 618004; Global developmental delay; Intellectual disability; Seizures; Postnatal microcephaly
Intellectual disability v2.542 Ellen McDonagh 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 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; GMS R29
Intellectual disability v2.542 RHOBTB2 Louise Daugherty commented on gene: RHOBTB2
Intellectual disability v2.541 FUT8 Louise Daugherty Classified gene: FUT8 as Green List (high evidence)
Intellectual disability v2.541 FUT8 Louise Daugherty Added comment: Comment on list classification: New gene added by external expert and reviewed by curation team, enough evidence to support gene-disease association and relevance to this panel to rate this gene Green
Intellectual disability v2.541 FUT8 Louise Daugherty Gene: fut8 has been classified as Green List (High Evidence).
Intellectual disability v2.540 FUT8 Louise Daugherty Added comment: Comment on phenotypes: Added phenotypes suggested from expert review that indicate relevance to inclusion on the intellectual disability panel
Intellectual disability v2.540 FUT8 Louise Daugherty Phenotypes for gene: FUT8 were changed from Congenital disorder of glycosylation with defective fucosylation, 618005 to Congenital disorder of glycosylation with defective fucosylation, 618005; Intellectual disability
Intellectual disability v2.539 FUT8 Louise Daugherty Publications for gene: FUT8 were set to 29304374
Intellectual disability v2.538 ATP6V1A Louise Daugherty Classified gene: ATP6V1A as Green List (high evidence)
Intellectual disability v2.538 ATP6V1A Louise Daugherty Added comment: Comment on list classification: New gene added by external expert and reviewed by curation team, enough evidence to support gene-disease association and relevance to this panel to rate this gene Green
Intellectual disability v2.538 ATP6V1A Louise Daugherty Gene: atp6v1a has been classified as Green List (High Evidence).
Intellectual disability v2.537 GNB5 Konstantinos Varvagiannis gene: GNB5 was added
gene: GNB5 was added to Intellectual disability. Sources: Literature,Expert Review
Mode of inheritance for gene: GNB5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GNB5 were set to 27523599; 27677260; 28697420; 29368331
Phenotypes for gene: GNB5 were set to Intellectual developmental disorder with cardiac arrhythmia, 617173; Language delay and ADHD/cognitive impairment with or without cardiac arrhythmia, 617182
Penetrance for gene: GNB5 were set to Complete
Review for gene: GNB5 was set to GREEN
gene: GNB5 was marked as current diagnostic
Added comment: Biallelic GNB5 pathogenic variants cause Intellectual developmental disorder with cardiac arrhythmia (MIM 617173) or language delay and ADHD/cognitive impairment with or without cardiac arrhythmia (MIM 617182).

PMID: 27523599 is the first report on the associated phenotype. A total of 9 individuals from 6 different families (from various ethnic backgrounds) are described.

The common features included hypotonia (noted in 6 out of 9 patients), intellectual disability (9/9 - in 3 cases mild, in 6 severe), heart rate disturbance (9/9 - in most cases sick sinus syndrome), seizures (4/9), ophthalmological problems (nystagmus in 6 out of 7 for whom this information was available) as well as gastric problems (5/8 with G-E reflux).

The 6 variants (summarized in table S1) included : 2 nonsense mutations, 1 synonymous (demonstrated to affect splicing and leading to retention of 25 intronic bp), 2 further splice variants (positions +1 and +3) and a missense one (S81L).

Nonsense mediated decay was the case for the product of the synonymous/splice variant as well as for a stopgain one.

As noted by the authors, individuals homozygous for the S81L variant had a less severe phenotype - among others - with mild degree of intellectual disability.

Functional studies included knockout of gnb5 in zebrafish, which was able to reproduce the human neurological, cardiac and ophthalmological phenotypes.

Alternative causes for these phenotypes (incl. chromosomal or metabolic disorders) were ruled out.

Affected individuals might benefit interventions for their heart rate disturbance as appears to be the case in the article as well as subsequent studies.

PMID: 27677260 describes an extended consanguineous Saudi family with 5 individuals homozygous for the S81L variant. Common features included severe language delay, ADHD, but normal cognition in those available for evaluation. Seizures were not reported. Pathogenicity of the S81L variant is further supported by functional studies.

PMID: 28697420 describes in detail 2 individuals from a large consanguineous pedigree confirmed to be homozygous for a single nucleotide deletion in GNB5. The phenotype included severe DD/ID, seizures, sinus bradycardia with frequent sinus pauses and ophthalmological problems. Sinus arrhythmia and or seizures were documented in several other relatives deceased and unavailable for testing.

PMID: 28327206 reports on 2 subjects previously included in PMID: 27523599.

PMID: 29368331 describes a child with severe developmental delay, nystagmus and sinus arrhythmia necessitating a pacemaker. EEG was abnormal although no frank seizures were observed. The child was compound heterozygous for a novel missense variant (R246Q) as well a 5 basepair deletion.

GNB5 is included in diagnostic gene panels for intellectual disability offered by different laboratories.

As a result this gene can be considered for inclusion in this panel as green.
Sources: Literature, Expert Review
Intellectual disability v2.537 ATP6V1A Louise Daugherty Phenotypes for gene: ATP6V1A were changed from # 618012 EPILEPTIC ENCEPHALOPATHY, INFANTILE OR EARLY CHILDHOOD, 3; IECEE3 to Epileptic encephalopathy, infantile or early childhood, 3 618012; Cutis laxa, autosomal recessive, type IID 617403
Intellectual disability v2.536 ATP6V1A Louise Daugherty commented on gene: ATP6V1A
Intellectual disability v2.536 ATP1A1 Louise Daugherty Classified gene: ATP1A1 as Green List (high evidence)
Intellectual disability v2.536 ATP1A1 Louise Daugherty Added comment: Comment on list classification: New gene added by external expert and reviewed by curation team, enough evidence to support gene-disease association and relevance to this panel to rate this gene Green
Intellectual disability v2.536 ATP1A1 Louise Daugherty Gene: atp1a1 has been classified as Green List (High Evidence).
Intellectual disability v2.535 ATP1A1 Louise Daugherty commented on gene: ATP1A1
Intellectual disability v2.535 KDM5B Konstantinos Varvagiannis reviewed gene: KDM5B: Rating: GREEN; Mode of pathogenicity: None; Publications: 29276005, 30409806; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v2.535 EIF3F Konstantinos Varvagiannis gene: EIF3F was added
gene: EIF3F was added to Intellectual disability. Sources: Literature,Expert Review
Mode of inheritance for gene: EIF3F was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EIF3F were set to 30409806
Phenotypes for gene: EIF3F were set to Intellectual disability; Seizures; Behavioral abnormality; Sensorineural hearing impairment
Penetrance for gene: EIF3F were set to Complete
Review for gene: EIF3F was set to GREEN
Added comment: EIF3F was identified in a recent DDD publication (PMID: 30409806) as a cause of autosomal recessive intellectual disability.

All 9 individuals reported were homozygous for a missense variant (Phe232Val - rs141976414) which has a frequency of 0.12% in non-Finnish Europeans.

Features included intellectual disability (9/9), seizures (6/9), behavioral problems (3/9) and sensorineural hearing loss (3/9). Facial features were not specific.

Extensive functional studies were performed and support pathogenicity of the variant in the homozygous state (reduced protein levels, reduced translation rate in line with the role of EIF3F encoding a subunit for eukaryotic translation initiation factor 3, as well as reduced proliferation rates).

As a result this gene can be considered for inclusion in this panel as green.
Sources: Literature, Expert Review
Intellectual disability v2.535 FUT8 Konstantinos Varvagiannis gene: FUT8 was added
gene: FUT8 was added to Intellectual disability. Sources: Literature,Expert Review
Mode of inheritance for gene: FUT8 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FUT8 were set to 29304374
Phenotypes for gene: FUT8 were set to Congenital disorder of glycosylation with defective fucosylation, 618005
Penetrance for gene: FUT8 were set to Complete
Review for gene: FUT8 was set to GREEN
Added comment: PMID: 29304374 reports on 3 unrelated individuals with biallelic pathogenic variants in FUT8.

Two of the patients were born to consanguineous parents and were found to be homozygous for stopgain variants (p.Arg239* in one family and p.Arg315* in the other). A third patient was compound heterozygous for a missense as well as a splice variant.

All three presented with similar phenotype consisting of polyhydramnios (2 out of 3), IUGR and failure to thrive with short stature (3/3), severe developmental delay (3/3) with microcephaly (3/3) and seizures (3/3). Variable respiratory problems were also noted in all.

Western blot demonstrated loss of FUT8 protein expression in one individual homozygous for a stopgain mutation as well as the patient who was compound heterozygous for the missense and the splice variant. The splice variant was further shown to produce a shorter transcript due to lack of exon 9, leading to an in-frame deletion of 59 residues critical for the protein function.

Additional studies confirmed the fucosylation defect compared to controls.

The authors note that while Fut8 knockout mice are born normal, 70% die within the first 3 days due to severe growth retardation and respiratory deficiency (similarly to what is observed in humans, though to a lesser extent).

As a result this gene can be considered for inclusion in this panel probably as green (3 unrelated families, strong additional functional data, consistent phenotype) or amber.
Sources: Literature, Expert Review
Intellectual disability v2.535 ATP6V1A Konstantinos Varvagiannis gene: ATP6V1A was added
gene: ATP6V1A was added to Intellectual disability. Sources: Literature,Expert Review
Mode of inheritance for gene: ATP6V1A was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ATP6V1A were set to 29668857; 28065471
Phenotypes for gene: ATP6V1A were set to # 618012 EPILEPTIC ENCEPHALOPATHY, INFANTILE OR EARLY CHILDHOOD, 3; IECEE3
Penetrance for gene: ATP6V1A were set to unknown
Review for gene: ATP6V1A was set to GREEN
Added comment: Heterozygous mutations in ATP6V1A cause Epileptic encephalopathy, infantile or early childhood, type 3 (MIM 618012).

PMID: 29668857 reports 4 individuals from 4 families with de novo pathogenic variants in ATP6V1A. The phenotype was consistent with a developmental encephalopathy with epilepsy.

All patients were found to harbor missense variants. The variants resulted in altered lysosomal homeostasis, abnormal neuritogenesis and synaptic density. However in one of the variants tested (p.Asp100Tyr) pathogenicity was mediated by loss-of-function mechanism while for another (p.Asp349Asn) by gain-of-function mechanism.

Differences in severity were noted, with two variants (incl. Asp100Tyr) being associated with a more severe phenotype and the two other (incl. Asp349Asn) with milder degrees of ID and epilepsy.

Biallelic ATP6V1A mutations cause Cutis laxa type IID (MIM 617403). PMID: 28065471 is the first report on 3 individuals from 3 different families (2 of which were consanguineous). All patients were homozygous for ATP6V1A pathogenic variants. All three presented with hypotonia, one (or possibly two) with developmental delay and two with seizures although the developmental phenotype is not further commented on. (Additional patients described in the article harbored mutations in other genes and were not considered).

As a result, this gene can be considered for inclusion in this panel as green (or amber).
Sources: Literature, Expert Review
Intellectual disability v2.535 ATP1A1 Konstantinos Varvagiannis gene: ATP1A1 was added
gene: ATP1A1 was added to Intellectual disability. Sources: Expert Review,Literature
Mode of inheritance for gene: ATP1A1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ATP1A1 were set to 30388404
Phenotypes for gene: ATP1A1 were set to Hypomagnesemia; Seizures; Intellectual disability
Penetrance for gene: ATP1A1 were set to unknown
Review for gene: ATP1A1 was set to GREEN
Added comment: PMID: 30388404 reports on 3 subjects from 3 families with de novo pathogenic variants in ATP1A1. All 3 presented with similar phenotype consisting of hypomagnesemia, early onset refractory seizures as well as intellectual disability.

Alternative causes of hypomagnesemia with seizures (eg. due to TRPM6 mutations) were excluded while the phenotype of the 3 patients differed from similar disorder in that hypomagnesemia as well as seizures were not responsive to magnesium supplementation.

Three different missense variants are reported (L302R, G303R, M859R) all as de novo occurences and after confirmation of paternity.

Functional studies were suggestive of loss of the ATPase function, abnormal cation permeabilities as well as reduced level of expression (the latter was significant for at least for 2 of the 3 variants).

Mutations in ATP1A1 have also been reported in patients with Charcot-Marie-Tooth type 2 (CMT2DD - MIM: 618036) although the variants reported to date map seem to cluster within the helical linker region (residues 592 to 608). The young age of the patients with epilepsy and intellectual disability did not allow conclusions on eventual peripheral neuropathy in these individuals.

As a result this gene can be considered for inclusion in this panel as green (or amber).
Sources: Expert Review, Literature
Intellectual disability v2.535 GM2A Louise Daugherty Added comment: Comment on publications: added missing publications to support gene-disease association.
Intellectual disability v2.535 GM2A Louise Daugherty Publications for gene: GM2A were set to
Intellectual disability v2.534 Ellen McDonagh 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 to Coarse facial features including Coffin-Siris-like disorders; ID; Moderate; severe or profound intellectual disability; Schizophrenia plus additional features
Intellectual disability v2.533 Ellen McDonagh List of related panels changed from Coarse facial features including Coffin-Siris-like disorders; ID;Moderate; severe or profound intellectual disability to Coarse facial features including Coffin-Siris-like disorders;ID;Moderate; severe or profound intellectual disability;Schizophrenia plus additional features
Intellectual disability v2.532 TBR1 Konstantinos Varvagiannis reviewed gene: TBR1: Rating: AMBER; Mode of pathogenicity: None; Publications: 30268909, 25356899, 23160955, 22495311, 30250039; Phenotypes: Intellectual disability, Autism, Abnormal cortical gyration; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Intellectual disability v2.532 FBXL4 Louise Daugherty Added comment: Comment on phenotypes: added OMIM phenotype and MIMid
Intellectual disability v2.532 FBXL4 Louise Daugherty Phenotypes for gene: FBXL4 were changed from FATAL ENCEPHALOPATHY, LACTIC ACIDOSIS, AND SEVERE MTDNA DEPLETION IN MUSCLE to Mitochondrial DNA depletion syndrome 13 (encephalomyopathic type), 615471; FATAL ENCEPHALOPATHY, LACTIC ACIDOSIS, AND SEVERE MTDNA DEPLETION IN MUSCLE
Intellectual disability v2.531 NFIB Konstantinos Varvagiannis gene: NFIB was added
gene: NFIB was added to Intellectual disability. Sources: Expert Review,Literature
Mode of inheritance for gene: NFIB was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: NFIB were set to 30388402
Phenotypes for gene: NFIB were set to Global developmental delay; Intellectual disability; Macrocephaly
Penetrance for gene: NFIB were set to unknown
Review for gene: NFIB was set to GREEN
Added comment: Schanze et al. (PMID: 30388402) report on the phenotype related to NFIB haploinsufficiency.

10 individuals with intragenic NFIB or larger deletions encompassing also other genes as well as 8 individuals with nucleotide variants (5 loss-of-function and 3 missense ones) are described.

Intellectual disability was a universal feature while macrocephaly was noted in the majority of the patients. The phenotype of individuals deletions was similar to the phenotype of intragenic mutations as also seems to be the case with the degree of ID.

Functional studies support loss of function for the pathogenic missense variants reported. Cortical-specific knockout of Nfib in mice results in enlargement of the cortex.

While most of the variants occurred as de novo events, a few individuals had inherited a variant (deletion or nucleotide variant) from a similarly affected parent.

As a result, this gene can be considered for inclusion in the ID panel as green.
Sources: Expert Review, Literature
Intellectual disability v2.531 PCGF2 Louise Daugherty edited their review of gene: PCGF2: Changed rating: GREEN
Intellectual disability v2.531 Ellen McDonagh Panel types changed to Rare Disease 100K; GMS Rare Disease Virtual
Intellectual disability v2.530 DCPS Konstantinos Varvagiannis gene: DCPS was added
gene: DCPS was added to Intellectual disability. Sources: Expert Review,Literature
Mode of inheritance for gene: DCPS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DCPS were set to 25712129; 25701870; 30289615
Phenotypes for gene: DCPS were set to Al-Raqad syndrome (OMIM 616459)
Penetrance for gene: DCPS were set to Complete
Review for gene: DCPS was set to GREEN
gene: DCPS was marked as current diagnostic
Added comment: Biallelic pathogenic DCPS variants cause Al-Raqad syndrome (OMIM 616459).

7 patients from 3 families have been reported to date, all summarized in PMID 30289615 (first reports on the disorder - PMIDs : 25712129, 25701870).

Most individuals belong to consanguineous families although a compound heterozygous patient belonging to a broader consanguineous family (in PMID 25701870) and a further individual was born to unrelated parents originating from the same region (in PMID 30289615) have been described.

Overall, 2 splice site and 2 missense variants have been reported. Functional studies were carried out and support pathogenicity of the variants in the first 2 studies.

Developmental delay and intellectual disability are universal features.

DCPS is included in gene panels for intellectual disability offered by different diagnostic labs.

As a result this gene can be considered for inclusion in this panel as green.
Sources: Expert Review, Literature
Intellectual disability v2.530 CHD3 Konstantinos Varvagiannis gene: CHD3 was added
gene: CHD3 was added to Intellectual disability. Sources: Expert Review,Literature
Mode of inheritance for gene: CHD3 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CHD3 were set to 30397230
Phenotypes for gene: CHD3 were set to Global developmental delay; Intellectual disability; Macrocephaly
Penetrance for gene: CHD3 were set to unknown
Review for gene: CHD3 was set to GREEN
Added comment: PMID 30397230 is a collaborative study reporting on the phenotype of 35 individuals including 4 subjects from the DDD study, (most) with de novo mutations in CHD3.

Common features include developmental delay, variable degrees of intellectual disability, impaired speech and language (all 3 were universal features) as well as macrocephaly (in approximately 60%) or vision problems. Widely spaced eyes and high/broad/prominent forehead were among the most constant facial features (noted in around 80% each).

The majority of the variants reported are missense and cluster within the helicase domain although exceptions of missense variants in other domains or loss-of-function variants are provided. A few variants were recurrent and/or concerned the same residue.

Two pairs of affected siblings are reported, in one case this was explained by maternal mosaicism for the mutation.

Perturbed ATPase and/or chromatin remodeling activity relative to wild-type were demonstrated although both gain and loss of these activities were noted depending on the variant tested.

CHD3 is intolerant to both loss-of-function and missense variants (pLI of 1.0 and Z-score of +7.15).

As a result this gene can be considered for inclusion in the ID panel as green.
Sources: Expert Review, Literature
Intellectual disability v2.530 RHOBTB2 Konstantinos Varvagiannis gene: RHOBTB2 was added
gene: RHOBTB2 was added to Intellectual disability. Sources: Expert Review,Literature
Mode of inheritance for gene: RHOBTB2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: RHOBTB2 were set to 29276004; 29768694; 26740508
Phenotypes for gene: RHOBTB2 were set to Global developmental delay; Intellectual disability; Seizures; Postnatal microcephaly
Penetrance for gene: RHOBTB2 were set to unknown
Mode of pathogenicity for gene: RHOBTB2 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: RHOBTB2 was set to GREEN
gene: RHOBTB2 was marked as current diagnostic
Added comment: PMID: 29276004 reports on 10 unrelated patients with de novo pathogenic missense variants in RHOBTB2. The phenotype in all individuals was compatible with a developmental and epileptic encephalopathy including early-onset seizures, severe intellectual disability, postnatal onset microcephaly (6/10) and movement disorders (8/10).

The variants occured as de novo events and clustered within the BTB-domain encoding region (within and between the 2 BTB domains). Three missense variants were recurrent and/or concerned the same residue (p.Arg483His in 4 individuals, Arg511Gln was reported in 2, and Arg511Trp was was found in another 2 individuals).

Functional studies in HEK293 cells suggested increased abundance of the mutant protein secondary to decreased proteasome degradation. Using Drosophila as a model organism, altered expression of RhoBTB (the single ortholog of the 3 vertebrate paralogs, closest to RHOBTB2) was shown to result in neurological phenotypes. RhoBTB overexpression in particular was associated with increased bang sensitivity (which was not the case or milder in the case if knockdown of this gene) and impaired performance upon the negative geotaxis assay, similar to the human neurological phenotypes. Altered RhoBTB dosage was shown to be associated with impaired dendrite development.

As commented by the authors, these results as well as the clustering of missense variants and the pLI score of 0.51 reported for RHOBTB2 are consistent with altered protein function (due to the missense variants) rather than haploinsufficiency or loss-of-function.

PMID: 29768694 describes 3 additional individuals, all found to harbor de novo missense variants again within the BTB-domain encoding region. Two of the variants had been reported in the previous study (Arg511Gln and Arg483His) while the third was a private one (Arg507Cys). The phenotype was similar to the previous descriptions. Functional studies were suggestive of impaired degradation of the mutant protein by the CUL3 complex although this was not secondary to decreased binding with CUL3.

PMID: 26740508 (cited by the two aforementioned publications) reports briefly on an individual with de novo missense variant in the same region of RHOBTB2 (Asn510Asp) and Rett-like phenotype.

RHOBTB2 is included in gene panels for intellectual disability offered by different diagnostic laboratories.

As a result the gene can be considered for inclusion in the intellectual disability and epilepsy panels as green.
Sources: Expert Review, Literature
Intellectual disability v2.530 TUBA8 Rebecca Foulger Tag watchlist tag was added to gene: TUBA8.
Intellectual disability v2.530 TUBA8 Rebecca Foulger Classified gene: TUBA8 as Amber List (moderate evidence)
Intellectual disability v2.530 TUBA8 Rebecca Foulger Added comment: Comment on list classification: Demoted from Green to Amber based on re-review of evidence. Demotion agreed by Clinical Fellow Helen Brittain.

TUBA8 was originally rated Green on the panel because TUBA8 is a confirmed DD-G2P gene for 'POLYMICROGYRIA WITH OPTIC NERVE HYPOPLASIA' (the former name for Cortical dysplasia, complex, with other brain malformations 8, 613180) and TUBA8 is on the UKGTN 43 gene panel for brain malformations:
https://ukgtn.nhs.uk/find-a-test/search-by-disorder-gene/brain-malformation-disorders-cortical-43-gene-panel-886/.

However, the reported evidence comes from one 2009 paper (PMID:19896110) with 4 literature cases coming from 2 consaguineous families (1 variant); at least PMID:25008804 questions whether the families are related. A 2017 paper identifies an additional VUS (compound heterozygous) in a chinese EE patient (PMID:29588952).

Anna de Burca confirmed that there are lots of cases with CNVs involving TUBA8 in DECIPHER but there are only two cases with SNVs in the gene. One of them is classified as unknown pathogenicity, the other likely benign.

I contacted Usha Kini at Oxford, and also the Leeds and Cardiff genetic testing groups (as recommended by Usha) since they all offer cortical malformation panels. All three confirmed (pers. comm. via email) that they have no further cases for TUBA8.

The literature evidence and communications from Oxford, Leeds and Cardiff all support demotion of TUBA8 to Amber rating: The phenotype is still appropriate for the panel but insufficient cases for diagnostic rating.

Added 'watchlist' tag to look out for further cases.
Intellectual disability v2.530 TUBA8 Rebecca Foulger Gene: tuba8 has been classified as Amber List (Moderate Evidence).
Intellectual disability v2.529 PIK3CA Rebecca Foulger Added comment: Comment on mode of inheritance: Changed MOI from 'Other' in order to capture variants within this gene in our current tiering pipeline.
Intellectual disability v2.529 PIK3CA Rebecca Foulger Mode of inheritance for gene: PIK3CA was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v2.528 ADPRHL2 Louise Daugherty Tag watchlist tag was added to gene: ADPRHL2.
Intellectual disability v2.528 ADPRHL2 Louise Daugherty Classified gene: ADPRHL2 as Amber List (moderate evidence)
Intellectual disability v2.528 ADPRHL2 Louise Daugherty Added comment: Comment on list classification: New gene added by external reviewer as Amber. However, majority of people have seizures and only a minority have some intellectual component and this seems to later onset /developmental regression, the clinical picture is one of a stress-induced neurodegenerative disease of variable progression with developmental delay, intellectual disability, mild cerebellar atrophy and recurring seizures. However I am not sure if this gene is within the scope of the ID panel and as they all present with seizures so is better presented on Genetic Epilepsy Syndromes panel. So pending further cases/evidence will leave gene as Amber and watchlist
Intellectual disability v2.528 ADPRHL2 Louise Daugherty Gene: adprhl2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v2.527 CUX2 Louise Daugherty Classified gene: CUX2 as Green List (high evidence)
Intellectual disability v2.527 CUX2 Louise Daugherty Added comment: Comment on list classification: More than three unrelated individuals reported in the literature, ID is part of the phenotype. Recent publications support gene-disease association and rating of this gene to Green.
Intellectual disability v2.527 CUX2 Louise Daugherty Gene: cux2 has been classified as Green List (High Evidence).
Intellectual disability v2.526 CUX2 Louise Daugherty Added comment: Comment on phenotypes: added phenotype from OMIM/MIMid and external review
Intellectual disability v2.526 CUX2 Louise Daugherty Phenotypes for gene: CUX2 were changed from to Epileptic encephalopathy, early infantile, 67, 618141; Seizures; Intellectual disability; Autistic behavior
Intellectual disability v2.525 CUX2 Louise Daugherty Added comment: Comment on mode of inheritance: added MOI from publication and external review
Intellectual disability v2.525 CUX2 Louise Daugherty Mode of inheritance for gene: CUX2 was changed from to MONOALLELIC, autosomal or pseudoautosomal, paternally imprinted (maternal allele expressed)
Intellectual disability v2.524 CUX2 Louise Daugherty Added comment: Comment on publications: added publications suggested by external reviewer which support gene-disease association and rating of this gene to Green. Intellectual disability is a prominent feature, all nine unrelated patients reported by PubMed: 29630738 had severe intellectual disability, and 7 were nonverbal.
Intellectual disability v2.524 CUX2 Louise Daugherty Publications for gene: CUX2 were set to 21331220; 26350204
Intellectual disability v2.523 GTPBP2 Louise Daugherty Classified gene: GTPBP2 as Green List (high evidence)
Intellectual disability v2.523 GTPBP2 Louise Daugherty Added comment: Comment on list classification: New gene suggested by external reviewer and reviewed by curation team. More than three unrelated individuals reported in the literature, ID is part of the phenotype. Publications support gene-disease association and rating of this gene to Green. At least 4 variants homozygous variants identified in 4 unrelated cases, common features included developmental delay and severe intellectual disability.
Intellectual disability v2.523 GTPBP2 Louise Daugherty Gene: gtpbp2 has been classified as Green List (High Evidence).
Intellectual disability v2.522 GTPBP2 Louise Daugherty Added comment: Comment on phenotypes: added phenotype from OMIM and MIMid
Intellectual disability v2.522 GTPBP2 Louise Daugherty Phenotypes for gene: GTPBP2 were changed from Global developmental delay; Intellectual disability; Seizures to Jaberi-Elahi syndrome, 617988; Global developmental delay; Intellectual disability; Seizures
Intellectual disability v2.521 IRF2BPL Louise Daugherty Added comment: Comment on phenotypes: added MIMid from OMIM and phenotype data
Intellectual disability v2.521 IRF2BPL Louise Daugherty Phenotypes for gene: IRF2BPL were changed from Global developmental delay; Developmental regression; Seizures; Ataxia to Neurodevelopmental disorder with regression, abnormal movements, loss of speech, and seizures; Global developmental delay, Developmental regression, Seizures, Ataxia
Intellectual disability v2.520 IRF2BPL Louise Daugherty Classified gene: IRF2BPL as Green List (high evidence)
Intellectual disability v2.520 IRF2BPL Louise Daugherty Added comment: Comment on list classification: New gene suggested by external reviewer and reviewed by curation team. More than three unrelated individuals reported in the literature, ID is part of the phenotype. Publications support gene-disease association and rating of this gene to Green.
Intellectual disability v2.520 IRF2BPL Louise Daugherty Gene: irf2bpl has been classified as Green List (High Evidence).
Intellectual disability v2.519 IRF2BPL Louise Daugherty Added comment: Comment on publications: Added publication suggested by external reviewer. PMID: 30166628 is a recent publication on IRF2BPL-related phenotypes and reports on 11 unrelated individuals with de novo heterozygous truncating variants. Most individuals displayed complex neurological phenotypes, including delayed psychomotor development, variable Intellectual disability, developmental stagnation or cognitive decline preceded, accompanied or followed by the onset of seizures
Intellectual disability v2.519 IRF2BPL Louise Daugherty Publications for gene: IRF2BPL were set to 30057031; 28135719; 25363768
Intellectual disability v2.518 RORA Louise Daugherty Classified gene: RORA as Green List (high evidence)
Intellectual disability v2.518 RORA Louise Daugherty Added comment: Comment on list classification: New gene suggested by external reviewer and reviewed by curation team. More than three affected individuals from unrelated families reported with at least 5 variants in this gene being reported, Intellectual disability was reported in the majority of cases and is a main feature of the phenotype. Publications support gene-disease association and rating of this gene to Green.
Intellectual disability v2.518 RORA Louise Daugherty Gene: rora has been classified as Green List (High Evidence).
Intellectual disability v2.517 SLC1A4 Louise Daugherty Classified gene: SLC1A4 as Green List (high evidence)
Intellectual disability v2.517 SLC1A4 Louise Daugherty Added comment: Comment on list classification: New gene suggested by external reviewer and reviewed by curation team. More than three unrelated individuals reported in the literature, ID is part of the phenotype. Publications support gene-disease association and rating of this gene to Green.
Intellectual disability v2.517 SLC1A4 Louise Daugherty Gene: slc1a4 has been classified as Green List (High Evidence).
Intellectual disability v2.516 SLC1A4 Louise Daugherty gene: SLC1A4 was added
gene: SLC1A4 was added to Intellectual disability. Sources: Expert Review
Mode of inheritance for gene: SLC1A4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC1A4 were set to 29989513; 27193218; 26138499; 26041762; 25930971
Phenotypes for gene: SLC1A4 were set to Spastic tetraplegia, thin corpus callosum, and progressive microcephaly, 616657; Intellectual disability
Review for gene: SLC1A4 was set to GREEN
Added comment: From review left on the Genetic Epilepsy Syndromes panel by Zornitza Stark (Australian Genomics) 4 Sep 2018, 3:29 a.m. Multiple affected individuals reported in the literature, seizures/EE are part of the phenotype. While initial reports identified a recurrent missense variant in individuals of Ashkenazi Jewish ancestry, there have been more recent reports of individuals from other ethnic backgrounds with different variants. Gene is also relevant to the ID panel.
Sources: Expert Review
Intellectual disability v2.515 PCGF2 Louise Daugherty Mode of pathogenicity for gene: PCGF2 was changed from to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Intellectual disability v2.514 PCGF2 Louise Daugherty Added comment: Comment on publications: Added PMID: 30343942 to support upgrading of this gene to green
Intellectual disability v2.514 PCGF2 Louise Daugherty Publications for gene: PCGF2 were set to 25529582; 25533962
Intellectual disability v2.513 PCGF2 Louise Daugherty Phenotypes for gene: PCGF2 were changed from Intellectual disability; dysmorphic features; Global developmental delay; Intellectual disability; Abnormality of the cardiovascular system; Abnormality of the cerebrum; Abnormality of the skeletal system to Intellectual disability; dysmorphic features; Global developmental delay; Abnormality of the cardiovascular system; Abnormality of the cerebrum; Abnormality of the skeletal system
Intellectual disability v2.512 PCGF2 Louise Daugherty Added comment: Comment on phenotypes: added phenotype suggested by external reviewer/ from PMID:30343942
Intellectual disability v2.512 PCGF2 Louise Daugherty Phenotypes for gene: PCGF2 were changed from Intellectual disability; dysmorphic features to Intellectual disability; dysmorphic features; Global developmental delay; Intellectual disability; Abnormality of the cardiovascular system; Abnormality of the cerebrum; Abnormality of the skeletal system
Intellectual disability v2.511 PCGF2 Louise Daugherty Classified gene: PCGF2 as Green List (high evidence)
Intellectual disability v2.511 PCGF2 Louise Daugherty Added comment: Comment on list classification: Recent publication suggested by external reviewer PMID: 30343942 supports the rating of this gene to be Green
Intellectual disability v2.511 PCGF2 Louise Daugherty Gene: pcgf2 has been classified as Green List (High Evidence).
Intellectual disability v2.510 PCGF2 Louise Daugherty commented on gene: PCGF2: removed watchlist tag
Intellectual disability v2.510 PCGF2 Louise Daugherty Deleted their comment
Intellectual disability v2.510 PCGF2 Louise Daugherty commented on gene: PCGF2: removed watchlist tag
Intellectual disability v2.510 PCGF2 Louise Daugherty Tag watchlist was removed from gene: PCGF2.
Intellectual disability v2.510 MUT Louise Daugherty Tag new-gene-name tag was added to gene: MUT.
Intellectual disability v2.510 MUT Louise Daugherty commented on gene: MUT
Intellectual disability v2.510 REEP1 Eleanor Williams Deleted their review
Intellectual disability v2.510 REEP1 Eleanor Williams commented on gene: REEP1
Intellectual disability v2.510 EMC1 Konstantinos Varvagiannis gene: EMC1 was added
gene: EMC1 was added to Intellectual disability. Sources: Expert Review,Literature
Mode of inheritance for gene: EMC1 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Publications for gene: EMC1 were set to 26942288; 29271071
Phenotypes for gene: EMC1 were set to Cerebellar atrophy, visual impairment, and psychomotor retardation, MIM 616875
Penetrance for gene: EMC1 were set to Complete
Review for gene: EMC1 was set to GREEN
gene: EMC1 was marked as current diagnostic
Added comment: Harel et al. (PMID: 26942288) describe 7 individuals from 3 families with biallelic pathogenic variants in EMC1.

In the first family, a single individual (born to non-consanguineous parents) was found to harbor a homozygous frameshift variant in a small (approx. 100 kb) stretch of absence of heterozygosity. The patients in the other two families were homozygous for missense variants (private to each family) in the context of parental consanguinity.

The common phenotype was suggestive of a progressive neurodegenerative disorder and consisted of hypotonia, severe developmental delay with marked speech delay, diminished deep tendon reflexes, cerebellar atrophy, vision as well as skeletal problems. Seizures were a feature in one subject.

One further patient from an additional (fourth) family was found to have a similar but milder phenotype and was only found to harbor a de novo missense variant in EMC1 following trio exome sequencing. Sanger sequencing of the promoter region as well as CNV calling from the exome data failed to reveal other variants in this specific individual.

Similarly to what has been observed in other genes the authors propose that both monoallelic and biallelic pathogenic variants may be causative of the specific phenotype, though the presentation may be more severe in case of biallelic variants.

Altogether this study reports 1 homozygous frameshift and 3 missense variants (2 of the latter found in homozygous state and one as a de novo heterozygous mutation). //

Geetha et al. (PMID: 29271071) describe an individual born to consanguineous parents presenting with hypotonia, developmental delay, and cerebellar atrophy as well as early onset epilepsy. Exome sequencing demonstrated a homozygous splice variant in EMC1. This variant was demonstrated to result to retention of intron 11 upon RNA sequencing. This was predicted to lead to premature truncation of the protein. //

EMC1 is associated in OMIM with Cerebellar atrophy, visual impairment, and psychomotor retardation (MIM 616875) for which an autosomal recessive inheritance mode is retained. //

Apart from the variants reported in the previous studies [p.Pro874Argfs*21, p.Thr82Met, p.Gly868Arg, p.Gly471Arg, c.1212+1G>A - NM_015047.2] further variants have been submitted in ClinVar as likely pathogenic (Variation IDs : 521479, 445564). //

The gene has been included in intellectual disability gene panels offered by a few other diagnostic labs. //

As a result this gene can be considered for inclusion in the panel as green (or amber).
Sources: Expert Review, Literature
Intellectual disability v2.510 CACNA1E Konstantinos Varvagiannis gene: CACNA1E was added
gene: CACNA1E was added to Intellectual disability. Sources: Expert Review,Literature
Mode of inheritance for gene: CACNA1E was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CACNA1E were set to 29942082
Phenotypes for gene: CACNA1E were set to Global developmental delay; Intellectual disability; Seizures; Dystonia; Congenital contracture; Macrocephaly
Penetrance for gene: CACNA1E were set to Incomplete
Mode of pathogenicity for gene: CACNA1E was set to Other
Review for gene: CACNA1E was set to GREEN
Added comment: Helbig et al. (https://doi.org/10.1016/j.ajhg.2018.09.006) report on 30 individuals with pathogenic variants in CACNA1E.

The phenotype was consistent with a developmental and epileptic encephalopathy, with hypotonia, early-onset and refractory seizures, severe to profound developmental delay and intellectual disability. Additional relatively common features included hyperkinetic movement disorder (severe dystonia which was observed in 40%, other dyskinesias in another 20%), congenital joint contractures of variable degree and joint involvement (approx. 40% of individuals) and macrocephaly (approx. 40%). There were no common facial dysmorphic features observed.

Of note, epilepsy was not a feature in 4 cases (age 1 to 4 years) so few of these individuals may be investigated for their developmental delay/intellectual disability or other features.

Missense variants:
All the 30 subjects described harbored a missense variant in CACNA1E which in all cases where parental studies were possible (29/30) occurred as a de novo event. There were 4 recurrent variants, explaining the phenotype in 20 patients in total while the rest of the individuals had private mutations. Functional studies were performed and suggested a gain-of-function effect for these variants (increased calcium inward currents).

Loss-of-function (LoF) variants:
Apart from the main cohort of patients, the authors note the presence of 3 individuals with such variants incl.:
- one individual with a nonsense variant present in the mosaic state (6/22 reads) in peripheral blood.
- one individual with a frameshift variant inherited from his unaffected parent.
- one individual with a nonsense variant for whom parental studies were not possible.

The authors comment that these indivdiduals presented with milder phenotype compared to those with missense variants. More information on these subjects is provided in the supplement as the article focuses on missense SNVs.

As the authors also note, several LoF variants exist in gnomAD, although the gene appears to be LoF intolerant (pLI=1).

Penetrance:
Seems to be complete for missense SNVs and possibly incomplete for LoF ones.

---

A previous study by Heyne et al. (PMID: 29942082) implicated de novo variants (DNVs) in CACNA1E with neurodevelopmental disorders for the first time. This study however does not provide clinical details on the phenotype of the affected individuals, while it seems to present overlap as to the individuals reported (eg. includes subjects from the DDD study and others).

---

Details as to a few - possibly further - de novo coding variants reported to date can be found at the denovo-db:
http://denovo-db.gs.washington.edu/denovo-db/QueryVariantServlet?searchBy=Gene&target=CACNA1E

---

As a result this gene can be considered for inclusion in this panel as green.
Sources: Expert Review, Literature
Intellectual disability v2.510 DLG4 Konstantinos Varvagiannis reviewed gene: DLG4: Rating: GREEN; Mode of pathogenicity: None; Publications: 29460436, 27479843, 28135719, 23020937; Phenotypes: Intellectual disability, Marfanoid habitus; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v2.510 PCGF2 Konstantinos Varvagiannis reviewed gene: PCGF2: 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: Global developmental delay, Intellectual disability, Abnormality of the cardiovascular system, Abnormality of the cerebrum, Abnormality of the skeletal system; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v2.510 ZNF81 Eleanor Williams Deleted their review
Intellectual disability v2.510 ZNF81 Eleanor Williams reviewed gene: ZNF81: Rating: RED; Mode of pathogenicity: None; Publications: 12345; Phenotypes: test phenotype; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v2.510 TRIM8 Konstantinos Varvagiannis gene: TRIM8 was added
gene: TRIM8 was added to Intellectual disability. Sources: Expert Review,Literature
Mode of inheritance for gene: TRIM8 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: TRIM8 were set to 30244534; 27346735; 23934111
Phenotypes for gene: TRIM8 were set to Global developmental delay; Intellectual disability; Seizures
Penetrance for gene: TRIM8 were set to Complete
Review for gene: TRIM8 was set to GREEN
Added comment: PMID: 30244534 is a collaborative study reporting on the phenotype of TRIM8-related epileptic encephalopathy and summarizing the findings in previously published patients. Developmental delay, intellectual disability, seizures are common findings in the 6 unrelated individuals reported. Proteinuria was observed in 3 subjects.

Seizures were universal feature with highly variable age of onset (2 months to 3 years and 5 months).

Several individuals were investigated for developmental delay prior to seizure onset (eg. pat.1 had an MRI at 10 months, sat at 16 months, walked at 22 months and developed seizures at 2 years, pat.3 sat at 12 months, walked at 22 and developed seizures at 3 years and 5 months, pat. 4 and 5 had significant/severe delay prior to the age of 21 months when they started having seizures).

All variants reported to date are truncating, affecting the last (sixth exon) and as a result may escape nonsense-mediated decay. Since TRIM8 homodimerizes via its (upstream) coiled-coil domain and its C-terminal domain is required for nuclear localization, a dominant-negative effect is postulated by the authors. Haploinsufficiency appears less likely.

A previously reported patient (from PMID: 27346735) as well as an individual reported by the Epi4K consortium (PMID: 23934111 - among the co-authors of the present study) are included in the table of this article.

As a result this gene can be considered for inclusion in the intellectual disability and epilepsy panels as green.
Sources: Expert Review, Literature
Intellectual disability v2.510 VARS Konstantinos Varvagiannis gene: VARS was added
gene: VARS was added to Intellectual disability. Sources: Expert Review,Literature
Mode of inheritance for gene: VARS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: VARS were set to 26539891; 29691655; 30275004
Phenotypes for gene: VARS were set to # 617802. NEURODEVELOPMENTAL DISORDER WITH MICROCEPHALY, SEIZURES, AND CORTICAL ATROPHY; NDMSCA
Penetrance for gene: VARS were set to Complete
Review for gene: VARS was set to GREEN
gene: VARS was marked as current diagnostic
Added comment: PMID: 26539891 is the first report on individuals with biallelic pathogenic variants in VARS. 3 individuals from 2 consanguineous families are briefly reported. The phenotype was similar in all 3, consisting of severe developmental delay, microcephaly, seizures and cortical atrophy. Subjects from the first family were homozygous for a missense variant in the tRNA synthetase catalytic domain [p.(L885F)]. The patient from the second family was homozygous for a missense SNV affecting the anticodon-binding domain [p.(R1058Q)].

PMID: 29691655 reports on a further patient born to non-consanguineous parents, with 2 in-trans pathogenic variants in VARS. The phenotype consisted of progressive microcephaly (OFC at birth -2SD, at the age of 2 months -4SD), global developmental delay, seizures and progressive cerebral and cerebellar atrophy. An affected brother presented with more severe phenotype (OFC -6SD at birth and -8SD at 2 months of age), seizures, hearing loss but was deceased and unavailable for genetic testing. cDNA studies demonstrated absence of the reference allele for the missense mutation downstream the splice variant (in line with a reduced or absent mRNA allele harboring the splice variant). Similarly, mRNA expression studies demonstrated 50-60% reduction in the transcripts (due to NMD of the allele with the splice SNV). Western blot showed severe reduction in protein levels (more pronounced compared to what would be expected by mRNA expression) presumably secondary to decreased protein stability due to the missense variant. Severe defects in aminoacylation were further confirmatory of a pathogenic role of these variants. The missense variant was affecting the anticodon-binding domain, important for aminoacylation.

PMID: 30275004 reports on 2 siblings with developmental delay, intellectual disability, severe speech impairment and microcephaly, similar to what has been described for the disorder. Clinical findings were somewhat different from previous studies in that microcephaly was acquired, while seizures and cortical atrophy were not part of the phenotype. Both sibs were compound heterozygous for 2 missense variants, though only one of these mutations affected the anticodon binding domain and the other was in the N-terminal region of the protein. Previous metabolic studies and extensive genetic testing (karyotype, CMA, MECP2, FMR1) was normal.

Epilepsy was a feature in 4 of the 6 individuals for whom genetic testing was possible (or 5/7 in total).

VARS belongs to the family of amino acyl-tRNA synthetases (ARSs). Mutations in several cytoplasmic ARSs are associated with severe neurological manifestations including seizures, intellectual disability associated with microcephaly.

VARS is included in gene panels for intellectual disability (but not for epilepsy) offered by different diagnostic labs.

As a result this gene can be considered for inclusion in the ID and epilepsy panel as green (or amber).
Sources: Expert Review, Literature
Intellectual disability v2.510 KARS Konstantinos Varvagiannis reviewed gene: KARS: Rating: GREEN; Mode of pathogenicity: None; Publications: 29615062, 30252186, 28496994; Phenotypes: Global developmental delay, Intellectual disability, Seizures, Charcot-Marie-Tooth disease, recessive intermediate, B - 613641, Deafness, autosomal recessive 89 - 613916; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability v2.510 ARL13B Konstantinos Varvagiannis reviewed gene: ARL13B: Rating: GREEN; Mode of pathogenicity: None; Publications: 18674751, 25138100, 29255182, 16541367; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability v2.510 ARL13B Konstantinos Varvagiannis Deleted their review
Intellectual disability v2.510 ARL13B Konstantinos Varvagiannis reviewed gene: ARL13B: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability v2.510 PIGW Konstantinos Varvagiannis reviewed gene: PIGW: Rating: GREEN; Mode of pathogenicity: None; Publications: 30078644; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability v2.510 ADAT3 Konstantinos Varvagiannis gene: ADAT3 was added
gene: ADAT3 was added to Intellectual disability. Sources: Expert Review,Literature
Mode of inheritance for gene: ADAT3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ADAT3 were set to 23620220; 26842963; 30296593; 29796286
Phenotypes for gene: ADAT3 were set to # 615286. MENTAL RETARDATION, AUTOSOMAL RECESSIVE 36; MRT36
Penetrance for gene: ADAT3 were set to Complete
Review for gene: ADAT3 was set to GREEN
gene: ADAT3 was marked as current diagnostic
Added comment: Initially reported in PMID 23620220, the findings in several individuals with biallelic ADAT3 pathogenic variants (including also those from the first report) are summarized in PMID 26842963.

A total of 39 individuals from 19 consanguineous families are described in the two studies. These individuals were homozygous for a specific missense variant (probably a Saudi Arabian founder mutation).

The common phenotype consists of intellectual disability (39/39 patients) and strabismus (32/39). Additional features included failure to thrive (33/39), microcephaly (22/39), short stature (11 of 15 individuals for whom this was information was available).

Epilepsy was observed in some of these individuals (6/39).

A few facial features were more common, although there was no distinct facial gestalt. //

PMID 30296593 reports on 2 additional subjects born to consanguineous parents and found to be homozygous for the same missense variant. These individuals presented with features similar to the previous reports (although none of them was reported to have seizures). //

Of note, the variant is either referred to as V144M (using NM_138422.2 or NM_138422.3) or as V128M (using NM_138422.1 as a reference / c.382G>A) as in the initial report. [ClinVar : https://www.ncbi.nlm.nih.gov/clinvar/variation/183301/#summary-evidence]

PMID 29796286 describes a 6-year-old female, born to consanguineous Iranian parents, investigated for developmental delay,intellectual disability, behavioral difficulties as well as microcephaly. A homozygous 8-basepair duplication in ADAT3 was identified by exome and was further confirmed by Sanger sequencing. This individual did not have seizures. //

This gene is included in DD/ID (but not epilepsy) panels offered by different diagnostic labs. //

As a result this gene can be considered for inclusion in the intellectual disability panel as green.
Sources: Expert Review, Literature
Intellectual disability v2.510 NBEA Konstantinos Varvagiannis reviewed gene: NBEA: Rating: GREEN; Mode of pathogenicity: None; Publications: 30269351, 28554332, 12746398, 12826745, 11450821, 3377648, 23277425, 22109531, 23153818; Phenotypes: Global developmental delay, Intellectual disability, Seizures; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Intellectual disability v2.510 NBEA Konstantinos Varvagiannis Deleted their review
Intellectual disability v2.510 NBEA Konstantinos Varvagiannis gene: NBEA was added
gene: NBEA was added to Intellectual disability. Sources: Literature,Expert Review
Mode of inheritance for gene: NBEA was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: NBEA were set to Global developmental delay; Intellectual disability; Seizures
Penetrance for gene: NBEA were set to unknown
Review for gene: NBEA was set to GREEN
gene: NBEA was marked as current diagnostic
Added comment: PMID: 30269351 is a collaborative study reporting in 24 individuals with pathogenic de novo variants affecting NBEA.

All subjects presented with neurodevelopmental disorder including developmental delay or intellectual disability. Half of the patients (12/24) had autistic features or autism.

Epilepsy was a feature in 15/24 (62.5%) of patients with onset before the age of 4 years in the majority (approx. 85%). Of the 15 patients with seizures, 80% presented with generalized seizures of variable type (myoclonic, atonic and/or myoclonic-atonic, absence, tonic, clonic or tonic-clonic), 6.67% with focal seizures only and 13.33% with unclassified seizure type.

Other features included developmental microcephaly (or borderilne microcephaly) in 3/24 individuals or developmental regression in 2/24.

Among the variants identified:
8/24 were stopgain SNVs
5/24 were frameshift
4/24 were missense SNVs
1/24 was a splice site SNV
5/24 concerned an intragenic NBEA deletion
1/24 concerned a 2.87 Mb deletion spanning NBEA as well as additional genes (none of latter associated with disease in OMIM).

Two of these individuals were reported in a previously published study of children with DD/ID (PMID: 28554332).

Individuals with developmental disorders and de novo coding mutations in NBEA have been reported in further publications including the DDD study (PMID: 28135719 - subject DDD4K.01714), most summarized in the denovo-db (http://denovo-db.gs.washington.edu/denovo-db/QueryVariantServlet?searchBy=Gene&target=NBEA).

As also commented in the article, a patient with autism and a de novo balanced translocation disrupting NBEA has been reported (PMID: 12746398) as has also been the case with other deletions spanning NBEA (PMIDs: 12826745, 11450821, 3377648).

Previous studies have suggested a role for NBEA in regulation of synaptic structure and function (PMID: 23277425,22109531) as well as a role of neurobeachin in autism-like behaviors in mice (PMID: 23153818).

NBEA is intolerant to loss-of-function mutations (pLI=1 in ExAC). Most variants in the study predict loss-of-function. As a result happloinsufficiency seems to be the underlying mechanism.

As the authors propose, loss-of-function variants might be associated with more specific (eg. microcephaly or myoclonic-atonic seizures) or severe phenotypic presentations, although the size of the cohort did not not allow safe conclusions. //

NBEA is included in DD/ID (but not epilepsy) gene panels offered by different diagnostic labs. //

As a result this gene can be considered for inclusion as green in the intellectual disability and epilepsy panels.
Sources: Literature, Expert Review
Intellectual disability v2.510 TRAF7 Konstantinos Varvagiannis gene: TRAF7 was added
gene: TRAF7 was added to Intellectual disability. Sources: Expert Review,Literature
Mode of inheritance for gene: TRAF7 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: TRAF7 were set to 29961569; 27479843; 28135719; 25363760; 25961944
Phenotypes for gene: TRAF7 were set to Global developmental delay; Abnormal heart morphology; Abnormality of digit; Abnormality of limbs
Penetrance for gene: TRAF7 were set to unknown
Review for gene: TRAF7 was set to GREEN
Added comment: PMID: 29961569 reports on 7 unrelated individuals with pathogenic variants in TRAF7. Common features included developmental delay, congenital heart defects, limb and digital anomalies as well as shared facial features (including epicanthal folds, ptosis, abnormal ears, excess nuchal skin). Two (or possibly three) of these patients had seizures. Some of these individuals had been investigated in the past for disorders of the Ras-MAPK pathway (CFC, Noonan and Costello syndrome).

The SNVs reported are missense and occured de novo in all patients for whom parental studies were possible (6 out of 7). A recurrent mutation [p.(Arg655Gln)] was found in 4 of the 7 individuals. One patient was found to harbor a mutation in the mosaic state, as a de novo occurrence.

The variants resulted in reduced activation of ERK1/2 (also known as MAPK3/MAPK1). //

7 individuals with de novo coding variants have previously been reported in large cohorts of patients with intellectual disability (PMIDs : 27479843, 28135719 - DDD study) and/or ASD (25363760, 25961944). One of the individuals from the DDD study had a stopgain variant.

The individuals from these studies are summarized in the denovo-db (http://denovo-db.gs.washington.edu/denovo-db/QueryVariantServlet?searchBy=Gene&target=TRAF7). //

As a result this gene can be considered for inclusion in the ID panel as green (or amber).
Sources: Expert Review, Literature
Intellectual disability v2.510 PIGG Konstantinos Varvagiannis gene: PIGG was added
gene: PIGG was added to Intellectual disability. Sources: Literature,Expert Review
Mode of inheritance for gene: PIGG was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PIGG were set to 26996948; 28581210
Phenotypes for gene: PIGG were set to # 616917 MENTAL RETARDATION, AUTOSOMAL RECESSIVE 53; MRT53
Penetrance for gene: PIGG were set to Complete
Review for gene: PIGG was set to GREEN
gene: PIGG was marked as current diagnostic
Added comment: PMID: 26996948 reports on 5 individuals from 3 families, with biallelic pathogenic variants in PIGG.

Individuals from first family, were born to consanguineous parents from Egypt and were homozygous for a stopgain variant [p.(Gln310*)]. The patient from the second family had a rare missense SNV [p.(Arg669Cys)] and a de novo microdeletion affecting PIGG on her other allele. In the third family (consanguineous parents from Pakistan), two affected sibs were found to be homozygous for a splice variant.

The phenotype consisted of hypotonia, early-onset seizures and intellectual disability. Ataxia was an additional feature in one of the families.

Seizures, were observed in most of patients but do not appear to be a universal feature as they were absent in one of the sibs from the third family (10 years of age), while the other had a single episode by the age of 12 years.

In vitro testing of lymphoblastoid cell lines (generated from individuals from the 1st and 3rd family) indicated that the variants abolished completely the function of PIGG, whereas the surface level of GPI anchored proteins was normal. //

PMID: 28581210 describes the phenotype of 2 sibs from Palestine, homozygous for a stopgain variant [p.(Trp547*)]. Hypotonia, feeding difficulties, severe non-progressive ataxia (with cerebellar hypoplasia), intellectual disability and seizures were common features. Differences in severity and/or additional features might be explained by other homozygous variants (the girl had a concurrent diagnosis of MCAD deficiency).

The authors demonstrated that the PIGG transcript levels were significantly lower (approximately half) in the two siblings compared to their parents, while the transcripts with the mutation in the heterozygous parents were very low due to nonsense-mediated decay.

Patient fibroblasts showed decreased surface level of GPI-anchored proteins, in contrast with what was noted in lymphoblastoid cells in the previous study. //

PIGG has been included in gene panels for intellectual disability offered by different diagnostic labs. //

As a result this gene can be considered for inclusion in this panel as green (or amber).
Sources: Literature, Expert Review
Intellectual disability v2.510 MEIS2 Konstantinos Varvagiannis reviewed gene: MEIS2: Rating: GREEN; Mode of pathogenicity: None; Publications: 30291340, 30055086; Phenotypes: Oral cleft, Abnormal heart morphology, Intellectual disability; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Intellectual disability v2.510 MAP1B Konstantinos Varvagiannis gene: MAP1B was added
gene: MAP1B was added to Intellectual disability. Sources: Literature,Expert Review
Mode of inheritance for gene: MAP1B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MAP1B were set to 30150678; 29738522
Phenotypes for gene: MAP1B were set to Intellectual disability
Penetrance for gene: MAP1B were set to unknown
Review for gene: MAP1B was set to AMBER
Added comment: In PMID 30150678 the authors report on a family with 5 individuals diagnosed with intellectual disability (ID, IQ <= 70 and associated impairments in adaptive function) and 3 further relatives with IQ below 70, not fulfilling the criteria for a clinical diagnosis of ID. A frameshift variant in MAP1B segregated with the ID/low IQ phenotype. This variant was not found in 31463 Icelanders for whom whole genome sequencing data were available.

The authors confirmed association of MAP1B loss-of-function (LoF) variants by demonstrating the presence of 2 other stopgain mutations in 2 further families. Among the 6 mutation carriers in these families, the average IQ was 81 with 2 of these subjects fulfilling the criteria for intellectual disability. 3 of the 6 mutation carriers had a diagnosis of autism spectrum disorder. Carriers demonstrated 24% less white matter volume (-2.1 SD) and 47% less corpus callosum volume (-2.4 SD) compared to controls.

Mean full-scale IQ, performance IQ and verbal IQ were 68.3 (with a SD of 10.5), 66.4 (SD of 9.3) and 74.5 (SD of 14.8) in MAP1B LoF carriers.

All 3 LoF variants reported result in a truncated but stable MAP1B protein as demonstrated by western blot analysis.

MAP1B undergoes post-translational modification and is cleaved (at position 2206) into a heavy chain and a light chain. The authors note that all LoF variants lead to truncation prior to the cleavage site.

As commented by the authors, LoF variants are found in publicly available databases at a frequency of approx. 1 in 10000.

One individual with de novo frameshift variant in Decipher ( https://decipher.sanger.ac.uk/search?q=gene%3AMAP1B#research-variants/results ).

De novo and inherited MAP1B variants have previously been described in individuals with periventricular nodular heterotopia (PMID: 29738522). This was also a feature in 9 individuals in the previous ID study.

Although PMID 30150678 is entitled "MAP1B mutations cause intellectual disability and extensive white matter deficit", intellectual disability was not a feature in all individuals or was rather mild when present.
Sources: Literature, Expert Review
Intellectual disability v2.510 CAMK2G Konstantinos Varvagiannis reviewed gene: CAMK2G: Rating: AMBER; 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: 30184290; Phenotypes: Generalized hypotonia, Global developmental delay, Intellectual disability; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Intellectual disability v2.510 AGO1 Konstantinos Varvagiannis reviewed gene: AGO1: Rating: GREEN; Mode of pathogenicity: None; Publications: 30213762, 22495306, 23020937, 25363768, 25356899, 27620904, 29346770; Phenotypes: Generalized hypotonia, Global developmental delay, Intellectual disability, Autism; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Intellectual disability v2.510 AGO1 Konstantinos Varvagiannis Deleted their review
Intellectual disability v2.510 AGO1 Konstantinos Varvagiannis reviewed gene: AGO1: Rating: GREEN; Mode of pathogenicity: None; Publications: 30213762, 22495306, 23020937, 25363768, 25356899, 27620904, 29346770; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v2.510 NSD2 Konstantinos Varvagiannis gene: NSD2 was added
gene: NSD2 was added to Intellectual disability. Sources: Literature,Expert Review
Mode of inheritance for gene: NSD2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: NSD2 were set to 29892088; 29760529; 29884796; 30244530
Phenotypes for gene: NSD2 were set to Intrauterine growth retardation; Growth delay; Microcephaly; Muscular hypotonia; Neurodevelopmental delay; Intellectual disability
Penetrance for gene: NSD2 were set to unknown
Review for gene: NSD2 was set to GREEN
gene: NSD2 was marked as current diagnostic
Added comment: PMID: 29892088 reports on 2 individuals with de novo SNVs affecting NSD2 (WHSC1). Both individuals presented with pre- and postnatal growth retardation, hypotonia, developmental delay / intellectual disability, as well as microcephaly. The authors suggest partial overlap with the phenotype of Wolf-Hirschhorn syndrome (WHS). Seizures are not part of the phenotype.The first subject had a splice site mutation while the second individual had a stopgain variant (affecting the PWWP domain).

PMID: 29760529 describes a further patient with de novo nonsense mutation in NSD2. The boy was evaluated for probable growth delay ("low physical development"), hypotonia, psychomotor delay and microcephaly. The variant affected the SET domain.

Three individuals with de novo likely loss-of-function (two frameshift and one stop gained) variants in Decipher [ https://decipher.sanger.ac.uk/search?q=NSD2#research-variants/results ].

A further patient with de novo frameshift mutation in NSD2 and a phenotype overlapping WHS reported in ClinVar [ https://www.ncbi.nlm.nih.gov/clinvar/variation/547999/ ]

PMID: 29884796 (Zollino M and Doronzio PN) comments that NSD2 (WHSC1) is a neurodevelopmental gene with a role in growth delay, intellectual disability and dysmorphic facial features.

PMID: 30244530 describes patients with 4p16.3 microdeletions spanning (exclusively) NSD2 and reviews the literature on patients with small microdeletions reported to date. All relevant individuals present with developmental delay and (rather mild) intellectual disability apart from other characteristics such as microcephaly, growth retardation and some facial features also observed in WHS.

In Decipher one individual (286913) with a single CNV spanning exclusively NSD2 presenting with IUGR, failure to thrive, feeding difficulties, postnatal microcephaly, hypotonia, developmental delay as well as possibly relevant facial features.

The gene is included in ID gene panels offered by various labs (either as NSD2 or WHSC1).

As a result it can be considered for inclusion in the panel as green.
Sources: Literature, Expert Review
Intellectual disability v2.510 KCNK4 Konstantinos Varvagiannis gene: KCNK4 was added
gene: KCNK4 was added to Intellectual disability. Sources: Literature,Expert Review
Mode of inheritance for gene: KCNK4 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: KCNK4 were set to 30290154
Phenotypes for gene: KCNK4 were set to Neurodevelopmental delay; Intellectual disability; Seizures; Gingival overgrowth; Hypertrichosis
Penetrance for gene: KCNK4 were set to unknown
Mode of pathogenicity for gene: KCNK4 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: KCNK4 was set to AMBER
Added comment: PMID: 30290154 reports on 3 unrelated individuals with de novo missense KCNK4 variants. All three individuals presented with developmental delay and epilepsy. Severe intellectual disability was a feature in two of these individuals while the third displayed low average intellectual functioning (IQ of 85). Other features common in all included facial dysmorphism (bushy eyebrows, long eyelashes, thin everted upper lip, micrognathia), generalized hypertrichosis and gingival overgrowth.

The two missense variants reported [(p.Ala172Glu) and (p.Ala244Pro)] occurred as de novo events in all subjects, while the first SNV was observed in 2 (of the 3) patients with severe intellectual disability.

Functional studies were suggestive of a gain-of-function effect. In line with this mechanism, Kcnk4 knockout mice did not seem to exhibit seizures, deficits in cognition or other neurodevelopmental phenotypes in a study conducted earlier and cited by the authors (PMID: 15175651).

As a result this gene can be considered for inclusion in the panel as amber (or green).
Sources: Literature, Expert Review
Intellectual disability v2.510 PORCN Ellen McDonagh Added comment: Comment on mode of inheritance: For Focal dermal hypoplasia, heterozygous females are affected. Confirmed with the Genomics England Clinical Team prior to revision from biallelic in females.
Intellectual disability v2.510 PORCN Ellen McDonagh Mode of inheritance for gene: PORCN was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Intellectual disability v2.509 RAC3 Konstantinos Varvagiannis gene: RAC3 was added
gene: RAC3 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: RAC3 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: RAC3 were set to 30293988; 29276006
Phenotypes for gene: RAC3 were set to Abnormality of brain morphology; Abnormal muscle tone; Neurodevelopmental delay; Intellectual disability
Penetrance for gene: RAC3 were set to unknown
Mode of pathogenicity for gene: RAC3 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: RAC3 was set to GREEN
Added comment: PMID: 30293988 reports on 5 individuals (from 4 different families) with de novo missense variants in RAC3. All individuals demonstrated structural anomalies on brain MRI (notably agenesis/dysgenesis of the corpus callosum, variable degrees of polymicrogyria and ventricular anomalies) as well as shared non-specific neurological features including abnormal muscular tone, global developmental delay and severe to profound intellectual disability. Feeding difficulties were observed in 4/5 patients.

All variants reported are missense and are presumed to result in constitutive protein activation, as suggested by previous observations either in RAC3 [eg. the p.(Gln61Leu) mutation] or the highly homologous RAC1 and RAC2. According to the authors this is further supported by the fact that Rac3 -/- mice do not show a severe phenotype while missense variants are underrepresented in the ExAC database (z=1.97) as opposed to loss-of-function variants (pLI=0.04 / probability of loss-of-function intolerance).

Of the 3 SNVs reported, 2 variants were in adjacent amino-acid positions [p.(Gln61Leu) and p.(Glu62Lys)]. The latter variant was found in 2 half-sibs born to different fathers, due to suspected maternal gonadal mosaicism (variant absent in all sequencing reads in the maternal DNA sample). The specific variant was also found in a further affected individual from an unrelated family.

Finally, as the authors point out a further individual with de novo RAC3 missense variant [p.(Ala59Gly)] was reported previously in an individual with thin corpus callosum and global developmental delay, although the phenotype was felt to be more reminiscent of Robinow syndrome (PMID: 29276006).

As a result, this gene can be considered for inclusion in the ID panel as green (or amber).
Sources: Literature
Intellectual disability v2.509 PCGF2 Louise Daugherty commented on gene: PCGF2: Added watchlist tag.
Intellectual disability v2.509 PCGF2 Louise Daugherty Tag watchlist tag was added to gene: PCGF2.
Intellectual disability v2.509 MSL3 Konstantinos Varvagiannis reviewed gene: MSL3: Rating: GREEN; Mode of pathogenicity: None; Publications: 30224647; Phenotypes: Muscular hypotonia, Feeding difficulties, Neurodevelopmental delay, Intellectual disability; 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 v2.509 LAMA1 Louise Daugherty Publications for gene: LAMA1 were set to 21937992
Intellectual disability v2.508 FBXO11 Helen Brittain Classified gene: FBXO11 as Green List (high evidence)
Intellectual disability v2.508 FBXO11 Helen Brittain Added comment: Comment on list classification: Appropriate phenotype, sufficient number of cases.
Intellectual disability v2.508 FBXO11 Helen Brittain Gene: fbxo11 has been classified as Green List (High Evidence).
Intellectual disability v2.507 FBXO11 Helen Brittain Classified gene: FBXO11 as Green List (high evidence)
Intellectual disability v2.507 FBXO11 Helen Brittain Added comment: Comment on list classification: Appropriate phenotype, sufficient number of cases.
Intellectual disability v2.507 FBXO11 Helen Brittain Gene: fbxo11 has been classified as Green List (High Evidence).
Intellectual disability v2.507 FBXO11 Helen Brittain Classified gene: FBXO11 as Green List (high evidence)
Intellectual disability v2.507 FBXO11 Helen Brittain Added comment: Comment on list classification: Appropriate phenotype, sufficient number of cases.
Intellectual disability v2.507 FBXO11 Helen Brittain Gene: fbxo11 has been classified as Green List (High Evidence).
Intellectual disability v2.507 FBXO11 Helen Brittain Classified gene: FBXO11 as Green List (high evidence)
Intellectual disability v2.507 FBXO11 Helen Brittain Added comment: Comment on list classification: Appropriate phenotype, sufficient cases
Intellectual disability v2.507 FBXO11 Helen Brittain Gene: fbxo11 has been classified as Green List (High Evidence).
Intellectual disability v2.507 FBXO11 Helen Brittain Classified gene: FBXO11 as Green List (high evidence)
Intellectual disability v2.507 FBXO11 Helen Brittain Added comment: Comment on list classification: Appropriate phenotype, sufficient cases
Intellectual disability v2.507 FBXO11 Helen Brittain Gene: fbxo11 has been classified as Green List (High Evidence).
Intellectual disability v2.507 FBXO11 Helen Brittain Classified gene: FBXO11 as Green List (high evidence)
Intellectual disability v2.507 FBXO11 Helen Brittain Added comment: Comment on list classification: Sufficient cases with appropriate phenotype
Intellectual disability v2.507 FBXO11 Helen Brittain Gene: fbxo11 has been classified as Green List (High Evidence).
Intellectual disability v2.507 FBXO11 Helen Brittain Classified gene: FBXO11 as Green List (high evidence)
Intellectual disability v2.507 FBXO11 Helen Brittain Added comment: Comment on list classification: Sufficient cases with appropriate phenotype
Intellectual disability v2.507 FBXO11 Helen Brittain Gene: fbxo11 has been classified as Green List (High Evidence).
Intellectual disability v2.506 FBXO11 Helen Brittain Marked gene: FBXO11 as ready
Intellectual disability v2.506 FBXO11 Helen Brittain Added comment: Comment when marking as ready: Appropriate phenotype and sufficient cases
Intellectual disability v2.506 FBXO11 Helen Brittain Gene: fbxo11 has been classified as Amber List (Moderate Evidence).
Intellectual disability v2.506 C3orf58 Louise Daugherty commented on gene: C3orf58
Intellectual disability v2.506 C3orf58 Louise Daugherty Tag new-gene-name tag was added to gene: C3orf58.
Intellectual disability v2.506 CHKB Louise Daugherty Added comment: Comment on phenotypes: added OMIM MIMid
Intellectual disability v2.506 CHKB Louise Daugherty Phenotypes for gene: CHKB were changed from Muscular dystrophy, congenital, megaconial type to Muscular dystrophy, congenital, megaconial type, 602541
Intellectual disability v2.505 MAPT Louise Daugherty Classified gene: MAPT as Red List (low evidence)
Intellectual disability v2.505 MAPT Louise Daugherty Added comment: Comment on list classification: This gene was rated as Red in v2.467 and incorrectly automatically promoted to Amber in v2.468. This was due to a defect in the automatic PanelApp uploading tool where a reference gene list was added as a new Source (Victorian Clinical Genetics Services), and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Intellectual disability v2.505 MAPT Louise Daugherty Gene: mapt has been classified as Red List (Low Evidence).
Intellectual disability v2.504 MAPT Louise Daugherty Classified gene: MAPT as Red List (low evidence)
Intellectual disability v2.504 MAPT Louise Daugherty Added comment: Comment on list classification: Changed rating of gene from Amber to Red. This gene was rated as Red in v2.467 and incorrectly automatically promoted to Amber in v2.468. This was due to a defect in the automatic PanelApp uploading tool where a reference gene list was added as a new Source (Victorian Clinical Genetics Services), and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Intellectual disability v2.504 MAPT Louise Daugherty Gene: mapt has been classified as Red List (Low Evidence).
Intellectual disability v2.504 CPA6 Louise Daugherty Classified gene: CPA6 as Red List (low evidence)
Intellectual disability v2.504 CPA6 Louise Daugherty Added comment: Comment on list classification: Changed rating of gene from Amber to Red. This gene was rated as Red in v2.467 and incorrectly automatically promoted to Amber in v2.468. This was due to a defect in the automatic PanelApp uploading tool where a reference gene list was added as a new Source (Victorian Clinical Genetics Services), and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Intellectual disability v2.504 CPA6 Louise Daugherty Gene: cpa6 has been classified as Red List (Low Evidence).
Intellectual disability v2.503 CIC Louise Daugherty Classified gene: CIC as Green List (high evidence)
Intellectual disability v2.503 CIC Louise Daugherty Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.467 and incorrectly automatically demoted to Red in v2.468. This was due to a defect in the automatic PanelApp uploading tool where a reference gene list was added as a new Source (Victorian Clinical Genetics Services), and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Intellectual disability v2.503 CIC Louise Daugherty Gene: cic has been classified as Green List (High Evidence).
Intellectual disability v2.503 CACNA1C Louise Daugherty Classified gene: CACNA1C as Green List (high evidence)
Intellectual disability v2.503 CACNA1C Louise Daugherty Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.467 and incorrectly automatically demoted to Red in v2.468. This was due to a defect in the automatic PanelApp uploading tool where a reference gene list was added as a new Source (Victorian Clinical Genetics Services), and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Intellectual disability v2.503 CACNA1C Louise Daugherty Gene: cacna1c has been classified as Green List (High Evidence).
Intellectual disability v2.502 PET100 Louise Daugherty Classified gene: PET100 as Amber List (moderate evidence)
Intellectual disability v2.502 PET100 Louise Daugherty Gene: pet100 has been classified as Amber List (Moderate Evidence).
Intellectual disability v2.501 PET100 Louise Daugherty commented on gene: PET100: Changed rating of gene from Red to Amber. This gene was rated as Amber in v2.467 and incorrectly automatically demoted to Red in v2.468. This was due to a defect in the automatic PanelApp uploading tool where a reference gene list was added as a new Source (Victorian Clinical Genetics Services), and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Intellectual disability v2.501 DRD2 Louise Daugherty Classified gene: DRD2 as Red List (low evidence)
Intellectual disability v2.501 DRD2 Louise Daugherty Added comment: Comment on list classification: Changed rating of gene from Amber to Red. This gene was rated as Red in v2.467 and incorrectly automatically promoted to Amber in v2.468. This was due to a defect in the automatic PanelApp uploading tool where a reference gene list was added as a new Source (Victorian Clinical Genetics Services), and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Intellectual disability v2.501 DRD2 Louise Daugherty Gene: drd2 has been classified as Red List (Low Evidence).
Intellectual disability v2.501 CP Louise Daugherty Classified gene: CP as Red List (low evidence)
Intellectual disability v2.501 CP Louise Daugherty Added comment: Comment on list classification: Changed rating of gene from Amber to Red. This gene was rated as Red in v2.467 and incorrectly automatically promoted to Amber in v2.468. This was due to a defect in the automatic PanelApp uploading tool where a reference gene list was added as a new Source (Victorian Clinical Genetics Services), and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Intellectual disability v2.501 CP Louise Daugherty Gene: cp has been classified as Red List (Low Evidence).
Intellectual disability v2.500 CPA6 Louise Daugherty Classified gene: CPA6 as Red List (low evidence)
Intellectual disability v2.500 CPA6 Louise Daugherty Added comment: Comment on list classification: Changed rating of gene from Amber to Red. This gene was rated as Red in v2.467 and incorrectly automatically promoted to Amber in v2.468. This was due to a defect in the automatic PanelApp uploading tool where a reference gene list was added as a new Source (Victorian Clinical Genetics Services), and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Intellectual disability v2.500 CPA6 Louise Daugherty Gene: cpa6 has been classified as Red List (Low Evidence).
Intellectual disability v2.500 DRD2 Louise Daugherty Classified gene: DRD2 as Red List (low evidence)
Intellectual disability v2.500 DRD2 Louise Daugherty Added comment: Comment on list classification: Changed rating of gene from Amber to Red. This gene was rated as Red in v2.467 and incorrectly automatically promoted to Amber in v2.468. This was due to a defect in the automatic PanelApp uploading tool where a reference gene list was added as a new Source (Victorian Clinical Genetics Services), and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Intellectual disability v2.500 DRD2 Louise Daugherty Gene: drd2 has been classified as Red List (Low Evidence).
Intellectual disability v2.500 MAPT Louise Daugherty Classified gene: MAPT as Red List (low evidence)
Intellectual disability v2.500 MAPT Louise Daugherty Added comment: Comment on list classification: Changed rating of gene from Amber to Red. This gene was rated as Red in v2.467 and incorrectly automatically promoted to Amber in v2.468. This was due to a defect in the automatic PanelApp uploading tool where a reference gene list was added as a new Source (Victorian Clinical Genetics Services), and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Intellectual disability v2.500 MAPT Louise Daugherty Gene: mapt has been classified as Red List (Low Evidence).
Intellectual disability v2.499 PYGL Louise Daugherty Classified gene: PYGL as Red List (low evidence)
Intellectual disability v2.499 PYGL Louise Daugherty Added comment: Comment on list classification: Changed rating of gene from Amber to Red. This gene was rated as Red in v2.467 and incorrectly automatically promoted to Amber in v2.468. This was due to a defect in the automatic PanelApp uploading tool where a reference gene list was added as a new Source (Victorian Clinical Genetics Services), and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Intellectual disability v2.499 PYGL Louise Daugherty Gene: pygl has been classified as Red List (Low Evidence).
Intellectual disability v2.499 RHEB Louise Daugherty Classified gene: RHEB as Red List (low evidence)
Intellectual disability v2.499 RHEB Louise Daugherty Added comment: Comment on list classification: Changed rating of gene from Amber to Red. This gene was rated as Red in v2.467 and incorrectly automatically promoted to Amber in v2.468. This was due to a defect in the automatic PanelApp uploading tool where a reference gene list was added as a new Source (Victorian Clinical Genetics Services), and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Intellectual disability v2.499 RHEB Louise Daugherty Gene: rheb has been classified as Red List (Low Evidence).
Intellectual disability v2.498 SPAST Louise Daugherty Classified gene: SPAST as Red List (low evidence)
Intellectual disability v2.498 SPAST Louise Daugherty Added comment: Comment on list classification: Changed rating of gene from Amber to Red. This gene was rated as Red in v2.467 and incorrectly automatically demoted to Amber in v2.468. This was due to a defect in the automatic PanelApp uploading tool where a reference gene list was added as a new Source (Victorian Clinical Genetics Services), and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Intellectual disability v2.498 SPAST Louise Daugherty Gene: spast has been classified as Red List (Low Evidence).
Intellectual disability v2.497 TINF2 Louise Daugherty Classified gene: TINF2 as Red List (low evidence)
Intellectual disability v2.497 TINF2 Louise Daugherty Added comment: Comment on list classification: Changed rating of gene from Amber to Red. This gene was rated as Red in v2.467 and incorrectly automatically demoted to Amber in v2.468. This was due to a defect in the automatic PanelApp uploading tool where a reference gene list was added as a new Source (Victorian Clinical Genetics Services), and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Intellectual disability v2.497 TINF2 Louise Daugherty Gene: tinf2 has been classified as Red List (Low Evidence).
Intellectual disability v2.496 ATP1A2 Louise Daugherty Classified gene: ATP1A2 as Amber List (moderate evidence)
Intellectual disability v2.496 ATP1A2 Louise Daugherty Added comment: Comment on list classification: Changed rating of gene from Red to Amber. This gene was rated as Amber in v2.467 and incorrectly automatically demoted to Red in v2.468. This was due to a defect in the automatic PanelApp uploading tool where a reference gene list was added as a new Source (Victorian Clinical Genetics Services), and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Intellectual disability v2.496 ATP1A2 Louise Daugherty Gene: atp1a2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v2.495 ATP1A2 Louise Daugherty Classified gene: ATP1A2 as Amber List (moderate evidence)
Intellectual disability v2.495 ATP1A2 Louise Daugherty Added comment: Comment on list classification: Changed rating of gene from Red to Amber. This gene was rated as Amber in v2.467 and incorrectly automatically demoted to Red in v2.468. This was due to a defect in the automatic PanelApp uploading tool where a reference gene list was added as a new Source (Victorian Clinical Genetics Services), and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Intellectual disability v2.495 ATP1A2 Louise Daugherty Gene: atp1a2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v2.494 D2HGDH Louise Daugherty Classified gene: D2HGDH as Green List (high evidence)
Intellectual disability v2.494 D2HGDH Louise Daugherty Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.467 and incorrectly automatically demoted to Red in v2.468. This was due to a defect in the automatic PanelApp uploading tool where a reference gene list was added as a new Source (Victorian Clinical Genetics Services), and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Intellectual disability v2.494 D2HGDH Louise Daugherty Gene: d2hgdh has been classified as Green List (High Evidence).
Intellectual disability v2.494 CIC Louise Daugherty Classified gene: CIC as Green List (high evidence)
Intellectual disability v2.494 CIC Louise Daugherty Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.467 and incorrectly automatically demoted to Red in v2.468. This was due to a defect in the automatic PanelApp uploading tool where a reference gene list was added as a new Source (Victorian Clinical Genetics Services), and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Intellectual disability v2.494 CIC Louise Daugherty Gene: cic has been classified as Green List (High Evidence).
Intellectual disability v2.494 CACNA1C Louise Daugherty Classified gene: CACNA1C as Green List (high evidence)
Intellectual disability v2.494 CACNA1C Louise Daugherty Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.467 and incorrectly automatically demoted to Red in v2.468. This was due to a defect in the automatic PanelApp uploading tool where a reference gene list was added as a new Source (Victorian Clinical Genetics Services), and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Intellectual disability v2.494 CACNA1C Louise Daugherty Gene: cacna1c has been classified as Green List (High Evidence).
Intellectual disability v2.493 TRIP12 Louise Daugherty Classified gene: TRIP12 as Green List (high evidence)
Intellectual disability v2.493 TRIP12 Louise Daugherty Added comment: Comment on list classification: Changed rating of gene from Amber to Green. This gene was rated as Green in v2.467 and incorrectly automatically demoted to Amber in v2.468. This was due to a defect in the automatic PanelApp uploading tool where a reference gene list was added as a new Source (Victorian Clinical Genetics Services), and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Intellectual disability v2.493 TRIP12 Louise Daugherty Gene: trip12 has been classified as Green List (High Evidence).
Intellectual disability v2.492 GABRG2 Louise Daugherty Classified gene: GABRG2 as Green List (high evidence)
Intellectual disability v2.492 GABRG2 Louise Daugherty Added comment: Comment on list classification: Changed rating of gene from Amber to Green. This gene was rated as Green in v2.467 and incorrectly automatically demoted to Amber in v2.468. This was due to a defect in the automatic PanelApp uploading tool where a reference gene list was added as a new Source (Victorian Clinical Genetics Services), and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Intellectual disability v2.492 GABRG2 Louise Daugherty Gene: gabrg2 has been classified as Green List (High Evidence).
Intellectual disability v2.491 THRB Louise Daugherty Classified gene: THRB as Amber List (moderate evidence)
Intellectual disability v2.491 THRB Louise Daugherty Added comment: Comment on list classification: Changed rating of gene from Red to Amber. This gene was rated as Amber in v2.467 and incorrectly automatically demoted to Red in v2.468. This was due to a defect in the automatic PanelApp uploading tool where a reference gene list was added as a new Source (Victorian Clinical Genetics Services), and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Intellectual disability v2.491 THRB Louise Daugherty Gene: thrb has been classified as Amber List (Moderate Evidence).
Intellectual disability v2.491 TBX1 Louise Daugherty Classified gene: TBX1 as Amber List (moderate evidence)
Intellectual disability v2.491 TBX1 Louise Daugherty Added comment: Comment on list classification: Changed rating of gene from Red to Amber. This gene was rated as Amber in v2.467 and incorrectly automatically demoted to Red in v2.468. This was due to a defect in the automatic PanelApp uploading tool where a reference gene list was added as a new Source (Victorian Clinical Genetics Services), and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Intellectual disability v2.491 TBX1 Louise Daugherty Gene: tbx1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v2.490 PET100 Louise Daugherty Classified gene: PET100 as Amber List (moderate evidence)
Intellectual disability v2.490 PET100 Louise Daugherty Added comment: Comment on list classification: Changed rating of gene from Red to Amber. This gene was rated as Amber in v2.467 and incorrectly automatically demoted to Red in v2.468. This was due to a defect in the automatic PanelApp uploading tool where a reference gene list was added as a new Source (Victorian Clinical Genetics Services), and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Intellectual disability v2.490 PET100 Louise Daugherty Gene: pet100 has been classified as Amber List (Moderate Evidence).
Intellectual disability v2.490 MED23 Louise Daugherty Classified gene: MED23 as Amber List (moderate evidence)
Intellectual disability v2.490 MED23 Louise Daugherty Added comment: Comment on list classification: Changed rating of gene from Red to Amber. This gene was rated as Amber in v2.467 and incorrectly automatically demoted to Red in v2.468. This was due to a defect in the automatic PanelApp uploading tool where a reference gene list was added as a new Source (Victorian Clinical Genetics Services), and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Intellectual disability v2.490 MED23 Louise Daugherty Gene: med23 has been classified as Amber List (Moderate Evidence).
Intellectual disability v2.490 KIRREL3 Louise Daugherty Classified gene: KIRREL3 as Amber List (moderate evidence)
Intellectual disability v2.490 KIRREL3 Louise Daugherty Added comment: Comment on list classification: Changed rating of gene from Red to Amber. This gene was rated as Amber in v2.467 and incorrectly automatically demoted to Red in v2.468. This was due to a defect in the automatic PanelApp uploading tool where a reference gene list was added as a new Source (Victorian Clinical Genetics Services), and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Intellectual disability v2.490 KIRREL3 Louise Daugherty Gene: kirrel3 has been classified as Amber List (Moderate Evidence).
Intellectual disability v2.489 GSS Louise Daugherty Classified gene: GSS as Amber List (moderate evidence)
Intellectual disability v2.489 GSS Louise Daugherty Added comment: Comment on list classification: Changed rating of gene from Red to Amber. This gene was rated as Amber in v2.467 and incorrectly automatically demoted to Red in v2.468. This was due to a defect in the automatic PanelApp uploading tool where a reference gene list was added as a new Source (Victorian Clinical Genetics Services), and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been
Intellectual disability v2.489 GSS Louise Daugherty Gene: gss has been classified as Amber List (Moderate Evidence).
Intellectual disability v2.488 FGFR2 Louise Daugherty Classified gene: FGFR2 as Amber List (moderate evidence)
Intellectual disability v2.488 FGFR2 Louise Daugherty Added comment: Comment on list classification: Changed rating of gene from Red to Amber. This gene was rated as Amber in v2.467 and incorrectly automatically demoted to Red in v2.468. This was due to a defect in the automatic PanelApp uploading tool where a reference gene list was added as a new Source (Victorian Clinical Genetics Services), and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Intellectual disability v2.488 FGFR2 Louise Daugherty Gene: fgfr2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v2.487 FBN1 Louise Daugherty Classified gene: FBN1 as Amber List (moderate evidence)
Intellectual disability v2.487 FBN1 Louise Daugherty Added comment: Comment on list classification: Changed rating of gene from Red to Amber. This gene was rated as Amber in v2.467 and incorrectly automatically demoted to Red in v2.468. This was due to a defect in the automatic PanelApp uploading tool where a reference gene list was added as a new Source (Victorian Clinical Genetics Services), and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Intellectual disability v2.487 FBN1 Louise Daugherty Gene: fbn1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v2.486 C2CD3 Louise Daugherty Classified gene: C2CD3 as Amber List (moderate evidence)
Intellectual disability v2.486 C2CD3 Louise Daugherty Added comment: Comment on list classification: Changed rating of gene from Red to Amber. This gene was rated as Amber in v2.467 and incorrectly automatically demoted to Red in v2.468. This was due to a defect in the automatic PanelApp uploading tool where a reference gene list was added as a new Source (Victorian Clinical Genetics Services), and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Intellectual disability v2.486 C2CD3 Louise Daugherty Gene: c2cd3 has been classified as Amber List (Moderate Evidence).
Intellectual disability v2.486 CRBN Louise Daugherty Classified gene: CRBN as Amber List (moderate evidence)
Intellectual disability v2.486 CRBN Louise Daugherty Added comment: Comment on list classification: Changed rating of gene from Red to Amber. This gene was rated as Amber in v2.467 and incorrectly automatically demoted to Red in v2.468. This was due to a defect in the automatic PanelApp uploading tool where a reference gene list was added as a new Source (Victorian Clinical Genetics Services), and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Intellectual disability v2.486 CRBN Louise Daugherty Gene: crbn has been classified as Amber List (Moderate Evidence).
Intellectual disability v2.485 STAG1 Louise Daugherty Classified gene: STAG1 as Green List (high evidence)
Intellectual disability v2.485 STAG1 Louise Daugherty Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.467 and incorrectly automatically demoted to Red in v2.468. This was due to a defect in the automatic PanelApp uploading tool where a reference gene list was added as a new Source (Victorian Clinical Genetics Services), and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Intellectual disability v2.485 STAG1 Louise Daugherty Gene: stag1 has been classified as Green List (High Evidence).
Intellectual disability v2.485 ZBTB18 Louise Daugherty Classified gene: ZBTB18 as Green List (high evidence)
Intellectual disability v2.485 ZBTB18 Louise Daugherty Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.467 and incorrectly automatically demoted to Red in v2.468. This was due to a defect in the automatic PanelApp uploading tool where a reference gene list was added as a new Source (Victorian Clinical Genetics Services), and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Intellectual disability v2.485 ZBTB18 Louise Daugherty Gene: zbtb18 has been classified as Green List (High Evidence).
Intellectual disability v2.484 ZBTB18 Louise Daugherty Classified gene: ZBTB18 as Green List (high evidence)
Intellectual disability v2.484 ZBTB18 Louise Daugherty Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.467 and incorrectly automatically demoted to Red in v2.468. This was due to a defect in the automatic PanelApp uploading tool where a reference gene list was added as a new Source (Victorian Clinical Genetics Services), and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Intellectual disability v2.484 ZBTB18 Louise Daugherty Gene: zbtb18 has been classified as Green List (High Evidence).
Intellectual disability v2.484 WDR81 Louise Daugherty Classified gene: WDR81 as Green List (high evidence)
Intellectual disability v2.484 WDR81 Louise Daugherty Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.467 and incorrectly automatically demoted to Red in v2.468. This was due to a defect in the automatic PanelApp uploading tool where a reference gene list was added as a new Source (Victorian Clinical Genetics Services), and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Intellectual disability v2.484 WDR81 Louise Daugherty Gene: wdr81 has been classified as Green List (High Evidence).
Intellectual disability v2.483 STAG1 Louise Daugherty Classified gene: STAG1 as Green List (high evidence)
Intellectual disability v2.483 STAG1 Louise Daugherty Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.467 and incorrectly automatically demoted to Red in v2.468. This was due to a defect in the automatic PanelApp uploading tool where a reference gene list was added as a new Source (Victorian Clinical Genetics Services), and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Intellectual disability v2.483 STAG1 Louise Daugherty Gene: stag1 has been classified as Green List (High Evidence).
Intellectual disability v2.483 KCNJ6 Louise Daugherty Classified gene: KCNJ6 as Green List (high evidence)
Intellectual disability v2.483 KCNJ6 Louise Daugherty Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.467 and incorrectly automatically demoted to Red in v2.468. This was due to a defect in the automatic PanelApp uploading tool where a reference gene list was added as a new Source (Victorian Clinical Genetics Services), and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Intellectual disability v2.483 KCNJ6 Louise Daugherty Gene: kcnj6 has been classified as Green List (High Evidence).
Intellectual disability v2.482 ITPR1 Louise Daugherty Classified gene: ITPR1 as Green List (high evidence)
Intellectual disability v2.482 ITPR1 Louise Daugherty Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.467 and incorrectly automatically demoted to Red in v2.468. This was due to a defect in the automatic PanelApp uploading tool where a reference gene list was added as a new Source (Victorian Clinical Genetics Services), and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Intellectual disability v2.482 ITPR1 Louise Daugherty Gene: itpr1 has been classified as Green List (High Evidence).
Intellectual disability v2.482 DHX30 Louise Daugherty Classified gene: DHX30 as Green List (high evidence)
Intellectual disability v2.482 DHX30 Louise Daugherty Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.467 and incorrectly automatically demoted to Red in v2.468. This was due to a defect in the automatic PanelApp uploading tool where a reference gene list was added as a new Source (Victorian Clinical Genetics Services), and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Intellectual disability v2.482 DHX30 Louise Daugherty Gene: dhx30 has been classified as Green List (High Evidence).
Intellectual disability v2.481 DHX30 Louise Daugherty Classified gene: DHX30 as Green List (high evidence)
Intellectual disability v2.481 DHX30 Louise Daugherty Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.467 and incorrectly automatically demoted to Red in v2.468. This was due to a defect in the automatic PanelApp uploading tool where a reference gene list was added as a new Source (Victorian Clinical Genetics Services), and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Intellectual disability v2.481 DHX30 Louise Daugherty Gene: dhx30 has been classified as Green List (High Evidence).
Intellectual disability v2.481 D2HGDH Louise Daugherty Classified gene: D2HGDH as Green List (high evidence)
Intellectual disability v2.481 D2HGDH Louise Daugherty Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.467 and incorrectly automatically demoted to Red in v2.468. This was due to a defect in the automatic PanelApp uploading tool where a reference gene list was added as a new Source (Victorian Clinical Genetics Services), and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Intellectual disability v2.481 D2HGDH Louise Daugherty Gene: d2hgdh has been classified as Green List (High Evidence).
Intellectual disability v2.480 CIC Louise Daugherty Classified gene: CIC as Green List (high evidence)
Intellectual disability v2.480 CIC Louise Daugherty Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.467 and incorrectly automatically demoted to Red in v2.468. This was due to a defect in the automatic PanelApp uploading tool where a reference gene list was added as a new Source (Victorian Clinical Genetics Services), and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Intellectual disability v2.480 CIC Louise Daugherty Gene: cic has been classified as Green List (High Evidence).
Intellectual disability v2.480 CACNA1C Louise Daugherty Classified gene: CACNA1C as Green List (high evidence)
Intellectual disability v2.480 CACNA1C Louise Daugherty Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.467 and incorrectly automatically demoted to Red in v2.468. This was due to a defect in the automatic PanelApp uploading tool where a reference gene list was added as a new Source (Victorian Clinical Genetics Services), and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Intellectual disability v2.480 CACNA1C Louise Daugherty Gene: cacna1c has been classified as Green List (High Evidence).
Intellectual disability v2.479 BCS1L Louise Daugherty Classified gene: BCS1L as Green List (high evidence)
Intellectual disability v2.479 BCS1L Louise Daugherty Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.467 and incorrectly automatically demoted to Red in v2.468. This was due to a defect in the automatic PanelApp uploading tool where a reference gene list was added as a new Source (Victorian Clinical Genetics Services), and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Intellectual disability v2.479 BCS1L Louise Daugherty Gene: bcs1l has been classified as Green List (High Evidence).
Intellectual disability v2.479