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Intellectual disability v3.1154 EPHA7 Konstantinos Varvagiannis gene: EPHA7 was added
gene: EPHA7 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: EPHA7 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: EPHA7 were set to 34176129; 19664229
Phenotypes for gene: EPHA7 were set to Global developmental delay; Intellectual disability; Delayed speech and language development; Behavioral abnormality
Penetrance for gene: EPHA7 were set to Incomplete
Review for gene: EPHA7 was set to AMBER
Added comment: Lévy et al (2021 - PMID: 34176129) provide evidence that haploinssuficiency of EPHA7 results in a neurodevelopmental disorder.

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

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

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

The 6q microdeletion included additional ID-related genes in at least one case (eg. ZNF292 in P12) while one subject (P4) harbored also a 7q11.23 Williams syndrome deletion.

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

Sequencing of an ID gene panel was performed for 5 subjects (P1-4 (sibs) and P9) and exome for 4 ones (P1,2,10,11). CNVs in all these subjects were not limited to EPHA7. These investigations did not reveal other variants responsible for the phenotype of these subjects.

EPHA7 encodes ephrin receptor A7. As the authors comment, ephrin receptors are the largest family of transmembrane receptor tyrosine kinases. These receptors interact with membrane bound ephrins and binding activates the tyrosine kinase activity of the receptor.

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

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

Finally the authors comment on a previous report of a de novo 2.16 Mb microdeletion spanning EPHA7 and another gene (TSG1). This deletion, reported by Traylor et al (2009 - PMID: 19664229) was identified in a 15-month old male with DD, microcephaly and dysmorphic features.

Overall Lévy et al promote incomplete penetrance and variable expressivity with haploinsufficiency of this gene being a risk factor for NDD. [The gene has also an %HI of 2.76% and a pLI of 1].

In DECIPHER there are 2 indivuals (DDD participants) with de novo missense variants and abnormality of the nervous system.

As a result this gene can be considered for inclusion in the ID panel with amber rating pending further evidence.
Sources: Literature
Intellectual disability v3.1154 ARHGEF9 Arina Puzriakova edited their review of gene: ARHGEF9: Changed mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Intellectual disability v3.1154 ARHGEF9 Arina Puzriakova edited their review of gene: ARHGEF9: Changed publications to: 17893116, 18615734, 28589176, 27238888, 30048823, 33600053, 32939676
Intellectual disability v3.1154 ARHGEF9 Arina Puzriakova Added comment: Comment on mode of inheritance: Currently, the MOI in OMIM is set to XLR. Heterozygous mothers of affected males have been reported as unaffected, which combined with the fact that the first few affected females presented a skewed XCI pattern (PMIDs: 17893116; 18615734; 28589176), led to consider this defect as an XLR disorder affecting females when XCI is skewed.

However, review of the literature revealed that the chromosomal aberrations identified in these all of cases occurred de novo with one allele remaining as normal and cases with random XCI have since been reported (PMID: 27238888; 30048823). More recently, at least 4 unrelated affected females have also been identified with heterozygous SNVs and a random XCI pattern (PMIDs: 33600053; 32939676).

Overall this indicates that monoallelic variants in ARHGEF9 can cause disease in females and so the MOI should be changed from XLR to XLD (tagged)
Intellectual disability v3.1153 ARHGEF9 Arina Puzriakova Phenotypes for gene: ARHGEF9 were changed from Epileptic encephalopathy, early infantile, 8, 300607; EPILEPTIC ENCEPHALOPATHY, EARLY INFANTILE, 8 to Developmental and epileptic encephalopathy 8, OMIM:300607
Intellectual disability v3.1150 FBXO31 Ivone Leong commented on gene: FBXO31: There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Intellectual disability v3.1149 UFSP2 Sarah Leigh changed review comment from: The founder variant rs142500730 appears to the be causal for pediatric neurodevelopmental anomalies and epilepsy feautres in over seven Asian families form different locations.; to: The Q2_21_expert_review tag has been added to consider the evidence for the founder variant rs142500730, which appears to the be causal for pediatric neurodevelopmental anomalies and epilepsy feautres in over seven Asian families form different locations.
Intellectual disability v3.1149 CUX2 Tracy Lester reviewed gene: CUX2: Rating: GREEN; Mode of pathogenicity: Other; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Intellectual disability v3.1149 JMJD1C Arina Puzriakova changed review comment from: Comment on list classification: Following discussion with Helen Brittain (Genomics England Clinical Team) it was agreed that there is currently not enough evidence to support this gene-disease association. Rating Amber until further evidence emerges.; to: Comment on list classification: Following discussion with Helen Brittain (Genomics England Clinical Team) it was agreed that there is currently not enough evidence to support this gene-disease association. Rating Amber until further evidence emerges (added watchlist tag).
Intellectual disability v3.1149 JMJD1C Arina Puzriakova Added comment: Comment on list classification: Following discussion with Helen Brittain (Genomics England Clinical Team) it was agreed that there is currently not enough evidence to support this gene-disease association. Rating Amber until further evidence emerges.
Intellectual disability v3.1146 JMJD1C Arina Puzriakova reviewed gene: JMJD1C: Rating: AMBER; Mode of pathogenicity: None; Publications: 26181491, 31954878, 32996679, 28378413, 22495311, 25363768, 17290275, 33591602; Phenotypes: Intellectual disability, Autism; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.1145 KDM3B Ivone Leong commented on gene: KDM3B: After consulting with the Genomics England Clinical Team it was decided that this gene should be promoted to Green status at the next review.
Intellectual disability v3.1145 GEMIN5 Arina Puzriakova edited their review of gene: GEMIN5: Changed rating: GREEN
Intellectual disability v3.1145 GEMIN5 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). There is sufficient evidence to promote this gene to Green at the next GMS panel update (see details below).
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Kour et al. 2021 (PMID: 33963192) report 30 individuals from 22 unrelated families with biallelic variants in the GEMIN5 gene. All affected individuals displayed predominantly motor DD, although cognitive and speech delays were also seen in most patients (18/19). 23/30 had central hypotonia, and variable appendicular spasticity was observed in 13/30 cases. 8 individuals were nonambulatory, while all ambulatory patients (19) had a gait ataxia. Brain MRI in all cases showed cerebellar atrophy.

Variants perturbed the subcellular distribution, stability, and expression of GEMIN5 protein and its interacting partners, and disrupted snRNP complex assembly formation in patient iPSC-derived neurons, suggesting a LoF mechanism. Knockdown in Drosophila lead to developmental defects, motor dysfunction, and a reduced lifespan

GEMIN5 is associated with a relevant phenotype in OMIM (Neurodevelopmental disorder with cerebellar atrophy and motor dysfunction, MIM# 619333) but is not yet listed in G2P.
Intellectual disability v3.1144 GEMIN5 Arina Puzriakova Phenotypes for gene: GEMIN5 were changed from Neurodevelopmental disorder with cerebellar atrophy and motor dysfunction, MIM# 619333 to Neurodevelopmental disorder with cerebellar atrophy and motor dysfunction, OMIM:619333
Intellectual disability v3.1143 BCAS3 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). There is sufficient evidence to promote this gene to Green at the next GMS panel update (see details below).
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Hengel et al. 2021 (PMID: 34022130) report 8 unrelated families, all with different biallelic variants in the BCAS3 gene. All affected individuals (15 total, +1 additional proband but with unphased variants but consistent phenotype) had severe GDD and ID, with 10 subjects having minimal vocabulary and 4 never learning to speak. All probands had a severe motor disorder with pyramidal tract involvement resulting in hyperreflexia and spasticity of the lower limbs (15/15). Other variable features observed in the cohort include microcephaly, short stature, seizures, and dysmorphic facial features.
Intellectual disability v3.1142 CPE Arina Puzriakova changed review comment from: Comment on list classification: New gene added by Zornitza Stark. Two consanguineous families in literature with different homozygous variants in the CPE gene. Affected individuals presented with obesity, intellectual disability and hypogonadotropic hypogonadism. Rating Amber, awaiting further cases (added watchlist tag); to: Comment on list classification: New gene added by Zornitza Stark. Two consanguineous families in literature to date with different homozygous variants in the CPE gene (PMIDs: 26120850; 32936766). Affected individuals presented with obesity, intellectual disability and hypogonadotropic hypogonadism. Rating Amber, awaiting further cases (added watchlist tag)
Intellectual disability v3.1142 CPE Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. Two consanguineous families in literature with different homozygous variants in the CPE gene. Affected individuals presented with obesity, intellectual disability and hypogonadotropic hypogonadism. Rating Amber, awaiting further cases (added watchlist tag)
Intellectual disability v3.1140 PIGB Arina Puzriakova Phenotypes for gene: PIGB were changed from Epileptic encephalopathy, early infantile, 80, 618580; Generalized hypotonia; Global developmental delay; Intellectual disability; Seizures; Hearing abnormality; Abnormality of vision; Elevated alkaline phosphatase; Abnormality of the head; Abnormality of the hand; Abnormality of the foot to Developmental and epileptic encephalopathy 80, OMIM:618580
Intellectual disability v3.1137 SCN8A Arina Puzriakova Phenotypes for gene: SCN8A were changed from ?Cognitive impairment with or without cerebellar ataxia,614306; Epileptic encephalopathy, early infantile,614558; Seizures, benign familial infantile,617080 to Cognitive impairment with or without cerebellar ataxia, OMIM:614306; Developmental and epileptic encephalopathy 13, OMIM:614558
Intellectual disability v3.1136 RUBCN Arina Puzriakova edited their review of gene: RUBCN: Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1136 RUBCN Arina Puzriakova reviewed gene: RUBCN: Rating: ; Mode of pathogenicity: None; Publications: 32450808; Phenotypes: Spinocerebellar ataxia, autosomal recessive 15, OMIM:615705; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.1135 RUBCN Arina Puzriakova Phenotypes for gene: RUBCN were changed from SYNDROMIC MR WITH ATAXIA, DYSARTHRIA AND EPILEPSY to Spinocerebellar ataxia, autosomal recessive 15, OMIM:615705
Intellectual disability v3.1133 POLR3B Arina Puzriakova Added comment: Comment on mode of inheritance: Both biallelic and monoallelic variants have been linked to ID. There is enough evidence for a Green rating for both allelic requirements, so POLR3B has been tagged Q2_21_MOI to change the MOI from biallelic to both biallelic/monoallelic at the next GMS review.
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Biallelic variants in POLR3B are a well-established cause of hypomyelinating leukodystrophy (OMIM:614381), associated with variable ID.

Recently, heterozygous variants were also linked to ID. Djordjevic et al. 2021 (PMID:33417887) identified different de novo POLR3B variants in 6 unrelated individuals. The majority had some degree of DD, with 5/6 participants being diagnosed with intellectual disability ranging from mild to moderate severity. Four individuals required assistance with basic activities of daily living, however none had developmental regression. Protein modelling and proteomic analysis shows variants caused aberrant association of individual enzyme subunits rather than affecting overall enzyme assembly or stability.
Intellectual disability v3.1132 POLR3B Arina Puzriakova Phenotypes for gene: POLR3B were changed from Leukodystrophy, hypomyelinating, 8, with or without oligodontia and/or hypogonadotropic hypogonadism, OMIM:614381 to Leukodystrophy, hypomyelinating, 8, with or without oligodontia and/or hypogonadotropic hypogonadism, OMIM:614381; POLR3B-related neurodevelopmental disorder; Ataxia, spasticity, and demyelinating neuropathy
Intellectual disability v3.1131 POLR3B Arina Puzriakova Phenotypes for gene: POLR3B were changed from Leukodystrophy, hypomyelinating, 8, with or without oligodontia and/or hypogonadotropichypogonadism, 614381; LEUKODYSTROPHY, HYPOMYELINATING, 8, WITH OR WITHOUT OLIGODONTIA AND/OR HYPOGONADOTROPIC HYPOGONADISM to Leukodystrophy, hypomyelinating, 8, with or without oligodontia and/or hypogonadotropic hypogonadism, OMIM:614381
Intellectual disability v3.1130 RORB Arina Puzriakova Phenotypes for gene: RORB were changed from generalized epilepsies with predominant absence seizures, intellectual disability to {Epilepsy, idiopathic generalized, susceptibility to, 15}, OMIM:618357
Intellectual disability v3.1129 PHACTR1 Arina Puzriakova Phenotypes for gene: PHACTR1 were changed from Global developmental delay; Intellectual disability; Seizures:Epileptic encephalopathy, early infantile, 70 618298; PHACTR1-associated neurodevelopment disorder to Developmental and epileptic encephalopathy 70, OMIM:618298
Intellectual disability v3.1127 CUX2 Arina Puzriakova Phenotypes for gene: CUX2 were changed from Epileptic encephalopathy, early infantile, 67, 618141; Seizures; Intellectual disability; Autistic behavior to Developmental and epileptic encephalopathy 67, OMIM:618141; Seizures; Intellectual disability; Autistic behaviour
Intellectual disability v3.1126 CTC1 Zornitza Stark reviewed gene: CTC1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Cerebroretinal microangiopathy with calcifications and cysts, MIM# 612199; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1125 PGM2L1 Zornitza Stark gene: PGM2L1 was added
gene: PGM2L1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: PGM2L1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PGM2L1 were set to 33979636
Phenotypes for gene: PGM2L1 were set to Neurodevelopmental disorder
Review for gene: PGM2L1 was set to GREEN
Added comment: PMID: 33979636:
- Bi-allelic PTVs in 4 unrelated individuals. All four affected individuals had severe developmental and speech delay, dysmorphic facial features, ear anomalies, high arched palate, strabismus, hypotonia, and keratosis pilaris. Early obesity and seizures were present in three individuals.
- Studies on patient fibroblasts and cell lines indicated that PGM2L1 deficiency causes a decrease, but not a disappearance, of the sugar bisphosphates needed for the formation of NDP-sugars and that there is no evidence that this leads to a glycosylation defect.
Sources: Literature
Intellectual disability v3.1125 ATXN2L Zornitza Stark gene: ATXN2L was added
gene: ATXN2L was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: ATXN2L was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ATXN2L were set to 33283965; 33057194
Phenotypes for gene: ATXN2L were set to Intellectual disability; Macrocephaly
Review for gene: ATXN2L was set to AMBER
Added comment: Combined data from three large exome groups identified several de novo variants, including frameshift and missense, in ATXN2L in patients with developmental delay (Kaplanis et al., 2020). pLI=1.0 Limited other data available.
Single case report of a novel de novo missense variant in a child with macrocephaly and developmental delay. No functional work.
Sources: Literature
Intellectual disability v3.1125 SIN3B Arina Puzriakova Added comment: Comment on list classification: New gene added and reviewed by Zornitza Stark (Green) and Konstantinos Varvagiannis (Green/Amber). Overall there are sufficient unrelated cases (>3) of ID associated with SNVs in this gene to warrant a Green rating on this panel at the next GMS review. Deletions of the region containing SIN3B have also been linked to ID, lending further support to this gene-disease association.
Intellectual disability v3.1124 EMC10 Arina Puzriakova Added comment: Comment on list classification: There is now enough evidence to warrant a Green rating at the next GMS panel update.
Intellectual disability v3.1123 EMC10 Arina Puzriakova edited their review of gene: EMC10: Added comment: There are now at least 15 individuals from 8 families reported with biallelic variants in the EMC10 gene associated with disease. One variant found in a single population is likely to be a founder variant; however, the identification of a different variant in a family presenting with a similar phenotype corroborates causality. Both variants were shown to significantly reduce EMC10 RNA expression. All affected individuals show a core phenotype of GDD/ID with variable severity. Seizures were noted in 7/15 individuals, typically during childhood or in the neonatal period, and included multifocal as well as generalized tonic–clonic seizures.; Changed rating: GREEN; Changed publications to: 32869858, 33531666; Changed phenotypes to: Neurodevelopmental disorder with dysmorphic facies and variable seizures, OMIM:619264; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1123 BCAS3 Zornitza Stark gene: BCAS3 was added
gene: BCAS3 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: BCAS3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BCAS3 were set to 34022130
Phenotypes for gene: BCAS3 were set to Syndromic neurodevelopmental disorder
Review for gene: BCAS3 was set to GREEN
Added comment: 15 individuals from eight unrelated families with germline bi-allelic loss-of-function variants in BCAS3. All probands share a global developmental delay accompanied by pyramidal tract involvement, microcephaly, short stature, strabismus, dysmorphic facial features, and seizures. Patient fibroblasts confirmed absence of BCAS3 protein.
Sources: Literature
Intellectual disability v3.1123 SRCAP Zornitza Stark reviewed gene: SRCAP: Rating: GREEN; Mode of pathogenicity: None; Publications: 33909990; Phenotypes: Neurodevelopmental disorder, non-Floating Harbor; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.1122 EMC10 Arina Puzriakova Added comment: Comment on phenotypes: EMC10 is now associated with a relevant phenotype in OMIM - 'Neurodevelopmental disorder with dysmorphic facies and variable seizures, OMIM:619264' and is listed in G2P with a 'probable' disease confidence rating for 'EMC10-related neurodevelopmental disorder'
Intellectual disability v3.1122 EMC10 Arina Puzriakova Phenotypes for gene: EMC10 were changed from Neurodevelopmental disorder with dysmorphic facies and variable seizures, OMIM:619264 to Neurodevelopmental disorder with dysmorphic facies and variable seizures, OMIM:619264
Intellectual disability v3.1121 EMC10 Arina Puzriakova Phenotypes for gene: EMC10 were changed from Intellectual disability to Neurodevelopmental disorder with dysmorphic facies and variable seizures, OMIM:619264
Intellectual disability v3.1120 GEMIN5 Zornitza Stark gene: GEMIN5 was added
gene: GEMIN5 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: GEMIN5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GEMIN5 were set to 33963192
Phenotypes for gene: GEMIN5 were set to Neurodevelopmental disorder with cerebellar atrophy and motor dysfunction, MIM# 619333
Review for gene: GEMIN5 was set to GREEN
gene: GEMIN5 was marked as current diagnostic
Added comment: Neurodevelopmental disorder with cerebellar atrophy and motor dysfunction (NEDCAM) is an autosomal recessive disorder characterized by global developmental delay with prominent motor abnormalities, mainly axial hypotonia, gait ataxia, and appendicular spasticity. Affected individuals have cognitive impairment and speech delay; brain imaging shows cerebellar atrophy.

30 individuals from 22 unrelated families reported.
Sources: Literature
Intellectual disability v3.1120 PARP6 Zornitza Stark gene: PARP6 was added
gene: PARP6 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: PARP6 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PARP6 were set to 34067418
Phenotypes for gene: PARP6 were set to Intellectual disability; Epilepsy; Microcephaly
Review for gene: PARP6 was set to GREEN
Added comment: Four unrelated individuals reported with de novo variants in this gene and a neurodevelopmental phenotype. Supportive functional data. One pair of siblings with a homozygous missense: limited evidence for bi-allelic variants causing disease.
Sources: Literature
Intellectual disability v3.1120 MYCN Zornitza Stark reviewed gene: MYCN: Rating: GREEN; Mode of pathogenicity: None; Publications: 21224895, 8470948; Phenotypes: Feingold syndrome 1, Megalencephaly, intellectual disability; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.1120 SMARCA5 Zornitza Stark reviewed gene: SMARCA5: Rating: GREEN; Mode of pathogenicity: None; Publications: 33980485; Phenotypes: Neurodevelopmental disorder, microcephaly, dysmorphic features; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.1120 CAPN15 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. Sufficient number of cases presenting with DD/ID (5/7 individuals from 3 unrelated families - PMIDs: 33410501; 32885237) to warrant a Green rating on this panel.
Intellectual disability v3.1118 ANKRD17 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. There is sufficient evidence to rate this gene Green at the next GMS panel update.

Chopra et al. 2021 (PMID: 33909992) report 34 individuals from 32 families with a heterozygous variant or microdeletion of ANKRD17. GDD/ID was the most common feature, affecting 31/33 individuals with variable severity - 7 severe, 12 moderate, 5 mild, 7 borderline. Deletions of the region containing ANKRD17 have also been associated with ID.
Intellectual disability v3.1117 SMARCA5 Arina Puzriakova Added comment: Comment on list classification: New gene added and reviewed Green by Julia Baptista (RD&E NHS FT). SMARCA5 should be promoted to Green at the next GMS panel update.

Variants have been associated with a variable neurodevelopmental phenotype including predominantly mild DD, short stature, and microcephaly (PMID:33980485). Regarding cognition, four probands had mild ID and one had severe ID. Although relatively mild in most patients, the number of unrelated families presenting ID is sufficient for a Green rating and inclusion on this panel should increase the likelihood of detecting cases.
Intellectual disability v3.1116 LRRC32 Arina Puzriakova Phenotypes for gene: LRRC32 were changed from Intellectual disability; cleft palate; proliferative retinopathy to Cleft palate, proliferative retinopathy, and developmental delay, OMIM:619074
Intellectual disability v3.1111 LAMB1 Arina Puzriakova Phenotypes for gene: LAMB1 were changed from COBBLESTONE BRAIN MALFORMATION WITHOUT MUSCULAR OR OCULAR ABNORMALITIES to Lissencephaly 5, OMIM:615191
Intellectual disability v3.1110 PDCD6IP Arina Puzriakova changed review comment from: Comment on list classification: Phenotype is relevant to this panel but additional cases required to validate pathogenicity of variants in this gene. Therefore Rating Amber, awaiting further publications.; to: Comment on list classification: Phenotype is relevant to this panel with a supportive animal model that recapitulates features such as microcephaly. However, additional cases required to validate pathogenicity prior to inclusion as diagnostic-grade. Therefore Rating Amber, awaiting further publications.
Intellectual disability v3.1110 PDCD6IP Arina Puzriakova changed review comment from: Comment on list classification: Phenotype is relevant to this panel but additional cases required to validate pathogenicity of variants in this gene.; to: Comment on list classification: Phenotype is relevant to this panel but additional cases required to validate pathogenicity of variants in this gene. Therefore Rating Amber, awaiting further publications.
Intellectual disability v3.1103 DPH1 Arina Puzriakova Phenotypes for gene: DPH1 were changed from Developmental delay with short stature, dysmorphic features, and sparse hair, 616901 to Developmental delay with short stature, dysmorphic facial features, and sparse hair, OMIM:616901
Intellectual disability v3.1101 SLC6A1 Arina Puzriakova Phenotypes for gene: SLC6A1 were changed from EPILEPSY WITH MYOCLONIC-ATONIC SEIZURES to Myoclonic-atonic epilepsy, OMIM:616421
Intellectual disability v3.1100 SMARCA5 Julia Baptista gene: SMARCA5 was added
gene: SMARCA5 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: SMARCA5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SMARCA5 were set to 33980485
Phenotypes for gene: SMARCA5 were set to intellectual disability; postnatal microcephaly; hypotonia; failure to thrive
Penetrance for gene: SMARCA5 were set to unknown
Review for gene: SMARCA5 was set to GREEN
Added comment: The authors identified seven missense variants, one splice-altering variant that led to exon skipping and in-frame deletion, and one recurrent in-frame deletion in 12 individuals from
10 unrelated families. The variant was de novo in nine individuals. They presented a broad range of clinical features from isolated autism to syndromic intellectual disability.
Sources: Literature
Intellectual disability v3.1100 UFSP2 Sarah Leigh changed review comment from: Comment on list classification: A founder variant (rs142500730) reported in four South Asian families (haplotype analysis available for two of the families proves relatedness). Functional studies suggest that although mRNA expression seems to be unaffected, protein stability maybe responsible for the reduced protein detected by immunoblotting in patients fibroblasts (PMID 33473208).
Homozygous rs142500730 has also been reported in individuals (2 Asian and 1 white) in the Genoimcs England 100K study, with epilepsy and intellectual disabilities.; to: Comment on list classification: A founder variant (rs142500730) reported in four South Asian families (haplotype analysis available for two of the families proves relatedness). Functional studies suggest that although mRNA expression seems to be unaffected, protein stability maybe responsible for the reduced protein detected by immunoblotting in patients fibroblasts (PMID 33473208).
Homozygous rs142500730 has also been reported in individuals (Asian and white) in the Genoimcs England 100K study, with epilepsy and intellectual disabilities.
Intellectual disability v3.1099 RAB11B Arina Puzriakova Phenotypes for gene: RAB11B were changed from Neurodevelopmental disorder with ataxic gait, absent speech, and decreased cortical white matter, 617807; Intellectual disability to Neurodevelopmental disorder with ataxic gait, absent speech, and decreased cortical white matter, OMIM:617807
Intellectual disability v3.1097 SCYL1 Sarah Leigh reviewed gene: SCYL1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.1096 SCYL1 Sarah Leigh Phenotypes for gene: SCYL1 were changed from Spinocerebellar ataxia, autosomal recessive 21, 616719 to Spinocerebellar ataxia, autosomal recessive 21 OMIM:616719; acute infantile liver failure-cerebellar ataxia-peripheral sensory motor neuropathy syndrome MONDO:0014744
Intellectual disability v3.1094 UFSP2 Sarah Leigh changed review comment from: Comment on list classification: A founder variant (rs142500730) reported in four South Asian families (haplotype analysis available for two of the families proves relatedness). Functional studies suggest that although mRNA expression seems to be unaffected, protein stability maybe responsible for the reduced protein detected by immunoblotting in patients fibroblasts (PMID 33473208).
rs142500730 has also been reported in individuals in the Genoimcs England 100K study, with epilepsy and intellectual disabilities.; to: Comment on list classification: A founder variant (rs142500730) reported in four South Asian families (haplotype analysis available for two of the families proves relatedness). Functional studies suggest that although mRNA expression seems to be unaffected, protein stability maybe responsible for the reduced protein detected by immunoblotting in patients fibroblasts (PMID 33473208).
Homozygous rs142500730 has also been reported in individuals (2 Asian and 1 white) in the Genoimcs England 100K study, with epilepsy and intellectual disabilities.
Intellectual disability v3.1094 UFSP2 Sarah Leigh edited their review of gene: UFSP2: Added comment: The founder variant rs142500730 appears to the be causal for pediatric neurodevelopmental anomalies and epilepsy feautres in over seven Asian families form different locations.; Changed rating: GREEN
Intellectual disability v3.1094 UFSP2 Konstantinos Varvagiannis changed review comment from: Ni et al (2021 - PMID: 33473208) describe the phenotype of 8 children (belonging to 4 families - 2 of which consanguineous) homozygous for a UFSP2 missense variant [NM_018359.5:c.344T>A; p.(Val115Glu)].

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

You may consider inclusion in the current panel with amber/green rating.
Sources: Literature
Intellectual disability v3.1094 UFSP2 Sarah Leigh changed review comment from: Comment on list classification: A founder variant (rs142500730) reported in four South Asian families (haplotype analysis available for two of the families proves relatedness). Functional studies suggest that although expression seems to be unaffected, immunoblotting indicates that protein stability maybe affected (PMID 33473208).
rs142500730 has also been reported in individuals in the Genoimcs England 100K study, with epilepsy and intellectual disabilities.; to: Comment on list classification: A founder variant (rs142500730) reported in four South Asian families (haplotype analysis available for two of the families proves relatedness). Functional studies suggest that although mRNA expression seems to be unaffected, protein stability maybe responsible for the reduced protein detected by immunoblotting in patients fibroblasts (PMID 33473208).
rs142500730 has also been reported in individuals in the Genoimcs England 100K study, with epilepsy and intellectual disabilities.
Intellectual disability v3.1094 UFSP2 Sarah Leigh Added comment: Comment on list classification: A founder variant (rs142500730) reported in four South Asian families (haplotype analysis available for two of the families proves relatedness). Functional studies suggest that although expression seems to be unaffected, immunoblotting indicates that protein stability maybe affected (PMID 33473208).
rs142500730 has also been reported in individuals in the Genoimcs England 100K study, with epilepsy and intellectual disabilities.
Intellectual disability v3.1093 UFSP2 Sarah Leigh Added comment: Comment on phenotypes: No OMIM reference for the pediatric neurodevelopmental anomalies and epilepsy feautres. Monoallelic variants have previously been associated with skeletal dysplasias (PMIDs 28892125;26428751;32755715), but there does not appear to be any phenotypic overlap between these and the phenotype seen for the biallelic rs142500730.
Intellectual disability v3.1092 UFSP2 Konstantinos Varvagiannis gene: UFSP2 was added
gene: UFSP2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: UFSP2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: UFSP2 were set to 33473208
Phenotypes for gene: UFSP2 were set to Abnormal muscle tone; Seizures; Global developmental delay; Delayed speech and language development; Intellectual disability; Strabismus
Penetrance for gene: UFSP2 were set to Complete
Added comment: Ni et al (2021 - PMID: 33473208) describe the phenotype of 8 children (belonging to 4 families - 2 of which consanguineous) homozygous for a UFSP2 missense variant [NM_018359.5:c.344T>A; p.(Val115Glu)].

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

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

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

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

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

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

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

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

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

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

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

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

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

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

You may consider inclusion in the current panel with amber/green rating.
Sources: Literature
Intellectual disability v3.1092 SIN3B Konstantinos Varvagiannis reviewed gene: SIN3B: Rating: AMBER; Mode of pathogenicity: None; Publications: 33811806; Phenotypes: Global developmental delay, Intellectual disability, Behavioral abnormality; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.1088 UNC80 Arina Puzriakova Phenotypes for gene: UNC80 were changed from Hypotonia, infantile, with psychomotor retardation and characteristic facies 2 616801 to Hypotonia, infantile, with psychomotor retardation and characteristic facies 2, OMIM:616801
Intellectual disability v3.1087 UGP2 Arina Puzriakova Phenotypes for gene: UGP2 were changed from Epileptic encephalopathy, early infantile, 83, 618744; Global developmental delay; Intellectual disability; Feeding difficulties; Abnormality of vision; Abnormality of the face to Developmental and epileptic encephalopathy 83, OMIM:618744
Intellectual disability v3.1084 AFG3L2 Sarah Leigh commented on gene: AFG3L2: Disease causing variants are both monoallelic and biallelic
Intellectual disability v3.1083 AFG3L2 Sarah Leigh reviewed gene: AFG3L2: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Spastic ataxia 5, autosomal recessive OMIM:614487, spastic ataxia 5 MONDO:0013776, Spinocerebellar ataxia 28 OMIM:610246, spinocerebellar ataxia type 28 MONDO:0012450; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.1081 TRIO Arina Puzriakova Phenotypes for gene: TRIO were changed from INTELLECTUAL DISABILITY to Intellectual developmental disorder, autosomal dominant 44, with microcephaly, OMIM:617061; Intellectual developmental disorder, autosomal dominant 63, with macrocephaly, OMIM:618825
Intellectual disability v3.1078 TRAPPC6B Arina Puzriakova Phenotypes for gene: TRAPPC6B were changed from Neurodevelopmental disorder with microcephaly, epilepsy, and brain atrophy, 617862 to Neurodevelopmental disorder with microcephaly, epilepsy, and brain atrophy, OMIM:617862
Intellectual disability v3.1075 NSF Sarah Leigh reviewed gene: NSF: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.1074 FXN_GAA Sarah Leigh Phenotypes for STR: FXN_GAA were changed from Friedreich ataxia 229300 to Friedreich ataxia OMIM:229300; Friedreich ataxia with retained reflexes OMIM:229300; Friedreich ataxia 1 MONDO:0100340
Intellectual disability v3.1073 CAD Arina Puzriakova Phenotypes for gene: CAD were changed from Epileptic encephalopathy, early infantile, 50 - MIM 616457 to Developmental and epileptic encephalopathy 50, OMIM:616457
Intellectual disability v3.1072 TMEM222 Sarah Leigh edited their review of gene: TMEM222: Added comment: Not associated with relevant phenotype in OMIM or Gen2Phen (TMEM222 not listed on OMIM 11/05/2021). At least ten variants reported in at least nine unrelated families. Moderate to severe intellectual disability was evident in all families.; Changed rating: GREEN
Intellectual disability v3.1072 TMEM222 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Intellectual disability v3.1070 FARSA Ivone Leong gene: FARSA was added
gene: FARSA was added to Intellectual disability. Sources: Literature,Expert Review Red
Mode of inheritance for gene: FARSA was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FARSA were set to 31355908
Phenotypes for gene: FARSA were set to ?Rajab interstitial lung disease with brain calcifications 2, OMIM:619013
Intellectual disability v3.1069 CAPN15 Zornitza Stark gene: CAPN15 was added
gene: CAPN15 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: CAPN15 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CAPN15 were set to 33410501; 32885237
Phenotypes for gene: CAPN15 were set to Oculogastrointestinal neurodevelopmental syndrome, MIM# 619318
Review for gene: CAPN15 was set to GREEN
gene: CAPN15 was marked as current diagnostic
Added comment: 5 families reported, including DD/ID in 3. Profound in one family with bi-allelic LoF variant, PMID 33410501.
Sources: Literature
Intellectual disability v3.1069 CHD5 Zornitza Stark gene: CHD5 was added
gene: CHD5 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: CHD5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CHD5 were set to 33944996
Phenotypes for gene: CHD5 were set to Intellectual disability; Epilepsy
Review for gene: CHD5 was set to GREEN
gene: CHD5 was marked as current diagnostic
Added comment: 16 unrelated individuals reported with language deficits (81%), behavioral symptoms (69%), intellectual disability (64%), epilepsy (62%), and motor delay (56%).
Sources: Literature
Intellectual disability v3.1069 FBXO31 Zornitza Stark edited their review of gene: FBXO31: Added comment: PMIDs 33675180; 32989326: three unrelated individuals with de novo missense variant, (p.Asp334Asn) and spastic-dystonic CP, including ID.

AR ID: Single consanguineous family reported with homozygous truncating variant, limited functional evidence.; Changed rating: GREEN; Changed publications to: 24623383, 33675180, 32989326
Intellectual disability v3.1069 PTPN4 Zornitza Stark gene: PTPN4 was added
gene: PTPN4 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: PTPN4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PTPN4 were set to 17953619; 25424712; 30238967; DOI: https://doi.org/10.1016/j.xhgg.2021.100033
Phenotypes for gene: PTPN4 were set to Intellectual disability
Review for gene: PTPN4 was set to GREEN
gene: PTPN4 was marked as current diagnostic
Added comment: >3 unrelated probands and supportive mouse model
PMID: 17953619 - knockout mouse model has impaired motor learning and cerebellar synaptic plasticity
PMID: 25424712 - twins with a de novo whole gene deletion and a Rett-like neurodevelopmental disorder
PMID: 30238967 - mosaic de novo variant (p.Leu72Ser) identified in a child with developmental delay, autistic features, hypotonia, increased immunoglobulin E and dental problems. Also supporting mouse assays demonstrating loss of protein expression in dendritic spines
DOI: https://doi.org/10.1016/j.xhgg.2021.100033 - missense and truncating variants in six unrelated individuals with varying degrees of intellectual disability or developmental delay. 5 were able to undergo segregation analysis and found to be de novo.
Sources: Literature
Intellectual disability v3.1069 SIN3B Zornitza Stark gene: SIN3B was added
gene: SIN3B was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: SIN3B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SIN3B were set to 33811806
Phenotypes for gene: SIN3B were set to Syndromic intellectual disability
Review for gene: SIN3B was set to GREEN
gene: SIN3B was marked as current diagnostic
Added comment: PMID: 33811806
- 9 affected individuals, variants all de novo (2 PTCs, 2 missense, multigenic CNVs)
- syndrome hallmarked by intellectual disability, developmental delay, and dysmorphic facial features with variably penetrant ASD, congenital malformations, corpus callosum defects, and impaired growth.
Sources: Literature
Intellectual disability v3.1069 DPYSL5 Zornitza Stark gene: DPYSL5 was added
gene: DPYSL5 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: DPYSL5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: DPYSL5 were set to 33894126
Phenotypes for gene: DPYSL5 were set to Neurodevelopmental disorder with corpus callosum agenesis and cerebellar abnormalities
Review for gene: DPYSL5 was set to GREEN
gene: DPYSL5 was marked as current diagnostic
Added comment: Nine individuals with brain malformations, including corpus callosum agenesis and/or posterior fossa abnormalities, associated with variable degrees of intellectual disability. The recurrent de novo p.Glu41Lys was found in eight unrelated patients, and a p.Gly47Arg variant was identified in one individual from the first family reported with Ritscher-Schinzel syndrome. Both impaired DPYSL5 function on dendritic outgrowth regulation by preventing the formation of the ternary complex with MAP2 and βIII-tubulin, ultimately leading to abnormal brain development.
Sources: Literature
Intellectual disability v3.1069 EMC10 Zornitza Stark edited their review of gene: EMC10: Added comment: PMID 33531666: Additional 12 individuals from 7 Middle Eastern families reported. Same variant in all, suggestive of founder effect (but different to the previously reported family).; Changed rating: GREEN; Changed publications to: 32869858, 33531666; Changed phenotypes to: Neurodevelopmental disorder with dysmorphic facies and variable seizures, MIM# 619264
Intellectual disability v3.1069 TMEM222 Konstantinos Varvagiannis gene: TMEM222 was added
gene: TMEM222 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: TMEM222 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TMEM222 were set to 33824500
Phenotypes for gene: TMEM222 were set to Motor delay; Delayed speech and language development; Intellectual disability; Generalized hypotonia; Broad-based gait; Abnormality of nervous system morphology; Seizures; Microcephaly; Behavioral abnormality
Penetrance for gene: TMEM222 were set to Complete
Review for gene: TMEM222 was set to GREEN
Added comment: Polla et al (2021 - PMID: 33824500) report 17 individuals from 9 unrelated families, with biallelic TMEM222 pathogenic variants.

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

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

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

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

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

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

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

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

In OMIM there is currently no associated phenotype.

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

Please consider inclusion in the ID panel with green (or amber) rating. This gene may also be included in other panels e.g. for epilepsy, microcephaly, etc.
Sources: Literature
Intellectual disability v3.1068 UBTF Arina Puzriakova Mode of pathogenicity for gene: UBTF was changed from to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Intellectual disability v3.1066 UBTF Arina Puzriakova Phenotypes for gene: UBTF were changed from developmental regression; motor and language regression; developmental delay; Neurodegeneration, childhood-onset, with brain atrophy, 617672 to Neurodegeneration, childhood-onset, with brain atrophy, OMIM:617672
Intellectual disability v3.1065 DYNC1I2 Arina Puzriakova Phenotypes for gene: DYNC1I2 were changed from Abnormality of nervous system morphology; Abnormality of head or neck; Microcephaly; Intellectual disability to Neurodevelopmental disorder with microcephaly and structural brain anomalies, OMIM:618492
Intellectual disability v3.1064 DNA2 Arina Puzriakova reviewed gene: DNA2: Rating: RED; Mode of pathogenicity: None; Publications: 24389050, 31045292; Phenotypes: Seckel syndrome 8, OMIM:615807; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1062 WDR4 Ivone Leong reviewed gene: WDR4: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.1062 WDR4 Ivone Leong Phenotypes for gene: WDR4 were changed from Primordial dwarfism; motor and speech delay; intellectual disability; global developmental delay. to Galloway-Mowat syndrome 6, OMIM:61834; Microcephaly, growth deficiency, seizures, and brain malformations, OMIM:618347
Intellectual disability v3.1059 OCRL Eleanor Williams reviewed gene: OCRL: Rating: ; Mode of pathogenicity: None; Publications: 33517444; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.1057 CDH11 Arina Puzriakova Added comment: Comment on mode of inheritance: Association with biallelic variants well-established, with ID reported in all cases to date. On the other hand, DD/ID is variable in individuals with monoallelic variants (PMID: 33811546) - 7/19 cases (4 families) presented a developmental phenotype including very mild speech delays in 5/7, mild-moderate DD in 1/7, and global delay in 1/7 individuals.

Overall, given the mostly mild degree of cognitive delay, as well as intra- and interfamilial reduced penetrance of this feature, there is currently not enough evidence to rate as Green on this panel for the monoallelic disease.
Intellectual disability v3.1056 HTT Eleanor Williams changed review comment from: PMID: 33432339 - Jung et al 2021 - further characterisation of the family previously reported in PMID: 27329733 (Rodan et al 2016) - using WGS they confirm they are the most likely cause of the LOMARS phenotype and clarify their locations as NM_002111.8(HTT): c.8157T>A (p.Phe2719Leu) and NM_002111.8(HTT)c.4469+1G>A (Note there are incorrect Clinvar entries). Functional studies show them each to be a hypomorphic mutation, resulting in severe deficiency of huntingtin in compound heterozygotes.; to: PMID: 33432339 - Jung et al 2021 - further characterisation of the family previously reported in PMID: 27329733 (Rodan et al 2016) - using WGS they confirm they are the most likely cause of the LOMARS phenotype and clarify their locations as NM_002111.8(HTT): c.8157T>A (p.Phe2719Leu) and NM_002111.8(HTT)c.4469+1G>A (Note there are incorrect Clinvar entries). Functional studies show them each to be a hypomorphic mutation, resulting in severe deficiency of huntingtin in compound heterozygotes.

Still only 2 cases reported to date (PMID: 27329733/33432339 and 26740508) with biallelic LOF variants in HTT associated with the LOMARS phenotype although this study add further weight with some functional data.
Intellectual disability v3.1056 HTT Eleanor Williams reviewed gene: HTT: Rating: ; Mode of pathogenicity: None; Publications: 33432339; Phenotypes: Lopes-Maciel-Rodan syndrome OMIM:617435; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1055 FAR1 Arina Puzriakova reviewed gene: FAR1: Rating: ; Mode of pathogenicity: None; Publications: 25439727, 30561787, 33239752; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.1050 INPP4A Arina Puzriakova Added comment: Comment on list classification: Upgraded from Red to Amber. 2 unrelated families with severe ID and biallelic variants in this gene reported to date (PMIDs: 25338135; 31978615)
Intellectual disability v3.1049 UBE4A Arina Puzriakova changed review comment from: Comment on list classification: New gene added by Zornitza Stark. Sufficient evidence to rate this gene Green at the next GMS panel update - 4 unrelated families with different homozygous LoF variants in UBE4A, supported by some functional data and animal model. Severe ID and GDD was a feature in all affected individuals (8 total).

UBE4A is not associated with any phenotype in OMIM (last edited on 17/09/2010) but has a 'probable' disease confidence rating for 'UBE4A-associated neurodevelopmental disorder' in Gene2Phenotype.; to: Comment on list classification: New gene added by Zornitza Stark. Sufficient evidence to rate this gene Green at the next GMS panel update - PMID:33420346 report 4 unrelated families with different homozygous LoF variants in UBE4A, supported by some functional data and animal model. Severe ID and GDD was a feature in all affected individuals (8 total).

UBE4A is not associated with any phenotype in OMIM (last edited on 17/09/2010) but has a 'probable' disease confidence rating for 'UBE4A-associated neurodevelopmental disorder' in Gene2Phenotype.
Intellectual disability v3.1049 UBE4A Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. Sufficient evidence to rate this gene Green at the next GMS panel update - 4 unrelated families with different homozygous LoF variants in UBE4A, supported by some functional data and animal model. Severe ID and GDD was a feature in all affected individuals (8 total).

UBE4A is not associated with any phenotype in OMIM (last edited on 17/09/2010) but has a 'probable' disease confidence rating for 'UBE4A-associated neurodevelopmental disorder' in Gene2Phenotype.
Intellectual disability v3.1048 NCDN Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. Sufficient evidence to rate this gene as Green with 'monoallelic' MOI at next GMS panel update.

- PMID: 33711248 (2021) - Six affected individuals (3 sibs with homozygous missense, and 3 unrelated patients with different de novo missense variants) with variable degrees of DD, ID, and seizures. Severity of ID in individuals with heterozygous variants is severe, moderate, and mild (but also learning disabilities), respectively. ID in the 3 sibs was determined as mild. Supportive functional data included.

NCDN is not yet associated with any phenotype in OMIM (last edited on 08/08/2012) but in Gene2Phenotype monoallelic disease has a 'probable' confidence rating while biallelic variants have a 'possible' disease confidence rating.
Intellectual disability v3.1047 NCDN Arina Puzriakova Added comment: Comment on mode of inheritance: Setting MOI to 'Monoallelic' as only one biallelic case reported to date, and patients with biallelic variants would still be picked up by the Genomics England pipeline.
Intellectual disability v3.1047 NCDN Arina Puzriakova Mode of inheritance for gene: NCDN was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.1045 MAPKAPK5 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. Rating Amber, awaiting further cases (added watchlist tag)

- PMID: 33442026 report on 2 unrelated families with a comparable phenotype including severe GDD, who harbour different homozygous truncating variants in MAPKAPK5. Some functional evidence indicating the variants impact expression and function of MAPKAPK5 protein.

MAPKAPK5 is not yet associated with any phenotype in OMIM (last edited on 06/04/2016) but has a 'probable' disease confidence rating for 'MAPKAPK5-associated syndrome with synpolydactyly' in Gene2Phenotype.
Intellectual disability v3.1044 COPB1 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. PMID:33632302 reports on six individuals from two unrelated families with different homozygous variants in this gene. All affected patients had severe ID. Rating Amber, awaiting further cases.
Intellectual disability v3.1041 PIGC Arina Puzriakova Added comment: Comment on list classification: There are now at least 3 unrelated families with biallelic variants in this gene, and severe DD/ID is evident in all cases (PMIDs: 27694521; 32707268) . Therefore, PIGC can be upgraded to Green status at the next GMS panel update.
Intellectual disability v3.1040 PIGC Arina Puzriakova Phenotypes for gene: PIGC were changed from Glycosylphosphatidylinositol biosynthesis defect 16, 617816 to Glycosylphosphatidylinositol biosynthesis defect 16, OMIM:617816
Intellectual disability v3.1038 PIGC Arina Puzriakova reviewed gene: PIGC: Rating: GREEN; Mode of pathogenicity: None; Publications: 32707268; Phenotypes: Glycosylphosphatidylinositol biosynthesis defect 16, OMIM:617816; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1037 JMJD1C Zornitza Stark gene: JMJD1C was added
gene: JMJD1C was added to Intellectual disability. Sources: Expert Review
Mode of inheritance for gene: JMJD1C was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: JMJD1C were set to 26181491; 32996679
Phenotypes for gene: JMJD1C were set to Intellectual disability
Review for gene: JMJD1C was set to GREEN
gene: JMJD1C was marked as current diagnostic
Added comment: Reported in ID cohort (with Rett-like phenotypic overlap) with supporting functional studies (PMID: 26181491). 7 individuals with rare variants identified, and variants demonstrated to be de novo in 2, one with a Rett-like phenotype and the other with ID. Functional study of the JMJD1C mutant Rett syndrome patient demonstrated that the altered protein had abnormal subcellular localization, diminished activity to demethylate the DNA damage-response protein MDC1, and reduced binding to MECP2. JMJD1C protein shown to be widely expressed in brain regions and that its depletion compromised dendritic activity.

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

Disruption of gene due to balanced translocation (PMID 33591602) implicated in autism spectrum disease phenotype.
Sources: Expert Review
Intellectual disability v3.1037 LAMA1 Sarah Leigh reviewed gene: LAMA1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.1037 LAMA1 Sarah Leigh Phenotypes for gene: LAMA1 were changed from CEREBELLAR DYSPLASIA WITH CYSTS WITH OR WITHOUT RETINAL DYSTROPHY to Poretti-Boltshauser syndrome OMIM:615960; ataxia - intellectual disability - oculomotor apraxia - cerebellar cysts syndrome MONDO:0014419
Intellectual disability v3.1035 NEUROD2 Arina Puzriakova Added comment: Comment on list classification: There is enough evidence to rate this gene as Green at the next GMS panel update - sufficient number of unrelated cases (4, plus 1 unpublished), all presenting GDD as an early feature. Particularly pertinent to less severely affected individuals who do not develop seizures.
Intellectual disability v3.1034 NEUROD2 Arina Puzriakova gene: NEUROD2 was added
gene: NEUROD2 was added to Intellectual disability. Sources: Literature
Q2_21_rating tags were added to gene: NEUROD2.
Mode of inheritance for gene: NEUROD2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: NEUROD2 were set to 16504944; 30323019; 33438828
Phenotypes for gene: NEUROD2 were set to Developmental and epileptic encephalopathy 72, OMIM:618374
Review for gene: NEUROD2 was set to GREEN
Added comment: NEUROD2 is associated with a relevant phenotype in OMIM (MIM# 618374), but is not yet listed in Gene2Phenotype.

- PMID: 30323019 (2019) - Two unrelated children with refractory early-infantile epileptic encephalopathy. Developmental delay (DD) preceded onset of seizures in both cases, with signs of DD becoming evident at 2-4 months and seizures arising at 5 months of age. Patient 1 became seizure-free after introducing a ketogenic diet at 16 months; however, an EEG at 22 months remained abnormal and she continues to have severe GDD with no independent sitting, walking or speaking at the chronological age of 3 years and 2 months. Patient 2 became seizure-free when a vagal nerve stimulator (VNS) was placed at 16 months of age. He displayed significant improvement on EEG and subsequently began regaining neurodevelopmental milestones.
WES revealed different de novo variants in the NEUROD2 gene (P1: c.388G>C, p.E130Q; P2: c.401T>C, p.M134T, respectively). Knockdown of the neurod2 in Xenopus tropicalis tadpoles resulted in abnormal swimming behaviour and progressive seizures followed by periods of immobility. Overexpression of wild-type human NEUROD2 in tadpoles induced non-neuronal cells to differentiate into neurons - on the other hand, overexpression of the mutant alleles failed to to cause any (p.E130Q) or a comparable degree (p.M134T) of ectopic neuronal induction as seen with the wild-type protein.

- Conference poster (Genomics of Rare Disease 2021) - 'Neuronal Differentiation Factor 2 (NEUROD2) Pathogenic Variant as a Molecular Aetiology of Infantile Spasm ' by Sakpichaisakul et al, QSNICH, Thailand -
In a 15 month-old female with infantile spasm, trio exome sequencing revealed a de novo variant in NEUROD2 (c.388G>C, p.E130Q). She was born of non-consanguineous healthy parents with no family history of epilepsy. Poor eye contact and no social smile were noted in the first few months, followed by the first infantile spasm at 5 months of age. This was initially controlled by combined vigabatrin and prednisolone therapy - however relapsing seizures were detected at 15 months. Sequential treatment with vigabatrin following prednisolone resulted in cessation of seizures, and subsequently regaining of neurodevelopmental milestones (sitting without support, grabbing objects without pincer grasp and speaking one single word)

----- Cases without seizures -

- PMID: 33438828 (2021) - Adolescent (14 yrs old) with GDD but without seizures who was found to have a novel de novo NEUROD2 missense variant (c.488 T > C, p.L163P). An additional individual (12 yrs) with DD and a different missense NEUROD2 (c.703G>A, p.A235T) was also identified, but lacking parental samples for segregation analysis.
Functional analysis in Xenopus laevis revealed that injection of the p.L163P mRNA variant resulted in a defective ability to induce ectopic neurons in tadpoles as compared with wild-type NEUROD2 mRNA, while the p.A235T variant functioned similarly to wild-type.
Sources: Literature
Intellectual disability v3.1033 NCKAP1 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update. Guo et al 2020 (PMID:33157009) describe multiple families with inherited and de novo deleterious NCKAP1 variants. Neurodevelopmental features represent the core phenotypes, including autistic features, psychomotor delays, and ID or learning disabilities (10/16 individuals had a diagnosis of mild to severe ID)
Intellectual disability v3.1028 DPYS Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. Overall variable clinical presentation, even including asymptomatic subjects. However, DD and/or ID have been reported in multiple published cases (PMIDs: 9266350; 17383919; 20362666; 27604308; 26771602; 29054612). Sufficient unrelated cases (>3) to rate Green but will seek opinion from the GMS expert group due to highly variable penetrance of this phenotype.
Intellectual disability v3.1025 DPM2 Arina Puzriakova Added comment: Comment on list classification: Associated with relevant phenotype in OMIM (MIM# 615042). Sufficient number of unrelated cases (3) with DPM2-CDG to rate Green at the next GMS panel update. Phenotypes include intellectual disability in all affected individuals.
Intellectual disability v3.1022 B4GALT1 Arina Puzriakova Added comment: Comment on list classification: Upgraded from Red to Amber as now there are 2 families (4 total) exhibiting severe cognitive impairment, albeit this resolved in the singleton by age 11 (remaining patients were age 2.5, 11 and 11 years at the time of reporting)
Intellectual disability v3.1021 B4GALT1 Arina Puzriakova reviewed gene: B4GALT1: Rating: AMBER; Mode of pathogenicity: None; Publications: 11901181, 21920538, 30653653, 32157688; Phenotypes: Congenital disorder of glycosylation, type IId, OMIM:607091; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1018 UBE4A Zornitza Stark gene: UBE4A was added
gene: UBE4A was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: UBE4A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: UBE4A were set to 33420346
Phenotypes for gene: UBE4A were set to Intellectual disability
Review for gene: UBE4A was set to GREEN
gene: UBE4A was marked as current diagnostic
Added comment: 8 individuals, from 4 unrelated families, with syndromic intellectual disability and global developmental delay (other clinical features included hypotonia, short stature, seizures, and behaviour disorder. Exome sequencing identified biallelic loss-of-function variants in UBE4A in the 4 families, with variants segregating with disease and parents carriers. They demonstrated that UBE4A loss-of-function variants reduced RNA expression and protein levels in clinical samples. Mice generated to mimic patient-specific Ube4a loss-of-function variant exhibited muscular and neurological/behavioural abnormalities, some of which are suggestive of the clinical abnormalities seen in the affected individuals.
Sources: Literature
Intellectual disability v3.1018 MAPKAPK5 Zornitza Stark gene: MAPKAPK5 was added
gene: MAPKAPK5 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: MAPKAPK5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MAPKAPK5 were set to 3344202
Phenotypes for gene: MAPKAPK5 were set to Developmental delay, variable brain anomalies, congenital heart defects, dysmorphism
Review for gene: MAPKAPK5 was set to GREEN
gene: MAPKAPK5 was marked as current diagnostic
Added comment: 3 individuals from 2 families with severe developmental delay, variable brain anomalies, congenital heart defects, dysmorphic facial features, and a distinctive type of synpolydactyly with an additional hypoplastic digit between the fourth and fifth digits of hands and/or feet. Exome sequencing identified different homozygous truncating variants in MAPKAPK5 in both families, segregating with disease and unaffected parents as carriers.

Patient-derived cells showed no expression of MAPKAPK5 protein isoforms and reduced levels of the MAPKAPK5-interacting protein ERK3. F-actin recovery after latrunculin B treatment was found to be less efficient in patient-derived fibroblasts than in control cells, supporting a role of MAPKAPK5 in F-actin polymerization.

Borderline Amber/Green but high impact variants and a distinctive phenotype with some functional data.
Sources: Literature
Intellectual disability v3.1018 FAR1 Zornitza Stark edited their review of gene: FAR1: Added comment: PMID 33239752: 12 patients with paediatric onset spastic paraparesis and bilateral congenital/juvenile cataracts. Most also had speech and gross motor developmental delay and truncal hypotonia. Exome sequencing identified de novo variants affecting the Arg480 residue in FAR1 (p.Arg480Cys/His/Leu). Further functional studies in fibroblasts showed that these variants cause a disruption of the plasmalogen-dependent feedback regulation of FAR1 protein levels leading to uncontrolled ether lipid production.; Changed rating: GREEN; Changed publications: 25439727, 33239752; Changed phenotypes: Peroxisomal fatty acyl-CoA reductase 1 disorder, MIM#616154, spastic paraparesis and bilateral cataracts; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.1018 NCDN Zornitza Stark gene: NCDN was added
gene: NCDN was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: NCDN was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: NCDN were set to 33711248
Phenotypes for gene: NCDN were set to Intellectual disability; epilepsy
Review for gene: NCDN was set to GREEN
Added comment: Four families reported, all with de novo missense variants except for 1 consanguineous family where 3 affecteds were homozygous and carrier parents unaffected. ID ranged from mild to severe, several had seizures. Green for mono-allelic disease, Red for bi-allelic.
Sources: Literature
Intellectual disability v3.1018 CDH11 Zornitza Stark reviewed gene: CDH11: Rating: GREEN; Mode of pathogenicity: None; Publications: 33811546, 27431290, 28988429, 29271567, 33811546; Phenotypes: Elsahy-Waters syndrome, MIM# 211380, Teebi hypertelorism syndrome; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability v3.1018 INPP4A Zornitza Stark reviewed gene: INPP4A: Rating: AMBER; Mode of pathogenicity: None; Publications: 31978615, 31938306, 25338135, 20011524; Phenotypes: Intellectual disability; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1018 LOXHD1 Arina Puzriakova Mode of inheritance for gene: LOXHD1 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1017 KCNH1 Arina Puzriakova Phenotypes for gene: KCNH1 were changed from Temple-Baraitser syndrome, OMIM:611816; Temple-Baraitser syndrome, MONDO:0012735; Zimmermann-Laband syndrome 1, OMIM:135500; Zimmermann-Laband syndrome 1, MONDO:0024526 to Temple-Baraitser syndrome, OMIM:611816; Zimmermann-Laband syndrome 1, OMIM:135500; Intellectual disability; Encephalopathy without features of TBS/ZLS
Intellectual disability v3.1015 KCNH1 Arina Puzriakova edited their review of gene: KCNH1: Changed phenotypes: Intellectual disability, Encephalopathy without features of TBS/ZLS
Intellectual disability v3.1015 KCNH1 Arina Puzriakova reviewed gene: KCNH1: Rating: GREEN; Mode of pathogenicity: None; Publications: 33811134; Phenotypes: Intellectual disability; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.1015 IRF2BPL Sarah Leigh Phenotypes for gene: IRF2BPL were changed from Neurodevelopmental disorder with regression, abnormal movements, loss of speech, and seizures; Global developmental delay, Developmental regression, Seizures, Ataxia to Neurodevelopmental disorder with regression, abnormal movements, loss of speech, and seizures OMIM:618088; neurodevelopmental disorder with regression, abnormal movements, loss of speech, and seizures MONDO:0060759
Intellectual disability v3.1014 FBXL4 Sarah Leigh Added comment: Comment on phenotypes: FATAL ENCEPHALOPATHY, LACTIC ACIDOSIS, AND SEVERE MTDNA DEPLETION IN MUSCLE
Intellectual disability v3.1014 FBXL4 Sarah Leigh Phenotypes for gene: FBXL4 were changed from Mitochondrial DNA depletion syndrome 13 (encephalomyopathic type), 615471; FATAL ENCEPHALOPATHY, LACTIC ACIDOSIS, AND SEVERE MTDNA DEPLETION IN MUSCLE to Mitochondrial DNA depletion syndrome 13 (encephalomyopathic type) OMIM:615471; mitochondrial DNA depletion syndrome 13 MONDO:0014198
Intellectual disability v3.1012 DOCK3 Sarah Leigh Phenotypes for gene: DOCK3 were changed from Neurodevelopmental disorder with impaired intellectual development, hypotonia, and ataxia, 618292 to Neurodevelopmental disorder with impaired intellectual development, hypotonia, and ataxia OMIM:618292; neurodevelopmental disorder with impaired intellectual development, hypotonia, and ataxia MONDO:0032661
Intellectual disability v3.1010 KCNQ2 Arina Puzriakova Phenotypes for gene: KCNQ2 were changed from Seizures, benign neonatal, 1, 121200Myokymia, 121200Epileptic encephalopathy, early infantile, 7, 613720; BENIGN NEONATAL EPILEPSY TYPE 1 (EBN1) to Developmental and epileptic encephalopathy 7, OMIM:613720
Intellectual disability v3.1006 LARS2 Arina Puzriakova changed review comment from: Comment on list classification: While are a few cases with neurological symptoms including developmental delay have been reported, this manifestation is part of a broader phenotype where cognitive impairment is unlikely to represent a main feature. In the majority of cases, cognitive function is preserved.

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

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

Therefore, rating Amber on this panel. The phenotypes associated with LARS2 are better represented in other panels (e.g. Hearing loss) where this gene is already Green.
Intellectual disability v3.1003 NCKAP1 Zornitza Stark reviewed gene: NCKAP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 33157009; Phenotypes: Intellectual disability, autism; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.1003 LARS2 Zornitza Stark reviewed gene: LARS2: Rating: GREEN; Mode of pathogenicity: None; Publications: 29205794, 32423379, 30737337, 26537577, 23541342; Phenotypes: Perrault syndrome 4, Hydrops, lactic acidosis, and sideroblastic anemia, MIM# 617021, Leukodystrophy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1003 DPM2 Zornitza Stark edited their review of gene: DPM2: Added comment: Further unrelated individual reported, main clinical features were truncal hypotonia, hypertonicity, congenital heart defects, intellectual disability, and generalized muscle wasting.; Changed rating: GREEN; Changed publications: 23109149, 33129689
Intellectual disability v3.1003 B4GALT1 Zornitza Stark reviewed gene: B4GALT1: Rating: AMBER; Mode of pathogenicity: None; Publications: 11901181, 30653653, 21920538; Phenotypes: Congenital disorder of glycosylation, type Iid, MIM#607091; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1003 AGO1 Zornitza Stark reviewed gene: AGO1: Rating: GREEN; Mode of pathogenicity: None; Publications: 30213762, 22495306, 23020937, 25363768, 25356899, 27620904, 29346770, 28135719; Phenotypes: Intellectual disability, autism; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Intellectual disability v3.996 SPEN Arina Puzriakova Added comment: Comment on list classification: There is now enough evidence to promote this gene to Green at the next review - sufficient cases (>20) with truncating SPEN variants and GDD/ID of relevant severity to this panel.
Intellectual disability v3.994 MED27 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next review - at least 11 unrelated families reported with MED27 variants presenting overlapping phenotypes that include ID of relevant severity to this panel.
Intellectual disability v3.993 MED27 Arina Puzriakova reviewed gene: MED27: Rating: GREEN; Mode of pathogenicity: None; Publications: 33443317; Phenotypes: Intellectual disability, Axial hypotonia, Spasticity, Dystonia, Cerebellar hypoplasia, Cataracts, Epilepsy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.993 EIF5A Arina Puzriakova Added comment: Comment on list classification: There is enough evidence to rate this gene Green at the next review - PMID: 33547280 (2021) reports 7 unrelated individuals with different de novo heterozygous variants in the EIF5A gene. All were affected by variable degrees of DD and/or ID, mostly within the moderate severity range. Other features such as microcephaly and craniofacial dysmorphism were prominent but overall, the phenotype is best represented by this panel. Supportive functional data included.

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

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

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

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

Variants in other CRL4 complex components, such as CUL4B (MIM# 300304) and PHIP (MIM# 612870), have been shown to cause overlapping phenotypes consisting of syndromic ID with hypotonia and obesity.
Sources: Literature
Intellectual disability v3.982 DDB1 Arina Puzriakova gene: DDB1 was added
gene: DDB1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: DDB1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: DDB1 were set to 33743206
Phenotypes for gene: DDB1 were set to Intellectual disability
Review for gene: DDB1 was set to GREEN
Added comment: - PMID: 33743206 (2021) - 8 unrelated individuals with de novo variants in DDB1, including one recurrent variant in four individuals (c.637G>A, p.Glu213Lys) and two different substitutions at the same amino acid residue (p.Arg188Trp and p.Arg188Gln). Clinical features were consistent and include hypotonia (7/8) and mild-moderate developmental delay or intellectual disability (8/8) and similar facial gestalt. Brachydactyly was common and most noticeable in the feet (6/8), and two individuals had cutaneous toe syndactyly. All three older individuals had a BMI in the obese range for their age. Functional studies using patient-derived lymphoblasts showed altered DDB1 function resulting in abnormal DNA damage signatures and histone methylation following UV-induced DNA damage.
Sources: Literature
Intellectual disability v3.981 PIGU Arina Puzriakova Phenotypes for gene: PIGU were changed from Glycosylphosphatidylinositol biosynthesis defect 2, 618590; Global developmental delay; Intellectual disability; Seizures; Cerebral atrophy; Cerebellar hypoplasia; Scoliosis to Neurodevelopmental disorder with brain anomalies, seizures, and scoliosis, OMIM:618590
Intellectual disability v3.979 SMARCA4 Arina Puzriakova Added comment: Comment on phenotypes: This gene is also associated with {Rhabdoid tumor predisposition syndrome 2}, OMIM:613325
Intellectual disability v3.977 SIAH1 Arina Puzriakova Added comment: Comment on list classification: There are sufficient unrelated cases (5) to promote this gene to Green at the next GMS panel update. Developmental delay, including cognitive impairment, was a key presenting feature of the disease phenotype. Inclusion on this panel would also cover the infantile hypotonia element as the ID panel is a component panel of the 'Hypotonic infant, R69' super panel.
Intellectual disability v3.976 SIAH1 Arina Puzriakova gene: SIAH1 was added
gene: SIAH1 was added to Intellectual disability. Sources: Literature
Q2_21_rating tags were added to gene: SIAH1.
Mode of inheritance for gene: SIAH1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SIAH1 were set to 32430360
Phenotypes for gene: SIAH1 were set to Developmental delay; Infantile hypotonia; Dysmorphic features; Laryngomalacia
Review for gene: SIAH1 was set to GREEN
Added comment: - PMID: 32430360 (2021) - Five unrelated individuals with shared features of developmental delay, infantile hypotonia, dysmorphic features and laryngomalacia. All had speech delay and where cognitive assessment was age appropriate individuals exhibited learning difficulties. Trio WES revealed distinct de novo variants in SIAH1. In vitro assays demonstrated that SIAH1 mutants induce loss of Wnt stimulatory activity.
Sources: Literature
Intellectual disability v3.975 EIF5A Zornitza Stark gene: EIF5A was added
gene: EIF5A was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: EIF5A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: EIF5A were set to 33547280
Phenotypes for gene: EIF5A were set to Intellectual disability; microcephaly; dysmorphism
Review for gene: EIF5A was set to GREEN
Added comment: 7 unrelated individuals reported with de novo variants in this gene and variable combinations of developmental delay, microcephaly, micrognathia and dysmorphism.
Sources: Literature
Intellectual disability v3.975 SPEN Zornitza Stark edited their review of gene: SPEN: Added comment: PMID: 33596411
- 34 individuals with truncating variants in SPEN reported, most are de novo variants.
- Clinical profile includes developmental delay/intellectual disability, autism spectrum disorder, anxiety, aggressive behavior, attention deficit disorder, hypotonia, brain and spine anomalies, congenital heart defects, high/narrow palate, facial dysmorphisms, and obesity/increased BMI, especially in females.
- Authors showed haploinsufficiency of SPEN is associated with a distinctive DNA methylation episignature of the X chromosome in affected females.; Changed rating: GREEN; Changed publications: 33057194, 33596411; Changed phenotypes: Developmental delay/intellectual disability, autism spectrum disorder, anxiety, aggressive behavior, attention deficit disorder, hypotonia, brain and spine anomalies, congenital heart defects, high/narrow palate, facial dysmorphisms, and obesity/increased BMI; Set current diagnostic: yes
Intellectual disability v3.973 ERBB4 Sarah Leigh changed review comment from: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review depending on the interpretation of structural variants.; to: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review depending on the interpretation of copy number variants.
Intellectual disability v3.973 ERBB4 Sarah Leigh edited their review of gene: ERBB4: Added comment: Not associated with relevant phenotype in OMIM or Gen2Phen. PMID 33603162 reports that at least six 2q34 deletions resulting in exon loss in ERBB4 may cause autosomal dominant mild to moderate developmental delay, ID or epilepsy. Rhodent knock out models support this finding (PMID 15219717;30498032).; Changed rating: GREEN; Changed publications: 15219717, 30498032; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.973 ERBB4 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review depending on the interpretation of structural variants.
Intellectual disability v3.972 ERBB4 Sarah Leigh Added comment: Comment on phenotypes: Amyotrophic lateral sclerosis 19 615515 is not appropriate for this panel At present there is no precise ID phenotype associated with variants in this gene.
Intellectual disability v3.969 SETD1B Arina Puzriakova Phenotypes for gene: SETD1B were changed from Epilepsy, developmental delay, intellectual disability, autistic behavior and craniofacial dysmorphic features to Intellectual developmental disorder with seizures and language delay, OMIM:619000; Intellectual developmental disorder with seizures and language delay, MONDO:0033559
Intellectual disability v3.966 KCNN3 Arina Puzriakova edited their review of gene: KCNN3: Added comment: Now at least 6 unrelated individuals with different gain-of-function KCNN3 variants (PMIDs: 31155282 and 33594261). Phenotypes include mild-to-moderate DD and/or ID.; Changed publications: 31155282, 33594261
Intellectual disability v3.966 KCNN3 Arina Puzriakova changed review comment from: Comment on mode of pathogenicity: Gain-of-function variants identified in all patients, reported to date.; to: Comment on mode of pathogenicity: Gain-of-function variants identified in all patients reported to date.
Intellectual disability v3.963 CDK19 Sarah Leigh edited their review of gene: CDK19: Added comment: There is enough evidence for this gene to be rated GREEN at the next major review.; Changed rating: GREEN
Intellectual disability v3.963 ERBB4 Julia Baptista gene: ERBB4 was added
gene: ERBB4 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: ERBB4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ERBB4 were set to 33603162
Phenotypes for gene: ERBB4 were set to intellectual disability; epilepsy
Penetrance for gene: ERBB4 were set to Incomplete
Review for gene: ERBB4 was set to GREEN
Added comment: Heterozygous intragenic multi-exonic ERBB4 deletions were identified in nine individuals from five unrelated families. Affected individuals had either non-syndromic ID or generalised epilepsy.
The deletion segregated with the phenotype in five affected individuals in one family, it was de novo in a second family and the inheritance was unknown in two families. In the fifth family, the deletion was inherited from a normal parent.
Sources: Literature
Intellectual disability v3.963 KCNH1 Julia Baptista reviewed gene: KCNH1: Rating: GREEN; Mode of pathogenicity: None; Publications: 33594261; Phenotypes: Temple-Baraitser syndrome, Zimmermann-Laband syndrome 1; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Intellectual disability v3.963 KCNN3 Julia Baptista reviewed gene: KCNN3: Rating: GREEN; Mode of pathogenicity: Other; Publications: 33594261; Phenotypes: developmental delay, ID, hypotonia, gingival enlargement, hypertrichosis, nail anomalies; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Intellectual disability v3.963 CDK19 Julia Baptista changed review comment from: De novo missense variants mapped to the kinase domain of CDK19 were described in 11 unrelated individuals (age range: 9 months to 14 years).Two recurrent changes at residues Tyr32 and Gly28 were identified.
One additional case report (PMID:33568421) described a 10-month-old male patient who presented with a neurodevelopmental syndrome characterized by infantile spasms and a de novo missense variant c.92C>A (p.Thr31Asn) (also in the kinase domain). This brings the total of cases reported in the literature to 15.; to: De novo missense variants mapped to the kinase domain of CDK19 were described in 11 unrelated individuals (age range: 9 months to 14 years).Two recurrent changes at residues Tyr32 and Gly28 were identified.
One additional case report (PMID:33568421) described a 10-month-old male patient who presented with a neurodevelopmental syndrome characterized by infantile spasms and a de novo missense variant c.92C>A (p.Thr31Asn) (also in the kinase domain). This brings the total of cases reported in the literature to 15.
Intellectual disability v3.963 CDK19 Julia Baptista reviewed gene: CDK19: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 33495529, 33568421, 32330417; Phenotypes: developmental delay, hypotonia, seizures, autism/autistic traits; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Intellectual disability v3.868 HECW2 Ivone Leong Phenotypes for gene: HECW2 were changed from Neurodevelopmental disorder with hypotonia, seizures, and absent language to Neurodevelopmental disorder with hypotonia, seizures, and absent language, OMIM:617268
Intellectual disability v3.867 HECW2 Ivone Leong Mode of pathogenicity for gene: HECW2 was changed from to Other
Intellectual disability v3.865 HECW2 Ivone Leong gene: HECW2 was added
gene: HECW2 was added to Intellectual disability. Sources: Expert Review Green,BRIDGE study SPEED NEURO Tier1 Gene,Victorian Clinical Genetics Services
Mode of inheritance for gene: HECW2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: HECW2 were set to Neurodevelopmental disorder with hypotonia, seizures, and absent language
Intellectual disability v3.861 Ivone Leong removed gene:HECW2 from the panel
Intellectual disability v3.847 THOC2 Ivone Leong Source: Expert Review Red was removed from gene: THOC2
Intellectual disability v3.780 CCDC186 Sarah Leigh changed review comment from: Not associated with relevant phenotype in OMIM or Gen2Phen. At least 2 terminating variants reported in unrelated cases.
Sources: Literature; to: Not associated with a relevant phenotype in OMIM or Gen2Phen. At least 2 terminating variants reported in cases with failure to thrive and developmental delay.
Sources: Literature
Intellectual disability v3.780 CCDC186 Sarah Leigh gene: CCDC186 was added
gene: CCDC186 was added to Intellectual disability. Sources: Literature
watchlist tags were added to gene: CCDC186.
Mode of inheritance for gene: CCDC186 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CCDC186 were set to 33259146; 28600779
Phenotypes for gene: CCDC186 were set to failure to thrive and developmental delay
Review for gene: CCDC186 was set to AMBER
Added comment: Not associated with relevant phenotype in OMIM or Gen2Phen. At least 2 terminating variants reported in unrelated cases.
Sources: Literature
Intellectual disability v3.779 LMBRD2 Sarah Leigh Added comment: Comment on mode of pathogenicity: Both of the references for this entry suggest a gain-of-function action for LMBRD2 variants.
Intellectual disability v3.779 LMBRD2 Sarah Leigh Mode of pathogenicity for gene: LMBRD2 was changed from None to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Intellectual disability v3.778 ADAM22 Sarah Leigh Added comment: Comment on list classification: There is just enough evidence for this gene to be rated GREEN at the next major review, which may make it a boarderline case.
Intellectual disability v3.777 KCNN2 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. There is enough evidence to promote this gene to Green at the next GMS panel update - variable degrees of cognitive impairment were a universal feature amongst individuals with KCNN2 variants (at least 10 unrelated cases with unique variants). Pathogenicity was supported by functional data.
Intellectual disability v3.776 KCNN2 Arina Puzriakova reviewed gene: KCNN2: Rating: GREEN; Mode of pathogenicity: None; Publications: 33242881; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.775 SATB1 Arina Puzriakova Deleted their comment
Intellectual disability v3.775 SATB1 Arina Puzriakova Added comment: Comment on list classification: There is now enough evidence to promote this gene to Green at the next major review.
Intellectual disability v3.775 SATB1 Arina Puzriakova Added comment: Comment on list classification: There is now enough evidence to promote this gene to Green at the next major review.
Intellectual disability v3.774 SATB1 Arina Puzriakova reviewed gene: SATB1: Rating: GREEN; Mode of pathogenicity: None; Publications: 33513338; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.774 OTUD5 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. There is enough evidence to rate this gene Green at the next GMS panel update.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Sufficient number of unrelated cases with relevant phenotype; however, early-onset epilepsy represents the main feature of the disorder and ID appears to be a secondary manifestation (see supplemental note in PMID:33245860 for clinical details). Therefore, rating Amber on this panel but will add the FGF13 gene to 'Genetic epilepsy syndromes'
Intellectual disability v3.725 FGF13 Arina Puzriakova Phenotypes for gene: FGF13 were changed from Intellectual disability; epilepsy to Developmental and epileptic encephalopathy; Intellectual disability; Infantile-onset seizures
Intellectual disability v3.724 FGF13 Arina Puzriakova Mode of inheritance for gene: FGF13 was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Intellectual disability v3.722 FBRSL1 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. There is enough evidence to promote this gene to Green at the next GMS panel update (added 'for-review' tag) - sufficient number of unrelated cases with distinct variants and relevant phenotype, supported by functional data.

Currently not associated with any phenotype in OMIM or Gene2Phenotype.
Intellectual disability v3.721 FBRSL1 Arina Puzriakova reviewed gene: FBRSL1: Rating: GREEN; Mode of pathogenicity: None; Publications: 32424618; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.721 DPH2 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. Currently not associated with any phenotype in OMIM or Gene2Phenotype.

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

Additional cases would help corroborate this gene-disease association and so rating Amber, awaiting further cases/clinical evidence.
Intellectual disability v3.720 CDC40 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. CDC40 currently not associated with any phenotype in OMIM (last edited: 23/08/19) but has a 'possible' disease confidence for 'CDC40-related Neurodegenerative Pontocerebellar Hypoplasia with Microcephaly' in Gene2Phenotype.

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

Therefore, ABCC9 will be flagged for review by the GMS team with regards to phenotypic fit for this panel and determine whether it should be demoted from Green to Amber (added for-review tag).
Intellectual disability v3.717 ABCC9 Arina Puzriakova reviewed gene: ABCC9: Rating: ; Mode of pathogenicity: None; Publications: 31575858; Phenotypes: mild ID, similar facies, myopathy, cerebral white matter hyperintensities, cardiac systolic dysfunction; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.716 TRAPPC12 Arina Puzriakova Phenotypes for gene: TRAPPC12 were changed from Encephalopathy, progressive, early-onset, with brain atrophy and spasticity, 617669; Developmental delay to Encephalopathy, progressive, early-onset, with brain atrophy and spasticity, OMIM:617669; Early-onset progressive encephalopathy-hearing loss-pons hypoplasia-brain atrophy syndrome, MONDO:0044696
Intellectual disability v3.714 TRAPPC12 Arina Puzriakova reviewed gene: TRAPPC12: Rating: GREEN; Mode of pathogenicity: None; Publications: 32369837; Phenotypes: Encephalopathy, progressive, early-onset, with brain atrophy and spasticity, OMIM:617669, Early-onset progressive encephalopathy-hearing loss-pons hypoplasia-brain atrophy syndrome, MONDO:0044696; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.714 FGF13 Helen Lord Deleted their review
Intellectual disability v3.714 GLS_GCA Arina Puzriakova changed review comment from: Comment on list classification: Early developmental delay, which preceded other progressive neurological concerns, was reported in the three unrelated cases from PMID:30970188. Following discussion with Helen Brittain (Genomics England Clinical Team) it was agreed that this is sufficient for inclusion on this panel.

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

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

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

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

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

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

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

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

Gene referred to as PRP17 in paper.
Sources: Literature
Intellectual disability v3.694 CCDC40 Zornitza Stark Deleted their comment
Intellectual disability v3.694 CCDC40 Zornitza Stark Deleted their comment
Intellectual disability v3.694 CCDC40 Zornitza Stark changed review comment from: ID is not part of the phenotype.; to: ID is not part of the phenotype.
Intellectual disability v3.694 CCDC40 Zornitza Stark edited their review of gene: CCDC40: Added comment: New publication: Single individual reported with bi-allelic variants in the gene and PCH, microcephaly, hypotonia, seizures, severe DD/ID, thrombocytopaenia, anaemia. Interaction with PPIL1 and mouse model support gene-disease association.; Changed publications: 33220177
Intellectual disability v3.694 PPIL1 Zornitza Stark gene: PPIL1 was added
gene: PPIL1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: PPIL1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PPIL1 were set to 33220177
Phenotypes for gene: PPIL1 were set to Pontocerebellar hypoplasia; microcephaly; seizures; intellectual disbility
Review for gene: PPIL1 was set to GREEN
Added comment: 17 individuals from 9 unrelated families reported with bi-allelic variants in the gene and PCH, microcephaly, hypotonia, seizures, severe DD/ID. Mouse models support gene-disease association.
Sources: Literature
Intellectual disability v3.692 TBCD Arina Puzriakova Phenotypes for gene: TBCD were changed from Encephalopathy, progressive, early-onset, with brain atrophy and thin corpus callosum 617193 to Encephalopathy, progressive, early-onset, with brain atrophy and thin corpus callosum, OMIM:617193; Early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome, MONDO:0044646
Intellectual disability v3.691 SMC1A Arina Puzriakova Phenotypes for gene: SMC1A were changed from CORNELIA DE LANGE SYNDROME TYPE 2 (CDLS2) to Cornelia de Lange syndrome 2, OMIM:300590; Cornelia de Lange syndrome 2, MONDO:0010370; Developmental and epileptic encephalopathy 85, with or without midline brain defects, OMIM:301044; Developmental and epileptic encephalopathy, 85, with or without midline brain defects, MONDO:0026771
Intellectual disability v3.690 SLC9A7 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. Associated with relevant phenotype in OMIM and Gene2Phenotype. However, only 2 unrelated families reported at present (PMID: 30335141) and therefore only sufficient for an Amber rating, awaiting further publications/clinical evidence (added 'watchlist' tag)
Intellectual disability v3.686 MPI Arina Puzriakova reviewed gene: MPI: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.686 AGO2 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. All patients reported in PMID: 33199684 presented GDD/ID, while other features were relatively heterogenous. However, cognitive impairment was perhaps too mild in majority of cases. Tagged 'for-review' to assess whether there is sufficient evidence for a Green rating in light of the scope of the ID panel.
Intellectual disability v3.685 AGO2 Arina Puzriakova reviewed gene: AGO2: Rating: AMBER; Mode of pathogenicity: None; Publications: 33199684; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.685 ZNF407 Arina Puzriakova Added comment: Comment on list classification: New gene added by Konstantinos Varvagiannis. Some evidence linking both mono- and biallelic variants with disease but currently not sufficient for a Green rating. Further cases would help validate this gene-disease association (added 'watchlist' tag)
Intellectual disability v3.683 SMG8 Arina Puzriakova Added comment: Comment on list classification: Additional cases reported in recent publication (PMID: 33242396) extend the total to at least 5 unrelated families with GDD/ID and different homozygous variants in the SMG8 gene. Also some supporting functional data provided.

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

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

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

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

- PMID: 33268356 (2020) - De novo missense variants identified in 13 unrelated individuals with a shared phenotype of GDD/ID, usually severe and often progressive, with mostly minor congenital anomalies. One individual was reported to have a normal IQ at 15 years. 8/13 patients showed abnormalities on brain MRI including hypomyelination (5), cortical atrophy (4), arachnoid cysts (3), and a thin corpus collosum (2). Variable seizure phenotypes were reported in 6/13 cases, all early-onset where specified, mostly during infancy (latest onset at 10 years of age).
Intellectual disability v3.674 H3F3B Arina Puzriakova Added comment: Comment on list classification: Upgraded from Red to Amber, but there is sufficient evidence to promoted to Green at the next GMS panel update (added 'for-review' tag).

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

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

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

9 unrelated individuals reported at present (PMID: 33232677). Although all presented GDD, only 1 individual had severe ID (IQ = 50) and 3 had mild ID. Although ID is too mild in majority of cases, developmental delay was the universal feature amongst affected individuals and other phenotypes were heterogenous (e.g. seizures, brain malformations). Therefore, there may be value in inclusion on this panel for capturing this phenotype.
Intellectual disability v3.667 HSPG2 Arina Puzriakova Added comment: Comment on list classification: While there are sufficient cases to support a gene-disease association, DD/ID is part of a broader phenotype and cognitive impairment is unlikely to represent a main feature of the disease presentation.

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

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

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

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

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

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

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

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

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

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

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

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

In a knockout mouse the total brain volume was significantly reduced with decreased
size of the hippocampal dentate gyrus, partial agenesis of the corpus callosum, and ventriculomegaly.
Sources: Literature
Intellectual disability v3.644 SMG8 Zornitza Stark edited their review of gene: SMG8: Added comment: Four more families reported in PMID 33242396. Some functional data also provided.; Changed rating: GREEN; Changed publications: 31130284, 33242396
Intellectual disability v3.644 H3F3B Zornitza Stark reviewed gene: H3F3B: Rating: GREEN; Mode of pathogenicity: None; Publications: 33268356; Phenotypes: Intellectual disability, regression, seizures; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.644 H3F3A Zornitza Stark reviewed gene: H3F3A: Rating: GREEN; Mode of pathogenicity: None; Publications: 33268356; Phenotypes: Intellectual disability, regression, seizures; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.644 HDAC4 Zornitza Stark edited their review of gene: HDAC4: Added comment: New report of 4 different missense present in the 14-3-3 binding site, identified de novo in 7 individuals with an intellectual disability syndrome, and supporting in vitro functional assays.; Changed rating: GREEN; Changed publications: 24715439, 20691407, 31209962, https://doi.org/10.1016/j.xhgg.2020.100015
Intellectual disability v3.641 MORC2 Arina Puzriakova Phenotypes for gene: MORC2 were changed from Charcot-Marie-Tooth disease, axonal, type 2Z, MIM #616688 to Developmental delay; Intellectual disability; Growth retardation; Microcephaly; Craniofacial dysmorphism; Charcot-Marie-Tooth disease, axonal, type 2Z, OMIM:616688
Intellectual disability v3.639 MORC2 Arina Puzriakova Added comment: Comment on list classification: Though signs suggestive of neuropathy were observed in the cohort presented by Sacoto et al (PMID:32693025), these were not the predominant feature of the disease presentation or the primary indication for diagnostic testing. Inclusion on this panel would be of value for detecting such cases, and so this gene should be promoted to Green at the next GMS panel update (added 'for-review' tag)
Intellectual disability v3.638 MORC2 Arina Puzriakova reviewed gene: MORC2: Rating: GREEN; Mode of pathogenicity: None; Publications: 32693025; Phenotypes: Developmental delay, Intellectual disability, Growth retardation, Microcephaly, Craniofacial dysmorphism; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.638 LARS Arina Puzriakova Added comment: Comment on list classification: New gene added by Konstantinos Varvagiannis. Developmental delay is prevalent among affected individuals, and there are sufficient unrelated cases (>3) presenting with relevant severity to this panel. This may serve as a possible route for diagnostic testing as currently there are no relevant panels for detecting the hepatic phenotype of the disease presentation, and so there may be value in rating Green at the next major panel review (added 'for-review tag).
Intellectual disability v3.636 SOX3 Arina Puzriakova Phenotypes for gene: SOX3 were changed from Mental retardation, X-linked, with isolated growth hormone deficiency, 300123Panhypopituitarism, X-linked, 312000; SEX REVERSAL TYPE 3 (SRXX3) to Mental retardation, X-linked, with isolated growth hormone deficiency, OMIM:300123; Intellectual disability, X-linked, with panhypopituitarism, MONDO:0010252
Intellectual disability v3.633 PRKAR1A Arina Puzriakova Phenotypes for gene: PRKAR1A were changed from Gene2Phenotype confirmed gene with ID HPO to Acrodysostosis 1, with or without hormone resistance, OMIM:101800
Intellectual disability v3.632 SH3PXD2B Arina Puzriakova Added comment: Comment on list classification: Following discussion with the Genomics England clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark (Australian Genomics)
Intellectual disability v3.631 SEC23B Arina Puzriakova Added comment: Comment on list classification: Following discussion with the Genomics England clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark (Australian Genomics)
Intellectual disability v3.630 SCN11A Arina Puzriakova Added comment: Comment on list classification: Following discussion with the Genomics England clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark (Australian Genomics)
Intellectual disability v3.629 SCARF2 Arina Puzriakova Added comment: Comment on list classification: Following discussion with the Genomics England clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark (Australian Genomics)
Intellectual disability v3.628 SBDS Arina Puzriakova Added comment: Comment on list classification: Following discussion with the Genomics England clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark (Australian Genomics)
Intellectual disability v3.627 SALL4 Arina Puzriakova Added comment: Comment on list classification: Following discussion with the Genomics England clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark (Australian Genomics)
Intellectual disability v3.626 PRSS56 Arina Puzriakova Added comment: Comment on list classification: Following discussion with the Genomics England clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark (Australian Genomics)
Intellectual disability v3.625 PROP1 Arina Puzriakova Added comment: Comment on list classification: Following discussion with the Genomics England clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark (Australian Genomics)
Intellectual disability v3.624 PRDM12 Arina Puzriakova Added comment: Comment on list classification: Following discussion with the Genomics England clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark (Australian Genomics)
Intellectual disability v3.623 PPA2 Arina Puzriakova Added comment: Comment on list classification: Following discussion with the Genomics England clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark (Australian Genomics)
Intellectual disability v3.622 POLR1D Arina Puzriakova Added comment: Comment on list classification: Following discussion with the Genomics England clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark (Australian Genomics)
Intellectual disability v3.621 POLD1 Arina Puzriakova Added comment: Comment on list classification: Following discussion with the Genomics England clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark (Australian Genomics)
Intellectual disability v3.620 POC1B Arina Puzriakova Added comment: Comment on list classification: Following discussion with the Genomics England clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark (Australian Genomics)
Intellectual disability v3.619 PMS2 Arina Puzriakova Added comment: Comment on list classification: Following discussion with the Genomics England clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark (Australian Genomics)
Intellectual disability v3.618 PLOD2 Arina Puzriakova Added comment: Comment on list classification: Following discussion with the Genomics England clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark (Australian Genomics)
Intellectual disability v3.617 PKHD1 Arina Puzriakova Added comment: Comment on list classification: Following discussion with the Genomics England clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark (Australian Genomics)
Intellectual disability v3.616 PKD1L1 Arina Puzriakova Added comment: Comment on list classification: Following discussion with the Genomics England clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark (Australian Genomics)
Intellectual disability v3.615 PITX3 Arina Puzriakova Added comment: Comment on list classification: Following discussion with the Genomics England clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark (Australian Genomics)
Intellectual disability v3.614 PITX2 Arina Puzriakova Added comment: Comment on list classification: Following discussion with the Genomics England clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark (Australian Genomics)
Intellectual disability v3.613 PIK3R1 Arina Puzriakova Added comment: Comment on list classification: Following discussion with the Genomics England clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark
Intellectual disability v3.610 POLR1C Arina Puzriakova Added comment: Comment on list classification: Cognitive impairment (ID and/or cognitive regression) may be variable amongst affected individuals; however, there are sufficient unrelated cases (>3) for inclusion on this panel as Green.
Intellectual disability v3.608 PNPT1 Arina Puzriakova Added comment: Comment on list classification: GDD/ID is a prominent feature of the disease presentation and there are sufficient unrelated cases (>3) presenting with relevant severity to this panel. This is a possible route for diagnostic testing and so there may be value in classifying as Green - PNPT1 will be flagged for review at the next GMS panel update (added 'for-review' tag)
Intellectual disability v3.607 SCN1B Arina Puzriakova Added comment: Comment on list classification: Biallelic variants associated with developmental epileptic encephalopathy characterised by early onset epileptic seizures followed by cognitive decline. At least 5 unrelated families in literature (PMIDs: 19710327; 23148524; 28218389).

Rating Amber as seizures are the prominent feature of the disease presentation, to which cognitive impairment is secondary. Cases would be detected via the epilepsy route (SCN1B is already Green on Genetic epilepsy syndromes panel).
Intellectual disability v3.606 SCN1B Arina Puzriakova Phenotypes for gene: SCN1B were changed from EPILEPSY, GENERALIZED, WITH FEBRILE SEIZURES PLUS, TYPE 1 to Developmental and epileptic encephalopathy 52, OMIM:617350; Developmental and epileptic encephalopathy, 52, MONDO:0033361
Intellectual disability v3.601 ZFHX4 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in OMIM. Based on the available evidence there is enough evidence to support a gene-disease association. This gene should be promoted to Green at the next review.
Intellectual disability v3.599 UPF1 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics).

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

-----


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

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

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

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

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

WES was carried out in all.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Rating Amber, but this may be reviewed if new evidence emerges indicating that neurodevelopmental impairment precedes onset of seizures.
Intellectual disability v3.452 USP7 Arina Puzriakova Added comment: Comment on list classification: Based on published evidence and expert reviews, this gene should be promoted from Amber to Green at the next GMS panel update (added 'for-review' tag)
Intellectual disability v3.451 USP7 Arina Puzriakova reviewed gene: USP7: Rating: GREEN; Mode of pathogenicity: None; Publications: 26365382, 30679821, 33012787; Phenotypes: Hao-Fountain syndrome, 616863; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.451 STT3A Arina Puzriakova Added comment: Comment on list classification: There is enough evidence to support a gene-disease association, and so STT3A should be promoted from Amber to Green at the next GMS panel update (added 'for-review' tag).

ID/DD reported in all cases (at least 7 individuals from 3 unrelated families, with 2 different homozygous variants in STT3A)
Intellectual disability v3.448 CARS2 Arina Puzriakova changed review comment from: Comment on list classification: Kept rating Amber as developmental regression and progressive cognitive decline appear secondary to seizures, which represent the key phenotypic feature of this disorder.

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

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

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

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

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

This gene is Green on the Genetic epilepsy syndromes (v2.170) panel, which should be a sufficient route for detecting these cases.
Intellectual disability v3.436 CARS2 Arina Puzriakova Added comment: Comment on list classification: Kept rating Amber as developmental regression and progressive cognitive decline appear secondary to seizures, which represent the key phenotypic feature of this disorder.

This gene is Green on the Inborn errors of metabolism (v2.2) panel, a component the Epilepsy super panel, which should be a sufficient route for detecting these cases.
Intellectual disability v3.435 C2CD3 Arina Puzriakova Added comment: Comment on list classification: Despite phenotypic diversity among cases with C2CD3 variants, ID/DD is consistently reported in living patients.

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

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

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

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

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

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

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

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

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

Calling variants in this gene in a cohort of ID patients is therefore unlikely to be of benefit and so the rating has been kept Red.
Intellectual disability v3.420 ITFG2 Konstantinos Varvagiannis gene: ITFG2 was added
gene: ITFG2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: ITFG2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ITFG2 were set to 28397838; https://doi.org/10.1038/s41525-020-00150-z
Phenotypes for gene: ITFG2 were set to Neurodevelopmental abnormality; Intellectual disability; Developmental regression; Ataxia
Penetrance for gene: ITFG2 were set to Complete
Review for gene: ITFG2 was set to AMBER
Added comment: ITFG2 was suggested to be a candidate gene for autosomal recessive ID in the study by Harripaul et al (2018 - PMID: 28397838). The authors performed microarray and exome sequencing in 192 consanguineous families and identified a homozygous ITGF2 stopgain variant (NM_018463.3:c.472G>T / p.Glu158*) along with 3 additional variants segregating with ID within an investigated family (PK51).

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

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

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

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

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

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

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

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

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

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

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

Overall this gene can be considered for inclusion with (probably) green rating in gene panels for ID, metabolic / mitochondrial disorders, cardiomyopathy, congenital microcephaly, corpus callosum anomalies, etc.
Sources: Literature
Intellectual disability v3.420 ABCB11 Arina Puzriakova Added comment: Comment on list classification: Downgraded from Amber to Red in context of the review by Konstantinos Varvagiannis
Intellectual disability v3.419 ACAN Arina Puzriakova Added comment: Comment on list classification: Downgraded from Amber to Red in context of the review by Konstantinos Varvagiannis
Intellectual disability v3.417 ATP8B1 Arina Puzriakova changed review comment from: Following discussion with the clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark; to: Following discussion with the clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark and Konstantinos Varvagiannis
Intellectual disability v3.417 KAT5 Arina Puzriakova Phenotypes for gene: KAT5 were changed from to Severe global developmental delay; Intellectual disability; Seizures; Microcephaly; Behavioral abnormality; Sleep disturbance; Morphological abnormality of the central nervous system; Short stature; Oral cleft; Abnormality of the face
Intellectual disability v3.414 KAT5 Arina Puzriakova Added comment: Comment on list classification: Rating upgraded from Red to Amber. There is a sufficient number of unrelated cases reported in PMID:32822602 to promoted this gene to Green at the next GMS panel update.
Intellectual disability v3.412 SCAF4 Arina Puzriakova Added comment: Comment on list classification: At least 8 unrelated individuals reported in PMID:32730804 with a neurodevelopmental disorder characterised by DD/ID, mostly in the mild range (severe in only one individual).

Rating Amber in view of the mild ID presentation. This may be reviewed if further cases are reported with more severe manifestations of relevant phenotypes.
Intellectual disability v3.410 NEDD4L Eleanor Williams changed review comment from: Associated with Periventricular nodular heterotopia 7 #617201 (AD) in OMIM.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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



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

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

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

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

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



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

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

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

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

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

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

GDD was reported in all 6 patients (5 families). At ages 4-11yrs, the best achieved social and language skills were limited to sounds in 4 individuals, and partial babbling or vocalisation in the remaining two, respectively.
Intellectual disability v3.379 UGDH Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to rate this gene Green at the next GMS panel update.

Multiple patients from over 20 unrelated families, all with moderate-to-severe ID in association with biallelic variants in UGDH.
Intellectual disability v3.378 SPTBN4 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to rate this gene Green at the next GMS panel update.

Severe-to-profound DD and/or ID reported in all but one family with a milder phenotype (at least 9 total families described with different biallelic variants in SPTBN4).
Intellectual disability v3.377 NR4A2 Arina Puzriakova Added comment: Comment on list classification: This gene will be flagged for review at the date of next GMS panel update (added 'for-review' tag).

The recent paper flagged by Konstantinos Varvagiannis (PMID:32366965) includes 2 unrelated patients with severe ID and 2 with moderate-severe ID. This is within the scope of the panel and the number of cases now reach threshold for inclusion with a Green rating.
Intellectual disability v3.375 TNRC6B Arina Puzriakova Added comment: Comment on list classification: This is a borderline Amber/Green gene, and should be reviewed at the date of next GMS panel update (added 'for-review' tag).

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Therefore, keeping rating Red awaiting further cases to clarify the relevance of ID to the phenotype associated with RAD50 variants.
Intellectual disability v3.330 RAD50 Arina Puzriakova changed review comment from: Comment on list classification: Borderline ID in second patient (at age 15 estimated IQ: 85). Therefore, keeping rating Red awaiting further cases to ascertain the contribution of RAD50 variants to an ID phenotype.; to: Comment on list classification: Borderline ID in second patient (at age 15 estimated IQ: 85). Therefore, keeping rating Red awaiting further cases to clarify the relevance of ID to the overall phenotype.
Intellectual disability v3.328 RAD50 Arina Puzriakova Added comment: Comment on list classification: Borderline ID in second patient (at age 15 estimated IQ: 85). Therefore, keeping rating Red awaiting further cases to ascertain the contribution of RAD50 variants to an ID phenotype.
Intellectual disability v3.326 WASHC4 Arina Puzriakova Added comment: Comment on list classification: Rating Amber in view of mild/borderline ID in 2/3 families. Additional cases with a more significant manifestation of ID required before inclusion of WASHC4 on a diagnostic panel.
Intellectual disability v3.325 WASHC4 Arina Puzriakova reviewed gene: WASHC4: Rating: ; Mode of pathogenicity: None; Publications: 21498477, 31953988; Phenotypes: Mental retardation, autosomal recessive 43, 615817; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.324 AFG3L2 Arina Puzriakova Added comment: Comment on list classification: This gene should be downgraded from Green to Red at the next major review, in accordance with the review by Zornitza Stark.
Intellectual disability v3.321 LRP5 Sarah Leigh Added comment: Comment on mode of inheritance: Other phenotypes associated with LRP5 variants (https://www.omim.org/entry/603506?search=LRP5&highlight=lrp5#geneMap) have monoallelic inheritance, however, these phenotypes are not relevant for this panel as ID has not been reported.
Intellectual disability v3.320 WDFY3 Arina Puzriakova Added comment: Comment on list classification: There is a sufficient number of cases with moderate ID to meet the threshold for inclusion on a diagnostic ID panel. Furthermore, ID is currently the most applicable clinical indication for detecting these cases using PanelApp panels.

Therefore, recommending a rating upgrade from Amber to Green at the next major review.
Intellectual disability v3.319 TRAK1 Arina Puzriakova Phenotypes for gene: TRAK1 were changed from to Epileptic encephalopathy, early infantile, 68, 618201
Intellectual disability v3.316 TRAK1 Arina Puzriakova changed review comment from: Comment on list classification: Rating Amber - with ID seemingly following seizures, and being in association with a single recurrent variant, there is currently insufficient evidence to say that variants in this gene cause ID. This may, however, be reviewed if new evidence emerges.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Therefore, recommending a rating downgrade from Green to Amber/Red at the next major review, awaiting further publications/clinical evidence.
Intellectual disability v3.301 TRIM32 Arina Puzriakova Added comment: Comment on list classification: Recommended Green-to-Red rating downgrade on the next major review - only one family reported to date for association with BBS. Currently also Red on the Bardet-Biedl Syndrome (Version 1.5) gene panel.
Intellectual disability v3.300 VARS2 Arina Puzriakova Added comment: Comment on list classification: There is enough evidence to rate this gene GREEN at the next major review - >3 unrelated families with different variants. Severe psychomotor delay was an early and significant manifestation on clinical evaluation.
Intellectual disability v3.299 SUCLA2 Arina Puzriakova Added comment: Comment on list classification: Although sufficient number of cases with relevant clinical presentation, psychomotor delay is a component of a broader phenotype. Patients are more likely to be recognised via other routes (Metabolic/White Matter Disorders/Mitochondrial) - SUCLA2 is already Green on these PanelApp panels.

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

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

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

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

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

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

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

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

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

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

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

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

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


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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Four unrelated patients with homozygous LOF variants in this gene all exhibited a consistent phenotype which included global developmental delay. All variants segregated with disease, but no functional studies of the variants or patient cells were not performed.
Intellectual disability v3.260 SPOP Arina Puzriakova Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.

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

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

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

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

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

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

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

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

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

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

As a result, TAF1C may be considered for inclusion in the ID panel with amber rating pending further evidence.
Sources: Literature
Intellectual disability v3.247 PDP1 Arina Puzriakova Added comment: Comment on list classification: Rating Amber, given the mild delay in psychomotor development seen in these patients. This gene is Green on other panels which are more relevant to the phenotype.
Intellectual disability v3.246 PDP1 Arina Puzriakova reviewed gene: PDP1: Rating: ; Mode of pathogenicity: None; Publications: 15855260, 19184109, 31392110; Phenotypes: Pyruvate dehydrogenase phosphatase deficiency, 608782; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.245 PDHB Arina Puzriakova Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review - moderate ID/DD reported in multiple surviving patients.
Intellectual disability v3.244 CNTNAP1 Sarah Leigh changed review comment from: Comment on list classification: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least four variants reported four unrelated cases of Lethal congenital contracture syndrome 7 616286 and seven variants reported in four cases of Hypomyelinating neuropathy, congenital, 3 618186. Both of these conditions include intellectual disability.; to: Comment on list classification: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene for Lethal congenital contracture syndrome 7 61628. At least four variants reported four unrelated cases of Lethal congenital contracture syndrome 7 616286 and seven variants reported in four cases of Hypomyelinating neuropathy, congenital, 3 618186. Both of these conditions include intellectual disability.
Intellectual disability v3.244 B9D2 Sarah Leigh commented on gene: B9D2: There is enough evidence for this gene to be rated GREEN at the next major review.
Intellectual disability v3.244 CNTNAP1 Sarah Leigh edited their review of gene: CNTNAP1: Added comment: There is enough evidence for this gene to be rated GREEN at the next major review.; Changed rating: GREEN
Intellectual disability v3.244 CNTNAP1 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least four variants reported four unrelated cases of Lethal congenital contracture syndrome 7 616286 and seven variants reported in four cases of Hypomyelinating neuropathy, congenital, 3 618186. Both of these conditions include intellectual disability.
Intellectual disability v3.243 CNTNAP1 Sarah Leigh Phenotypes for gene: CNTNAP1 were changed from Hypomyelinating neuropathy, congenital, 3, MIM#618186; Lethal congenital contracture syndrome 7, MIM# 616286 to Hypomyelinating neuropathy, congenital, 3 618186; Lethal congenital contracture syndrome 7 616286
Intellectual disability v3.242 B9D2 Sarah Leigh edited their review of gene: B9D2: Added comment: Three variants were reported in two unrelated cases of Joubert syndrome 34, which includes intellectual impairment, together with supportive functional studies (PMID 21763481).; Changed rating: GREEN
Intellectual disability v3.242 B9D2 Sarah Leigh Deleted their comment
Intellectual disability v3.242 B9D2 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least five variants reported in four unrelated cases. Three of the variants were reported in two unrelated cases of Joubert syndrome 34, which includes intellectual impairment and the remaining three variants were found in two unrelated fetuses with Meckel syndrome 10, with brain malformations.
Intellectual disability v3.241 B9D2 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least five variants reported in four unrelated cases. Three of the variants were reported in two unrelated cases of Joubert syndrome 34, which includes intellectual impairment and the remaining three variants were found in two unrelated fetuses with Meckel syndrome 10, with brain malformations.
Intellectual disability v3.239 MADD Konstantinos Varvagiannis reviewed gene: MADD: Rating: GREEN; Mode of pathogenicity: None; Publications: 28940097, 29302074, 32761064; Phenotypes: Global developmental delay / Intellectual disability / Seizures, Global developmental delay / Intellectual disability / Seizures / Abnormality of the endocrine system / Exocrine pancreatic insufficiency / Constipation / Diarrhea / Anemia / Thrombocytopenia / Abnormality of the autonomic nervous system; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.239 FAM50A Konstantinos Varvagiannis gene: FAM50A was added
gene: FAM50A was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: FAM50A was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Publications for gene: FAM50A were set to 32703943
Phenotypes for gene: FAM50A were set to Mental retardation syndrome, X-linked, Armfield type (MIM #300261)
Penetrance for gene: FAM50A were set to unknown
Review for gene: FAM50A was set to GREEN
Added comment: Lee et al (2020 - PMID: 32703943) provide evidence that Armfield X-Linked intellectual disability syndrome is caused by monoallelic FAM50A pathogenic variants. The current review is based only on this reference.

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

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

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

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

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

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

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

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

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

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

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

Please consider inclusion in the ID panel with green rating and epilepsy panel with amber (seizures in individuals from 2 families).
Sources: Literature
Intellectual disability v3.239 TET3 Sarah Leigh changed review comment from: Comment on list classification: Associated with relevant phenotype including mild to severe intellectual disability in OMIM and as probable Gen2Phen gene for TET3 DNA Demethylation Disorder biallelic and TET3 DNA Demethylation Disorder monoallelic. At least 9 variants reported in total, with 5 variants associated with the biallelic version of the condition in 3 unrelated cases and 4 variants associated with the monoallelic version in 4 unrelated cases.; to: Comment on list classification: Associated with relevant phenotype OMIM and as probable Gen2Phen gene for TET3 DNA Demethylation Disorder biallelic and TET3 DNA Demethylation Disorder monoallelic. At least 9 variants reported in total, with 5 variants associated with the biallelic version of the condition in 3 unrelated cases and 4 variants associated with the monoallelic version in 4 unrelated cases. Mild to severe intellectual disability was reported in 2 unrelated cases of monoallelic and 2 unrelated cases of biallelic 2 cases TET3 DNA Demethylation Disorder.
Intellectual disability v3.239 TET3 Sarah Leigh commented on gene: TET3: There is enough evidence for this gene to be rated GREEN at the next major review.
Intellectual disability v3.239 TET3 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype including mild to severe intellectual disability in OMIM and as probable Gen2Phen gene for TET3 DNA Demethylation Disorder biallelic and TET3 DNA Demethylation Disorder monoallelic. At least 9 variants reported in total, with 5 variants associated with the biallelic version of the condition in 3 unrelated cases and 4 variants associated with the monoallelic version in 4 unrelated cases.
Intellectual disability v3.238 TET3 Sarah Leigh Added comment: Comment on phenotypes: This recognized as TET3 DNA Demethylation Disorder biallelic and TET3 DNA Demethylation Disorder monoallelic in Gen2Phen (https://www.ebi.ac.uk/gene2phenotype/search?panel=ALL&search_term=TET3#).
Intellectual disability v3.238 TET3 Sarah Leigh Phenotypes for gene: TET3 were changed from Global developmental delay; Intellectual disability; Macrocephaly; Growth abnormality; Seizures; Autistic behavior; Abnormality of movement; Abnormality of the face to Beck-Fahrner syndrome 618798
Intellectual disability v3.237 AFF3 Sarah Leigh reviewed gene: AFF3: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.236 SUZ12 Sarah Leigh Phenotypes for gene: SUZ12 were changed from Overgrowth; Global developmental delay; Intellectual disability; Accelerated skeletal maturation; Abnormality of the skeletal system; Abnormality of the genitourinary system; Abnormality of the corpus callosum; Abnormality of the respiratory system; Abnormality of the abdominal wall to Imagawa-Matsumoto syndrome 618786
Intellectual disability v3.235 SUZ12 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least 5 variants reported in at least 13 affected individuals from 12 families, of whome 7 had mostly mild intellectual disability.
Intellectual disability v3.234 OXR1 Sarah Leigh edited their review of gene: OXR1: Added comment: There is enough evidence for this gene to be rated GREEN at the next major review.; Changed rating: GREEN
Intellectual disability v3.234 OXR1 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene for Autosomal-Recessive Neurological Disease with Cerebellar Atrophy and Lysosomal Dysfunction. At least 4 variants reported in at least 3 unrelated cases, who all had epilepsy and global developmental delay.
Intellectual disability v3.234 OXR1 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene for Autosomal-Recessive Neurological Disease with Cerebellar Atrophy and Lysosomal Dysfunction. At least 4 variants reported in at least 3 unrelated cases, who all had epilepsy and global developmental delay.
Intellectual disability v3.232 OXR1 Sarah Leigh Phenotypes for gene: OXR1 were changed from Central hypotonia; Global developmental delay; Delayed speech and language development; Intellectual disability; Seizures; Abnormality of the cerebellum to Cerebellar hypoplasia/atrophy, epilepsy, and global developmental delay 213000
Intellectual disability v3.230 SFXN4 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 5 variants reported in at least 3 unreleated cases, with mild to severe intellectual disability.
Intellectual disability v3.228 MTHFS Sarah Leigh edited their review of gene: MTHFS: Added comment: There is enough evidence for this gene to be rated GREEN at the next major review.; Changed rating: GREEN
Intellectual disability v3.228 MTHFS Sarah Leigh Tag for-review tag was added to gene: MTHFS.
Intellectual disability v3.228 MTHFS Sarah Leigh Classified gene: MTHFS as Amber List (moderate evidence)
Intellectual disability v3.228 MTHFS Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 4 variants reported in at least 3 unrelated cases.
Intellectual disability v3.228 MTHFS Sarah Leigh Gene: mthfs has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.227 YARS Sarah Leigh Added comment: Comment on phenotypes: Monoallelic variants are associated with Charcot-Marie-Tooth disease, dominant intermediate C 608323, while biallelic variants are associated with a complex phenotype that may include intellectual disability, hearing loss and liver damage.
Intellectual disability v3.227 YARS Sarah Leigh Phenotypes for gene: YARS were changed from Intellectual disability; deafness; nystagmus; liver dysfunction to Charcot-Marie-Tooth disease, dominant intermediate C 608323; Intellectual disability; deafness; nystagmus; liver dysfunction
Intellectual disability v3.226 PJA1 Zornitza Stark reviewed gene: PJA1: Rating: AMBER; Mode of pathogenicity: None; Publications: 32530565; Phenotypes: Intellectual disability, trigonocephaly; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.226 SCAF4 Zornitza Stark reviewed gene: SCAF4: Rating: GREEN; Mode of pathogenicity: None; Publications: 32730804; Phenotypes: intellectual disability, seizures, behavioral abnormalities; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Intellectual disability v3.226 PIGQ Konstantinos Varvagiannis reviewed gene: PIGQ: Rating: GREEN; Mode of pathogenicity: None; Publications: 32588908, 24463883, 25558065, 31148362; Phenotypes: Epileptic encephalopathy, early infantile, 77 (MIM #618548); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.226 EIF2AK2 Arina Puzriakova Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Intellectual disability v3.225 EIF2AK2 Arina Puzriakova reviewed gene: EIF2AK2: Rating: GREEN; Mode of pathogenicity: None; Publications: 32197074; Phenotypes: Leukoencephalopathy, developmental delay, and episodic neurologic regression syndrome, 618877; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.225 FARSB Arina Puzriakova Added comment: Comment on list classification: Rating Amber following consultation with the clinical team in view of the inconsistent phenotype. Patients are more likely to be recognised on the basis of other phenotypic features, for which FARSB has been rated Green
Intellectual disability v3.224 FARSB Arina Puzriakova reviewed gene: FARSB: Rating: AMBER; Mode of pathogenicity: None; Publications: 29573043, 29979980, 30014610; Phenotypes: Rajab interstitial lung disease with brain calcifications, 613658; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.224 IREB2 Arina Puzriakova Added comment: Comment on list classification: Phenotype is appropriate for this panel, but additional cases necessary to support causation. Therefore rated Amber, awaiting further publications/clinical evidence (added to watchlist).
Intellectual disability v3.223 IREB2 Arina Puzriakova reviewed gene: IREB2: Rating: ; Mode of pathogenicity: None; Publications: 30915432, 31243445; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.223 CHD1 Arina Puzriakova changed review comment from: Gene is associated with Pilarowski-Bjornsson syndrome in OMIM, but not in G2P.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Biallelic variants:

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

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


Monoallelic disruption of ZNF407:

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

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

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

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

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

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

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

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

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

Overall this gene can be considered for inclusion in the ID panel with green rating.
Sources: Literature
Intellectual disability v3.218 NCAPH Arina Puzriakova gene: NCAPH was added
gene: NCAPH was added to Intellectual disability. Sources: Literature
watchlist tags were added to gene: NCAPH.
Mode of inheritance for gene: NCAPH was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NCAPH were set to 27737959
Phenotypes for gene: NCAPH were set to Microcephaly 23, primary, autosomal recessive, 617985
Added comment: Associated with Microcephaly 23 in OMIM and a possible gene for microcephaly in G2P.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

As discussed by Pohl et al:

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

All subjects harbored biallelic pLoF variants.

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

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

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

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

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

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

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

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

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

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

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

Gene not associated with any phenotype on OMIM or G2P.
Intellectual disability v3.156 GNAI2 Arina Puzriakova reviewed gene: GNAI2: Rating: AMBER; Mode of pathogenicity: None; Publications: 31036916, 27787898; Phenotypes: Syndromic developmental disorder; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.156 NRROS Sarah Leigh Phenotypes for gene: NRROS were changed from neurodegeneration; intracranial calcification; epilepsy to Seizures, early-onset, with neurodegeneration and brain calcification 618875
Intellectual disability v3.155 NRROS Sarah Leigh Deleted their comment
Intellectual disability v3.155 NRROS Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene for NRROS-related Infantile-Onset Neurodegeneration with Intracranial Calcification. At least 6 variants reported in at least 5 unrelated cases (PMIDs 32100099;32197075), together with supportive mouse model (PMID 28459434).
Intellectual disability v3.154 NRROS Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene for NRROS-related Infantile-Onset Neurodegeneration with Intracranial Calcification. At least 6 variants reported in at least 5 unrelated cases (PMIDs 32100099;32197075), together with supportive mouse model (PMID 28459434).
Intellectual disability v3.153 NRROS Sarah Leigh reviewed gene: NRROS: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.153 FEM1B Arina Puzriakova reviewed gene: FEM1B: Rating: RED; Mode of pathogenicity: None; Publications: 31036916; Phenotypes: Global developmental delay; Mode of inheritance: None
Intellectual disability v3.153 NOVA2 Sarah Leigh Deleted their comment
Intellectual disability v3.153 NOVA2 Sarah Leigh edited their review of gene: NOVA2: Added comment: There is enough evidence for this gene to be rated GREEN at the next major review.; Changed rating: GREEN
Intellectual disability v3.153 NOVA2 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least 6 terminating variants reported in unrelated cases, together supportive functional studies in a zebrafish knockdown of the NOVA2 ortholog (nova1a) (PMID 32197073).
Intellectual disability v3.152 NOVA2 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least 6 terminating variants reported in unrelated cases, together supportive functional studies in a zebrafish knockdown of the NOVA2 ortholog (nova1a) (PMID 32197073).
Intellectual disability v3.151 NOVA2 Sarah Leigh Phenotypes for gene: NOVA2 were changed from Intellectual disability; autism; hypotonia; spasticity; ataxia to Neurodevelopmental disorder with or without autistic features and/or structural brain abnormalities 618859
Intellectual disability v3.150 CDK19 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least 2 variants reported in 3 unrelated cases, together with supportive Drosophila, demonstating the effects of the variants (PMID 32330417).
Intellectual disability v3.149 CDK19 Sarah Leigh Phenotypes for gene: CDK19 were changed from microcephaly, congenital bilateral falciform retinal folds, nystagmus, and mental retardation to Epileptic encephalopathy, early infantile, 87 618916
Intellectual disability v3.147 WIPI2 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 1 homozygous variant was reported in 4 members of a consanguineous family.
Intellectual disability v3.146 WIPI2 Sarah Leigh Phenotypes for gene: WIPI2 were changed from Intellectual developmental disorder with short stature and variable skeletal anomalies 618453 to ?Intellectual developmental disorder with short stature and variable skeletal anomalies 618453
Intellectual disability v3.145 GSX2 Sarah Leigh changed review comment from: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 2 variants reported in at least 2 unrealated cases.; to: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 2 variants reported in at least 2 unrealated cases, together with supportive functional studies (PMID 31412107).
Intellectual disability v3.145 GSX2 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 2 variants reported in at least 2 unrealated cases.
Intellectual disability v3.144 YARS Sarah Leigh changed review comment from: Comment on list classification: Biallelic variants in three families with complex clinical conditions including developmental delay.; to: Comment on list classification: Biallelic variants in three families with complex clinical conditions including developmental delay. PMID 30304524 reports an extended family with microcephaly, expressive language delay, hearing loss, amongst other features. PMID 29232904 reports a proband whose phenotype included hearing loss, retnititis pigmentosa and hypotonia, but did not include intellectual disability. PMID 27633801 reports two sibblings with hypotionia, the older brother at 15 years of age has mild delays, he attends school on an individualized educational program and functions at a grade 3 level. He speaks and understands English and Polish.
Intellectual disability v3.144 YARS Sarah Leigh Added comment: Comment on list classification: Biallelic variants in three families with complex clinical conditions including developmental delay.
Intellectual disability v3.143 CACNB4 Sarah Leigh Deleted their comment
Intellectual disability v3.141 CACNB4 Sarah Leigh Mode of inheritance for gene: CACNB4 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.139 RSRC1 Sarah Leigh commented on gene: RSRC1: There is enough evidence for this gene to be rated GREEN at the next major review.
Intellectual disability v3.139 RSRC1 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least 9 variants reported in unrelated families.
Intellectual disability v3.135 RIC1 Sarah Leigh Deleted their comment
Intellectual disability v3.134 RIC1 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as possible Gen2Phen gene. At least one variant reported in numerous members of two families, who shared an autozygous interval, confirming Founder effect (PMID 27878435). Segregation was demonstrated, together with supportive functional and zebra fish model (PMID 31932796).
Intellectual disability v3.134 RIC1 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as possible Gen2Phen gene. At least one variant reported in numerous members of two families, who shared an autozygous interval, confirming Founder effect (PMID 27878435). Segregation was demonstrated, together with supportive functional and zebra fish model (PMID 31932796).
Intellectual disability v3.133 RIC1 Sarah Leigh Phenotypes for gene: RIC1 were changed from Cleft lip; cataract; tooth abnormality; intellectual disability; facial dysmorphism; ADHD to CATIFA syndrome 618761; Cleft lip; cataract; tooth abnormality; intellectual disability; facial dysmorphism; ADHD
Intellectual disability v3.132 OTUD7A Sarah Leigh Added comment: Comment on list classification: Not associated with phenotype in OMIM or in Gen2Phen, Although the region ISCA-46295-Loss, which encompasses the OTUD7A locus, is associated with seizures 20236110, mental retardation 22775350, dysmorphic features, developmental delay and severe epileptic encephalopathy. PMID 31997314 report a homozygous variant in a case of severe global developmental delay, language impairment and epileptic encephalopathy; segregation and functional studies support this gene disease association.
Intellectual disability v3.130 TOMM70 Eleanor Williams changed review comment from: Not associated with a disease phenotype in OMIM or Gene2Phenotype

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

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

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

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

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

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

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

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

3 cases but different mode of inheritance and phenotypic presentation.
Sources: Literature
Intellectual disability v3.127 CAPZA2 Eleanor Williams gene: CAPZA2 was added
gene: CAPZA2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: CAPZA2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CAPZA2 were set to 32338762
Review for gene: CAPZA2 was set to AMBER
Added comment: Not associated with a disease phenotype in OMIM.

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

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

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

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

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

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

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

The gene has ubiquitous expression, highest in brain.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

YIF1B encodes an intracellular transmembrane protein.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

There were no studies performed for the identified variants.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Overexpression in HEK293T cells demonstrated predominantly nuclear localization.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

The nonsense variant demonstrated abnormal subnuclear localization.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[Review modified to add additional reference/case report]
Intellectual disability v2.1140 AKAP17A Rebecca Foulger Deleted their review
Intellectual disability v2.1140 AKAP17A Rebecca Foulger Deleted their comment
Intellectual disability v2.1140 AKAP17A Rebecca Foulger changed review comment from: Comment on mode of inheritance: Set MOI to BIALLELIC. Pseudoautosomal region 1. Mode of inheritance has not been thoroughly checked, but assumed to be biallelic.; to: Comment on mode of inheritance: This gene is in the pseudoautosomal region shared between chromosomes X and Y. The mode of inheritance should therefore be set to Biallelic or Monoallelic once more cases establish the inheritance pattern.
Intellectual disability v2.1140 CSF2RA Rebecca Foulger Mode of inheritance for gene: CSF2RA was changed from X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v2.1139 AKAP17A Rebecca Foulger Added comment: Comment on mode of inheritance: Set MOI to BIALLELIC. Pseudoautosomal region 1. Mode of inheritance has not been thoroughly checked, but assumed to be biallelic.
Intellectual disability v2.1138 FA2H Rebecca Foulger Phenotypes for gene: FA2H were changed from Spastic paraplegia 35, autosomal recessive, 612319 to Spastic paraplegia 35, autosomal recessive, 612319; spastic paraplegia with ID; cognitive defects; Seizures
Intellectual disability v2.1136 FA2H Rebecca Foulger Added comment: Comment on list classification: Upgraded from Amber to Green based on Green review by Alistair Pagnamenta: PMID:31135052 analysed a cohort of 19 cases with biallelic FA2H variants. Phenotype includes spastic paraplegia associated with ID: mild cognitive deficits were noted from childhood in 93% of cases, and were considered progressive in all but two cases.
Intellectual disability v2.1135 TRAPPC4 Konstantinos Varvagiannis gene: TRAPPC4 was added
gene: TRAPPC4 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: TRAPPC4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TRAPPC4 were set to 31794024
Phenotypes for gene: TRAPPC4 were set to Feeding difficulties; Progressive microcephaly; Intellectual disability; Seizures; Spastic tetraparesis; Abnormality of the face; Scoliosis; Cortical visual impairment; Hearing impairment
Penetrance for gene: TRAPPC4 were set to Complete
Review for gene: TRAPPC4 was set to GREEN
Added comment: Van Bergen et al. (2019 - PMID: 31794024) report on 7 affected individuals from 3 famillies (only 1 of which consanguineous), all homozygous for a TRAPPC4 splicing variant.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

4 affected individuals from 3 families have been reported.

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

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

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

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

4 affected individuals from 3 families have been reported.

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

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

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

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

4 affected individuals from 3 families have been reported.

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

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

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

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

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

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

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

Identified variants affected (probably all - fig1D) transcripts expressed in the CNS, namely NM_018002.3, NM_001198532.1, NM_181354.4. The 3 transcripts not expressed in the CNS are NM_001198533.1, NM_001198534.1 and NM_001198535.1.

Western blot with 2 different antibodies which would bind upstream of the truncation site failed to detect presence of truncated proteins in 2 affected individuals from 2 families.

The Drosophila homolog of OXR is mustard (mtd). The authors provide evidence that loss of mtd is lethal. This was however rescued by expression of an 80kb fly BAC clone covering mtd, or the fly mtd-RH isoform cDNA, or a short human OXR1 cDNA containing only the TLDc domain or a human NCOA7 cDNA. The latter is another human mtd homolog which also contains the TLDc domain. As a result the TLDc domain compensated sufficiently for loss of mtd.

Flies that survived displayed bang sensitivity and climbing defects the former assay being suggestive of susceptibility to seizures and the latter of impaired neurological/muscular function.

The authors provided evidence that mtd is broadly expressed in the fly CNS. RNAi mediated mtd knockdown specific to neurons (elav/nSyb-GAL4 expression of mtd RNAi) led to lethal eclosion defects for RNAis targeting most (18)/all(23) mtd isoforms. Lifespan was increased upon expression of human OXR1 cDNA. Neuronal loss and vacuolization was demonstrated and additional experiments in R7 photoreceptors showed presence of aberrant lysosomal structures (autolysosomes, autophagosomes and/or endolysosomes).

Aberrant lysosomal structures were also observed in fibroblasts from affected individuals (accumulation of lysosomes and/or presence of highly aberrant compartments with content typical of lysosomal dysfunction).

Overall the data presented suggest a critical role for OXR1 in lysosomal biology.

Although previous reports suggested that OXR1 is involved in oxidative stress resistance, studies performed by the authors suggested that oxidative stress is probably not the driver of the mutant fly defects.
Sources: Literature
Intellectual disability v2.1133 PCYT2 Ellen McDonagh Added comment: Comment on list classification: This gene was added by an external reviewer and rated Green. This is currently Green on the Hereditary spastic paraplegia gene panel (Version 1.210), and confirmed with Zerin Hyder (Genomics England Clinical Team) that this is appropriate to be Green on the ID panel.
Intellectual disability v2.1132 SVBP Rebecca Foulger Added comment: Comment on list classification: Updated rating to Green to match Green review by Catherine Snow. Phenotypes include global DD and intellectual disability in >3 families.
Intellectual disability v2.1129 PNPT1 Konstantinos Varvagiannis changed review comment from: Biallelic PNPT1 pathogenic variants cause Combined oxidative phosphorylation deficiency 13 (MIM 614932). Despite phenotypic variability - common to disorders resulting from mitochondrial dysfunction - DD and ID of relevant severity to the current panel have been reported in several individuals published in the literature. Seizures may also be observed.

Rius et al (2019 - PMID: 31752325) provide an overview of 24 affected individuals (7 new and 17 from previous studies). Neurodevelopmental features are summarized in fig.1 and additional details are provided in the supplement. Based on this review, seizures were present in 7 individuals (of the 18 for whom this information was available).

PNPT1 encodes the mitochondrial polynucleotide phosphorylase, involved in the import of nuclear-encoded RNA to mitochondria. Loss of its activity has been shown to result in combined respiratory chain deficiency. However, as discussed by Rius et al and previous articles as well, OXPHOS studies in affected individuals may be normal or suggestive of only mild impairement due to tissue specificity and different assay methods used (eg. spectrophotometric vs dipstick activity assays). The same applies to lactate which was normal or mildly elevated in some affected individuals.

Missense, pLoF function variants as well as a synonymous one leading to aberrant splicing (NM_033109.4:c.1818T>G) have been reported.

Overall, this gene might be considered for upgrade to green rating.; to: Biallelic PNPT1 pathogenic variants cause Combined oxidative phosphorylation deficiency 13 (MIM 614932). Despite phenotypic variability - common to disorders resulting from mitochondrial dysfunction - DD and ID of relevant severity to the current panel have been reported in several individuals published in the literature. Seizures may also be observed.

Rius et al (2019 - PMID: 31752325) provide an overview of 24 affected individuals (7 new and 17 from previous studies). Neurodevelopmental features are summarized in fig.1 and additional details are provided in the supplement. Based on this review, seizures were present in 7 individuals (of the 18 for whom this information was available).

PNPT1 encodes the mitochondrial polynucleotide phosphorylase, involved in the import of nuclear-encoded RNA to mitochondria. Loss of its activity has been shown to result in combined respiratory chain deficiency. However, as discussed by Rius et al and previous articles as well, OXPHOS studies in affected individuals may be normal or suggestive of only mild impairment due to tissue specificity and different assay methods used (eg. spectrophotometric vs dipstick activity assays). The same applies to lactate which was normal or mildly elevated in some affected individuals.

Missense, pLoF function variants as well as a synonymous one leading to aberrant splicing (NM_033109.4:c.1818T>G) have been reported.

Overall, this gene might be considered for upgrade to green rating.
Intellectual disability v2.1129 PNPT1 Konstantinos Varvagiannis reviewed gene: PNPT1: Rating: GREEN; Mode of pathogenicity: None; Publications: 31752325; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v2.1128 NTNG2 Ellen McDonagh Added comment: Comment on list classification: Gene added by external reviewer and rated Green. 11 unrelated families reported with homozygous variants in this gene with a neurodevelopmental disorder including global developmental delay, plus functional evidence. Promoted to Green.
Intellectual disability v2.1128 PIK3C2A Catherine Snow gene: PIK3C2A was added
gene: PIK3C2A was added to Intellectual disability. Sources: Expert Review
Mode of inheritance for gene: PIK3C2A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PIK3C2A were set to 31034465
Phenotypes for gene: PIK3C2A were set to Oculoskeletodental syndrome, 618440
Review for gene: PIK3C2A was set to AMBER
Added comment: PIK3C2A is on a number of panels including a Green rating on Skeletal dysplasia (Version 1.244) clinical support advised that as PIK3C2A phenotype includes DD, gene should be rated as Amber on this panel.
Sources: Expert Review
Intellectual disability v2.1127 ZNF292 Catherine Snow Deleted their review
Intellectual disability v2.1127 ZNF292 Catherine Snow edited their review of gene: ZNF292: Changed rating: AMBER
Intellectual disability v2.1127 ZNF292 Catherine Snow reviewed gene: ZNF292: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v2.1127 FAM160B1 Ellen McDonagh Added comment: Comment on list classification: Gene added by external reviewer, and promoted from grey to Red as the function of the protein/gene is still unknown at this stage. One family and another unrelated individual reported with developmental delay/ID and variants in this gene, however this will be kept red until further evidence arises.
Intellectual disability v2.1125 ZNF292 Ellen McDonagh Added comment: Comment on list classification: Gene added by external reviewer. Promoted from grey to Amber due to the evidence presented, and reflecting the rating of 'probable' in Gene2Phenotype for ZNF292-related developmental disorder. At this stage, this has not been made Green due to uncertainty regarding the penetrance and the comment from the reviewer regarding manual review of some relevant LoF variants in gnomAD suggested that they represent false positive calls.
Intellectual disability v2.1123 AP1B1 Catherine Snow reviewed gene: AP1B1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v2.1122 FDFT1 Catherine Snow reviewed gene: FDFT1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v2.1122 TMX2 Konstantinos Varvagiannis edited their review of gene: TMX2: Changed publications: 31586943, 31270415, 31735293
Intellectual disability v2.1122 TMX2 Konstantinos Varvagiannis edited their review of gene: TMX2: Added comment: A recent report by Vandervore, Schot et al. following the previous review (Am J Hum Genet. 2019 Nov 12 - PMID: 31735293), provides further evidence that biallelic TMX2 mutations cause malformations of cortical development, microcephaly, DD and ID and epilepsy.

As a result this gene should probably be considered for inclusion in the ID/epilepsy panels with green rating.

Overall, 14 affected subjects from 10 unrelated families are reported in the aforementioned study. The majority had severe DD/ID (failure to achieve milestones, absent speech/ambulation and signs of cerebral palsy) with few having a somewhat milder impairment. 12 (of the 14) presented with epilepsy (spasms, myoclonic seizures, focal seizures with/without generalization or generalized tonic-clonic seizures) with onset most often in early infancy. Upon brain MRI (in 12 individuals), 5 presented polymicrogyria, 2 others pachygyria, 4 with brain atrophy, etc.

All individuals were found to harbor biallelic TMX2 mutations by exome sequencing while previous investigations in several had ruled out alternative causes (infections, metabolic or chromosomal anomalies). Missense variants, an in-frame deletion as well as pLoF (stopgain/frameshift) variants were reported. [NM_015959.3 used as ref below].

The effect of variants was supported by mRNA studies, eg. RT-qPCR/allele specific RT-qPCR. The latter proved reduced expression for a frameshift variant (c.391dup / p.Leu131Profs*6) most likely due to NMD. Total mRNA levels were also 23% lower in an individual compound htz for a missense variant and a stopgain one localized in the last exon (c.757C>T / p.Arg253*). As for the previously reported c.614G>A (p.Arg205Gln), affecting the last nucleotide of exon 6, total mRNA in skin fibroblasts from a homozygous individual was not significantly decreased. RNA-Seq however demonstrated the presence of 4 different transcripts (roughly 25% each), one representing the regular mRNA, one with intron 6 retention (also present at low levels in healthy individuals), one with loss of 11 nucleotides within exon 6 and a fourth one due to in-frame skipping of exon 6.

*To the best of my understanding :

Thioredoxin (TRX)-related transmembrane proteins (TMX) belong to the broader family of oxidoreductases of protein disulfide isomerase (PDI) having an important role in protein folding.

Study of the data from the Allen Human Brain Atlas suggest relevant fetal expression also increasing during postnatal life.

As RNA-seq was carried out for 2 individuals, GO analysis suggested that the most deregulated clusters of genes are implicated in post-translational protein modifications (as would be expected for PDIs), membranes and synapse while pathway analysis suggested that relevant categories were inhibited eg. nervous system development/function and cell growth/proliferation/survival.

Upon transfection of HEK293T cells, exogenous TMX2 was shown to co-localize with calnexin (CNX) to the (ER) mitochondria-associated-membrane. Mass-spectrometry based analysis of co-immunoprecipitated proteins confirmed interaction with CNX but also other regulators of calcium homeostasis, mitochondrial membrane components and respiratory chain NADH dehydrogenase.

Study of the mitochondrial activity of TMX2-deficient fibroblasts suggested reduced respiratory reserve capacity, compensated by increased glycolytic activity.

TMX2 occurs in both reduced and oxidized monomeric form. It also forms (homo)dimers with the ratio of dimers/monomers increasing under conditions of oxidative stress. Variant TMX2 increased propensity to form dimers, thus mimicking increased oxidative state. This was observed under stress but also under native conditions.

---------; Changed rating: GREEN
Intellectual disability v2.1122 WDFY3 Ivone Leong Added comment: Comment on list classification: Gene promoted from Red to Amber based on evidence provided by expert reviewer. All affected individuals have mild-moderate ID, therefore the gene has been rated Amber.
Intellectual disability v2.1119 IQSEC1 Catherine Snow reviewed gene: IQSEC1: Rating: AMBER; Mode of pathogenicity: None; Publications: 31607425; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v2.1119 SVBP Catherine Snow Phenotypes for gene: SVBP were changed from Neurodevelopmental disorder with ataxia, hypotonia, and microcephaly, 618569 to Neurodevelopmental disorder with ataxia, hypotonia, and microcephaly, 618569
Intellectual disability v2.1119 SVBP Catherine Snow Phenotypes for gene: SVBP were changed from Neurodevelopmental disorder with ataxia, hypotonia, and microcephaly, 618569 to Neurodevelopmental disorder with ataxia, hypotonia, and microcephaly, 618569
Intellectual disability v2.1119 SVBP Catherine Snow Phenotypes for gene: SVBP were changed from to Neurodevelopmental disorder with ataxia, hypotonia, and microcephaly, 618569
Intellectual disability v2.1117 SVBP Catherine Snow reviewed gene: SVBP: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with ataxia, hypotonia, and microcephaly, 618569; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v2.1117 NSF Ivone Leong Added comment: Comment on list classification: New gene submitted by expert reviewed. Based on the evidence provided it was decided that there is currently not enough evidence to establish a gene-phenotype association. Therefore, this gene has been given a Red rating.
Intellectual disability v2.1116 KCNT2 Ivone Leong Added comment: Comment on list classification: New gene submitted by expert reviewer. Based on the evidence provided it was decided that there is enough evidence for this gene to be given Green status.
Intellectual disability v2.1115 KCNT2 Ivone Leong Added comment: Comment on mode of pathogenicity: Variants have gain-of-function effect.
Intellectual disability v2.1115 KCNT2 Ivone Leong Mode of pathogenicity for gene: KCNT2 was changed from None to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Intellectual disability v2.1114 KCNT2 Ivone Leong Phenotypes for gene: KCNT2 were changed from ?Epileptic encephalopathy, early infantile 57, MIM 617771 to ?Epileptic encephalopathy, early infantile 57, 617771
Intellectual disability v2.1113 TMX2 Ivone Leong Added comment: Comment on list classification: New gene submitted by expert reviewer. Based on the submitted evidence the gene has been given an Amber rating until further evidence is available to promote it to Green status.
Intellectual disability v2.1112 CNOT2 Ivone Leong Added comment: Comment on list classification: New gene added by expert reviewer. There is enough evidence to promote this gene to Green status.
Intellectual disability v2.1111 CNOT2 Ivone Leong Phenotypes for gene: CNOT2 were changed from Intellectual developmental disorder with nasal speech, dysmorphic facies, and variable skeletal anomalies, MIM 618608 to Intellectual developmental disorder with nasal speech, dysmorphic facies, and variable skeletal anomalies, 618608
Intellectual disability v2.1109 DMXL2 Ivone Leong Phenotypes for gene: DMXL2 were changed from Sensorineural Hearing Loss; ORPHA90636; OMIM:612186 to Sensorineural Hearing Loss; ORPHA90636; Epileptic encephalopathy, early infantile, 81, 618663; ?Polyendocrine-polyneuropathy syndrome, 616113
Intellectual disability v2.1107 VAMP7 Eleanor Williams Added comment: Comment on mode of inheritance: This gene is in the pseudoautosomal region shared between chromosomes X and Y. The mode of inheritance should therefore be set to Biallelic or Monoallelic once more cases establish the inheritance pattern.
Intellectual disability v2.1107 VAMP7 Eleanor Williams Mode of inheritance for gene: VAMP7 was changed from X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) to Unknown
Intellectual disability v2.1106 SPRY3 Eleanor Williams Added comment: Comment on mode of inheritance: This gene is in the pseudoautosomal region shared between chromosomes X and Y. The mode of inheritance should therefore be set to Biallelic or Monoallelic once more cases establish the inheritance pattern.
Intellectual disability v2.1106 SPRY3 Eleanor Williams Mode of inheritance for gene: SPRY3 was changed from X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) to Unknown
Intellectual disability v2.1105 SLC25A6 Eleanor Williams Added comment: Comment on mode of inheritance: This gene is in the pseudoautosomal region shared between chromosomes X and Y. The mode of inheritance should therefore be set to Biallelic or Monoallelic once more cases establish the inheritance pattern.
Intellectual disability v2.1105 SLC25A6 Eleanor Williams Mode of inheritance for gene: SLC25A6 was changed from X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) to Unknown
Intellectual disability v2.1104 P2RY8 Eleanor Williams Added comment: Comment on mode of inheritance: This gene is in the pseudoautosomal region shared between chromosomes X and Y. The mode of inheritance should therefore be set to Biallelic or Monoallelic once more cases establish the inheritance pattern.
Intellectual disability v2.1104 P2RY8 Eleanor Williams Mode of inheritance for gene: P2RY8 was changed from X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) to Unknown
Intellectual disability v2.1103 PLCXD1 Eleanor Williams Added comment: Comment on mode of inheritance: This gene is in the pseudoautosomal region shared between chromosomes X and Y. The mode of inheritance should therefore be set to Biallelic or Monoallelic once more cases establish the inheritance pattern.
Intellectual disability v2.1103 PLCXD1 Eleanor Williams Mode of inheritance for gene: PLCXD1 was changed from X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) to Unknown
Intellectual disability v2.1102 DMXL2 Konstantinos Varvagiannis changed review comment from: This gene can be considered for upgrade to green rating (ID and epilepsy with >=4 relevant individuals/families/variants and >=2 studies, role of the protein, effect of variants in most cases demonstrated, phenotypic similarities with other disorders affecting autophagy, some evidence from animal models, etc).

Rare heterozygous variants disrupting DMXL2 (intragenic losses/gains, SNVs, CNVs affecting also additional genes) have been reported in individuals with variable neurodevelopmental disorders (ASD and ID) or psychiatric phenotypes [Costain et al. 2019 - PMID: 30732576 - summarized in Table 1]. (Highly) variable expressivity and possibly incomplete penetrance were proposed in the respective study. As a result evidence for ID/seizures due to monoallelic variants appears to be relatively limited.

DD, ID and (probably) epilepsy appear however to be features in several individuals with biallelic pathogenic variants as summarized in the studies below.

OMIM recently added a relevant entry with the DMXL2-associated phenotypes being the following:
- Epileptic encephalopathy, early infantile, 81; EIEE81 - 618663 (AD) [based on refs 2,3]
- ?Deafness, autosomal dominant 71 - 617605 (AD) [DD/ID/seizures are not part of the phenotype]
- ?Polyendocrine-polyneuropathy syndrome - 616113 (AR) [based on ref1]

DMXL2 is not associated with any phenotype in G2P. In SysID it is listed as a candidate ID gene based on the report by Tata et al (ref1). This gene is included in some gene panels for ID.

[1] Tata el al. (2014 - PMID: 25248098) reported on 3 sibs born to consanguineous Senegalese parents, presenting with a progressive endocrine and neurodevelopmental disorder. Features incl. incomplete puberty, central hypothyroidism, abnormal glucose regulation, moderate ID (3/3) and peripheral polyneuropathy. Seizures were not part of the phenotype. Linkage analysis suggested 2 candidate regions on chromosomes 13 and 15 with a LOD score of 2.5. High throughput sequencing of genes within these regions (~500) in an affected member and parent revealed a 15 bp in-frame deletion of DMXL2 (NM_015263.4:c.5827_5841del / p.Asp1943_Ser1947del). Sanger sequencing of other affected and unaffected members supported AR inheritance. RT-qPCR demonstrated that DMXL2 mRNA levels in blood lymphocytes were significantly lower in homozygous patients compared to heterozygous or wt family members or controls. The authors demonstrated that the encoded protein (rabconnectin-3a) is a synaptic protein (expressed in exocytosis vesicles) at the ends of axons of GnRH producing neurons. Neuron-specific deletion of one allele in mice resulted in delayed puberty and very low fertility. Adult mice had lower number of GnRH neurons in hypothalamus. siRNA-mediated downregulation of Dmxl2 expression in an insulin-secreting cell line resulted in only slight insulin secretion in response to augmenting concentrations of glucose, providing evidence of involvement of the protein in control of regulated insulin secretion.
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[2] Maddirevula et al. (2019 - PMID: 30237576) reported briefly on a 36 months old boy, born to consanguineous parents, homozygous for a frameshift DMXL2 variant [individual 17-3220 | NM_001174117.1:c.4349_4350insTTACATGA or p.(Glu1450Aspfs*23)]. Features included focal seizures (onset at the age of 3m) with subsequent global DD, absent eye contact, cerebral atrophy and macrocephaly. This individual was identified following re-evaluation of exome data in a database of ~1550 exomes specifically for homozygous variants that would have been classified earlier as LP/P if the respective gene had sufficient evidence for association with a disorder. The family was not reported to have other affected members. As the authors noted, the boy was not known to have the multi-endocrine abnormalities reported by Tata et al. There are no additional information provided (eg. on confirmation of variants, etc).
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[3] Esposito et al. (2019 - PMID: 31688942) report on 3 sibling pairs (all 3 families unrelated) with biallelic DMXL2 mutations and summarize previous evidence on the gene and the DMXL2-related phenotypes.

All presented a highly similar phenotype of Ohtahara syndrome (seizures with onset in the first days of life, tonic/myoclonic/occasionaly focal, burst-suppression upon EEG), profound DD/ID, quadriparesis, sensorineural hearing loss and presence of dysmorphic features. Sibs from 2 families presented evidence of peripheral polyneuropathy. Early brain MRIs revealed thin CC and hypomyelination in all, with later scans suggestive of gray and white matter shrinkage with leukoencephalopathy. None achieved developmental skills following birth with 5/6 deceased by the age of 9 years.

Exome sequencing revealed biallelic DMXL2 variants in all, with compatible parental segregation studies (NM_015263.3):
- Fam1 (2 sibs) : c.5135C>T (p.Ala1712Val) in trans with c.4478C>G (p.Ser1493*)
- Fam2 (2 sibs) : homozygosity for c.4478C>A (p.Ser1493*)
- Fam3 (2 sibs) : homozygosity for c.7518-1G>A

Heterozygous parents (aged 39-59) did not exhibit hearing impairment [report of a single multigenerational family by Chen et al (2017 - PMID: 27657680) where a heterozygous missense variant segregated with hearing loss - respective OMIM entry: ?Deafness, autosomal dominant 71 - 617605].

In patients' fibroblasts, effect of the variants on mRNA/protein expression was demonstrated with mRNA expressed only in a patient from family 1, and degraded/absent for the 2 stopgain SNVs affecting codon 1493. Skipping of ex31 leading to frameshift/introduction of a PTC was shown for the splice variant (p.Trp2508Argfs*4 secondary to c.7518-1G>A). Protein was also absent upon western-blot.

DMXL2 encodes a vesicular protein, DmX-Like protein 2 or rabconnectin-3a (cited Tata et al).

The gene is expressed in brain ( https://www.gtexportal.org/home/gene/DMXL2 ).

As Esposito et al comment, it is known to regulate the trafficking and activity of v-ATPase the latter having a role in acidifying intracellular organelles and promoting endosomal maturation (cited PMIDs : 25248098, 19758563, 22875945, 24802872).

In line with this, staining of patients' fibroblasts using the acidotropic dye LysoTracker demonstrated increased signal, reversed by re-expression of DMXL2 protein. Overall an acidic shift in pH with impairment of lysosomal structures and function was suggested. The authors provided additional evidence for altered lysosomal function and associated autophagy with accumulation of autophagy receptors (eg p62) and substrates (polyubiquitinated proteins). Vacuolization and accumulation of atypical fusion-like structures was shown upon ultrastractural analysis.

shRNA-mediated downregulation/silencing of Dmxl2 in mouse hippocampal neurons resulted also in altered lysosomal structures and defective autophagy. The neurons exhibited impaired neurite elongation and synapse formation.

The authors suggest similarities with Vici syndrome, where biallelic EPG5 mutations result in autophagic defects and clinical manifestations of DD/ID/epilepsy.

Dmxl2 homozygous ko mice display embryonic lethality with heterozygous mice displaying macrocephaly and corpus callosum dysplasia (cited PMIDs: 25248098, 30735494) .; to: This gene can be considered for upgrade to green rating (ID and epilepsy with >=4 relevant individuals/families/variants and >=2 studies, role of the protein, effect of variants in most cases demonstrated, phenotypic similarities with other disorders affecting autophagy, some evidence from animal models, etc).

Rare heterozygous variants disrupting DMXL2 (intragenic losses/gains, SNVs, CNVs affecting also additional genes) have been reported in individuals with variable neurodevelopmental disorders (ASD and ID) or psychiatric phenotypes [Costain et al. 2019 - PMID: 30732576 - summarized in Table 1]. (Highly) variable expressivity and possibly incomplete penetrance were proposed in the respective study. As a result evidence for ID/seizures due to monoallelic variants appears to be relatively limited.

DD, ID and (probably) epilepsy appear however to be features in several individuals with biallelic pathogenic variants as summarized in the studies below.

OMIM recently added a relevant entry with the DMXL2-associated phenotypes being the following:
- Epileptic encephalopathy, early infantile, 81; EIEE81 - 618663 (AR) [based on refs 2,3]
- ?Deafness, autosomal dominant 71 - 617605 (AD) [DD/ID/seizures are not part of the phenotype]
- ?Polyendocrine-polyneuropathy syndrome - 616113 (AR) [based on ref1]

DMXL2 is not associated with any phenotype in G2P. In SysID it is listed as a candidate ID gene based on the report by Tata et al (ref1). This gene is included in some gene panels for ID.

[1] Tata el al. (2014 - PMID: 25248098) reported on 3 sibs born to consanguineous Senegalese parents, presenting with a progressive endocrine and neurodevelopmental disorder. Features incl. incomplete puberty, central hypothyroidism, abnormal glucose regulation, moderate ID (3/3) and peripheral polyneuropathy. Seizures were not part of the phenotype. Linkage analysis suggested 2 candidate regions on chromosomes 13 and 15 with a LOD score of 2.5. High throughput sequencing of genes within these regions (~500) in an affected member and parent revealed a 15 bp in-frame deletion of DMXL2 (NM_015263.4:c.5827_5841del / p.Asp1943_Ser1947del). Sanger sequencing of other affected and unaffected members supported AR inheritance. RT-qPCR demonstrated that DMXL2 mRNA levels in blood lymphocytes were significantly lower in homozygous patients compared to heterozygous or wt family members or controls. The authors demonstrated that the encoded protein (rabconnectin-3a) is a synaptic protein (expressed in exocytosis vesicles) at the ends of axons of GnRH producing neurons. Neuron-specific deletion of one allele in mice resulted in delayed puberty and very low fertility. Adult mice had lower number of GnRH neurons in hypothalamus. siRNA-mediated downregulation of Dmxl2 expression in an insulin-secreting cell line resulted in only slight insulin secretion in response to augmenting concentrations of glucose, providing evidence of involvement of the protein in control of regulated insulin secretion.
-----------
[2] Maddirevula et al. (2019 - PMID: 30237576) reported briefly on a 36 months old boy, born to consanguineous parents, homozygous for a frameshift DMXL2 variant [individual 17-3220 | NM_001174117.1:c.4349_4350insTTACATGA or p.(Glu1450Aspfs*23)]. Features included focal seizures (onset at the age of 3m) with subsequent global DD, absent eye contact, cerebral atrophy and macrocephaly. This individual was identified following re-evaluation of exome data in a database of ~1550 exomes specifically for homozygous variants that would have been classified earlier as LP/P if the respective gene had sufficient evidence for association with a disorder. The family was not reported to have other affected members. As the authors noted, the boy was not known to have the multi-endocrine abnormalities reported by Tata et al. There are no additional information provided (eg. on confirmation of variants, etc).
-----------
[3] Esposito et al. (2019 - PMID: 31688942) report on 3 sibling pairs (all 3 families unrelated) with biallelic DMXL2 mutations and summarize previous evidence on the gene and the DMXL2-related phenotypes.

All presented a highly similar phenotype of Ohtahara syndrome (seizures with onset in the first days of life, tonic/myoclonic/occasionaly focal, burst-suppression upon EEG), profound DD/ID, quadriparesis, sensorineural hearing loss and presence of dysmorphic features. Sibs from 2 families presented evidence of peripheral polyneuropathy. Early brain MRIs revealed thin CC and hypomyelination in all, with later scans suggestive of gray and white matter shrinkage with leukoencephalopathy. None achieved developmental skills following birth with 5/6 deceased by the age of 9 years.

Exome sequencing revealed biallelic DMXL2 variants in all, with compatible parental segregation studies (NM_015263.3):
- Fam1 (2 sibs) : c.5135C>T (p.Ala1712Val) in trans with c.4478C>G (p.Ser1493*)
- Fam2 (2 sibs) : homozygosity for c.4478C>A (p.Ser1493*)
- Fam3 (2 sibs) : homozygosity for c.7518-1G>A

Heterozygous parents (aged 39-59) did not exhibit hearing impairment [report of a single multigenerational family by Chen et al (2017 - PMID: 27657680) where a heterozygous missense variant segregated with hearing loss - respective OMIM entry: ?Deafness, autosomal dominant 71 - 617605].

In patients' fibroblasts, effect of the variants on mRNA/protein expression was demonstrated with mRNA expressed only in a patient from family 1, and degraded/absent for the 2 stopgain SNVs affecting codon 1493. Skipping of ex31 leading to frameshift/introduction of a PTC was shown for the splice variant (p.Trp2508Argfs*4 secondary to c.7518-1G>A). Protein was also absent upon western-blot.

DMXL2 encodes a vesicular protein, DmX-Like protein 2 or rabconnectin-3a (cited Tata et al).

The gene is expressed in brain ( https://www.gtexportal.org/home/gene/DMXL2 ).

As Esposito et al comment, it is known to regulate the trafficking and activity of v-ATPase the latter having a role in acidifying intracellular organelles and promoting endosomal maturation (cited PMIDs : 25248098, 19758563, 22875945, 24802872).

In line with this, staining of patients' fibroblasts using the acidotropic dye LysoTracker demonstrated increased signal, reversed by re-expression of DMXL2 protein. Overall an acidic shift in pH with impairment of lysosomal structures and function was suggested. The authors provided additional evidence for altered lysosomal function and associated autophagy with accumulation of autophagy receptors (eg p62) and substrates (polyubiquitinated proteins). Vacuolization and accumulation of atypical fusion-like structures was shown upon ultrastractural analysis.

shRNA-mediated downregulation/silencing of Dmxl2 in mouse hippocampal neurons resulted also in altered lysosomal structures and defective autophagy. The neurons exhibited impaired neurite elongation and synapse formation.

The authors suggest similarities with Vici syndrome, where biallelic EPG5 mutations result in autophagic defects and clinical manifestations of DD/ID/epilepsy.

Dmxl2 homozygous ko mice display embryonic lethality with heterozygous mice displaying macrocephaly and corpus callosum dysplasia (cited PMIDs: 25248098, 30735494) .
Intellectual disability v2.1102 DMXL2 Konstantinos Varvagiannis reviewed gene: DMXL2: Rating: GREEN; Mode of pathogenicity: None; Publications: 25248098, 30237576, 31688942; Phenotypes: Epileptic encephalopathy, early infantile, 81, MIM 618663, ?Polyendocrine-polyneuropathy syndrome, MIM 616113; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Intellectual disability v2.1102 IL3RA Eleanor Williams Added comment: Comment on mode of inheritance: This gene is in the pseudoautosomal region shared between chromosomes X and Y. The mode of inheritance should therefore be set to Biallelic or Monoallelic once more cases establish the inheritance pattern.
Intellectual disability v2.1102 IL3RA Eleanor Williams Mode of inheritance for gene: IL3RA was changed from X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) to Unknown
Intellectual disability v2.1101 DHRSX Eleanor Williams Added comment: Comment on mode of inheritance: This gene is in the pseudoautosomal region shared between chromosomes X and Y. The mode of inheritance should therefore be set to Biallelic or Monoallelic once more cases establish the inheritance pattern.
Intellectual disability v2.1101 DHRSX Eleanor Williams Mode of inheritance for gene: DHRSX was changed from X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) to Unknown
Intellectual disability v2.1100 CRLF2 Eleanor Williams Added comment: Comment on mode of inheritance: This gene is in the pseudoautosomal region shared between chromosomes X and Y. The mode of inheritance should therefore be set to Biallelic or Monoallelic once more cases establish the inheritance pattern.
Intellectual disability v2.1100 CRLF2 Eleanor Williams Mode of inheritance for gene: CRLF2 was changed from X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) to Unknown
Intellectual disability v2.1099 AKAP17A Eleanor Williams Added comment: Comment on mode of inheritance: This gene is in the pseudoautosomal region shared between chromosomes X and Y. The mode of inheritance should therefore be set to Biallelic or Monoallelic once more cases establish the inheritance pattern.
Intellectual disability v2.1099 AKAP17A Eleanor Williams Mode of inheritance for gene: AKAP17A was changed from X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) to Unknown
Intellectual disability v2.1098 ZNF292 Konstantinos Varvagiannis gene: ZNF292 was added
gene: ZNF292 was added to Intellectual disability. Sources: Radboud University Medical Center, Nijmegen,Literature
Mode of inheritance for gene: ZNF292 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ZNF292 were set to 31723249; 29904178
Phenotypes for gene: ZNF292 were set to Intellectual disability; Autism; Attention deficit hyperactivity disorder; Abnormality of the face; Abnormal muscle tone; Abnormality of nervous system morphology; Growth abnormality; Feeding difficulties; Abnormality of the skeletal system; Abnormality of the cardiovascular system; Microcephaly; Seizures
Penetrance for gene: ZNF292 were set to Incomplete
Review for gene: ZNF292 was set to GREEN
gene: ZNF292 was marked as current diagnostic
Added comment: Mirzaa et al. (2019 - PMID: 31723249) report on 28 individuals (from 27 families) with putatively pathogenic ZNF292 variants.

Main features consisted of DD and ID (27/28 - mild in 40%, moderate in 22%, severe in 11%) with or without ASD and ADHD. A single individual had no evidence of ID but had speech delay and ASD at the age of 6. Additional features (by diminishing order of frequency) included presence of non-specific dysmorphic features (~45%), abnormal tone, brain MRI abnormalities, growth failure, feeding difficulties, skeletal and cardiac anomalies, microcephaly and epilepsy (~11%).

As the authors comment, ZNF292 encodes a zinc finger protein, acting as a transcription factor.

Evidence is provided that gene has high expression in the developing human brain, with its expression being higher in prenatal development and diminishing postnatally. Znf292 is also expressed in adult mouse brain (highest in hippocampus/Purkinje cells).

Variants were identified by exome or targeted panel sequencing (targeted capture/molecular inversion probes). Previous investigations (eg. aCGH, analysis of relevant genes) had probably ruled out alternative causes in most with few having VUS or possibly relevant additional variants (eg. a KDM5C stopgain variant in a male).

24 putatively pathogenic variants were observed in this cohort, all predicting LoF (stopgain, frameshift or splice variants). All were de novo with the exception of one family where the variant was inherited from an affected parent. Almost all were absent from gnomAD and had CADD scores > 35.

Most variants lied within the last and largest exon that encodes a DNA binding domain. RT-PCR on RNA from 2 individuals harboring such variants confirmed that NMD does not apply. This exon however represents ~88% of the total coding length so the distribution of variants in this (NMD escaping) region was consistent with what would also be expected by chance.

ZNF292 has a pLI of 1 in gnomAD. Manual review of some relevant LoF variants in gnomAD suggested that they represent false positive calls.

As a result, the effect of variants is not clear although haploinsufficiency is still possible based also on phenotype of (larger) deletions spanning this gene (cited: Engwerda et al - PMID: 29904178 / The study focuses on deletions of the broader 6q. A possible role of ZNF292 is discussed as autism was present in 4/10 individuals with deletions encompassing this gene).

Based on the aforementioned cohort with one individual being diagnosed with mild ID only as an adult and/or presence of 5 pLoF variants in gnomAD the authors propose that some variants may be incompletely penetrant or associated with only mild features.

Finally, 15 additional individuals (belonging to 12 families) harbored variants for which pathogenicity was suspected (but could not be concluded) due to insufficient phenotypic information, lack of sufficient parental studies or missense variants. In this cohort variants were mostly pLoF, while 3 individuals (incl. 2 sibs) had a de novo missense SNV.
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Other studies were not here reviewed as some of the individuals reported were published previously in larger cohorts.
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There is no associated phenotype in OMIM / G2P. SysID includes this gene among the candidate ID ones.
ZNF292 is included in gene panels for ID offered by some diagnostic laboratories (incl. Radboudumc and GeneDx).
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Overall ZNF292 could be added to the ID panel probably with green (or amber) rating.

[Please consider inclusion in other possibly relevant panels eg. autism, epilepsy]
Sources: Radboud University Medical Center, Nijmegen, Literature
Intellectual disability v2.1098 CNOT2 Konstantinos Varvagiannis gene: CNOT2 was added
gene: CNOT2 was added to Intellectual disability. Sources: Literature,Radboud University Medical Center, Nijmegen
Mode of inheritance for gene: CNOT2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CNOT2 were set to 31512373; 31145527; 28135719; 28159701; 30768759; 21505450; 18076123; 22247066
Phenotypes for gene: CNOT2 were set to Intellectual developmental disorder with nasal speech, dysmorphic facies, and variable skeletal anomalies, MIM 618608
Penetrance for gene: CNOT2 were set to unknown
Review for gene: CNOT2 was set to GREEN
gene: CNOT2 was marked as current diagnostic
Added comment: Heterozygous pathogenic CNOT2 variants cause Intellectual developmental disorder with nasal speech, dysmorphic facies, and variable skeletal anomalies (MIM 618608 - recently added disorder in OMIM). Larger 12q15 deletions, spanning CNOT2 have been reported in patients with similar phenotype.

Relevant individuals - most discussed below - include 2 patients with truncating de novo mutation, 1 with de novo intragenic deletion, few with small deletions spanning also 2-3 additional proximal genes and others with larger 12q15 deletions encompassing CNOT2 and several other genes.

Overall the phenotype - summarized by Uehara et al. (Ref1 - below) - seems to consist of language delay, mild motor delay (in most), some suggestive facial features (upslanted palpebral fissures, anteverted nares, thin upper lip and micrognathia). Nasal speech has also been reported in some individuals.

As commented by Uehara et al. (Ref1), CNOT2 (CCR4-NOT transcription complex subunit 2) is a member of the carbon catabolite repressor 4 complex (CCR4-NOT), the latter having an important role in deadenylation of mRNA and global mRNA expression. Disruption of the complex - which can be caused by loss of one of its components - results in various human disorders incl. neural diseases. siRNA CNOT2 depletion has been shown to induce CCR4-NOT disruption (cited PMIDs: 16284618, 29438013, 31006510, 21299754).

The type of variants (truncating, intragenic deletion, larger deletions) and the highly overlapping phenotypes in the respective patients suggest happloinsufficiency as the underlying mechanism. CNOT2 has also a pLI of 1 in gnomAD (o/e =0.06) and a %HI in Decipher of 4.39.

The gene appears to have relevant expression (https://www.proteinatlas.org/ENSG00000111596-CNOT2/tissue).
Animal models have not been discussed (or phenotypes possibly not sufficiently studied - MGI for Cnot2 : http://www.informatics.jax.org/marker/MGI:1919318).

CNOT2 is not associated with any phenotype in G2P. It is listed among the ID candidate genes in SysID.
This gene is included in gene panels for ID offered by some diagnostic laboratories (incl. Radboudumc).

Overall CNOT2 could be considered for inclusion in the ID panel with amber (DD although outcome is not known, presumed dysfunction of the CCR4-NOT complex, variant studies or animal models not available) or green rating (sufficient cases and variants, consistent phenotype).
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Individuals with CNOT2-only disruption:
[1] PMID: 31512373 (Uehara et al., 2019) - A 6 y.o. male investigated for hypotonia, feeding problems, DD (speech and motor), macrocephaly (+3 SD) and some possibly suggestive facial/other features was found to harbor a de novo stopgain variant (NM_001199302.1: c.946A>T, p.Lys316Ter) after trio exome sequencing. The variant and its de novo occurrence were confirmed by Sanger sequencing. NMD was the predicted effect (variant in ex11 of 21 / effect not further studied). Previous metabolic work-up and chromosomal testing had not revealed an alternative diagnosis.
[2] PMID: 31145527 (Alesi et al. 2019) - A 13 y.o. boy with hypotonia, failure to thrive, DD and following a specific schooling program for children with learning difficulties is reported. The authors comment on the facial phenotype (incl. upslanted p-f, anteverted nares, etc). Other features included valvular/supravalvular pulm. stenosis, mid aortic insufficiency, renal anomalies/failure, skeletal anomalies. Speech was nasal. CMA revealed an 85-kb 12q15 deletion spanning only CNOT2 (exons 3-15). Real-time PCR in proband and parents confirmed the variant and its de novo occurrence.
[3] PMID: 28135719 (DDD study, 2017) - An individual with developmental disorder and a de novo (validated) frameshift variant was identified [DDD4K.00807 - NM_014515.5:c.1158del / p.(L387Sfs*3)]. Phenotype in Decipher incl. abnormality of head/neck, nervous, skeletal system and growth. [https://decipher.sanger.ac.uk/ddd/research-variant/16b4f7866652f08e25a194f65535b4c5#overview].

Individuals with disruption of additional proximal genes due to CNVs:
[4] PMID: 28159701 (Alesi et al. 2017) - The authors report on a 29 y.o. individual with history of DD, learning difficulties, ID (WAIS-R IQ of 48 at the age of 17 y), some dysmorphic facial features. Additional features incl. recurrent infections, nasal voice as well as skeletal anomalies. CMA revealed a 742 kb microdeletion spanning CNOT2, KCNMB4 and PTPRB. Real-time PCR confirmed deletion and it's de novo occurrence in the proband.
[5] PMID: 30768759 (Uehara et al. 2019) - A female investigated among others for global DD (walking/1st words at 24m), mild ID, submucosal cleft palate with some distinctive facial features (upslanted p-f, micrognathia, etc) was found to harbor a 1.32-Mb deletion of 12q15 encompassing CNOT2 and 14 other genes. Given the phenotypic resemblance to patients with 12q15 deletions, the previously defined smallest region of overlap (ref 4,6), the LoF SNV in Decipher the authors suggested that CNOT2 is the critical gene for the phenotype of 12q15 deletion syndrome.

Larger deletions defining the smallest region of overlap
[6] PMID: 21505450 (Vergult et al. 2011) - 3 patients with de novo microdeletions of ~ 2.5 Mb in size with a 1.34 MB common region of overlap are reported. Learning diability, DD, nasal speech and hypothyroidism were among the common features.
[7] PMID: 18076123 (Schluth et al. 2008) - A girl with large (~10 Mb) de novo deletion of 12q15 - q21.2 identified by BAC array was described. The phenotype consisted of hypotonia, DD, moderate ID, growth delay and facial dysmorphic features.
[8] PMID: 22247066 (Lopez et al. 2012) - A patient with ID and features of Floating-Harbor syndrome was found to harbor a 4.7 Mb de novo 12q15-q21.1 deletion spanning CNOT2 and 18 additional genes.
[..]
Sources: Literature, Radboud University Medical Center, Nijmegen
Intellectual disability v2.1098 TMX2 Konstantinos Varvagiannis gene: TMX2 was added
gene: TMX2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: TMX2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TMX2 were set to 31586943; 31270415
Phenotypes for gene: TMX2 were set to Global developmental delay; Intellectual disability; Seizures; Microcephaly; Abnormal cortical gyration
Penetrance for gene: TMX2 were set to Complete
Review for gene: TMX2 was set to AMBER
Added comment: PMID: 31586943 - Ghosh et al. 2019 - reported on 8 individuals from 4 consanguineous families from the Middle East and Central Asia, all with a phenotype of DD/ID, seizures and microcephaly with lissencephaly (microlissencephaly is the term applying to the combination of two) upon brain MRI.

All patients were investigated by exome sequencing and the variant localized within a region of ROH which was common to all 4 families. All were homozygous for a TMX2 missense variant (NM_001144012.2:c.500G>A or p.Arg167Gln / NM_015959.4:c.614G>A p.Arg205Gln or hg38 - Chr11:g.57739039G>A). The variant was considered to be the best candidate, upon review of all other homozygous ones.

Sanger sequencing confirmed homozygosity for the variant in affected subjects, with additional compatible segregation studies including parents in all families as well as unaffected sibs (in two families).

Despite presence of the same mutation in all, several proximal to this variant SNPs did not appear to be shared among the families studied, thus suggesting that the variant had arisen within different haplotype blocks.

The authors comment that the variant was not previously identified in public databases. (The variant seems to correspond to rs370455806, present in 10 htz individuals in gnomAD, as well as in the GME database [GME Genotype Count 992:0:1 (hmz?) | Allele Count: 2,1984] . GME includes primarily - although not necessarily - healthy individuals).

This SNV affecting the last nucleotide of an exon of several transcripts (correct ref. is NM_001144012.2 as appears in the supplement / using NM_001347898.1 as in the fig./text the variant would lie within an intron), an eventual splicing effect was studied. mRNA transcript levels were assessed following RT-PCR using different sets of primers. There was no evidence of novel splice isoforms but mRNA levels were reduced compared to controls (15-50% in affected individuals, to a lesser level in carriers). This led to the hypothesis that NMD of an aberrantly spliced mRNA might apply, although this was not proven.

TMX2 encodes a protein disulfide isomerase (PDI). PDIs are transmembrane ER proteins which have a critical role in protein folding (PMID cited: 12670024). There were no relevant studies carried out in the article.

As for animal models, the authors comment that mice homozygous for null mutations display preweaning lethality with complete penetrance.(http://www.informatics.jax.org/diseasePortal/popup?isPhenotype=true&markerID=MGI:1914208&header=mortality/aging).
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Previously, Schot el al. (ESHG Conference 2018 Oral Presentation - Mutations in the thioredoxin related gene TMX2 cause primary microcephaly, polymicrogyria and severe neurodegeneration with impaired mitochondrial energy metabolism - available in PMID: 31270415 / https://www.nature.com/articles/s41431-019-0407-4 ) reported on 7 individuals from 5 unrelated families with biallelic TMX2 mutations. A newborn with microcephaly, polymicrogyria who died of refractory epilepsy, was compound heterozygous for 2 TMX2 variants. 6 additional individuals (from 4 unrelated families) with similar phenotype were found to harbor biallelic TMX2 mutations. It was commented that TMX2 is enriched in mitochondria-associated membrane of the ER with a role in ER stress protection and regulation of neuronal apoptosis. In line with this, fibroblasts from 2 unrelated patients showed secondary OXPHOS deficiency and increased glycolytic activity (the latter possibly as a compensatory mechanism).
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There is no associated phenotype in OMIM/G2P/SysID.
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Overall this gene could be considered for inclusion in the ID/epilepsy panel probably with amber (/red) rating pending further evidence.
Sources: Literature
Intellectual disability v2.1098 KCNT2 Konstantinos Varvagiannis gene: KCNT2 was added
gene: KCNT2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: KCNT2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: KCNT2 were set to 29069600; 29740868
Phenotypes for gene: KCNT2 were set to ?Epileptic encephalopathy, early infantile 57, MIM 617771
Penetrance for gene: KCNT2 were set to unknown
Review for gene: KCNT2 was set to GREEN
Added comment: Heterozygous pathogenic KCNT2 variants cause ?Epileptic encephalopathy, early infantile, 57 (MIM 617771).

At least 3 unrelated affected individuals have been reported :

- PMID: 29069600 - Gururaj et al. 2017 : a male child with EOEE (hypotonia, profound DD and intractable infantile seizures) due to a de novo KCNT2 missense variant (NM_001287819.1:c.720T>A or p.Phe240Leu) identified by exome sequencing.

- PMID: 29740868 - Ambrosino et al. 2018 : A girl with phenotype corresponding to West syndrome later evolving to Lennox-Gastaut syndrome. At the age of 9 years the girl displayed severe ID. Trio exome sequencing revealed a de novo missense KCNT2 variant (NM_001287820.2:c.569G>A or p.Arg190His). A 14 y.o. female recruited through the DDD study with phenotype corresponding to epilepsy of infancy with migrating focal seizures. The girl had poor language development and severe learning disability. Infective and metabolic causes were initially ruled out. Trio exome sequencing revealed a de novo missense SNV (c.569G>C or Arg190Pro).

Overall KCNT2 has been commented to contribute to a phenotypic spectrum similar and overlapping to that of KCNT1 (Ambrosino et al.). [KCNT1 is rated green in both epilepsy and ID panels].

KCNT2 was recently included in the epilepsy panel as green (functional studies summarized in the respective reviews). The gene was also recently added to G2P, associated with 'Developmental and infantile epileptic encephalopathy'. It is not commonly included in gene panels for ID offered by diagnostic laboratories.

As a result, KCNT2 could be considered for inclusion in the ID panel with green (or amber) rating.
Sources: Literature
Intellectual disability v2.1098 NSF Konstantinos Varvagiannis gene: NSF was added
gene: NSF was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: NSF was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: NSF were set to 31675180
Phenotypes for gene: NSF were set to Seizures; EEG with burst suppression; Global developmental delay; Intellectual disability
Penetrance for gene: NSF were set to unknown
Mode of pathogenicity for gene: NSF was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: NSF was set to AMBER
Added comment: Suzuki et al. (2019 - PMID: 31675180) report on 2 unrelated individuals with de novo missense NSF variants. Overall the phenotype corresponded to an early infantile epileptic encephalopathy. The first patient developed vomiting and tonic seizures immediately after birth, with burst-suppression pattern upon EEG. Trio exome sequencing, followed by Sanger sequencing of proband and parents, revealed a de novo missense variant (NM_006178.3:c.1375G>A / p.Ala459Thr), absent from public databases and predicted in silico to be deleterious (CADD score of 30). The girl died 36 days after birth due to respiratory failure. Another subject, having necessitated mechanical ventilation due to absence of spontaneous respiration after birth, developed myoclonic seizures. EEG showed a burst-suppression pattern. At the age of 3, she was noted to have persistence of seizures and profound ID. Trio exome sequencing identified a missense NSF variant (c.1688C>T / p.Pro563Leu) also confirmed and shown to be de novo by Sanger sequencing. Again the variant was absent from public datasets and had a CADD score of 34. While expression of wt NSF allele in the developing eye of Drosophila had no effect, expression of mutants severely affected eye development - suggesting a dominant negative effect. NSF encodes a homo-hexameric AAA ATPase, which is recruited by SNAPs (Soluble NSF Attachment Proteins) - and the latter by SNAREs (SNAP REceptors) - thus having a role in vesicular transport and membrane fusion. There is currently no associated phenotype in OMIM/G2P. Overall, this gene could be considered for inclusion probably with amber/red rating pending further evidence (eg. additional work-up or alternative causes/explanations not discussed).
Sources: Literature
Intellectual disability v2.1098 WDFY3 Konstantinos Varvagiannis reviewed gene: WDFY3: Rating: GREEN; Mode of pathogenicity: None; Publications: 27008544, 31327001, 25198012, 28191889; Phenotypes: ?Microcephaly 18, primary, autosomal dominant - MIM 617520; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Intellectual disability v2.1098 SCAMP5 Konstantinos Varvagiannis gene: SCAMP5 was added
gene: SCAMP5 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: SCAMP5 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SCAMP5 were set to 31439720; 20071347
Phenotypes for gene: SCAMP5 were set to Global developmental delay; Intellectual disability; Seizures; Abnormality of nervous system morphology; Behavioral abnormality
Penetrance for gene: SCAMP5 were set to unknown
Mode of pathogenicity for gene: SCAMP5 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: SCAMP5 was set to AMBER
Added comment: PMID: 31439720 (Hubert et al. 2019) reported on 2 unrelated individuals with severe ID, seizures behavioral and brain MRI abnormalities (white matter hyperintensity and mesial temporal sclorosis), both harboring the same missense SCAMP5 mutation as a de novo event (NM_001178111.1:c.538G>T or p.Gly180Trp).

Previously aCGH +/- metabolic workup were non diagnostic.

The occurrence of the same de novo variant in both as well as the similar presentation (incl. MRI images) suggested SCAMP5 as the most probable candidate gene, despite presence of few other variants in both.

SCAMP5 is highly expressed in brain (https://www.proteinatlas.org/ENSG00000198794-SCAMP5) and previous studies have suggested a role in synaptic vesicle trafficking (PMIDs cited: 29562188, 25057210, etc).

Cultured skin fibroblasts from affected individuals failed to express SCAMP5.

Scamp is the Drosophila orthologue, with previous studies having demonstrated that mutants display defects in climbing, olfactory-assisted memory and susceptibility to heat induced seizures (PMIDs cited: 25478561, 19144841). Expression of the Scamp Gly302Trp variant in Drosophila ('equivalent' to the SCAMP5 Gly180Trp) revealed strongly reduced levels for the variant compared with wt upon Western Blot, either due to reduced expression or due to increased turnover. Overall the effect of Gly302Trp expression was similar to Scamp knockdown by RNAi (eg. rough eye phenotype, reduced ability to climb the walls of a graded tube after tapping, less/no flies reaching adult stage) but significantly different compared to wt.

As a result, a dominant-negative effect was presumed.
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PMID: 20071347 (Castermans et al. 2010) is cited as a previous report of a relevant affected individual. In this study a 40 y.o. male with early DD, mild ID (IQ of 63) and ASD was found to harbor a de novo apparently balanced t(1;15) translocation affecting CLIC4 and PPCDC (both not associated with ID). [1-Mb resolution aCGH revealed no relevant CNVs].

Studies were however focused on SCAMP5 given that the gene is located downstream of / proximal to PPCDC, has brain-enriched expression as well as involvement in synaptic trafficking and demonstrated:
- Less than 50% expression upon quantitative RT-PCR in patients leukocytes, compared to control.
- Silencing and overexpression of Scamp5 in mouse β-TC3 cells resulted in increased and suppressed respectively secretion of large dense-core vesicles (LDCVs).
- Given conservation of some components involved in secretion of dense core granules (DCGs) in platelets and LDCVs in neuronal cells, study of patient platelets - where SCAMP5 was confirmed to be expressed - suggested an altered pattern of DCGs.
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SCAMP5 is not associated with any phenotype in OMIM/G2P/SysID and not commonly included in gene panels for ID.
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Overall, this gene could be considered for inclusion in the ID and epilepsy panels probably with amber (# of unrelated individuals, 1 recurrent de novo variant and 1 regulatory effect, gene expressed in brain with a role in synaptic vesicle trafficking) or red rating (pending further evidence).
Sources: Literature
Intellectual disability v2.1098 FAM160B1 Konstantinos Varvagiannis gene: FAM160B1 was added
gene: FAM160B1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: FAM160B1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FAM160B1 were set to 27431290; 31353455
Phenotypes for gene: FAM160B1 were set to Central hypotonia; Global developmental delay; Intellectual disability; Abnormality of the face
Penetrance for gene: FAM160B1 were set to Complete
Review for gene: FAM160B1 was set to AMBER
Added comment: Anazi et al. (2017 - PMID: 27431290) in a study of 337 subjects with ID, reported on a consanguineous family (15DG2696) with 3 affected sibs. The proband, a 7 y.o. boy had hypotonia, DD, mild ID (IQ of 69), some facial dysmorphic features as well as increased skin elasticity and joint hypermobility. Initial investigations included metabolic testing for OA and CDGs, FMR1 and aCGH. A 4 y.o. sister and a 3 y.o. brother of the proband had similar presentation of DD. Exome sequencing, autozygosity mapping and segregation studies suggested a FAM160B1 hmz missense SNV as the likely causal variant (NM_001135051.1:c.248T>C or p.Leu83Pro). There were no other candidate variants. As the encoded protein has a yet unknown function, with uncertain in silico 3D modeling, the authors speculated disruption of helices affecting fold/(ligand binding) function as the underlying effect of this variant.

Mavioğlu et al. (2019 - PMID: 31353455) reported on a 38 y.o. female with history of motor and language delay, severe ID, ataxia, behavioral abrnormalities as well as some dysmorphic features. This individual was born to consanguineous parents (2nd cousins). There was history of a deceased, similarly affected sib. Initial investigations included metabolic work-up (plasma AA, urinary OA) and karyotyping. SNP genotyping in the family (parents, affected sib, 3 unaffected sibs) and multipoint linkage analysis for AR inheritance, yielded a maximum LOD score of 2.15. Selection of homozygous regions unique to the patient (but not present in unaffected sibs) did not suggest any known ID gene. Exome sequencing of the proband, with analysis of the variants in candidate regions revealed a homozygous stopgain SNV (NM_020940.4:c.115G>T or p.Glu39*) as the best candidate variant (with few others not considered to be relevant). FAM160B1 has a pLI of 1, LoF variants in public databases have MAFs below 0.000034 with no recorded homozygotes. In silico predictions suggested a deleterious effect (CADD score of 40, etc). The previous report by Anazi and fulfilment of the ACMG criteria for its classification of this variant as pathogenic led to its consideration as causal of the patient's phenotype.

Study of the expression of the 2 isoforms of the gene (isoform1: NM_020940, 2:NM_001135051) revealed that the first is ubiquitously expressed and the second only in testes. [To my understanding the 2 isoforms seem to differ only in their last exon, the 2 reported variants affecting both isoforms - http://genome.ucsc.edu/cgi-bin/hgTracks?db=hg19&lastVirtModeType=default&lastVirtModeExtraState=&virtModeType=default&virtMode=0&nonVirtPosition=&position=chr10%3A116577123%2D116663023&hgsid=777553295_dPP9DgaheaF82gTRTfZO6XS5lEzA ]

The function of this gene remains unknown. Animal models/phenotypes are probably not available.

There is no associated phenotype in OMIM/G2P. SysID lists FAM160B1 as a candidate ID gene.
FAM160B1 is not commonly included in gene panels for ID offered by diagnostic laboratories.

As a result this gene can be considered for inclusion in the current panel probably with amber (2 families/variants, variable ID as a feature) or red rating pending further evidence (given the partial phenotypic overlap, unknown function of the gene, variants not further studied, no animal models).
Sources: Literature
Intellectual disability v2.1098 PCYT2 Konstantinos Varvagiannis gene: PCYT2 was added
gene: PCYT2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: PCYT2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PCYT2 were set to 31637422
Phenotypes for gene: PCYT2 were set to Global developmental delay; Developmental regression; Intellectual disability; Spastic paraparesis; Seizures; Spastic tetraparesis; Cerebral atrophy; Cerebellar atrophy
Penetrance for gene: PCYT2 were set to Complete
Review for gene: PCYT2 was set to GREEN
Added comment: Vaz et al. (2019 - PMID: 31637422 - DDD study among the co-authors) report on 5 individuals - from 4 families - with biallelic PCYT2 mutations.

The phenotype corresponded to a complex hererditary paraplegia with global DD, regression (4/5), ID (mild in 3/5, severe in 2/5), spastic para-/tetraparesis, epilepsy (5/5 - variable onset 2-16 yrs - focal or tonic-clonic seizures) and progressive cerebral and cerebellar atrophy.

Exome sequencing in all revealed biallelic PCYT2 variants, confirmed with Sanger s. in probands and their parents (NM_001184917.2 - corresponding to the canonical transcript used as Ref below):
- P1 (Fam1) : 2 missense SNVs in trans configuration, c.730C>T or p.His244Tyr and c.920C>T or p.Pro307Leu
- P2 (Fam2 - consanguineous of White British origin), P3 (Fam3 - Consanguineous of Turkish origin), P4,5 (Fam4 - consanguineous, unspecified origin) : homozygosity for c.1129C>T or p.Arg377Ter) affecting the last exon of 8/12 transcripts, including the canonical one.

Individuals with the same genotype displayed variable degrees of ID (eg P3 - severe / P2, P4,5 - mild ID).

For sibs in Fam4, homozygosity for a missense SACS variant led to consideration of the respective disorder (AR spastic ataxia of Charlevoix-Saguenay) though the variant was predicted to be tolerated in silico and notably the MRI images not suggestive.

All variants were absent from / had extremely low AF in public databases, with no homozygotes.

Posphatidylethanolamine (PE) is a membrane lipid, particularly enriched in human brain (45% of phospholypid fraction). PE is synthesized either via the CDP-ethanolamine pathway or by decarboxylation of phosphatidylserine in mitochondria. PCYT2 encodes CTP:phosophoethanolamine cytidyltransferase (ET) which is an ubiquitously expressed rate-limiting enzyme for PE biosynthesis in the former pathway.

In silico, the 2 missense variants - localizing in the CTP catalytic domain 2 - were predicted to be damaging, as well as to affect protein stability.

Fibroblasts of 3 patients (P1, P2, P3) representing all variants were studied:
- Enzymatic activity was shown to be significantly reduced (though not absent) compared to controls. Abnormalities were noted upon Western Blot incl. absence in all 3 patients studied of one of the 2 bands normally found in controls (probably representing the longer isoform), reduced intensity in all 3 of another band probably corresponding to a shorter isoform, and presence of an additional band of intermediate molec. mass in patients with the truncating variant.
- RT-PCR on mRNA from patient fibroblasts did not reveal (significant) reduction compared to controls.
- Lipidomic profile of patient fibroblasts was compatible with the location of the block in the phospholipid biosynthesis pathway and different from controls.

The lipidomic profile had similarities with what has been reported for EPT1 deficiency, the enzyme directly downstream of ET. The SELENO1-related phenotype (/EPT1 deficiency) is also highly overlapping.

CRISPR-Cas9 was used to generate pcyt2 partial or complete knockout (ko) zebrafish, targeting either the final (ex13) or another exon (ex3) respectively. mRNA expression was shown to be moderately reduced in the first case and severely reduced/absent in the second, compared to wt. Similarly, complete-ko (ex3) led to significantly lower survival, with impaired though somewhat better survival of partial-ko (ex13) zebrafish.

Complete knockout of Pcyt2 in mice is embryonically lethal (PMID cited: 17325045) while heterozygous mice develop features of metabolic syndrome (PMID cited: 22764088).

Given lethality in knockout zebrafish / mice and the residual activity (15-20%) in patient fibroblasts, the variants reported were thought to be hypomorphic and complete loss of function possibly incompatible with life.

PCYT2 is not associated with any phenotype in OMIM/G2P/SysID and not commonly included in gene panels for ID.

As a result this gene could included in the ID / epilepsy panels with green (~/>3 indiv/fam/variants with the nonsense found in different populations, consistent phenotype, lipidomics, in silico/in vitro/in vivo evidence) or amber rating.

[Please consider inclusion in other possibly relevant panels eg. for metabolic disorders, etc].
Sources: Literature
Intellectual disability v2.1098 PDE6D Konstantinos Varvagiannis gene: PDE6D was added
gene: PDE6D was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: PDE6D was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PDE6D were set to 24166846; 30423442
Phenotypes for gene: PDE6D were set to ?Joubert syndrome 22 - MIM 615665
Penetrance for gene: PDE6D were set to Complete
Review for gene: PDE6D was set to AMBER
gene: PDE6D was marked as current diagnostic
Added comment: Thomas et al. (2014 - PMID: 24166846) reported on a consanguineous Pakistani family with 3 members presenting variable polydactyly, brain anomalies (incl. molar tooth sign), microphthalmia/coloboma with retinal disease, renal hypoplasia suggestive of Joubert syndrome.

Genotyping with a SNP array identified a unique 17-Mb region of homozygosity on chr2 with LOD score of 2.6. The region contained 208 genes, of which 15 present in ciliary gene databases. A homozygous splicing variant appeared to be the only relevant, PDE6D being a ciliary gene within this region [NM_002601.4:c.140-1G>A]. Status of all affected members, parents and 2 unaffected sibs was verified with Sanger sequencing.

PDE6D encodes a phosphodiesterase that binds to prenyl groups and has a critical role in ciliogenesis (Humbert et al. - PMID: 23150559 and OMIM).
Several lines of evidence provided support a role for PDE6D and the reported variants :
- Study of PDE6D expression during human embryogenesis suggests ubiquitous localization and highest levels in organs affected in ciliopathies (CNS, kidney tubules, respiratory tract epitherlial cells).
- RT-PCR of mRNA from control/patient fibroblasts and sequencing confirmed the splicing defect leading to an in-frame deletion of exon 3.
- Wt and mutant protein both localized in the basal body of primary cilia (patient/control fibroblasts). Cilia in both cases had normal morphology.
- Experiments in RPE cells confirmed that INPP5E (involved in Joubert/MORM syndrome) interacts (/is probably a cargo of) PDE6D, a process dependent on prenylation.
- Exon 3 deletion was confirmed to disrupt PDE6D binding to INPP5E.
- Analysis by immunofluoresence of INPP5E localization using control/patient fibroblasts and renal tissue showed absence of INPP5E from primary cilia in the case of patient cells (but not controls) suggesting that PDE6D is important for trafficking INPP5E to the cilium.
- Previous study in mice suggested altered photoreceptor physiology in Pde6d (-/-) animals, resulting in a slowly progressing rod/cone dystrophy. The effect was however limited to the eye. (PMID cited : 17496142 - Zhang et al., 2007).
- Morpholino knockdown of pde6d resulted in pericardial edema, eye abnormalities (microphthalmia and disorganized retinal cell layers) and kidney morphogenesis defects (distended, blocked pronephric openings and proximal tubule cysts). Edema was rescued upon coinjection of morpholino with wt (but not mutant) mRNA. Similarly coinjection led to complete or partial rescue of eye development in the case of wt and mutant mRNA respectively supporting pathogenicity and (partial) loss-of-function effect for the variant.
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Mégarbané et al. (2019 - PMID: 30423442) reported on an affected 6 month-old boy born to Lebanese first-cousin parents. Features included hypotonia, developmental delay, microcephaly, oculomotor apraxia, postaxial polydactyly of hands and feet and presence of a molar tooth sign upon brain MRI. Renal and retinal anomalies were absent (also given his age). Exome sequencing revealed homozygosity for a frameshift PDE6D variant [NM_002601.3:c.367_368insG or p.(Leu123Cysfs*13)]. Sanger sequencing confirmed presence of the variant in the proband and carrier status of the parents. The variant affected the penultimate exon (note : present in only this longest transcript) and was not predicted to trigger NMD but rather lead to elimination of a highly conserved PDZ-interaction domain.
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The phenotype associated with biallelic PDE6D variants in OMIM is ?Joubert syndrome 22 - MIM 615665 based only on the 1st report ('delayed psychomotor development' among the features). There is no relevant entry in G2P. PDE6D is listed as a Current primary (/confirmed) ID gene in SysID (the aforementioned PMIDs cited).

This gene is included in gene panels for ID offered by some diagnostic laboratories (eg. GeneDx).
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Overall PDE6D could be considered for inclusion in the ID panel probably with amber rating (2 families/variants, DD but outcome otherwise unknown - evidence for the the gene causing JS seems however sufficient).
Sources: Literature
Intellectual disability v2.1098 NTNG2 Konstantinos Varvagiannis gene: NTNG2 was added
gene: NTNG2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: NTNG2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NTNG2 were set to 31372774; 31668703
Phenotypes for gene: NTNG2 were set to Central hypotonia; Global developmental delay; Intellectual disability; Behavioral abnormality; Microcephaly; Seizures
Penetrance for gene: NTNG2 were set to Complete
Review for gene: NTNG2 was set to GREEN
Added comment: [1] Abu-Libdeh et al. (2019 - PMID: 31372774) reported 8 individuals from 4 unrelated consanguineous families of Arab Muslim origin, all homozygous for NM_032536.3:c.376dup - p.(Ser126PhefsTer241). Common features included hypotonia, failure to achieve milestones and developmental stagnation without regression during the first year (~9m) of life and severe ID. Minimal purposeful hand use (grasping and bringing objects to mouth), hand stereotypies and bruxism were also observed. Microcephaly and impaired growth were almost universal (with the exception of 2 having an OFC at ~10% percentile). Relevant previous investigations were normal in all and included MECP2, SMN1, aCGH, metabolic testing, etc. The variant was identified by exome in all, and Sanger confirmed with compatible segregation studies in parents and sibs. The variant was found within a shared haplotype of ~4.35 Mb, probably due to a founder effect.

[2] Dias et al. (2019 - PMID: 31668703) described 16 individuals from 7 unrelated families from Iran, Mexico, Turkey, Egypt and Bangladesh. Parents were known to be consanguineous or shown to be distantly related. All patients were homozygous for missense variants private to each family (7 variants) identified following exome sequencing. Shared features incl. hypotonia, GDD, severe to profound ID and behavioral anomalies incl. autistic features/stereotypies (most), screaming/laughing spells (most), bruxism. Microcephaly (5/14), growth below average/FTT and GI problems were also observed.

Epilepsy was reported in 5 individuals belonging to 4 different families in these 2 studies (5/24 overall / 4 variants).

Netrin-G2, the encoded protein, is bound to the plasma membrane by GPI-anchors. Netrins-G2 and G1 (another member of the Netrin-G subfamily) are enriched in presynaptic terminals. Interaction with their cognate Netrin-G ligand trans-synaptic partners / receptors (NGL2, NGL1 respectively) has been shown to promote axon outgrowth, induce and maintain excitatory synapse formation. Complementary and non-overlapping expression in the developping and mature CNS has been shown for Netrin-G2/1 in mice (several references provided by Abu-Libdeh / Dias).

Variant effect : The frameshift variant was not studied by Abu-Libdeh et al. Variants in the 2nd ref. were all missense, displayed no-specific localization and were suggested to affect protein stability and/or expression at the cell surface as 4/7 involved loss or addition of cystein residues (possibly creating unpaired cysteins) and 2 of the remaining 3 were predicted to affect the hydrophobic core. In line with this, overexpression of wt/variant constructs in HeLa cells demonstrated substantially decreased cell surface expression for all variants.

Mouse models/phenotypes : Dias et al. showed that siRNA-mediated Ntng2 knockdown in N2a cells led to significant reduction in neurite number and length. Studied previously, Ntng2 knockout mice display impaired learning, memory, visual and motor functioning (PMID cited : 26746425).

NTNG2 is not associated with any phenotype in OMIM/G2P. SysID lists it among the candidate ID genes, citing PMID: 29302074 (not here reviewed & NTNG2 not in the main text).

Overall this gene can be considered for inclusion in the ID panel probably as green (>3 individuals/families/variants, consistent phenotype in both reports, role of the gene, in silico and in vitro studies, animal model, etc) or amber.

[Please consider inclusion in other panels if relevant eg. ASD panel (many individuals having autistic / Rett-like features or epilepsy) or epilepsy (>3 individuals/families/variants although most families were also consanguineous)]
Sources: Literature
Intellectual disability v2.1098 AP1B1 Konstantinos Varvagiannis gene: AP1B1 was added
gene: AP1B1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: AP1B1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AP1B1 were set to 31630788; 31630791
Phenotypes for gene: AP1B1 were set to Failure to thrive; Abnormality of the skin; Hearing abnormality; Abnormality of copper homeostasis; Global developmental delay; Intellectual disability
Penetrance for gene: AP1B1 were set to Complete
Review for gene: AP1B1 was set to AMBER
Added comment: Boyden et al. (2019 - PMID: 31630788) and Alsaif et al (2019 - PMID: 31630791) report on the phenotype related to biallelic AP1B1 mutations.

Common features included failure to thrive, ichthyosis (with variable palmoplantar keratoderma/erythroderma/abnormal hair) and hearing loss. Each study focused on different additional features eg. thrombocytopenia or photophobia in all individuals reported by Boyden et al, while Alsaif et al. focused on abnormal copper metabolism (low plasma copper and ceruloplasmin) observed in all 3 affected individuals and enteropathy/hepatopathy observed in 2 sibs.

DD was observed in all 3 individuals (2 families) reported by Alsaif et al. and patient 424 reported by Boyden et al. ID was noted in all individuals of relevant age (2 from 2 families) in the study by Alsaif. Boyden commented that ID is not part of the phenotype. The adult (424) - despite his early DD - was noted to have normal intellect and had graduated college. The other patient (1325) was last followed up at 11 months (still DD was not reported).

AP1B1 encodes one of the large subunits (β1) of the adaptor protein complex 1. Each of the AP complexes is a heterotetramer composed of two large (one of γ, α, δ, ε and β1-β4 for AP-1 to AP-4 respectively), one medium (μ1-μ4) and one small (σ1-σ4) adaptin subunit. The complex is involved in vesicle-mediated transport.

Variants were confirmed in probands and carrier parents (NM_001127.3):
Boyden Pat424 (33y) : c.430T>C (p.Cys144Arg) in trans with c.2335delC (p.Leu779Serfs*26)
Boyden Pat1325 (11m) [consanguineous Ashkenazi Jewish family] : homozygosity for c.2374G>T (p.Glu792*)
Alsaif sibs P1,P2 (4y4m, 1y5m) [consanguineous - Pakistani origin] : homozygous for a chr22 75 kb deletion spanning only the promoter and ex1-2 of AP1B1
Alsaif P3 (4y6m) [consanguineous - Saudi origin] : homozygous for a c.38-1G>A

Variant / additional studies :
22q 75-kb deletion: PCR deletion mapping and Sanger delineated the breakpoints of the 22q12.2 del to chr22:29758984-29815476 (hg?). Complete absence of transcript upon RT-PCR (mRNA from fibrolasts).
Splicing variant (c.38-1G>A): RT-PCR confirmed replacement of the normal transcript by an aberrant harboring a 1 bp deletion (r.40del).
Stopgain variant (c.2374G>T): Western blot demonstrated loss of AP1B1 (and marked reduction also for AP1G1) in cultured keratinocytes of the homozygous patient.

Loss-of-function is the effect predicted by variants. Vesicular defects were observed in keratinocytes of an affected individual (homozygous for the nonsense variant). Rescue of these vesicular defects upon transduction with wt AP1B1 lentiviral construct confirmed the LoF effect. [Boyden et al.]

ATP7A and ATP7B, two copper transporters, have been shown to depend on AP-1 for their trafficking. Similar to MEDNIK syndrome, caused by mutations in AP1S1 and having an overlapping phenotype with AP1B1 (also including hypocupremia and hypoceruloplasminemia), fibroblasts from 2 affected individuals (from different families) demonstrated abnormal ATP7A trafficking. [Alsaif et al.]

Proteomic analysis of clathrin coated vesicles (2 ind from 2 fam) demonstrated that AP1B1 was the only AP1/AP2 CCV component consistently reduced in 2 individuals (from 2 families). [Alsaif et al.]

Boyden et al. provided evidence for abnormal differentiation and proliferation in skin from an affected individual. In addition E-cadherin and β-catenin were shown to be mislocalized in keratinocytes from this affected individual.

Loss of ap1b1 in zebrafish is not lethal but lead to auditory defects (/vestibular deficits). The inner ears appear to develop normally, although there is progressive degeneration of ear epithelia. There are no behavioral/neurological phenotypes listed for mouse models. [ http://www.informatics.jax.org/marker/MGI:1096368 ].

AP1B1 is not associated with any phenotype in OMIM/G2P/SysID.

Overall this gene could be considered for inclusion in the ID panel probably with amber rating.
Sources: Literature
Intellectual disability v2.1098 FDFT1 Konstantinos Varvagiannis gene: FDFT1 was added
gene: FDFT1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: FDFT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FDFT1 were set to 29909962
Phenotypes for gene: FDFT1 were set to Profound global developmental delay; Intellectual disability; Seizures; Abnormality of nervous system morphology; Cortical visual impairment; Abnormality of the skin; Abnormality of the face
Penetrance for gene: FDFT1 were set to Complete
Review for gene: FDFT1 was set to AMBER
Added comment: Biallelic pathogenic FDFT1 variants cause Squalene synthase deficiency (MIM 618156). 3 individuals from 2 families (and 3 variants) have been reported. DD, ID and seizures are part of the phenotype (3/3). The metabolic profile observed is specific and highly suggestive of disruption of the cholesterol biosynthesis pathway (at the specific level) while the clinical presentation is similar to other disorders of the pathway (SLO). The effect of 2 variants has been studied in detail (in one case mis-splicing demonstrated and in the other regulatory effect). Overall, this gene could be considered for inclusion in the ID/epilepsy panel with amber rating. As the gene is currently present only in the DDG2P panel, please consider adding it to relevant ones (eg. IEMs, undiagnosed metabolic disorders, etc). [Details provided below].
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Coman et al. (2018 - PMID: 29909962) reported on 3 relevant individuals from 2 unrelated families.

The phenotype consisted of seizures (3/3 - neonatal onset - generalized), profound DD (ID can be inferred from the description in the supplement), variable brain MRI abnormalities (white matter loss, hypoplastic CC), cortical visual impairment, dry skin with photosensitivity as well facial dysmorphic features. Male subjects presented genital anomalies (cryptorchidism/hypospadias).

FDFT1 encodes squalene synthase, the enzyme which catalyzes conversion of farnesyl-pyrophosphate to squalene - the first specific step in cholesterol biosynthesis.

A specific pattern of metabolites was observed in all, similar to a pattern previously observed in animal models/humans treated with squalene synthase inhibitor or upon loading with farnesol (in animals). Overall the pattern was suggestive of a cholesterol biosynthesis defect at the level of squalene synthase as suggested by increased total farnesol levels (farnesyl-pyrophosphate + free farnesol), reduced/normal squalene, low plasma cholesterol as well as other metabolites.

Clinical features also resembled those observed in Smith-Lemli-Opitz syndrome (another disorder of cholesterol biosynthesis).

WES was carried out in affected individuals and their parents and revealed for sibs of the first family, compound heterozygosity for a maternally inherited 120-kb deletion spanning exons 6-10 of FDFT1 and CTSB and a paternally inherited FDFT1 variant in intron 8 (TC deletion/AG insertion). Variant studies for the latter included:
- Minigene splice assay demonstrating retention of 22 bp in intron 8.
- Partial splicing defect with both nl and mis-spliced cDNA (patient fibroblasts)
- Reduced protein levels in lymphoblasts/fibroblasts from both sibs upon Western blot.
Contribution of the CTSB deletion was considered unlikely (carrier mother was unaffected).

As for the 2nd family, WES data allowed identification of a homozygous deep-intronic (although this is transcript-specific) 16-bp deletion in the proband. Parents were carriers. For the specific variant :
- cDNA studies failed to detect 3 (of 10) isoforms which are normally present in control fibroblasts. Eventual NMD (which would be predicted if the deletion resulted in splicing defect) was eliminated given the absent effect of cyclohexamide addition, thus suggesting a regulatory effect.
- Given a predicted promoter/enhancer effect of the deleted region, a luciferase assay performed, suggested that the sequence had promoter capacity, with the construct containing the 16-bp deletion showing reduced promoter activity.

Fdft1 knockout mice demonstrate embryonic lethality around mid-gestation while they exhibit severe growth retardation and defective neural tube closure.

In G2P FDFT1 is associated with 'Defect in Cholesterol Biosynthesis' (confidence:possible/biallelic/LoF). The gene belongs to the Current primary ID gene group of SysID. It is not commonly included in gene panels for ID offered by diagnostic laboratories.
Sources: Literature
Intellectual disability v2.1098 IQSEC1 Konstantinos Varvagiannis gene: IQSEC1 was added
gene: IQSEC1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: IQSEC1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: IQSEC1 were set to 31607425
Phenotypes for gene: IQSEC1 were set to Central hypotonia; Global developmental delay; Intellectual disability; Behavioral abnormality; Short stature
Penetrance for gene: IQSEC1 were set to Complete
Review for gene: IQSEC1 was set to AMBER
Added comment: Ansar et al. (2019 - PMID: 31607425) reported on 5 individuals with biallelic IQSEC1 variants.

Common features included hypotonia, DD, speech impairment, severe ID, behavioral problems as well as short stature. Early-onset seizures were observed in 3 sibs (for whom there was also a paternal family history of seizures).

These subjects belonging to 2 consanguineous families from Pakistan and S. Arabia were found to harbor homozygous missense variants private to each family (Fam1: NM_001134382.2:c.1028C>T or p.Thr354Met following SNP genotyping of several members and exome of the proband | Fam2: c.962G>A or p.Arg321Gln following exome in 2 affected members). Sanger confirmation and study of parents (+/- sibs) were compatible.

The homozygous variant was the only candidate in the 1st family (also following exclusion of other causes of ID/short stature), and most likely/compatible with the patient's phenotype in the 2nd.

As the authors note, IQSEC1-3 encode guanine exchange factors (GEFs) for the ARF family of GTPases. IQSEC2 is a known XLID gene, while biallelic IQSEC3 mutations in ID have been recently reported (PMID: 31130284), all presenting phenotypic similarities (ID, short stature, speech defect).

Previous studies cited had shown that IQSEC1 & 2 are concentrated at the postsynaptic density of glutamatergic synapses in mammalian brain, playing a role in actin-dependent processes incl. AMPA receptor trafficing at synapses (all refs in article).

Drosophila model: The ortholog of IQSEC1, 2 and 3 is schizo and the phenotype associated with its loss is a growth cone guidance defect through dysregulation of the Slit-Robo pathway (all refs in article). The authors studied overexpression of either reference IQSEC1 cDNA or variant cDNAs in wt flies, the former only being toxic/lethal. Loss of schizo was also embryonically lethal but was partially rescued by expression of reference IQSEC1 cDNA. Expression of cDNA for the 2 variants did not rescue lethality. As a result LoF appears to be the underlying effect of both variants. The authors provided evidence that schizo is localized in glia and neurons at various stages of development and is important for proper axon guidance in both CNS and PNS. In Drosophila, schizo is also localized in photoreceptors and RNAi-mediated knockdown resulted in severely impaired sight (also observed in 1 patient).

Mouse model: Through generation of Iqsec1-floxed mice, it was demonstrated that targeted depletion of Iqsec1 in the cortex resulted in increased density/immature morphology of dendritic spines.

IQSEC1 is not associated with any phenotype in OMIM / G2P / SysID and not commonly included in gene panels for ID.

As a result, this gene could be considered for inclusion in the ID panel as probably as amber (2 families/variants).
Sources: Literature
Intellectual disability v2.1095 TAOK1 Ellen McDonagh reviewed gene: TAOK1: Rating: GREEN; Mode of pathogenicity: None; Publications: 31230721; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v2.1092 SVBP Alistair Pagnamenta reviewed gene: SVBP: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 31363758, 30607023; Phenotypes: brain abnormalities, microcephaly, intellectual disability, delayed gross motor development, spasticity, delayed speech development; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v2.1091 NKAP Catherine Snow Added comment: Comment on list classification: NKAP reviewed by Konstantinos Varvagiannis following publication by Fiordaliso et al. (PMID:31587868) who identified 10 males from 8 unrelated families with missense mutations in NKAP (on Xq24) Hypotonia and tall stature with Marfanoid habitus was predominant phenotype. One variant (NM_024528:c.988G>A / p.Arg333Gln) was seen in 4 families and although origin was not provided for all families this variant was seen in brothers with parents from Slovakia and an individual with parents from Japan.
NKAP is not currently in OMIM or Gene2Phenotype.
Rating NKAP as Green as consistent phenotype observed, >3 unrelated individuals and some functional work in Zebrafish.
Intellectual disability v2.1090 METTL5 Rebecca Foulger Added comment: Comment on list classification: METTL5 was added to the panel and rated Green by Konstantinos Varvagiannis. There are just sufficient (3) cases from the literature (siblings in PMID:29302074 plus 2 families in PMID:31564433), and animal models (mice and zebrafish) exhibit microcephaly similar to the human phenotype. However, the Gly61Asp variant found in the PMID:29302074 siblings is currently classed as VUS and PMID:31564433 failed to demonstrate a functional impact for this variant on the encoded protein.

METTL5 has been recently added (October 2019) to DD-G2P with a probable rating for 'Autosomal-Recessive Intellectual Disability and Microcephaly'. METTL5 is not yet associated with a disorder in OMIM. Given the uncertainty of the functional significance of the Gly61Asp variant, on balance an Amber rating is appropriate at this time, pending further cases or functional evidence.
Intellectual disability v2.1087 TRAPPC6B Rebecca Foulger Added comment: Comment on list classification: Updated rating from Amber to Green based on Aug 2019 review by Konstantinos Varvagiannis. Konstantinos notes an additional 2019 paper (Nair et al) who report a Lebanese patient with global DD and ID, who is homozygous for a nonsense variant in TRAPPC6B (p.Leu8*). The unaffected mother was a heterozygous carrier. In contrast to previous cases, the patient did not show any seizures, but the authors note he was only 3.5 years old at the time of writing, and will be monitored for seizure events. ID/DD is a consistent phenotype across cases. This takes the number of cases to 3 (with the 3 families in Marin-Valencia forming 1 case), with 3 separate variants. Therefore Green rating is appropriate.
Intellectual disability v2.1086 CSDE1 Catherine Snow Added comment: Comment on list classification: CSDE1 identified by Konstantinos Varvagiannis based on a publication by Guo et al. (PMID: 31579823) This is the first time CSDE1 has been associated with any diseases therefore it not currently in OMIM or Gene2Phenotype. However consistent phenotype of DD/ID and autism seen among all individuals with variants. With functional work on both mice and Drosophila.
Intellectual disability v2.1083 SMG9 Catherine Snow edited their review of gene: SMG9: Added comment: Maintaining Amber rating as although another individual with a variant has been identified in PMID: 31390136 there are still only full details of serve developmental delays for 2 unrelated families due to the young age of death of one reported individual in 27018474; Changed publications: 31390136
Intellectual disability v2.1083 PMPCB Catherine Snow changed review comment from: PMPCB identified by Konstantinos Varvagiannis following publication by Vögtle et al. (2018 - PMID: 29576218) who reported on by Vögtle et al. (2018 - PMID: 29576218) who identified 5 individuals from 4 unrelated families (in one case consanguineous) who have biallelic pathogenic PMPCB variants.
PMPCB is in OMIM and Gene2Phenotype with relevant phenotype. Individuals reported have stagnation in their development before onset of symptoms. PMPCB is Green on relevant Mitochondrial disorders panel (Version 2.1). As phenotype of DD is relevant to ID panel PMPCB is classified as Green.; to: PMPCB identified by Konstantinos Varvagiannis following publication by Vögtle et al. (2018 - PMID: 29576218) who identified 5 individuals from 4 unrelated families (in one case consanguineous) who have biallelic pathogenic PMPCB variants.
PMPCB is in OMIM and Gene2Phenotype with relevant phenotype. Individuals reported have stagnation in their development before onset of symptoms including, delayed psychomotor development and ID. PMPCB is Green on relevant Mitochondrial disorders panel (Version 2.1). As phenotype of DD is relevant to ID panel PMPCB is classified as Green.
Intellectual disability v2.1082 PMPCB Catherine Snow reviewed gene: PMPCB: Rating: GREEN; Mode of pathogenicity: None; Publications: 29576218; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v2.1082 PCDH12 Catherine Snow Phenotypes for gene: PCDH12 were changed from intellectual disability; microcephaly; epilepsy; perithalamic hyperechogenicity; periventricular hyperechogenicity; midbrain abnormalities; hypothalamic abnormalities to intellectual disability; microcephaly; epilepsy; perithalamic hyperechogenicity; periventricular hyperechogenicity; midbrain abnormalities; hypothalamic abnormalities; Microcephaly, seizures, spasticity, and brain calcification, 251280
Intellectual disability v2.1081 PCDH12 Catherine Snow Added comment: Comment on list classification: Following review by Konstantinos Varvagiannis on PCDH12, highlighted that here is now a sufficient number of published variants from unrelated families to classify PCDH12 as Green with ID reported in all.
Intellectual disability v2.1079 CDH2 Catherine Snow reviewed gene: CDH2: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v2.1078 APC2 Catherine Snow Added comment: Comment on list classification: APC2 is in OMIM with a relevant clinical features but not in Gene2Phenotype. APC2 was identified by Konstantinos Varvagiannis who reviewed all variants. Sufficient number of individuals from unrelated families reported upon in the literature and three different variants identified. Therefore APC2 can be classified as Green
Intellectual disability v2.1078 APC2 Catherine Snow Gene: apc2 has been removed from the panel.
Intellectual disability v2.1076 TANC2 Rebecca Foulger edited their review of gene: TANC2: Changed rating: AMBER
Intellectual disability v2.1076 TANC2 Rebecca Foulger changed review comment from: Comment on list classification: Updated rating from Red to Amber based on PMID:31616000 2019 article suggested by Andrea Haworth. Sufficient unrelated cases (19/20) with an ID/DD phenotype but the pathogenicity of the variants has not yet been verified. Therefore Amber with 'watchlist' tag is appropriate pending functional studies.; to: Comment on list classification: Updated rating from Red to Amber based on PMID:31616000 2019 article suggested by Andrea Haworth. Sufficient unrelated cases (19/20) with an ID/DD phenotype but the pathogenicity of the variants has not yet been verified. Not yet associated with a disorder in Gene2Phenotype or OMIM. Currently only 1 paper, therefore Amber with 'watchlist' tag is appropriate pending functional studies.
Intellectual disability v2.1076 TANC2 Rebecca Foulger Added comment: Comment on list classification: Updated rating from Red to Amber based on PMID:31616000 2019 article suggested by Andrea Haworth. Sufficient unrelated cases (19/20) with an ID/DD phenotype but the pathogenicity of the variants has not yet been verified. Therefore Amber with 'watchlist' tag is appropriate pending functional studies.
Intellectual disability v2.1075 TANC2 Rebecca Foulger commented on gene: TANC2: Summary of PMID:31616000 (PMC:6794285) suggested by Andrea Haworth reviewer: Guo et al assembled phenotypic data for 19 probands and 1 affected sibling with TANC2 variants. Variants include 16 LGD (likely gene-disruptive) variants and three intragenic microdeletions. Phenotypes included ASD, ID, speech-language delay and childhood motor delay:
- 15/20 individuals had ASD/autism features (7 with a formal diagnosis).
- 19/20 individuals had some form of ID (17 with a formal diagnosis of borderline to severe ID, and 2 with learning difficulties without a formal diagnosis).
- 18/20 showed speech-language delay.
- 13/19 individuals had childhood motor delay.
- 11/20 individuals had a formal diagnosis of epilepsy (9) or suffered recurrent seizures (2).
Intellectual disability v2.1071 PIGP Rebecca Foulger Added comment: Comment on list classification: PIGP was added to the panel and rated Green by Konstantinos Varvagiannis. Upgraded rating from Grey to Amber, and added watchlist tag, following review of literature and Amber rating on the Genetic epilepsy syndromes panel. Not yet associated with a disorder in Gene2Phenotype. 2 unrelated cases from the literature plus a third case from LOVD. Therefore Amber rating is appropriate.
Intellectual disability v2.1070 PMPCA Rebecca Foulger Added comment: Comment on list classification: Updated rating from Grey to Amber. PMPCA was added and rated Green by Konstantinos Varvagiannis. Although there are sufficient (3) literature cases overall, the phenotype is variable across cases: 3 families with a possible Founder variant in PMID:25808372, no ID reported in PMID:26657514, 1 family in PMID:27148589 and 1 individual in PMID:30617178. Therefore rated Amber awaiting further cases.
Intellectual disability v2.1066 MED25 Rebecca Foulger Added comment: Comment on list classification: Updated rating from Amber to Green based on the recent Lebanese cases reported by Nair et al (DOI:10.1159/000501114 and PMID:30800049). Advice and a Green review by Helen Brittain supports the upgrade to Green.
Intellectual disability v2.1064 FBXW11 Catherine Snow reviewed gene: FBXW11: Rating: GREEN; Mode of pathogenicity: None; Publications: 31402090, 16865294; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v2.1063 SMPD4 Louise Daugherty Added comment: Comment on publications: Magini P et al. (October 2019) Loss of SMPD4 Causes a Developmental Disorder Characterized by Microcephaly and Congenital Arthrogryposis.
Intellectual disability v2.1062 TDP2 Konstantinos Varvagiannis gene: TDP2 was added
gene: TDP2 was added to Intellectual disability. Sources: Literature,Radboud University Medical Center, Nijmegen
Mode of inheritance for gene: TDP2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TDP2 were set to 24658003; 30109272; 31410782
Phenotypes for gene: TDP2 were set to Spinocerebellar ataxia, autosomal recessive 23, 616949)
Penetrance for gene: TDP2 were set to unknown
Review for gene: TDP2 was set to GREEN
gene: TDP2 was marked as current diagnostic
Added comment: Biallelic pathogenic TGP2 variants cause Spinocerebellar ataxia, autosomal recessive 23 (MIM 616949). At least 6 affected individuals from 4 families have been reported, in all cases homozygous for LoF variants (3 different). ID, epilepsy and ataxia are consistent features of the disorder.

TDP2 encodes a phosphodiesterase that is required for efficient repair of double strand breaks (DSBs) produced by abortive topoisomerase II (TOP2) activity.

The gene is expressed in fetal and adult human brain.

Evidence at the variant level (mRNA, protein levels) and additional studies for impairment of TOP2-induced DSB repair support a role.

Animal models (primarily mice) reproduce the DSB repair defect, provide some histopathological evidence, show transcriptional dysregulation of genes (in line with the role of TOP2 in transcription). They have however failed to reproduce relevant neurological phenotypes.

Published studies are summarized below.

TDP2 is included in gene panels for ID offered by some diagnostic laboratories (incl. Radboudumc and GeneDx). There is no associated phenotype in G2P. TDP2 is listed among the current primary ID genes in SysID.

Overall, this gene could be considered for inclusion in the ID and epilepsy panels probably as green (>=3 patients/families/variants, relevant ID and seizures in all, expression in brain, mRNA/protein levels tested, impaired activity) or amber (absence of neurological phenotypes in mouse model).
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[1] - PMID: 24658003 (Gómez-Herreros et al. 2014):
Reports 3 individuals from a consanguineous Irish family. Features included seizures (onset by 2m, 6m and 12y), ID (3/3) and ataxia (3/3).

A splicing variant (NM_016614.3:c.425+1G>A) was found in a 9.08-Mb region of homozygosity shared by all. A further ZNF193 missense variant localizing in the same region was thought unlikely to contribute to the phenotype (evidence also provided in subsequent study).

The effect of the specific variant was proven by abnormal mRNA size, lower mRNA levels due to NMD (corrected upon cyclohexamide treatment), loss of TDP2 protein upon WB, loss of protein activity in lymphoblastoid cells from affected individuals, decreased repair of DSBs and increased cell death upon addition of etoposide (which promotes TOP2 abortive activity).

The authors report very briefly on a further patient (from Egypt), with ID, 'reports of fits' and ataxia. This individual, with also affected sibs, was homozygous LoF (c.413_414delinsAA / p.Ser138*). Again, the authors were not able to detect TDP2 activity in blood from this subject.

As also commented:
- TDP2 has relevant expression in human (particularly adult) brain.
- Mouse model : Tdp2 is expressed in relevant tissues, absence of Tdp2 activity was observed in neural tissue of mice homoyzgous for an ex1-3 del, with impairment of DSB repair. The authors were unable to detect a neurological phenotype with behavioral analyses, preliminary assesment of seizure propensity. Mice did not show developmental defects. Histopathology however, revealed ~25% reduction in the density of interneurons in cerebellum (a 'hallmark of DSB repair' and associated with seizures and ataxia). Transcription of several genes was shown to be disregulated.
- Knockdown in zebrafish appears to affect left-right axis detremination (cited PMID: 18039968).

[2] - PMID: 30109272 (Zagnoli-Vieira et al. 2018):
A 6 y.o. male with seizures (onset by 5m), hypotonia, DD and ID, microcephaly and some additional clinical features and testing (ETC studies on muscle biopsy, +lactate, +(lactate/pyruvate) ratio) which could be suggestive of mitochondrial disorder. This individual from the US was homozygous for the c.425+1G>A variant but lacked the ZNF193 one (despite a shared haplotype with the Irish patients). Again absence of the protein was shown upon WB in patient fibroblasts, also supported by its activity. Complementation studies restored the DSB repair defect. The defect was specific to TOP2-induced DSBs as suggested by hypersensitivity to etoposide but not to ionizing radiation. CRISPR/Cas9 generated mutant human A549 cells demonstrated abnormal DSB repair. Fibroblasts / edited A549 cells failed to show mitochondrial defects (which were noted in muscle).

[3] - PMID: 31410782 (Ciaccio et al. 2019):
A girl born to consanguineous Italian parents, presented with moderate/severe ID, seizures (onset at 12y) and - among others - gait ataxia, tremor and dysmetria. MRI at the age of 12, demonstrated cerebellar atrophy (although previous exams were N). WES revealed a homozygous nonsense variant (c.400C>T / p.Arg134Ter) for which each parent was found to be carrier. Previous investigations included aCGH, NGS testing for epilepsy and metabolic testing.
Sources: Literature, Radboud University Medical Center, Nijmegen
Intellectual disability v2.1062 PCDH12 Konstantinos Varvagiannis reviewed gene: PCDH12: Rating: ; Mode of pathogenicity: None; Publications: 27164683, 28804758, 29556033, 30178464, 30459466, 18477666; Phenotypes: Microcephaly, seizures, spasticity, and brain calcification, 251280; Mode of inheritance: None; Current diagnostic: yes
Intellectual disability v2.1062 NKAP Konstantinos Varvagiannis reviewed gene: NKAP: Rating: GREEN; Mode of pathogenicity: None; Publications: DOI: 10.1016/j.ajhg.2019.09.009; Phenotypes: Global developmental delay, Intellectual disability, Tall stature, Scoliosis, Pectus excavatum, Pectus carinatum, Arachnodactyly, Camptodactyly, Abnormality of the cardiovascular system, Abnormality of the genitourinary system, Abnormality of the face, Obesity; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Intellectual disability v2.1062 APC2 Konstantinos Varvagiannis gene: APC2 was added
gene: APC2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: APC2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: APC2 were set to 31585108; 25753423; 19759310; 22573669
Phenotypes for gene: APC2 were set to Global developmental delay; Intellectual disability; Seizures; Morphological abnormality of the central nervous system
Penetrance for gene: APC2 were set to Complete
Review for gene: APC2 was set to GREEN
gene: APC2 was marked as current diagnostic
Added comment: Probably 14 individuals from 9 families (8 consanguineous) with biallelic APC2 LoF variants have been reported.

ID and brain abnormalities were features in all, although the presentation was quite different between sibs in the first report (PMID: 25753423 - mild/mod ID, ventriculomegaly and CC anomalies, macrocephaly with variable height, Sotos-like facial features) and 12 subsequently described patients (PMID: 31585108 - severe ID, P>A lissencephaly/CC anomalies/ventriculomegaly/paucity of white matter in (almost) all, gT-C/myoclonic seizures in 8/12 with onset 3m-6y, OFC in the low percentiles).

In all cases relevant alternative diagnoses (eg. macrocephaly/overgrowth syndromes - 1st report, mutations in other lissencephaly genes, metabolic disorders - 2nd) were ruled out.

APC2 encodes Adenomatous polyposis coli protein 2, expressed in the CNS.

All variants reported to date were LoF (stopgain/frameshift/splicing) and were supported by parental-only studies. Mutations in the 1st report as well as 4/8 variants from the 2nd report localized within the last exon (NM_005883.2 / longest of >=3 isoforms), although the 2nd report did not observe obvious genotype-phenotype correlations.

Despite a pLI of 1 in gnomAD, Lee et al. comment that heterozygous carriers did not have any noticeable phenotype. They further note that carriers were not examined by brain MRI, though. 27 heterozygous high-confidence variants appear in individuals in gnomAD. Finally as commented on, APC2 is not mutated in colon cancer.

Animal models: Apc -/- mice displayed disrupted neuronal migration, with defects of lamination of cerebral cortex and cerebellum supporting the observed brain abnormalities. In addition Apc2-deficient mice also presented impaired learning and memory abilities. Extensive additional studies have shown Apc2 co-localization with microtubules affecting their stabilization, distribution along actin fibers (all supporting a role in cytoskeletal organization) and regulation of Rac1 (a Rho GTPase). Generation of Neuro2a cells demonstrated abnormal localization mainly in cell bodies of mutant hAPC2 proteins (due to frameshift in the last exon / deletion of the C-terminal part) - different from wt (neurites, growth cones, cell bodies). The first patient report also provided evidence for Apc2 being a downstream effector of Nsd1, with Nsd1 knockdown brains displaying impaired migration / laminar positioning of cortical neurons (similar to Apc2-/- model) and rescued by forced expression of Apc2.

Relevant articles:
PMIDs: 19759310 and 22573669 (Shintani et al. 2009 & 2012) [mouse model]
PMID: 25753423 (Almuriekhi et al. 2015) [2 individuals + mouse model]
PMID: 31585108 (Lee et al. 2019) [12 individuals from 8 families]
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In OMIM, the APC2-related phenotype is ?Sotos syndrome 3 (MIM 617169 - AR). G2P does not have any associated phenotype for this gene. In SysID, APC2 belongs to the Current primary ID genes.
APC2 is included in gene panels for ID offered by some diagnostic laboratories (eg. Radboudumc, GeneDx).
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Overall, this gene could be considered for inclusion in the ID panel probably as green (>3 individuals/families/variants, highly specific pattern of lissencephaly in 12/14, mouse model supporting migration defects and impaired learning/memory) rather than amber (differences between the 1st and the other families reported as for the OFC and presence of lissencephaly).
Sources: Literature
Intellectual disability v2.1062 CDH2 Konstantinos Varvagiannis changed review comment from: Accogli et al. (2019 - PMID: 31585109) report on 9 individuals with de novo pathogenic CDH2 variants.

Overlapping features included axon pathfinding defects (corpus callosum agenesis/hypoplasia, mirror movements, Duane anomaly), cardiac, ocular and genital anomalies. Neurodevelopmental phenotypes included DD (8/9), ID (2/8 mild and 2/8 moderate, the remaining had either low-average/borderline int. functioning (2), did not present ID (2) or did not have relevant age for evaluation) and ASD (in 2).

CDH2 encodes cadherin-2 (N-cadherin) with high expression in neural tissue. As the authors note, the gene has important role in neural development, incl. proliferation and differentiation of neural progenitor cells, neural tube formation, synaptogenesis, neuronal migration and axon elongation. N-cadherin, similar to other classical cadherins has an extracellular domain with 5 extracellular cadherin (EC) domain repeats that mediate cell adhesion either in cis or in trans (between molecules of the same / different cells).

Mutations in other cadherins have been associated among others with neurodevelopmental disorders (eg. PCDH19, PCDH12, etc).

Variants in all cases were de novo, identified following trio-WES. 7 missense variants (6 of which clustering within the EC4-EC5 linker region or the EC5 domain - calculated p=1.37x10-4) and 2 frameshift ones predicted not to lead to NMD were identified.

One individual had an additional DNM1 variant, formally fulfilling ACMG criteria for pathogenic. The authors however felt that presentation of the specific subject (low-average/borderline int. functioning, absence of seizures and microcephaly) was not compatible with the phenotype of DNM1-encephalopathy .

Missense SNVs within the EC4-EC5 region, were shown to impair cell-cell adhesion by affecting both self-binding and trans adhesion to wt N-cadherin (in L cells studied). This supported a possible dominant-negative effect. A single variant in the EC2 domain - previously shown to be critical for adhesion - was thought to have a similar effect. The authors speculated that truncating variants may also act in a dominant-negative manner (as has been demonstrated for other cadherins) although LoF remains possible.

Cdh2 knockout in mice is embryonically lethal. Mouse with conditional inactivation of Cdh2 in the cerebral cortex leads to cortical disorganization and CCA similar to the human phenotypes (PMIDs cited: 9015265, 17222817). Other animal studies (mouse, zebrafish, chicken, dog, etc) are also cited to link with specific defects.

Heterozygous CDH2 variants affecting the ectodomain have been associated with ARVC (2 variants, one of which segregated with the disorder in a 3-generation family, the other identified in two unrelated families with several affecteds - refs. provided in the article). Cardiac abnormalities were noted in several subjects (incl. electrical activity in 2). [Amber rating of this gene in Arrhythmogenic cardiomyopathy panel].
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The gene is not associated with any phenotype in OMIM / G2P / SysID and not commonly included in panels for ID.
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As a result CDH2 could be considered for inclusion in the ID panel probably as amber (mild/moderate ID in 4/8, uncertainty regarding the underlying effect of some variants or additional phenotypes (ARVC)) or green (>3 individuals/variants/families, ID is a feature and in some cases of moderate degree).
Sources: Literature; to: Accogli et al. (2019 - PMID: 31585109) report on 9 individuals with de novo pathogenic CDH2 variants.

Overlapping features included axon pathfinding defects (corpus callosum agenesis/hypoplasia, mirror movements, Duane anomaly), cardiac, ocular and genital anomalies. Neurodevelopmental phenotypes included DD (8/9), ID (2/8 mild and 2/8 moderate, the remaining had either low-average/borderline int. functioning (2), did not present ID (2) or did not have relevant age for evaluation) and ASD (in 2).

CDH2 encodes cadherin-2 (N-cadherin) with high expression in neural tissue. As the authors note, the gene has important role in neural development, incl. proliferation and differentiation of neural progenitor cells, neural tube formation, synaptogenesis, neuronal migration and axon elongation. N-cadherin, similar to other classical cadherins has an extracellular domain with 5 extracellular cadherin (EC) domain repeats that mediate cell adhesion either in cis or in trans (between molecules of the same / different cells).

Mutations in other cadherins have been associated among others with neurodevelopmental disorders (eg. PCDH19, PCDH12, etc).

Variants in all cases were de novo, identified following trio-WES. 7 missense variants (6 of which clustering within the EC4-EC5 linker region or the EC5 domain - calculated p=1.37x10-4) and 2 frameshift ones predicted not to lead to NMD were identified.

One individual had an additional DNM1 variant, formally fulfilling ACMG criteria for pathogenic. The authors however felt that presentation of the specific subject (low-average/borderline int. functioning, absence of seizures and microcephaly) was not compatible with the phenotype of DNM1-encephalopathy .

Missense SNVs within the EC4-EC5 region, were shown to impair cell-cell adhesion by affecting both self-binding and trans adhesion to wt N-cadherin (in L cells studied). This supported a possible dominant-negative effect. A single variant in the EC2 domain - previously shown to be critical for adhesion - was thought to have a similar effect. The authors speculated that truncating variants may also act in a dominant-negative manner (as has been demonstrated for other cadherins) although LoF remains possible.

Cdh2 knockout in mice is embryonically lethal. Conditional inactivation of Cdh2 in the cerebral cortex leads to cortical disorganization and CCA similar to the human phenotypes (PMIDs cited: 9015265, 17222817). Other animal studies (mouse, zebrafish, chicken, dog, etc) are also cited to link with specific defects.

Heterozygous CDH2 variants affecting the ectodomain have been associated with ARVC (2 variants, one of which segregated with the disorder in a 3-generation family, the other identified in two unrelated families with several affecteds - refs. provided in the article). Cardiac abnormalities were noted in several subjects (incl. electrical activity in 2). [Amber rating of this gene in Arrhythmogenic cardiomyopathy panel].
------
The gene is not associated with any phenotype in OMIM / G2P / SysID and not commonly included in panels for ID.
------
As a result CDH2 could be considered for inclusion in the ID panel probably as amber (mild/moderate ID in 4/8, uncertainty regarding the underlying effect of some variants or additional phenotypes (ARVC)) or green (>3 individuals/variants/families, ID is a feature and in some cases of moderate degree).
Sources: Literature
Intellectual disability v2.1062 CDH2 Konstantinos Varvagiannis gene: CDH2 was added
gene: CDH2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: CDH2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CDH2 were set to 31585109; 9015265; 17222817
Phenotypes for gene: CDH2 were set to Abnormality of the corpus callosum; Abnormality of neuronal migration; Bimanual synkinesia; Duane anomaly; Abnormality of cardiovascular system; Abnormality of the eye; Abnormality of the genital system; Global developmental delay; Intellectual disability
Penetrance for gene: CDH2 were set to unknown
Review for gene: CDH2 was set to AMBER
Added comment: Accogli et al. (2019 - PMID: 31585109) report on 9 individuals with de novo pathogenic CDH2 variants.

Overlapping features included axon pathfinding defects (corpus callosum agenesis/hypoplasia, mirror movements, Duane anomaly), cardiac, ocular and genital anomalies. Neurodevelopmental phenotypes included DD (8/9), ID (2/8 mild and 2/8 moderate, the remaining had either low-average/borderline int. functioning (2), did not present ID (2) or did not have relevant age for evaluation) and ASD (in 2).

CDH2 encodes cadherin-2 (N-cadherin) with high expression in neural tissue. As the authors note, the gene has important role in neural development, incl. proliferation and differentiation of neural progenitor cells, neural tube formation, synaptogenesis, neuronal migration and axon elongation. N-cadherin, similar to other classical cadherins has an extracellular domain with 5 extracellular cadherin (EC) domain repeats that mediate cell adhesion either in cis or in trans (between molecules of the same / different cells).

Mutations in other cadherins have been associated among others with neurodevelopmental disorders (eg. PCDH19, PCDH12, etc).

Variants in all cases were de novo, identified following trio-WES. 7 missense variants (6 of which clustering within the EC4-EC5 linker region or the EC5 domain - calculated p=1.37x10-4) and 2 frameshift ones predicted not to lead to NMD were identified.

One individual had an additional DNM1 variant, formally fulfilling ACMG criteria for pathogenic. The authors however felt that presentation of the specific subject (low-average/borderline int. functioning, absence of seizures and microcephaly) was not compatible with the phenotype of DNM1-encephalopathy .

Missense SNVs within the EC4-EC5 region, were shown to impair cell-cell adhesion by affecting both self-binding and trans adhesion to wt N-cadherin (in L cells studied). This supported a possible dominant-negative effect. A single variant in the EC2 domain - previously shown to be critical for adhesion - was thought to have a similar effect. The authors speculated that truncating variants may also act in a dominant-negative manner (as has been demonstrated for other cadherins) although LoF remains possible.

Cdh2 knockout in mice is embryonically lethal. Mouse with conditional inactivation of Cdh2 in the cerebral cortex leads to cortical disorganization and CCA similar to the human phenotypes (PMIDs cited: 9015265, 17222817). Other animal studies (mouse, zebrafish, chicken, dog, etc) are also cited to link with specific defects.

Heterozygous CDH2 variants affecting the ectodomain have been associated with ARVC (2 variants, one of which segregated with the disorder in a 3-generation family, the other identified in two unrelated families with several affecteds - refs. provided in the article). Cardiac abnormalities were noted in several subjects (incl. electrical activity in 2). [Amber rating of this gene in Arrhythmogenic cardiomyopathy panel].
------
The gene is not associated with any phenotype in OMIM / G2P / SysID and not commonly included in panels for ID.
------
As a result CDH2 could be considered for inclusion in the ID panel probably as amber (mild/moderate ID in 4/8, uncertainty regarding the underlying effect of some variants or additional phenotypes (ARVC)) or green (>3 individuals/variants/families, ID is a feature and in some cases of moderate degree).
Sources: Literature
Intellectual disability v2.1062 MED25 Helen Brittain edited their review of gene: MED25: Added comment: There are now different variants (potentially each founders) in three populations, and several families, that have been reported in association with ID. Therefore the evidence for a green rating in terms of a gene:disease association now seems sufficient. To determine the extent of the phenotype, in terms of associated features, further cases would be beneficial. Therefore I would currently recommend a green rating for the ID panel.; Changed rating: GREEN; Changed phenotypes: Basel-Vanagait-Smirin-Yosef syndrome 616449; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v2.1062 INTS1 Rebecca Foulger Phenotypes for gene: INTS1 were changed from Hypotonia; Global developmental delay; Cataract; Abnormality of the skeletal system to Neurodevelopmental disorder with cataracts, poor growth, and dysmorphic facies, 618571; Hypotonia; Global developmental delay; Cataract; Abnormality of the skeletal system
Intellectual disability v2.1061 AP2M1 Rebecca Foulger Phenotypes for gene: AP2M1 were changed from Seizures; Ataxia; Generalized hypotonia; Intellectual disability; Global developmental delay; Autistic behavior to Intellectual developmental disorder 60 with seizures, 618587; Seizures; Ataxia; Generalized hypotonia; Intellectual disability; Global developmental delay; Autistic behavior
Intellectual disability v2.1060 RAC3 Rebecca Foulger Phenotypes for gene: RAC3 were changed from Abnormality of brain morphology, Abnormal muscle tone, Neurodevelopmental delay, Intellectual disability; Abnormality of brain morphology; Abnormal muscle tone; Neurodevelopmental delay; Intellectual disability to Neurodevelopmental disorder with structural brain anomalies and dysmorphic facies, 618577; Abnormality of brain morphology, Abnormal muscle tone, Neurodevelopmental delay, Intellectual disability; Abnormality of brain morphology; Abnormal muscle tone; Neurodevelopmental delay; Intellectual disability
Intellectual disability v2.1059 PIGU Rebecca Foulger Phenotypes for gene: PIGU were changed from Global developmental delay; Intellectual disability; Seizures; Cerebral atrophy; Cerebellar hypoplasia; Scoliosis to Glycosylphosphatidylinositol biosynthesis defect 2, 618590; Global developmental delay; Intellectual disability; Seizures; Cerebral atrophy; Cerebellar hypoplasia; Scoliosis
Intellectual disability v2.1058 PIGQ Rebecca Foulger Phenotypes for gene: PIGQ were changed from SEVERE EARLY-ONSET EPILEPSY to SEVERE EARLY-ONSET EPILEPSY; Epileptic encephalopathy, early infantile, 77, 618548
Intellectual disability v2.1057 PIGB Rebecca Foulger Phenotypes for gene: PIGB were changed from Generalized hypotonia; Global developmental delay; Intellectual disability; Seizures; Hearing abnormality; Abnormality of vision; Elevated alkaline phosphatase; Abnormality of the head; Abnormality of the hand; Abnormality of the foot to Epileptic encephalopathy, early infantile, 80, 618580; Generalized hypotonia; Global developmental delay; Intellectual disability; Seizures; Hearing abnormality; Abnormality of vision; Elevated alkaline phosphatase; Abnormality of the head; Abnormality of the hand; Abnormality of the foot
Intellectual disability v2.1055 HNRNPR Catherine Snow reviewed gene: HNRNPR: Rating: GREEN; Mode of pathogenicity: None; Publications: 31079900, 26795593; Phenotypes: Intellectual Disability; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v2.1054 DDX6 Catherine Snow reviewed gene: DDX6: Rating: GREEN; Mode of pathogenicity: None; Publications: 31422817; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v2.1054 TIMM50 Rebecca Foulger Added comment: Comment on list classification: TIMM50 was added to the ID panel and rated Green by Konstantinos Varvagiannis. Not yet associated with a disorder in Gene2Phenotype but upgraded rating from Grey to Green following review of literature evidence. PMID:27573165 and PMID:31058414 report 5 patients from 3 families with a consistent ID and epilepsy phenotype accompanied by 3-methylglutaconic aciduria. In addition, PMID:30190335 report pyschomotor regression in their patient, and a conference abstract (Serajee et al. 2015) adds an additional case of developmental delay. Therefore ID appears a consistent phenotype of 3-methylglutaconic aciduria and with sufficient reported cases, a Green rating is appropriate.
Intellectual disability v2.1053 TIMM50 Rebecca Foulger Phenotypes for gene: TIMM50 were changed from 3-methylglutaconic aciduria, type IX (MIM 617698) to 3-methylglutaconic aciduria, type IX, 617698
Intellectual disability v2.1052 GABRA5 Rebecca Foulger Added comment: Comment on list classification: Upgraded from Amber to Green following advice from Genomics England clinical team. The case reported in PMID:29961870 (Butler et al 2018) had delayed milestones and is reported to be non-verbal, which is a relevant phenotype for this panel. Overall 3 unrelated cases from 2 papers.
Intellectual disability v2.1051 KCNMA1 Catherine Snow Phenotypes for gene: KCNMA1 were changed from GENERALIZED EPILEPSY AND PAROXYSMAL DYSKINESIA to Cerebellar atrophy, developmental delay, and seizures, 617643; Paroxysmal nonkinesigenic dyskinesia, 3, with or without generalized epilepsy, 609446
Intellectual disability v2.1049 KCNMA1 Catherine Snow Mode of inheritance for gene: KCNMA1 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v2.1047 KCNMA1 Catherine Snow reviewed gene: KCNMA1: Rating: AMBER; Mode of pathogenicity: None; Publications: 31427379, 31152168; Phenotypes: Cerebellar atrophy, developmental delay, and seizures, 617643; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v2.1047 SMG9 Konstantinos Varvagiannis reviewed gene: SMG9: Rating: GREEN; Mode of pathogenicity: None; Publications: 27018474, 31390136; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability v2.1047 METTL5 Konstantinos Varvagiannis edited their review of gene: METTL5: Set current diagnostic: yes
Intellectual disability v2.1047 METTL5 Konstantinos Varvagiannis gene: METTL5 was added
gene: METTL5 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: METTL5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: METTL5 were set to 29302074; http://doi.org/10.1016/j.ajhg.2019.09.007; https://imgc2019.sciencesconf.org/data/abstract_book_complete.pdf
Phenotypes for gene: METTL5 were set to Delayed speech and language development; Intellectual disability; Microcephaly; Behavioral abnormality
Penetrance for gene: METTL5 were set to Complete
Review for gene: METTL5 was set to GREEN
Added comment: [1] - PMID: 29302074 :
In a WES/WGS study of 404 consanguineous families with two or more offspring affected by ID, Hu et al. identified two sibs homozygous for a METTL5 missense variant [NM_014168:c.182G>A / p.Gly61Asp]. These 2 subjects, born to first cousin parents from Iran, presented with early learning impairment, aggressive behaviour, severe microcephaly (-7SD and -8SD) and ID formally evaluated to be in the severe range. Sanger confirmation of variants and segregation studies were performed for all available and informative members in families participating in the study. In silico predictions were all in favour of a deleterious effect (PolyPhen2, MutationTaster, SIFT, CADD) and the variant was absent from ExAC. The effect of the specific variant was studied in ref. 2 (below).

[2] - DOI: 10.1016/j.ajhg.2019.09.007 :
Richard et al. (2019) reported on 5 additional individuals from 2 consanguineous families. Common phenotype consisted of speech delay, moderate/severe ID (4/4), microcephaly (4/4 - though milder than in the first report), behavioral problems (ADHD, aggressiveness, autistic feat.) and possibly some overlapping facial features (nose and ear abnormalities). 3 sibs from the 1st family, from Pakistan, were homozygous for a frameshift variant (NM_014167.2:c.344_345delGA / p.Arg115Asnfs*19) while sibs from the 2nd family, from Yemen, were homozygous for p.Lys191Valfs*1 (c.571_572delAA). Confirmation and segregation studies supported a role for the variants.

The authors performed additional studies for METTL5 and all 3 variants reported to date, notably:
- Based on RNA-seq data from the Allen Brain Atlas, METTL5 is expressed in the developing and adult human brain (incl. cerebellar cortex, hippocampus and striatum).
- Immunostaining in mouse brain demonstrated ubiquitous expression (postnatal day 30).
- In rat hippocampal neurons, enrichment of METTL5 was found in the soma, the nucleus and pre- and post- synaptic regions.
- Myc-/GFP-tagged METTL5 wt or mutants were transiently expressed in COS7 cells, and were found in the cytoplasm and nucleus. Levels of the 2 frameshift variants were significantly reduced compared with wt, although this was not the case for Gly61Asp.
- Upon transfection of rat hippocampal neurons, METTL5-GFP tagged wt and mt proteins showed similar localicalization in nucleus and dendrites.
- Western blot on HEK293T cells transfected with Myc-METTL5 wt or mt constructs demonstrated decreased amounts for the frameshift (but not the missense) variants while comparison after addition of a proteasome inhibitor or cyclohexamide suggested that this is not probably due to decreased mutant protein - rather than mRNA (NMD) - stability.
- In zebrafish, morpholino knockdown of mettl5 led to reduced head size and head/body ratio (reproducing the microcephaly phenotype) and curved tails. Forebrain and midbrain sizes were also significantly reduced.

Based on the ACMG criteria, Gly61Asp is classified as VUS (PM2, PP1, PP3) and the frameshift ones as pathogenic (PS3, PM2, PM4, PP1, PP3).

The authors comment that METTL5 is an uncharacterized member of the methyltransferase superfamily (of 33 METTL proteins). Variants in other methyltransferase-like genes (mainly METTL23) have been associated with ID, while various histone-/DNA-/tRNA-/rRNA- methyltransferases such as EHMT1, DNMT3A, NSUN2, FTSJ1, etc have been implicated in ID. Given the role of methyltransferases in neurodevelopment and neuroplasticity, homology comparisons suggesting presence of relevant domain in METTL5 and accumulation of the protein in the nucleus, a role as epigenetic regulator is proposed (see also ref. 3).

[3] - Conference abstract by Helmut et al. ["A novel m6A RNA methyltransferase in mammals - characterization of Mettl5 mutant mice in the German Mouse Clinic" - Oral presentation in the 33rd International Mammalian Genome Conference Sept. 2019 - available at : https://imgc2019.sciencesconf.org/data/abstract_book_complete.pdf ]
The group using an in vitro methyltransferase assay, identified METTL5 as a m6A RNA methyltransferase. Generation of Mettl5-knockout mice using the CRISPR/Cas technology, suggested that homozygous mice are subviable, with lower body mass and abnormal growth of nasal bones in half. Homozygous mice were hypoactive and hypoexploratory during an open field test at the age of 8 weeks, while further alterations were observed in neurological functions. Phenotypic deviations were absent or very mild in heterozygous animals. As a result, the mouse model appeared to recapitulate relevant human phenotypes (microcephaly, ID and growth retardation).

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There is no associated entry in OMIM (neither for the gene nor for a related disorder). G2P does not list any phenotype for this gene, either.

METTL5 is included in the SysID database as a current primary ID gene (cited: 27457812, 28097321 / Given the shared co-authors with the study by Richard et al. as well as the overlapping variants, these articles probably report on the same individuals recently described in more detail).

The gene is included in gene panels for ID offered by some diagnostic laboratories (eg. GeneDx).
----

Overall, METTL5 could be considered for inclusion in the ID panel probably as green (3 families, 3 variants, segregation, suggested role of the gene, relevant expression patterns, some evidence at the variant-level, zebrafish and mouse models) or amber (underlying effect of Gly61Asp unknown and variant classified as VUS).
Sources: Literature
Intellectual disability v2.1047 CSDE1 Konstantinos Varvagiannis gene: CSDE1 was added
gene: CSDE1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: CSDE1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CSDE1 were set to http://doi.org/10.1126/sciadv.aax2166
Phenotypes for gene: CSDE1 were set to Autism; Global developmental delay; Intellectual disability
Penetrance for gene: CSDE1 were set to unknown
Review for gene: CSDE1 was set to GREEN
Added comment: Guo et al. (2019 - DOI: 10.1126/sciadv.aax2166) report on 18 individuals from 18 unrelated families, with heterozygous likely gene disrupting (stopgain/frameshift/spice-site) CSDE1 variants.

Initial sequencing with MIPs found in 3 individuals from an autism cohort (4045 probands), while subsequent targeted sequencing of a larger cohort (autism spectrum/ID network) led to identification of 5 additional relevant individuals and Genematcher/collaborations a further 10 (the latter by WES).

Consistent phenotypes included ASD (10 of 15 formally evaluated), DD (motor: 15/17 - speech: 17/17) and ID (mild to severe in 14 of 16 assessed, in further 2 in the below-average range). Recurrent seizures or epilepsy were reported for 7 of 16 patients. Other variable features were anxiety or ADHD, increased OFC, ocular, hand and MRI anomalies.

The study was mainly focused on LGD variants with p.R123* (NM_001242891.1:c.367C>T) being a reccurrent one, found in 3 families.

8 of these variants were de novo, 8 further inherited (often from a less severely affected parent, although parental neuropsychiatric status was not available for individuals from all 3 groups). In 2 cases inheritance was unknown (only 1 parental sample available).

3 individuals with de novo missense variants were also identified. Features in those individuals also included ASD and/or DD and ID (2/3) [Table S1].

Arguments to support involvement of the CSDE1 variants included the:
- role of the gene encoding an RNA binding protein implicated in neuronal migration/differentiation (cited : 24012837, 29129916),
- statistically significant burden of the variants in the cohorts examined,
- relevant CSDE1 intolerance scores (pLI of 1 and %RVIS of 6.18),
- relevant human (mRNA) / mouse (protein) spatial and temporal expression patterns,
- exclusion of apparent alternative diagnoses to the extent possible in many subjects with CNVs/SNVs/ROH of uncertain significance in very few,
- cosegregation with rather similar neuropsychiatric phenotypes in case of carrier parents,
- enrichment of ASD-related genes (and FMRP targets) among CSDE1-binding targets,
- suppression of Ctnnb1 expression (at the protein level) affecting Wnt/β-catenin signalling,
- effect of knockdown and/or mutants in mouse (shRNA) and Drosophila (mt and siRNA) models affecting synapse formation and synaptic transmission,
- rescue of many of the previous phenotypes by expression of human CSDE1 (mice), expression of stabilized β-Catenin (mice) or RNAi-stable-dUNR (Drosophila) [also supporting LoF as the underlying effect of variants].

CSDE1 is not commonly included in gene panels for ID offered by diagnostic laboratories. There is no associated phenotype in OMIM/G2P.

Overall, this gene could be considered for inclusion in the ID panel probably as green (or amber).
Sources: Literature
Intellectual disability v2.1046 MED25 Rebecca Foulger changed review comment from: 10.1159/000501114 (Nair et al., 2019b) report an additional Lebanese family with 2 affected siblings with delayed psychomotor and language development, with craniofacial anomalies. A homozyogus p.Ile173Thr change in MED25 was found, which may be a Founder variant.; to: DOI:10.1159/000501114 (Nair et al., 2019b) report an additional Lebanese family with 2 affected siblings with delayed psychomotor and language development, with craniofacial anomalies. A homozyogus p.Ile173Thr change in MED25 was found, which may be a Founder variant.
Intellectual disability v2.1046 MED25 Rebecca Foulger commented on gene: MED25: 10.1159/000501114 (Nair et al., 2019b) report an additional Lebanese family with 2 affected siblings with delayed psychomotor and language development, with craniofacial anomalies. A homozyogus p.Ile173Thr change in MED25 was found, which may be a Founder variant.
Intellectual disability v2.1046 PMPCB Konstantinos Varvagiannis changed review comment from: Biallelic pathogenic PMPCB variants cause, Multiple mitochondrial dysfunctions syndrome 6 (MIM 617954).

5 relevant individuals from 4 unrelated families (in one case consanguineous) have been reported by Vögtle et al. (2018 - PMID: 29576218).

Onset of symptoms (eg. hypotonia) often preceded a period of developmental regression/stagnation which was common in all individuals and occurred within the first 2 years of life, usually following febrile illness. In all cases neurological features were severe (lack of ambulation/speech). Seizures were observed in 4 individuals from 3 families, with onset at the age of 11-24m. MRI images demonstrated T2 signal hyperintensities of the basal ganglia with cerebellar and cerebral atrophy in some. Deterioration with early death was reported on three occasions, though some years after symptom onset.

Following exclusion of other diagnoses in some cases (eg. aCGH, epilepsy panel), WES identified biallelic PMPCB missense variants, supported by Sanger confirmation and segregation studies. The following variants were reported (NM_004279.2):
- c.523C>T (p.Arg175Cys) in trans with c.601G>C (p.Ala201Pro) [Fam A and B]
- c.524G>A (p.Arg175His) in trans with c.530T>G (p.Val177Gly) [Fam C]
- c.1265T>C (p.Ile422Thr) in homozygous state [Fam D with 2 affected sibs]

The gene encodes the catalytic (beta) subunit of the mitochondrial processing protease (MPP) which is responsible for the cleavage/maturation of nuclear-encoded mitochondrial precursor proteins after their import in mitochondria. The alpha subunit is encoded by PMPCA (green rating proposed for this panel).

Extensive studies demonstrated (perhaps a better summary provided by OMIM):
- Reduced PMPCB protein levels in mitochondria isolated from patient fibroblasts or patient-derived pluripotent stem cells.
- Frataxin maturation was impaired with accumulation of the intermediate form and lower amounts of mature FXN, indicating decrease in MPP activity.
- Analysis of the homologous Mas1 S. cerevisiae mutants was carried out, with the exception of Ile422Thr (corresponding to Mas1 - Ile398Thr), the introduction of which did not yield viable yiest strains. Homologous mutations led to a temperature-sensitive phenotype with accumulation of immature/unprocessed precursor proteins and decrease of mature/processed forms both in vivo or in organello (following isolation of mitochondria). Under conditions of heat stress, Mas1 mutations decreased biogenesis of Fe-S clusters.
- Respiratory chain complexes I-III contain Fe-S clusters. In muscle biopsy from an affected individual, complex II activity was significantly reduced (although this was not the case in fibroblasts or liver biopsy). Dysfunction of mitochondrial and cytosolic Fe-S cluster-dependent enzymes (eg. aconitase) was also shown in muscle tissue.

Regression/stagnation with seizures/non-achievement of milestones may justify testing for an ID / epilepsy gene panel. In addition, metabolic studies or mitochondrial respiratory chain complex studies were sometimes non-informative (lactate elevated in 3/5 subjects) or not carried out at all / in relevant tissues (muscle biopsy in 2 individuals, fibroblasts/liver biopsy did not demonstrate reduced complex activity when tested).

PMPCB is included in the ID gene panel of Radboudumc, as well as the SysID database. The gene is included in the DD panel of G2P associated with "Neurodegeneration in Early Childhood" (disease confidence : probable).

As a result, PMPCB can be considered for inclusion in both epilepsy and ID panels as green (or amber).
Sources: Literature, Radboud University Medical Center, Nijmegen; to: Biallelic pathogenic PMPCB variants cause, Multiple mitochondrial dysfunctions syndrome 6 (MIM 617954).

5 relevant individuals from 4 unrelated families (in one case consanguineous) have been reported by Vögtle et al. (2018 - PMID: 29576218).

Onset of symptoms (eg. hypotonia) often preceded a period of developmental regression/stagnation which was common in all individuals and occurred within the first 2 years of life, usually following febrile illness. In all cases neurological features were severe (lack of ambulation/speech). Seizures were observed in 4 individuals from 3 families, with onset at the age of 11-24m. MRI images demonstrated T2 signal hyperintensities of the basal ganglia with cerebellar and cerebral atrophy in some. Deterioration with early death was reported on three occasions, though some years after symptom onset.

Following exclusion of other diagnoses in some cases (eg. aCGH, epilepsy panel), WES identified biallelic PMPCB missense variants, supported by Sanger confirmation and segregation studies. The following variants were reported (NM_004279.2):
- c.523C>T (p.Arg175Cys) in trans with c.601G>C (p.Ala201Pro) [Fam A and B]
- c.524G>A (p.Arg175His) in trans with c.530T>G (p.Val177Gly) [Fam C]
- c.1265T>C (p.Ile422Thr) in homozygous state [Fam D with 2 affected sibs]

The gene encodes the catalytic (beta) subunit of the mitochondrial processing protease (MPP) which is responsible for the cleavage/maturation of nuclear-encoded mitochondrial precursor proteins after their import in mitochondria. The alpha subunit is encoded by PMPCA (green rating proposed for this panel).

Extensive studies demonstrated (perhaps a better summary provided by OMIM):
- Reduced PMPCB protein levels in mitochondria isolated from patient fibroblasts or patient-derived pluripotent stem cells.
- Frataxin maturation was impaired with accumulation of the intermediate form and lower amounts of mature FXN, indicating decrease in MPP activity.
- Analysis of the homologous Mas1 S. cerevisiae mutants was carried out, with the exception of Ile422Thr (corresponding to Mas1 - Ile398Thr), the introduction of which did not yield viable yeast strains. Homologous mutations led to a temperature-sensitive phenotype with accumulation of immature/unprocessed precursor proteins and decrease of mature/processed forms both in vivo or in organello (following isolation of mitochondria). Under conditions of heat stress, Mas1 mutations decreased biogenesis of Fe-S clusters.
- Respiratory chain complexes I-III contain Fe-S clusters. In muscle biopsy from an affected individual, complex II activity was significantly reduced (although this was not the case in fibroblasts or liver biopsy). Dysfunction of mitochondrial and cytosolic Fe-S cluster-dependent enzymes (eg. aconitase) was also shown in muscle tissue.

Regression/stagnation with seizures/non-achievement of milestones may justify testing for an ID / epilepsy gene panel. In addition, metabolic studies or mitochondrial respiratory chain complex studies were sometimes non-informative (lactate elevated in 3/5 subjects) or not carried out at all / in relevant tissues (muscle biopsy in 2 individuals, fibroblasts/liver biopsy did not demonstrate reduced complex activity when tested).

PMPCB is included in the ID gene panel of Radboudumc, as well as the SysID database. The gene is included in the DD panel of G2P associated with "Neurodegeneration in Early Childhood" (disease confidence : probable).

As a result, PMPCB can be considered for inclusion in both epilepsy and ID panels as green (or amber).
Sources: Literature, Radboud University Medical Center, Nijmegen
Intellectual disability v2.1046 INTS6 Konstantinos Varvagiannis reviewed gene: INTS6: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v2.1046 PMPCB Konstantinos Varvagiannis edited their review of gene: PMPCB: Changed publications: 29576218
Intellectual disability v2.1046 PMPCB Konstantinos Varvagiannis gene: PMPCB was added
gene: PMPCB was added to Intellectual disability. Sources: Literature,Radboud University Medical Center, Nijmegen
Mode of inheritance for gene: PMPCB was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: PMPCB were set to Multiple mitochondrial dysfunctions syndrome 6, 617954
Penetrance for gene: PMPCB were set to Complete
Review for gene: PMPCB was set to GREEN
gene: PMPCB was marked as current diagnostic
Added comment: Biallelic pathogenic PMPCB variants cause, Multiple mitochondrial dysfunctions syndrome 6 (MIM 617954).

5 relevant individuals from 4 unrelated families (in one case consanguineous) have been reported by Vögtle et al. (2018 - PMID: 29576218).

Onset of symptoms (eg. hypotonia) often preceded a period of developmental regression/stagnation which was common in all individuals and occurred within the first 2 years of life, usually following febrile illness. In all cases neurological features were severe (lack of ambulation/speech). Seizures were observed in 4 individuals from 3 families, with onset at the age of 11-24m. MRI images demonstrated T2 signal hyperintensities of the basal ganglia with cerebellar and cerebral atrophy in some. Deterioration with early death was reported on three occasions, though some years after symptom onset.

Following exclusion of other diagnoses in some cases (eg. aCGH, epilepsy panel), WES identified biallelic PMPCB missense variants, supported by Sanger confirmation and segregation studies. The following variants were reported (NM_004279.2):
- c.523C>T (p.Arg175Cys) in trans with c.601G>C (p.Ala201Pro) [Fam A and B]
- c.524G>A (p.Arg175His) in trans with c.530T>G (p.Val177Gly) [Fam C]
- c.1265T>C (p.Ile422Thr) in homozygous state [Fam D with 2 affected sibs]

The gene encodes the catalytic (beta) subunit of the mitochondrial processing protease (MPP) which is responsible for the cleavage/maturation of nuclear-encoded mitochondrial precursor proteins after their import in mitochondria. The alpha subunit is encoded by PMPCA (green rating proposed for this panel).

Extensive studies demonstrated (perhaps a better summary provided by OMIM):
- Reduced PMPCB protein levels in mitochondria isolated from patient fibroblasts or patient-derived pluripotent stem cells.
- Frataxin maturation was impaired with accumulation of the intermediate form and lower amounts of mature FXN, indicating decrease in MPP activity.
- Analysis of the homologous Mas1 S. cerevisiae mutants was carried out, with the exception of Ile422Thr (corresponding to Mas1 - Ile398Thr), the introduction of which did not yield viable yiest strains. Homologous mutations led to a temperature-sensitive phenotype with accumulation of immature/unprocessed precursor proteins and decrease of mature/processed forms both in vivo or in organello (following isolation of mitochondria). Under conditions of heat stress, Mas1 mutations decreased biogenesis of Fe-S clusters.
- Respiratory chain complexes I-III contain Fe-S clusters. In muscle biopsy from an affected individual, complex II activity was significantly reduced (although this was not the case in fibroblasts or liver biopsy). Dysfunction of mitochondrial and cytosolic Fe-S cluster-dependent enzymes (eg. aconitase) was also shown in muscle tissue.

Regression/stagnation with seizures/non-achievement of milestones may justify testing for an ID / epilepsy gene panel. In addition, metabolic studies or mitochondrial respiratory chain complex studies were sometimes non-informative (lactate elevated in 3/5 subjects) or not carried out at all / in relevant tissues (muscle biopsy in 2 individuals, fibroblasts/liver biopsy did not demonstrate reduced complex activity when tested).

PMPCB is included in the ID gene panel of Radboudumc, as well as the SysID database. The gene is included in the DD panel of G2P associated with "Neurodegeneration in Early Childhood" (disease confidence : probable).

As a result, PMPCB can be considered for inclusion in both epilepsy and ID panels as green (or amber).
Sources: Literature, Radboud University Medical Center, Nijmegen
Intellectual disability v2.1046 NUP188 Konstantinos Varvagiannis reviewed gene: NUP188: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v2.1046 CPD Konstantinos Varvagiannis changed review comment from: The gene was present in the current panel with red rating, though with no reviews.

In Pubmed there are no publications concerning eventual CPD-related phenotypes. There is no associated phenotype in OMIM or G2P, either. The gene is not included in the SysID and SFARI databases. The denovo-db lists 1 individual with autism and de novo LoF variant (NM_001304.4:c.2478C>G - p.Tyr826* - Iossifov et al. - PMID: 25363768) and 2 further with congenital heart disease. Still the gene encodes an enzyme (carboxyptidase D), so AR inheritance would seem more likely (?). [The gene has also a pLI of 0 in gnomAD and Z-score of 2.59]. CPD is not included in gene panels for ID offered by diagnostic laboratories (including also the current ID panel of VCGS which was listed as a source).

As a result, red rating (or removal from the current panel) seems appropriate.; to: The gene was present in the current panel with red rating, though with no reviews.

In Pubmed there are no publications concerning eventual CPD-related phenotypes. There is no associated phenotype in OMIM or G2P, either. The gene is not included in the SysID and SFARI databases. The denovo-db lists 1 individual with autism and de novo LoF variant (NM_001304.4:c.2478C>G - p.Tyr826* - Iossifov et al. - PMID: 25363768) and 2 further with congenital heart disease. Still the gene encodes an enzyme (carboxyptidase D), so AR inheritance would seem more likely (?). [The gene has also a pLI of 0 in gnomAD and Z-score of 2.59. In Decipher %HI is 31.31]. CPD is not included in gene panels for ID offered by diagnostic laboratories (including also the current ID panel of VCGS which was listed as a source).

As a result, red rating (or removal from the current panel) seems appropriate.
Intellectual disability v2.1046 CPD Konstantinos Varvagiannis reviewed gene: CPD: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v2.1046 CA5A Konstantinos Varvagiannis reviewed gene: CA5A: Rating: RED; Mode of pathogenicity: None; Publications: 26913920, 25834911, 24530203; Phenotypes: Hyperammonemia due to carbonic anhydrase VA deficiency (MIM 615751); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v2.1046 PMPCA Konstantinos Varvagiannis gene: PMPCA was added
gene: PMPCA was added to Intellectual disability. Sources: Literature,Radboud University Medical Center, Nijmegen
Mode of inheritance for gene: PMPCA was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PMPCA were set to 25808372; 26657514; 27148589; 30617178
Phenotypes for gene: PMPCA were set to Spinocerebellar ataxia, autosomal recessive 2 (MIM 213200)
Penetrance for gene: PMPCA were set to Complete
Review for gene: PMPCA was set to GREEN
gene: PMPCA was marked as current diagnostic
Added comment: Biallelic pathogenic PMPCA variants cause Spinocerebellar ataxia, autosomal recessive 2 (SCAR2 - MIM 213200). More than 20 individuals from several unrelated families have been reported. At least 6 different pathogenic variants have been identified. Loss of PMPCA function is the suggested mechanism. ID is a feature of the disorder.

PMPCA encodes the α-subunit of mitochondrial processing peptidase (αMPP), a heterodimeric enzyme responsible for the cleavage of nuclear-encoded mitochondrial precursor proteins after import in the mitochondria (summary by Jobling et al and OMIM).

Arguments for involvement of the gene include the highly similar phenotype, segregation studies, expression of the gene in fetal and relevant adult tissues (in brain/cerebellum/cerebellar vermis), lower protein levels demonstrated for some variants, abnormal processing of frataxin (in line with the role of αMPP) demonstrated in most cases, rescue of the maturation defect upon transduction of wt PMPCA cDNA, disruption of REDOX balance in patient cells, etc.

Relevant studies are summarized below.

PMPCA is included in gene panels for ID offered by several diagnostic laboratories (incl. Radboud UMC, GeneDx, etc) and listed as a confirmed ID gene in SysID. It is not associated with any phenotype in G2P.

As a result, this gene can be considered for inclusion in the current panel probably as green (or amber).

----

[1] - Jobling et al. (2015 - PMID: 25808372) described the phenotype of 17 individuals from 4 families, all presenting with non-progressive cerebellar ataxia and the majority with ID of variable severity (15/17 - relevant to the current panel). Individuals from 3 of the families - all of Lebanese origin - were homozygous for NM_015160.3:c.1129G>A (p.Ala377Thr). A further similarly affected subject was compound heterozygous for c.287C>T (p.Ser96Leu) and c.1543G>A (p.Gly515Arg).

The homozygous variant in the first family was found within a 2.85 Mb linkage region on chr 9q34. An additional variant within this region (in CAMSAP1) was discarded following results in other families of the same origin.

Semi-quantitative RT-PCR demonstrated fetal expression of the PMPCA as well as relatively higher expression in adult brain, cerebellum and cerebellar vermis.

As for Ala377Thr, protein levels were shown to be lowest in affected individuals (LCLs, fibroblasts) and low - though somewhat higher - in carrier parents (LCL) compared to controls. RT-PCR on total RNA from LCLs did not show evidence of abnormal transcripts/additional splicing defect. Localization of mutant protein and morphology of mitochondrial reticulum was similar to controls. Maturation of frataxin - the protein depleted in Friedreich ataxia - was shown to be abnormal in patient lymphoblasts, compatible with the role of αMPP. In line with abnormal mitochondrial function, REDOX balance was increased in patient cells.

[2] - Choquet et al. (2016 - PMID: 26657514) reported on 2 sibs - born to distantly related parents. The authors noted a phenotype corresponding to SCAR2 although the presentation was somewhat milder, intellectual disability was not a feature (despite some learning difficulties in one) and ataxia was progressive. WES demonstrated homozygosity for NM_015160:c.766G>A (p.Val256Met). Western blot in patient lymphoblasts showed αMPP levels similar to carriers and controls. Abnormal maturation (accumulation of specific isoforms) was shown for frataxin.

[3] - Joshi et al. (2016 - PMID: 27148589) described the phenotype of 2 cousins belonging to a large Lebanese pedigree. Presentation in both was compatible with multisystem involvement incl. profound global DD, severe hypotonia, weakness, respiratory insufficiency, blindness suggestive of mitochondrial disorder. mtDNA, analyses of mitochondrial focused nuclear gene panel and aCGH were non-diagnostic. Both subjects were compound heterozygous for NM_015160.3:c.1066G>A (p.Gly356Ser) and c.1129G>A (p.Ala377Thr) following WES, with compatible segregation studies within the family. Western blot revealed PMPCA levels similar to control. Reduction of PMPCA staining and abnormally enlarged mitochondria were observed upon immunofluorescence in patient fibroblasts. Frataxin processing was abnormal. Lentiviral transduction of patient fibroblasts with wt PMPCA cDNA, led to increased PMPCA levels and correction of frataxin processing.

[4] - Rubegni et al. (2019 - PMID: 30617178) report on a 7-y.o. boy with global DD, spastic-ataxic gait and 'low IQ'. MRI images were suggestive of cerebellar atrophy with hyperintensity in the striatum. The child was homozygous for c.553C>T / p.Arg185Trp (reference not specified, although the variant would be compatible with NM_015160.3).
Sources: Literature, Radboud University Medical Center, Nijmegen
Intellectual disability v2.1046 TIMM50 Konstantinos Varvagiannis gene: TIMM50 was added
gene: TIMM50 was added to Intellectual disability. Sources: Literature,Radboud University Medical Center, Nijmegen
Mode of inheritance for gene: TIMM50 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TIMM50 were set to 27573165; 30190335; 31058414; Serajee et al. (ASHG conference 2015 - abstract Nr. 2299T)
Phenotypes for gene: TIMM50 were set to 3-methylglutaconic aciduria, type IX (MIM 617698)
Penetrance for gene: TIMM50 were set to Complete
Review for gene: TIMM50 was set to GREEN
gene: TIMM50 was marked as current diagnostic
Added comment: Biallelic pathogenic TIMM50 variants cause 3-methylglutaconic aciduria, type IX (MIM 617698).

At least 9 affected individuals from 5 unrelated (but often consanguineous) families of variable origin have been reported (based on a conference abstract and PMIDs : 27573165, 30190335, 31058414).

TIMM50 encodes encodes a subunit of the mitochondrial presequence import machinery called the TIM23 complex. TIMM50 serves as a major receptor in the intermembrane space that binds to proteins on their way to cross the mitochondrial inner membrane (summary by Shahrour et al., 2017 and OMIM).

The highly overlapping patient clinical features [seizures, DD and ID - the latter in all age-appropriate individuals (5 from 3 families - refs 2,4)], metabolic investigations (lactate elevations in many, elevated urinary 3MGA in almost all, variable mitochondrial complex deficiencies in some), additional extensive functional evidence of mitochondrial dysfunction or the similar phenotypes in other types of 3-methylglutaconic aciduria all support a role for the gene.

[AUH- / CLPB- / DNAJC19- / HTRA2- / OPA3- / SERAC1-related methylglutaconic acidurias are all included as relevant disorders in the ID panel, with the respective genes rated green.]

TIMM50 is included in gene panels for ID offered by some diagnostic laboratories (incl. Radboudumc and GeneDx).

The gene is not associated with any phenotype in G2P

As a result this gene could be considered for inclusion/upgrade as green in both ID and epilepsy panels respectively.

---------

[1] - Serajee et al. (ASHG conference 2015 - abstract Nr. 2299T) reported on a patient born to consanguineous parents of South Asian ancestry with intractable epilepsy, microcephaly, DD and spastic quadriplegia. Metabolic investigations revealed increased urinary 3MGA. Two similarly affected sisters with demonstrated increase of 3MGA, were deceased following an infection. WES in the affected child, 2 unaffected sibs and the parents suggested a homozygous missense variant as the likely cause of the disorder in the proband (c.1114G>A / p.G372S - Reference not specified though the variant probably corresponds to ENST00000314349.4 and ClinVar's entry VCV000208697.1 - www.ncbi.nlm.nih.gov/clinvar/variation/208697/).

[2] - Shahroor et al. (2017, PMID: 27573165) reported on 2 consanguineous families, each with 2 affected individuals. Two sibs from the 1st family (of Bedouin origin) presented with seizures (onset at 3m and 4m respectively), DD and ID with slightly elevated plasma lactate and increased urinary 3MGA upon metabolic investigations. Enzymatic activities of mitochondrial complex I-V were carried out for 1 sib and were normal also after normalization for citrate synthase. Following a SNP array, WES was carried out in affected children and their parents. Both sibs were homozygous for a missense SNV [NM_001001563.1:c.755C>T / p.Thr252Met]. Segregation studies - also in 3 unaffected sibs - supported a role for the variant.

Two sibs from the 2nd family (of Muslim origin) presented with seizures (myoclonic jerks at 3m, generalized tonic movements at 2m - respectively) with DD and ID. Urinary 3MGA was elevated for both, with CSF lactate also elevated in one. WES revealed homozygosity for p.Arg217Trp (NM_001001563.1:c.649C>T) and segregation studies in parents and an unaffected sib were again compatible.

The authors could not demonstrate pathogenicity of the variants in a yeast based system although - as also commented on in Ref 4 - the human TIMM50 could not rescue the yeast ΔΤim50 growth defect and global conservation between the two proteins is poor.

[3] - Reyes et al. (2018, PMID: 30190335) reported on one individual with onset of infantile spasms at the age of 2m with hypsarrythmia upon EEG and psychomotor regression. Leigh-like features were noted upon brain MRI. Lactate was elevated in both plasma and CSF. Urinary 3MGA was normal. WES, Sanger confirmation and segregation studies demonstrated compound htz for 2 variants (NM_001001563:c.335C>A or p.S112* and c.569G>C or p.G190A). Functional studies demonstrated among others decrease in all components of the TIM23 complex and decreased mitochondrial membrane potential. Patient fibroblasts grown in glucose had lower levels of all complex II and IV subunits and one complex I subunit (due to the impairment in import system) with decreased mitochondrial respiration and increase in ROS production. Growth in galactose - shifting energy production toward OxPhos - caused massive cell death. The phenotype was rescued/substantially improved following complementation of patient fibroblasts with wt TIMM50.

[4] - Tort et al. (2019, PMID: 31058414) reported on a boy with seizures and ID (diagnosis of West syndrome), Leigh-like MRI anomalies, cardiomyopathy with elevated plasma and CSF lactate and persistent urinary elevation of 3MGA. The proband was found to be compound heterozygous for 2 TIMM50 variants [NM_001001563.5:c.341 G>A (p.Arg114Gln) in trans with c.805 G>A (p.Gly269Ser)] following WES and Sanger confirmation/segregation studies. In patient fibroblasts TIMM50 protein levels were severely reduced upon WB although mRNA levels were similar to control. Muscle biopsy revealed decreased activity of the complexes I-IV, when normalized to the citrate synthase activity. Accumulation of lipidic material in muscle fibers was shown to be associated with mitochondria upon EM. Expression and sublocalization of mitochondria-targeted proteins were not found to be affected in patient fibroblasts. In extracts from muscle biopsy reduced protein levels of SDHA, COX4L and MTCO1 were demonstrated, in line with the disruptions in the activities of the MRC. Mitochondrial morphology and network were shown to be altered in patient fibroblasts. Patient fibroblasts showed marked reduction of max respiratory capacity. Similar reduction was noted in CRISPR/Cas9 generated TIMM50-ko HEK293T cells, but rescued upon transient transfection with a plasmid encoding for wt TIMM50.

(Functional studies better summarized in the respective articles).
Sources: Literature, Radboud University Medical Center, Nijmegen
Intellectual disability v2.1046 KATNB1 Rebecca Foulger Added comment: Comment on list classification: Updated rating from Grey to Amber. Gene was added to the ID panel and rated Green by Konstantinos Varvagiannis. Although there are 3 publications reporting biallelic variants, the ID phenotype is variable with only mild cognitive delay in some cases (PMID:25521378), and psychomotor delay in another (PMID:26640080). KATNB1 is Green on the 'malformations of cortical development' panel. Therefore have rated Amber on the ID panel awaiting further cases.
Intellectual disability v2.1045 KATNB1 Rebecca Foulger Phenotypes for gene: KATNB1 were changed from Lissencephaly 6, with microcephaly (MIM 616212) to Lissencephaly 6, with microcephaly, MIM 616212
Intellectual disability v2.1043 MED13 Rebecca Foulger changed review comment from: Comment on list classification: Updated rating from Grey to Amber. Gene was added to panel and rated Amber by Konstantinos Varvagiannis. Probable rating in Gene2Phenotype for 'Neurodevelopment disorder' based on PMID:29740699 (Snijders Blok et al., 2018) who report on 13 patients. 11 variants were de novo and 1 (patient B) was inherited from an affected mother (patient C). All patients had developmental delay to some extent (speech delay in most cases, with motor development delayed in 7/13). ID is mild/borderline in at least 9 cases. There is not a clear genotype-phenotype correlation between variants, and it's unclear how some variants are deleterious, and therefore Amber rating is appropriate until further studies are published.; to: Comment on list classification: Updated rating from Grey to Amber. Gene was added to panel and rated Amber by Konstantinos Varvagiannis. Not yet associated with a disorder in OMIM. Probable rating in Gene2Phenotype for 'Neurodevelopment disorder' based on PMID:29740699 (Snijders Blok et al., 2018) who report on 13 patients. 11 variants were de novo and 1 (patient B) was inherited from an affected mother (patient C). All patients had developmental delay to some extent (speech delay in most cases, with motor development delayed in 7/13). ID is mild/borderline in at least 9 cases. There is not a clear genotype-phenotype correlation between variants, and it's unclear how some variants are deleterious, and therefore Amber rating is appropriate until further studies are published.
Intellectual disability v2.1043 MED13 Rebecca Foulger Added comment: Comment on list classification: Updated rating from Grey to Amber. Gene was added to panel and rated Amber by Konstantinos Varvagiannis. Probable rating in Gene2Phenotype for 'Neurodevelopment disorder' based on PMID:29740699 (Snijders Blok et al., 2018) who report on 13 patients. 11 variants were de novo and 1 (patient B) was inherited from an affected mother (patient C). All patients had developmental delay to some extent (speech delay in most cases, with motor development delayed in 7/13). ID is mild/borderline in at least 9 cases. There is not a clear genotype-phenotype correlation between variants, and it's unclear how some variants are deleterious, and therefore Amber rating is appropriate until further studies are published.
Intellectual disability v2.1043 MED13 Rebecca Foulger Gene: med13 has been removed from the panel.
Intellectual disability v2.1042 PAK1 Rebecca Foulger Phenotypes for gene: PAK1 were changed from Intellectual developmental disorder with macrocephaly, seizures, and speech delay (MIM 618158) to Intellectual developmental disorder with macrocephaly, seizures, and speech delay, 618158
Intellectual disability v2.1040 PAK1 Rebecca Foulger Added comment: Comment on list classification: Updated rating from Amber to Green based on the additional 2019 paper reviewed by Konstantinos Varvagiannis. PMID:31504246 (Horn et al. 2019) report 4 unrelated individuals (2 Caucasian, 1 Moroccon, 1 Sephardi Jew). All 4 had developmental delay and moderate-profound ID amongst their phenotypes. All had novo missense PAK1 pathogenic variants: Leu470Arg, Ser133Pro, Pro121Ser, Ser110Thr. None of the variants were reported in gnomAD and all were predicted to be pathogenic. Two cases were previously reported in PMID:30290153 (Harms et al., 2018) and therefore this takes the total number over the threshold for a diagnostic-grade rating.
Intellectual disability v2.1039 SMARCD1 Rebecca Foulger commented on gene: SMARCD1: The Green review by Cristina Dias supports the current Green rating of SMARCD1.
Intellectual disability v2.1039 CACNA2D2 Rebecca Foulger Added comment: Comment on list classification: Gene was added to panel and rated Amber by Konstantinos Varvagiannis. Updated rating from Grey to Amber: phenotype is relevant to panel (MIM:618501) but developmental delay is variable amongst patients, and therefore Amber rating most appropriate.
Intellectual disability v2.1038 CACNA2D2 Rebecca Foulger Phenotypes for gene: CACNA2D2 were changed from Cerebellar atrophy with seizures and variable developmental delay (MIM 618501) to Cerebellar atrophy with seizures and variable developmental delay, 618501
Intellectual disability v2.1037 SLC25A12 Rebecca Foulger Added comment: Comment on list classification: Updated rating from Amber to Green based on additional publications reviewed by Konstantinos Varvagiannis and mouse model which includes developmental delay. PMID:31403263 (Kavanaugh et al., 2019) report a 12 year old patient with novel compound het SLC25A12 variants (p.A432V missense, and probable splice variant c.1447‐2_1447‐1delAG), each variant inherited from one parent. Clinical presentation included severe intellectual disability, and profound global developmental delay. Profound global DD was previously reported by PMID:24515575 (Falk et al, 2014), and pyschomotor delay previously reported by PMID:19641205 (Wilbom et al., 2009).
Intellectual disability v2.1035 PAX7 Louise Daugherty changed review comment from: Comment on list classification: removed from panel, this gene is not relevant for this panel; to: Comment on list classification: downgraded to Red again, this gene is not pertinent. I have left the gene on the panel as the gene is on the ID panel from the Victorian Clinical Genetics Services
Intellectual disability v2.1034 PAX7 Louise Daugherty Added comment: Comment on list classification: removed from panel, this gene is not relevant for this panel
Intellectual disability v2.1034 PAX7 Louise Daugherty Gene: pax7 has been removed from the panel.
Intellectual disability v2.1033 PAX7 Louise Daugherty edited their review of gene: PAX7: Added comment: changed rating agree with external reviewer (Konstantinos Varvagiannis this gene is RED for ID but GREEN for Neuromuscular disorders; Changed rating: RED
Intellectual disability v2.1033 PAX7 Konstantinos Varvagiannis reviewed gene: PAX7: Rating: RED; Mode of pathogenicity: None; Publications: 31092906; Phenotypes: ; Mode of inheritance: None
Intellectual disability v2.1033 PAX7 Konstantinos Varvagiannis Deleted their review
Intellectual disability v2.1033 PAX7 Konstantinos Varvagiannis reviewed gene: PAX7: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v2.1033 PAX7 Louise Daugherty Phenotypes for gene: PAX7 were changed from to Hypotonia; Axial hypotonia; Ptosis; Scoliosis; Delayed motor milestones; Myopathy, congenital, progressive, with scoliosis, 618578
Intellectual disability v2.1031 PAX7 Louise Daugherty Added comment: Comment on list classification: New gene added by external expert (Cristina Dias (The Francis Crick Institute) ) on Neuromuscular disorders panel v1.6 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 v2.1030 PAX7 Louise Daugherty edited their review of gene: PAX7: Changed publications: 31092906
Intellectual disability v2.1029 PAX7 Louise Daugherty reviewed gene: PAX7: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Hypotonia, Axial hypotonia, Ptosis, Scoliosis, Delayed motor milestones, Myopathy, congenital, progressive, with scoliosis, 618578; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v2.1029 GABRA5 Rebecca Foulger Added comment: Comment on list classification: Updated rating from Red to Amber following external review by Konstantinos Varvagiannis. Not yet associated with a disorder in Gene2Phenotype but linked to EIEE-70 in OMIM. There are three cases from 2 publications (PMIDs 29961870 and 31056671) of GABRA5 variants associated with early infantile epileptic encephalopathy and ID. However in Butler et al., development slowed at the time of seizure onset. Therefore rating Amber awaiting further clinical input.
Intellectual disability v2.1027 GABRA5 Rebecca Foulger Phenotypes for gene: GABRA5 were changed from to Epileptic encephalopathy, early infantile, 79, 618559; developmental delay
Intellectual disability v2.1025 GABRA2 Rebecca Foulger Added comment: Comment on list classification: Updated rating from Grey to Green: GABRA2 was added to the panel and rated Green by Konstantinos Varvagiannis. Not yet associated with a disorder in Gene2Phenotype but there are sufficient cases from from the literature (PMIDs:29422393, 29961870, 31032849, https://doi.org/10.1101/678219) of GABRA2 variants associated with developmental delay/intellectual disability.
Intellectual disability v2.1024 GABRA2 Rebecca Foulger commented on gene: GABRA2: Summary of evidence (refer to Konstantinos Varvagiannis' review for further details):

PMID:29422393, Orenstein et al., 2018 report a male of unrelated Ashkenazi Jewish parents with EIEE-78 and a de novo heterozygous variant in GABRA2 (N335H). Development was severely delayed. Functional studies were not performed but the variant was absent in ExAC and gnomAD controls.

PMID:29961870, Butler et al. 2018 report an 11 year old girl with EIEE-78 and a de novo heterozygous variant in GABRA2 (T292K). Development was delayed, the patient was nonverbal and had profound intellectual disability plus microcephaly.

PMID:31032849, Maljevic et al., 2019 decribe 5 patients (3 sporadic cases and 2 siblings) with four novel de novo GABRA2 missense variants (Val284Ala, Leu291Val, Met263Thr, Phe325Leu). All patients showed some degree of ID (mild to profound).

https://doi.org/10.1101/678219: Sanchis-Juan et al., 2019 identified a de novo missense variant in GABRA2 gene (Pro280Leu) in a 10 year old girl with EIEE and developmental delay. At age-10, she had severe
impairment of language, hand stereotypies, disruptive behavior and repetitive movements.
Intellectual disability v2.1024 GABRA2 Rebecca Foulger Phenotypes for gene: GABRA2 were changed from Epileptic encephalopathy, early infantile, 78, 618557) to Epileptic encephalopathy, early infantile, 78, 618557; intellectual disability; developmental delay
Intellectual disability v2.1024 GABRA2 Rebecca Foulger Phenotypes for gene: GABRA2 were changed from Epileptic encephalopathy, early infantile, 78 (MIM 618557) to Epileptic encephalopathy, early infantile, 78, 618557)
Intellectual disability v2.1023 PIGP Rebecca Foulger Phenotypes for gene: PIGP were changed from Generalized hypotonia; Global developmental delay; Seizures; Intellectual disability; Feeding difficulties; Cortical visual impairment to ?Epileptic encephalopathy, early infantile, 55, 617599; Generalized hypotonia; Global developmental delay; Seizures; Intellectual disability; Feeding difficulties; Cortical visual impairment
Intellectual disability v2.1022 SMARCD1 Cristina Dias reviewed gene: SMARCD1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 30879640; Phenotypes: developmental delay, intellectual disability, hypotonia, feeding difficulties, small hands, small feet; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v2.1022 CACNA2D2 Konstantinos Varvagiannis gene: CACNA2D2 was added
gene: CACNA2D2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: CACNA2D2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CACNA2D2 were set to 23339110; 24358150; 30410802; 29997391; 31402629; 11487633; 11756448; 4177347; 14660671; 15331424
Phenotypes for gene: CACNA2D2 were set to Cerebellar atrophy with seizures and variable developmental delay (MIM 618501)
Penetrance for gene: CACNA2D2 were set to Complete
Review for gene: CACNA2D2 was set to AMBER
gene: CACNA2D2 was marked as current diagnostic
Added comment: Gene reviewed for the epilepsy panel. Due to the phenotype of EE, with variable GDD (severe in many cases) and/or ID (either specifically commented on or inferred in some cases, although not universal) this gene might also be relevant for the current panel. CACNA2D2 is also included in gene panels for ID offered by some diagnostic laboratories (eg. GeneDx) as well as the SysID database. There is no associated phenotype in G2P.

Copied from the epilepsy panel:

Biallelic pathogenic CACNA2D2 variants cause Cerebellar atrophy with seizures and variable developmental delay (MIM 618501).

A recent OMIM update, a subsequent relevant publication by Punatha et al. as well as several additional LP/P variants in ClinVar for the phenotype of epileptic encephalopathy, support possible upgrade to green.

The following affected individuals appear to be relevant [NM_006030.3 used as RefSeq unless otherwise specified]:

[1] Edvardson et al. (PMID: 23339110) - 3 sibs born to consanguineous parents with EIEE, severe GDD / ID (inferred from the descritpion, at least for the oldest one), cerebellar atrophy and movement abnormalities. A CACNA2D2 variant (c.3137T>C / p.Leu1046Pro) was found in affected individuals by SNP-arrays and WES in one of them. Functional studies (reduction in current density of calcium channels in Xenopus laevis oocytes) supported the deleterious effect of the variant. A role of a rare hmz CESLR3 variant could not be ruled out.

[2] Pippucci et al. (PMID: 24358150) - 1 individual born to consanguineous parents, presenting with EE (onset at 1-2 m), severe GDD, cerebellar atrophy and choreiform movements. Homozygosity for a LoF variant (c.1294delA - p.Asn432fs) was found by WES. The role of the variant was further supported by expression studies (80% reduced mRNA levels, protein levels estimated at 3% of control / milder effect in htz parents). The proband was also hmz for a CESLR3 variant. Previous studies incl. 'high-resolution karyotype' and metabolic investigations.

[3] Butler et al. (PMID: 30410802) - A 5 y.o. male, with EE (seizure onset at 7m / GDD) and cerebellar atrophy. Compound heterozygosity for c.782C>T (p.Pro261Leu) and c.3137T>C (p.Leu1046Pro) was demonstrated by WES and supported by segregation studies.

[4] Valence et al. (PMID: 29997391) - Reported on a 20 y.o. male belonging to a cohort of 20 individuals with congenital ataxia, all from consaguineous families. This individual, who had cerebellar atrophy, ataxia, a single episode of febrile seizures and normal cognitive impairment was homozygosity for c.2971G>A (p.Asp991Asn). RT-PCR revealed presence of a normal length transcript as well as an additional, longer one, due to a concurrent splicing effect (activation of a cryptic donor splice site and retention of 4 bases of intronic sequence). Presence of both nl/abn length transcripts was presumed to explain the mild phenotype (variability also commented in OMIM).

[5] Punatha et al. (PMID: 31402629) - 3 affected individuals from 2 consanguineous families presenting with early onset EE (onset 1-7m), GDD/ID, cerebelar atrophy and ataxia. Sibs from the first family were homozygous for c.1778G>C (p.Arg593Pro). An affected 5 y.o. child from the 2nd family was homozygous for c.485_486delAT (p.Tyr162Ter). Mutations were found by WES in regions of AOH.

The following variants - not reported in the literature - have been submitted in ClinVar as LP / P for EE:
[VCV000645106.1] NM_006030.4:c.1389+2T>C - EIEE with suppression bursts - Likely Pathogenic (Invitae)
[VCV000570589.1] NM_006030.4:c.1956_1960del (p.Asn652fs) - EIEE - Pathogenic (Invitae)
[VCV000578284.1] NM_006030.4:c.1555C>T (p.Gln519Ter) - EIEE - Pathogenic (Invitae)
[VCV000653393.1] NM_006030.4:c.851dup (p.Ala286fs) - EIEE with suppression bursts - Pathogenic (Invitae)
[VCV000411003.1] NM_006030.4:c.485_486del (p.Tyr161_Tyr162insTer) - EIEE - Pathogenic (Invitae)

Additional ones have been reported as LP / P although the condition is not specified.
[VCV000620551.1] NM_006030.4:c.1023C>A (p.Cys341Ter) - Likely pathogenic (GeneDx)
[VCV000373439.2] NM_006030.4:c.1846-1G>A - Likely pathogenic (GeneDx)
[VCV000423330.2] NM_006030.4:c.200dup (p.His68fs) - Pathogenic (GeneDx).

The aforementioned laboratories include CACNA2D2 in gene panels for epilepsy (Invitae) and/or ID (GeneDx).

A role for the CACNA2D2 is supported by :
- The highly overlapping features (with the exception of the milder phenotype reported by Valence et al.) incl. early onset of seizures, GDD, cerebellar atrophy in all (9/9 incl. the individual reported by Valence, as evaluated Punatha et al). Ataxia was a feature in many (with movement abnormalities also in the remaining ones).
- The role of the gene encoding the alpha-2-delta-2 auxiliary subunit of high voltage-gated calcium channels. Auxiliary subunits modulate calcium current and channel activation and inactivation kinetics, and may be involved in proper assembly and membrane localization of the channels (summary by Edvardson and OMIM).
- Functional / expression studies for some of the variants (as in Refs 1,2,4).
- Relevant expression patterns (notably in cerebellum) [GTEx project]
- Mouse models recapitulating the human phenotypes (summarized by Edvardson et al) : The 'ducky' mouse model (due to biallelic Cacna2d2 mutations) presenting absence epilepsy, spike-wave seizures and ataxia. Dysgenesis of the cerebellum is among the neuropathological findings (PMIDs cited : 11487633, 11756448, 4177347). The 'entla' mouse model (also AR due to an in-frame duplication) presents also epilepsy and ataxia (PMID : 14660671). Targeted knockout in another mouse model resulted also in ataxic gait, seizure susceptibility and cerebellar anomalies/degeneration (PMID: 15331424).

[Please consider inclusion in other relevant panels eg. for cerebellar anomalies / ataxia].
Sources: Literature
Intellectual disability v2.1022 GABRA2 Konstantinos Varvagiannis changed review comment from: Heterozygous pathogenic GABRA2 variants cause Epileptic encephalopathy, early infantile, 78 (MIM 618557) [new OMIM entry].

At least 8 relevant individuals have been reported to date in the following studies:
- Orenstein et al. (2018 - PMID: 29422393) - 1 individual
- Butler et al. (2018 - PMID: 29961870) - 1 subject
- Maljevic et al. (2019 - PMID: 31032849 - 3 unrelated children as well as 2 affected sibs
- Sanchis-Juan et al. (2019 - bioRxiv / https://doi.org/10.1101/678219) - 1 further patient

In all affected individuals the variants were missense and - in almost all cases - had occurred as de novo events. The 2 sibs reported by Maljevic however, had inherited a missense variant from their unaffected mosaic parent.

Clinical descriptions for individuals from the 3 studies are provided in OMIM and also summarized in the suppl. table 1 by Sanchis-Juan et al. (https://www.biorxiv.org/content/biorxiv/early/2019/06/21/678219/DC2/embed/media-2.xlsx). Seizures, DD and ID (relevant to the current panel) are among the reported features. Functional studies have been performed for most of the variants and are summarized for each one in the OMIM entry for GABRG2 and the aforementioned table as well.

The following variants have been reported (NM_000807.2): c.1003A>C - p.Asn335His (dn) / c.875C>A - Thr292Lys (dn) / c.871C>G - p.Leu291Val (dn) / c.788T>C - p.Met263Thr (dn) / c.851T>C - p.Val284Ala (dn) / c.975C>A - p.Phe325Leu (inherited from mosaic parent) / c.839C>T - p.Pro280Leu (dn - Sanchis-Juan et al).

As commented by Jenkins and Escayg (2019 - PMID: 31032848 / both among the authors of the 1st report) as well as by Sanchis-Juan et al., both loss- and gain- of function effects explain the pathogenicity of the various mutations reported to date. [In gnomAD GABRA2 has a Z-score for missense variants of 3.13 as well as a pLI of 1].
------
GABRA2 is not associated with any phenotype in G2P.
This gene is not commonly included in gene panels for ID offered by diagnostic laboratories.
------
As a result, GABRA2 can be considered for inclusion in the epilepsy and ID panels probably as green (several relevant individuals, several reported variants with supporting functional studies for most, etc.).

[Consider inclusion in other possibly relevant gene panels eg. for ASD which was feature in some patients at relevant age and/or among those evaluated].; to: Heterozygous pathogenic GABRA2 variants cause Epileptic encephalopathy, early infantile, 78 (MIM 618557) [new OMIM entry].

At least 8 relevant individuals have been reported to date in the following studies:
- Orenstein et al. (2018 - PMID: 29422393) - 1 individual
- Butler et al. (2018 - PMID: 29961870) - 1 subject
- Maljevic et al. (2019 - PMID: 31032849 - 3 unrelated children as well as 2 affected sibs
- Sanchis-Juan et al. (2019 - bioRxiv / https://doi.org/10.1101/678219) - 1 further patient

In all affected individuals the variants were missense and - in almost all cases - had occurred as de novo events. The 2 sibs reported by Maljevic however, had inherited a missense variant from their unaffected mosaic parent.

Clinical descriptions for individuals from the 3 studies are provided in OMIM and also summarized, Maljevic - Table 1 (7 patients) and/or in the suppl. table 1 by Sanchis-Juan et al. (8 patients) (https://www.biorxiv.org/content/biorxiv/early/2019/06/21/678219/DC2/embed/media-2.xlsx). Seizures, DD and ID (relevant to the current panel) are among the reported features. Functional studies have been performed for most of the variants and are summarized for each one in the OMIM entry for GABRG2 and the aforementioned table as well.

The following variants have been reported (NM_000807.2): c.1003A>C - p.Asn335His (dn) / c.875C>A - Thr292Lys (dn) / c.871C>G - p.Leu291Val (dn) / c.788T>C - p.Met263Thr (dn) / c.851T>C - p.Val284Ala (dn) / c.975C>A - p.Phe325Leu (inherited from mosaic parent) / c.839C>T - p.Pro280Leu (dn - Sanchis-Juan et al).

As commented by Jenkins and Escayg (2019 - PMID: 31032848 / both among the authors of the 1st report) as well as by Sanchis-Juan et al., both loss- and gain- of function effects explain the pathogenicity of the various mutations reported to date. [In gnomAD GABRA2 has a Z-score for missense variants of 3.13 as well as a pLI of 1].
------
GABRA2 is not associated with any phenotype in G2P.
This gene is not commonly included in gene panels for ID offered by diagnostic laboratories.
------
As a result, GABRA2 can be considered for inclusion in the epilepsy and ID panels probably as green (several relevant individuals, several reported variants with supporting functional studies for most, etc.).

[Consider inclusion in other possibly relevant gene panels eg. for ASD which was feature in some patients at relevant age and/or among those evaluated].
Intellectual disability v2.1022 GABRA2 Konstantinos Varvagiannis reviewed gene: GABRA2: Rating: GREEN; Mode of pathogenicity: None; Publications: 29422393, 29961870, 31032849, 31032848, doi.org/10.1101/678219; Phenotypes: Epileptic encephalopathy, early infantile, 78 (MIM 618557); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v2.1022 GABRA2 Konstantinos Varvagiannis Deleted their review
Intellectual disability v2.1022 GABRA2 Konstantinos Varvagiannis gene: GABRA2 was added
gene: GABRA2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: GABRA2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: GABRA2 were set to 29422393; 29961870; 31032849; 31032848; doi.org/10.1101/678219
Phenotypes for gene: GABRA2 were set to Epileptic encephalopathy, early infantile, 78 (MIM 618557)
Penetrance for gene: GABRA2 were set to unknown
Review for gene: GABRA2 was set to GREEN
Added comment: Heterozygous pathogenic GABRA2 variants cause Epileptic encephalopathy, early infantile, 78 (MIM 618557) [new OMIM entry].

At least 8 relevant individuals have been reported to date in the following studies:
- Orenstein et al. (2018 - PMID: 29422393) - 1 individual
- Butler et al. (2018 - PMID: 29961870) - 1 subject
- Maljevic et al. (2019 - PMID: 31032849 - 3 unrelated children as well as 2 affected sibs
- Sanchis-Juan et al. (2019 - bioRxiv / https://doi.org/10.1101/678219) - 1 further patient

In almost all affected individuals, the variants were missense and had occurred as de novo events. The 2 sibs reported by Maljevic however, had inherited a missense variant from their unaffected mosaic parent.

Clinical descriptions for individuals from the 3 studies are provided in OMIM and also summarized in the suppl. table 1 by Sanchis-Juan et al. (https://www.biorxiv.org/content/biorxiv/early/2019/06/21/678219/DC2/embed/media-2.xlsx?download=true). Seizures, DD and ID (relevant to the current panel) are among the reported features. Functional studies have been performed for most of the variants and are summarized for each one in the OMIM entry for GABRG2 and the aforementionned table as well.

The following variants have been reported (NM_000807.2): c.1003A>C - p.Asn335His (dn) / c.875C>A - Thr292Lys (dn) / c.871C>G - p.Leu291Val (dn) / c.788T>C - p.Met263Thr (dn) / c.851T>C - p.Val284Ala (dn) / c.975C>A - p.Phe325Leu (inherited from mosaic parent) / c.839C>T - p.Pro280Leu (dn - Sanchis-Juan et al).

As commented by Jenkins and Escayg (2019 - PMID: 31032848 / both among the authors of the 1st report) as well as by Sanchis-Juan et al., both loss- and gain- of function effects explain the pathogenicity of the various reported (all) missense mutations. [In gnomAD GABRA2 has a Z-score for missense variants of 3.13 as well as a pLI of 1].
------
GABRA2 is not associated with any phenotype in G2P.
This gene is not commonly included in gene panels for ID offered by diagnostic laboratories.
------
As a result, GABRA2 can be considered for inclusion in the epilepsy and ID panels probably as green (several relevant individuals, several reported variants with supporting functional studies for most, etc.).

[Consider inclusion in other possibly relevant gene panels eg. for ASD which was feature in some patients at relevant age and/or among those evaluated].
Sources: Literature
Intellectual disability v2.1022 GABRA5 Konstantinos Varvagiannis reviewed gene: GABRA5: Rating: GREEN; Mode of pathogenicity: None; Publications: 29961870, 31056671; Phenotypes: Epileptic encephalopathy, early infantile, 79 (MIM 618559); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Intellectual disability v2.1022 PIGP Konstantinos Varvagiannis gene: PIGP was added
gene: PIGP was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: PIGP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PIGP were set to 28334793; 31139695
Phenotypes for gene: PIGP were set to Generalized hypotonia; Global developmental delay; Seizures; Intellectual disability; Feeding difficulties; Cortical visual impairment
Penetrance for gene: PIGP were set to Complete
Review for gene: PIGP was set to GREEN
gene: PIGP was marked as current diagnostic
Added comment: Johnstone et al. (2017 - PMID: 28334793) report on 2 sibs born to non-consanguineous parents of French-Irish ancestry. Both presented with seizures (onset at the age of 2 and 7 weeks respectively), hypotonia and profound DD. Other features included CVI and feeding difficulties. Extensive metabolic testing as well as prior genetic testing (ARX, STXBP1, MECP2, aCGH) in the family were non-diagnostic. WES suggested the presence of 2 PIGP variants with Sanger sequencing used for confirmation and segregation studies.

PIGP encodes a subunit of the enzyme that catalyzes the first step of glycophosphatidylinositol (GPI) anchor biosynthesis. Mutations in other genes whose proteins are in complex with PIGP (PIGA, PIGC, PIGQ, PIGY, DPM2) lead to similar phenotypes. The phenotype overall was also overlapping with the inherited GPI deficiencies (belonging to the broader group of CDGs).

PIGP has 2 isoforms, which differ by 24 amino acids due to utilization of alternative start codons [corresponding to NM_153681.2 (158 aa) and NM_153682.2 (134 aa)].

The variants identified affected both transcripts with the first SNV leading either to loss of the start codon (NM_153682.2:c.2T>C - p.Met1Thr) or to substitution of a methionine at position 25(NM_153681.2:c.74T>C;p.Met25Thr). The second variant led to frameshift in the last exon of both transcripts predicting a longer protein product (NM_153681.2:c.456delA / p.Glu153AsnfsTer34 or NM_153682.2:c.384delA / p.Glu129AsnfsTer34).

Overall extensive studies demonstrated decreased levels of PIGP mRNA in patient fibroblast, decreased amounts of mutant protein in transfected HEK293 cells. The decreased levels of GPI-APs further supported the effect of variants :

- mRNA levels in patient fibroblasts were reduced compared to controls. Conclusions could not be drawn from Western blot, since no antibodies could specifically detect PIGP. HEK293 cells transfected of mt or wt HA-tagged PIGP cDNA led to undetectable amounts for the first variant (both M1T/M25T) and a protein product of increased molecular weight for the frameshift one.
- Flow cytometry of patient granulocytes indicated reduced signal of CD16 (a GPI-anchored protein) and FLAER (binding directly to the GPI anchor).
- Reduced levels of GPI-APs were also observed in PIGP deficient HAP1 cells transfected with either wt, or mutant PIGP cDNA (of both isoforms for the M1T/M25T or isoform 2 for the frameshift mutation).

--------

Krenn et al. (2019 - PMID: 31139695) described a patient born to non-consanguineous Polish parents. Features were highly similar to those reported by Johnstone et al. and incl. intractable infantile seizures (onset at 7m), hypotonia, severe DD and feeding difficulties. Metabolic work-up failed to identify an alternative diagnosis. WES revealed homozygosity for the frameshift variant reported by Johnstone et al. Sanger sequencing confirmed the variant and carrier state in both parents. Identified ROH of less than 7 Mb in the WES data, suggested a founder mutation rather than unreported consanguinity. The variant is present 9 times in gnomAD (AF of 3.2e-5 / no homozygotes). Flow cytometry of patient granulocytes, revealed markedly reduced expression of GPI-APs (CD157, CD59, FLAER) compared to parents/controls.

ALP was normal in all aforementioned individuals (probably in line with PIGP being involved in the 1st step of the GPI anchor biosynthesis).

--------

A further individual with phenotype of EIEE-55;GPIBD-14 is reported in LOVD [Individual #00246132]. This individual, born to consanguineous parents, was tested by WES and found to be homozygous for a frameshift variant, also affecting the last exon in both transcripts (NM_153681.2:c.384delA (p.Glu129ArgfsTer7) / NM_153682.2:c.312delA (p.Glu105ArgfsTer7). This was probably in agreement with segregation studies according to the respective entry. The specific variant is reported as pathogenic [variant ID #0000500090].

--------

?Epileptic encephalopathy, early infantile, 55 (MIM 617599) is the corresponding phenotype in OMIM. There is no relevant G2P entry.
PIGP is included in gene panels for ID offered by some diagnostic laboratories (eg. GeneDx).

--------

As a result, PIGP can be considered for inclusion in the ID/epilepsy panels probably as green (3 individuals, role of the gene and similarity to other inherited GPI deficiencies, extensive supporting studies) or amber.

(Please consider inclusion in other possibly relevant panels eg. CDGs, etc).
Sources: Literature
Intellectual disability v2.1022 SLC25A12 Konstantinos Varvagiannis reviewed gene: SLC25A12: Rating: GREEN; Mode of pathogenicity: None; Publications: 31403263, 24515575, 19641205, 27290639, 26633542; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability v2.1022 QARS Louise Daugherty edited their review of gene: QARS: Added comment: Added new-gene-name tag, new approved HGNC gene symbol for QARS is QARS1; Changed publications: 28620870, 24656866, 25041233, 25471517, 25432320, 24709618; Changed phenotypes: Microcephaly, progressive, seizures, and cerebral and cerebellar atrophy, 615760, Intellectual disability
Intellectual disability v2.1021 MED25 Konstantinos Varvagiannis changed review comment from: Please consider the 2 additional articles by Nair et al. (2019 - DOI: 10.1159/000494465 - PMID: 30800049 & DOI: 10.1159/000501114 - PMID: NA) reporting on 3 individuals from 2 consanguineous Lebanese families. All affected individuals were homozygous for a MED25 missense variant [NM_030973.3:c.518T>C / p.Ile173Thr], possibly a founder mutation in the Lebanese population. The phenotype presented some similarities with the previously described patients. The variant has a very low AF in gnomAD (0.00003470) and was also absent from the Saudi Variant Database. In silico predictions from PolyPhen2, PROVEAN, MutationTaster were suggestive of a probably damaging effect. The individual from the first report (PMID: 30800049) had an additional homozygous COQ8A variant, with some features fitting with the phenotype of AR primary CoQ10 deficiency type 4 and others negating this diagnosis.

MED25 is included in gene panels for ID offered by several diagnostic laboratories (incl. Radboudumc, Victorian Clinical Genetics and many others). It is not however included in the DD panel of G2P.; to: Please consider the 2 additional articles by Nair et al. (2019 - DOI: 10.1159/000494465 - PMID: 30800049 & DOI: 10.1159/000501114 - PMID: NA) reporting on 3 individuals from 2 consanguineous Lebanese families. All affected individuals were homozygous for a MED25 missense variant [NM_030973.3:c.518T>C / p.Ile173Thr], possibly a founder mutation in the Lebanese population. The phenotype presented some similarities with the previously described patients. The variant has a very low AF in gnomAD (0.00003470) and was also absent from the Saudi Variant Database. In silico predictions from PolyPhen2, PROVEAN, MutationTaster were suggestive of a probably damaging effect. The individual from the first report (PMID: 30800049) had an additional homozygous COQ8A variant, with some features fitting with the phenotype of AR primary CoQ10 deficiency type 4 and others negating this (possibly concurrent) diagnosis.

MED25 is included in gene panels for ID offered by several diagnostic laboratories (incl. Radboudumc, Victorian Clinical Genetics and many others). It is not however included in the DD panel of G2P.
Intellectual disability v2.1021 MED25 Konstantinos Varvagiannis reviewed gene: MED25: Rating: AMBER; Mode of pathogenicity: None; Publications: 30800049, DOI:10.1159/000501114, 25527630, 25792360; Phenotypes: Basel-Vanagait-Smirin-Yosef syndrome (MIM 616449); Mode of inheritance: None; Current diagnostic: yes
Intellectual disability v2.1021 KATNB1 Konstantinos Varvagiannis gene: KATNB1 was added
gene: KATNB1 was added to Intellectual disability. Sources: Literature,Radboud University Medical Center, Nijmegen
Mode of inheritance for gene: KATNB1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KATNB1 were set to 25521378; 25521379; 26640080
Phenotypes for gene: KATNB1 were set to Lissencephaly 6, with microcephaly (MIM 616212)
Penetrance for gene: KATNB1 were set to Complete
Review for gene: KATNB1 was set to GREEN
gene: KATNB1 was marked as current diagnostic
Added comment: Biallelic pathogenic KATNB1 variants cause Lissencephaly 6, with microcephaly (MIM 616212). At least 13 affected individuals from 9 (mostly consanguineous) families have probably been reported in the following articles:

- Mishra-Gorur et al. (2014 - PMID: 25521378) [7 individuals from 5 unrelated families]
- Hu et al. (2014 - PMID: 25521379) [5 individuals from 3 families]
- Yigit el al. (2016 - PMID: 26640080) [1 subject born to consanguineous parents]

The phenotype appears to be relevant to the current panel. Several different variants have been reported to date. Extensive studies as for the impact of mutations at the cellular level as well as animal models (zebrafish, mouse, drosophila) support involvement of KATNB1. These arguments, provided mainly by the first two studies, are summarized in the respective OMIM entry for the disorder : https://omim.org/entry/616212 (variants and their effect are discussed in the entry for KATNB1 - https://omim.org/entry/602703).

The individual reported by Yigit el al. was a 5 year-old girl with - among others - severely delayed psychomotor development. The child was found to harbor a homozygous splice site variant (removing the acceptor AG signature). Confirmation of the variant and segregation studies were performed with Sanger sequencing. cDNA studies were carried out and demonstrated aberrant splicing.

KATNB1 is not associated with any disorder in G2P.
The gene is included in panels for ID offered by several diagnostic laboratories (incl. Radboudumc).

As a result, this gene can be considered for inclusion in the current panel probably as green (or amber).
Sources: Literature, Radboud University Medical Center, Nijmegen
Intellectual disability v2.1021 MED13 Konstantinos Varvagiannis changed review comment from: Snijders Blok et al. (2018 - PMID: 29740699) report on 13 individuals with MED13 mutations.

Features included DD with speech difficulties (both universal) and motor delay in some. ID was observed in at least 9/13 and in most cases was in the borderline/mild range (moderate ID reported for 1 individual). Other features were ASD (5/13), ADHD, eye/vision abnormalities and in few individuals obstipation or congenital heart anomalies. Some possibly overlapping facial characteristics were also noted.

MED13 and MED13L are mutually exclusive components of the CDK8 kinase module that regulates the activity of the Mediator complex. The Mediator transmits signals from various transcription factors to RNA polymerase II (Pol II). Reversible binding of the CDK8 kinase controls Mediator - Pol II interaction (prevents Pol II recruitment) and thus acts as a molecular switch in Pol II - mediated transcription. DD and ID are features of the MED13L- and CDK8- related disorders.

3 stopgain, 2 frameshift, 6 missense variants and 1 in-frame deletion were reported. In 11 cases, the variants had occurred as de novo events, while 1 individual had inherited a nonsense variant from a similarly affected mother (unknown inheritance in her case).

Effect of a stopgain variant was studied with similar (total) transcript levels between the affected patient and his parents/controls upon qPCR. Sanger sequencing of cDNA amplicons was suggestive of the presence of an aberrant transcript at ~70% levels relative to the normal transcript. Truncated protein was undetectable by Western Blot in mononuclear blood cells from affected subjects. Total MED13 protein levels were not clearly different when comparing an affected individual with his unaffected parent (?).

Missense variants and the inframe deletion clustered either in the N- or the C-terminal domain, with the N-terminal ones all (T326I, T326del, P327S, P327Q / NM_005121.2 - NP_005112.2) affecting positions of a known phosphodegron sequence, important for the protein's ubiquitination and degradation. Another previously studied variant (T326A) had been shown to prevent degradation. As a result, the variants affecting aa 326-327 might lead to altered (increased) levels of MED13.

The remaining missense variants affected the C-terminal portion (Q2060L, A2064V).

As a result the impact of the different subcategories of variants remains unclear/inconclusive.

MED13 is not associated with any phenotype in OMIM. This gene is part of the DD panel of G2P, associated with "MED13 - Neurodevelopment disorder" (dis. confidence : probable / mutation consequence : LoF / GDD, speech/language delay, ID, autistic behavior among the assigned phenotypes).

MED13 is included in gene panels for ID offered by some diagnostic laboratories (incl. Radboudumc).

ID is part of the phenotype of MED13-related disorder, however as the severity in most individuals - when present - was in the borderline/mild range (not relevant for the present panel) and/or the underlying effect of mutations remains unclear, amber rating can probably be considered for this gene.
Sources: Radboud University Medical Center, Nijmegen, Literature; to: Snijders Blok et al. (2018 - PMID: 29740699) report on 13 individuals with MED13 mutations.

Features included DD with speech difficulties (both universal) and motor delay in some. ID was observed in at least 9/13 and in most cases was in the borderline/mild range (moderate ID reported for 1 individual). Other features were ASD (5/13), ADHD, eye/vision abnormalities and in few individuals obstipation or congenital heart anomalies. Some possibly overlapping facial characteristics were also noted.

MED13 and MED13L are mutually exclusive components of the CDK8 kinase module that regulates the activity of the Mediator complex. The Mediator transmits signals from various transcription factors to RNA polymerase II (Pol II). Reversible binding of the CDK8 kinase controls Mediator - Pol II interaction (prevents Pol II recruitment) and thus acts as a molecular switch in Pol II - mediated transcription. DD and ID are features of the MED13L- and CDK8- related disorders.

3 stopgain, 2 frameshift, 6 missense variants and 1 in-frame deletion were reported. In 11 cases, the variants had occurred as de novo events, while 1 individual had inherited a nonsense variant from a similarly affected mother (unknown inheritance in her case).

Effect of a stopgain variant was studied with similar (total) transcript levels between the affected patient and his parents/controls upon qPCR. Sanger sequencing of cDNA amplicons was suggestive of the presence of an aberrant transcript at ~70% levels relative to the normal transcript. Truncated protein was undetectable by Western Blot in mononuclear blood cells from affected subjects. Total MED13 protein levels were not clearly different when comparing an affected individual with his unaffected parent (?).

Missense variants and the inframe deletion clustered either in the N- or the C-terminal domain, with the N-terminal ones all (T326I, T326del, P327S, P327Q / NM_005121.2 - NP_005112.2) affecting positions of a known phosphodegron sequence, important for the protein's ubiquitination and degradation. Another previously studied variant (T326A) had been shown to prevent degradation. As a result, the variants affecting aa 326-327 might lead to altered (increased) levels of MED13.

The remaining missense variants affected the C-terminal portion (Q2060L, A2064V).

As a result the impact of the different subcategories of variants remains unclear/inconclusive.

MED13 is not associated with any phenotype in OMIM. This gene is part of the DD panel of G2P, associated with "MED13 - Neurodevelopment disorder" (dis. confidence : probable / mutation consequence : LoF / GDD, speech/language delay, ID, autistic behavior among the assigned phenotypes).

MED13 is included in gene panels for ID offered by some diagnostic laboratories (incl. Radboudumc).

ID is part of the phenotype of MED13-related disorder. However as the severity in most individuals - when present - was in the borderline/mild range (not relevant for the present panel) and/or the underlying effect of mutations remains unclear, amber rating seems more appropriate.
Sources: Radboud University Medical Center, Nijmegen, Literature
Intellectual disability v2.1021 MED13 Konstantinos Varvagiannis gene: MED13 was added
gene: MED13 was added to Intellectual disability. Sources: Radboud University Medical Center, Nijmegen,Literature
Mode of inheritance for gene: MED13 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: MED13 were set to 29740699
Phenotypes for gene: MED13 were set to Delayed speech and language development; Motor delay; Intellectual disability; Autistic behavior; Attention deficit hyperactivity disorder; Abnormality of the eye; Constipation
Penetrance for gene: MED13 were set to unknown
Review for gene: MED13 was set to AMBER
gene: MED13 was marked as current diagnostic
Added comment: Snijders Blok et al. (2018 - PMID: 29740699) report on 13 individuals with MED13 mutations.

Features included DD with speech difficulties (both universal) and motor delay in some. ID was observed in at least 9/13 and in most cases was in the borderline/mild range (moderate ID reported for 1 individual). Other features were ASD (5/13), ADHD, eye/vision abnormalities and in few individuals obstipation or congenital heart anomalies. Some possibly overlapping facial characteristics were also noted.

MED13 and MED13L are mutually exclusive components of the CDK8 kinase module that regulates the activity of the Mediator complex. The Mediator transmits signals from various transcription factors to RNA polymerase II (Pol II). Reversible binding of the CDK8 kinase controls Mediator - Pol II interaction (prevents Pol II recruitment) and thus acts as a molecular switch in Pol II - mediated transcription. DD and ID are features of the MED13L- and CDK8- related disorders.

3 stopgain, 2 frameshift, 6 missense variants and 1 in-frame deletion were reported. In 11 cases, the variants had occurred as de novo events, while 1 individual had inherited a nonsense variant from a similarly affected mother (unknown inheritance in her case).

Effect of a stopgain variant was studied with similar (total) transcript levels between the affected patient and his parents/controls upon qPCR. Sanger sequencing of cDNA amplicons was suggestive of the presence of an aberrant transcript at ~70% levels relative to the normal transcript. Truncated protein was undetectable by Western Blot in mononuclear blood cells from affected subjects. Total MED13 protein levels were not clearly different when comparing an affected individual with his unaffected parent (?).

Missense variants and the inframe deletion clustered either in the N- or the C-terminal domain, with the N-terminal ones all (T326I, T326del, P327S, P327Q / NM_005121.2 - NP_005112.2) affecting positions of a known phosphodegron sequence, important for the protein's ubiquitination and degradation. Another previously studied variant (T326A) had been shown to prevent degradation. As a result, the variants affecting aa 326-327 might lead to altered (increased) levels of MED13.

The remaining missense variants affected the C-terminal portion (Q2060L, A2064V).

As a result the impact of the different subcategories of variants remains unclear/inconclusive.

MED13 is not associated with any phenotype in OMIM. This gene is part of the DD panel of G2P, associated with "MED13 - Neurodevelopment disorder" (dis. confidence : probable / mutation consequence : LoF / GDD, speech/language delay, ID, autistic behavior among the assigned phenotypes).

MED13 is included in gene panels for ID offered by some diagnostic laboratories (incl. Radboudumc).

ID is part of the phenotype of MED13-related disorder, however as the severity in most individuals - when present - was in the borderline/mild range (not relevant for the present panel) and/or the underlying effect of mutations remains unclear, amber rating can probably be considered for this gene.
Sources: Radboud University Medical Center, Nijmegen, Literature
Intellectual disability v2.1021 PAK1 Konstantinos Varvagiannis changed review comment from: Horn et al. (2019 - doi.org/10.1093/brain/awz264) report on 4 additional individuals with de novo missense PAK1 pathogenic variants. ID, seizures and macrocephaly and walking difficulties were observed in all (4/4). ASD was reported in 3 (but was not among the features in the study by Harms et al).

PAK1 encodes p21 protein-activated kinase 1. The protein has 2 major domains, an autoregulatory and a protein kinase domain. Homodimerization masks the active site of the kinase, leading to autoinhibition (inactive form). PAK1 is activated by dissociation into monomers upon binding of the GTP-bound forms of the Rho GTPases CDC42 and RAC1. TRIO and HACE1 are indirect regulators of PAK1, via RAC1. PAK1 in turn, activates LIMK1 which plays a critical role in dendritic spine morphogenesis and brain function.

CDC42, RAC1, TRIO, HACE1 are all associated with neurodevelopmental disorders. Activation of RAC-PAK1-LIMK1 pathway has been demonstrated for Fragile-X syndrome (sharing ID, macrocephaly and seizures).

Mutations in PAK3, another member of the group I PAK subfamily with similar activation mechanism to PAK1 (by CDC42 / RAC1), cause Mental retardation, X-linked 30/47 (MIM 300558) (Green rating in the current panel).

4 additional missense variants - further to the 2 previously described ones - were found, all as de novo events:
c.397T>C (p.Ser133Pro) / c.361C>T p.(Pro121Ser) / c.328T>A p.(Ser110Thr) / c.1409T>G (p.Leu470Arg) [For the specific variants, cDNA and aa change are the same for both NM_001128620.1 and NM_002576].

The 3 former variants located within the autoinhibitory domain while the latter in the protein kinase domain though - again - close to the autoinhibitory one (in tertiary structure). A gain of function effect by reduced ability of autoinhibition (leading to autophosphorylation) and activation of PAK1 is the suggested mechanism. Gain of function is also supported by the fact that Pak1-/- do not exhibit neurodevelopmental anomalies / abnormal head size. PAK1 is not particularly intolerant to LoF variants as suggested by its pLI of 0.67.

The corresponding phenotype in OMIM is Intellectual developmental disorder with macrocephaly, seizures, and speech delay (MIM 618158). The gene is part of the DD panel of G2P, associated with "Neurodevelopmental Disorder" (monoallelic, activating / disease confidence : probable).

PAK1 is included in the gene panel for ID offered by Radboudumc.; to: Based on a further recent study, PAK1 can probably be upgraded to green in both ID and epilepsy gene panels:

Horn et al. (2019 - doi.org/10.1093/brain/awz264) report on 4 additional individuals with de novo missense PAK1 pathogenic variants. ID, seizures and macrocephaly and walking difficulties were observed in all (4/4). ASD was reported in 3 (but was not among the features in the study by Harms et al).

PAK1 encodes p21 protein-activated kinase 1. The protein has 2 major domains, an autoregulatory and a protein kinase domain. Homodimerization masks the active site of the kinase, leading to autoinhibition (inactive form). PAK1 is activated by dissociation into monomers upon binding of the GTP-bound forms of the Rho GTPases CDC42 and RAC1. TRIO and HACE1 are indirect regulators of PAK1, via RAC1. PAK1 in turn, activates LIMK1 which plays a critical role in dendritic spine morphogenesis and brain function.

CDC42, RAC1, TRIO, HACE1 are all associated with neurodevelopmental disorders. Activation of RAC-PAK1-LIMK1 pathway has been demonstrated for Fragile-X syndrome (sharing ID, macrocephaly and seizures).

Mutations in PAK3, another member of the group I PAK subfamily with similar activation mechanism to PAK1 (by CDC42 / RAC1), cause Mental retardation, X-linked 30/47 (MIM 300558) (Green rating in the current panel).

4 additional missense variants - further to the 2 previously described ones - were found, all as de novo events:
c.397T>C (p.Ser133Pro) / c.361C>T p.(Pro121Ser) / c.328T>A p.(Ser110Thr) / c.1409T>G (p.Leu470Arg) [For the specific variants, cDNA and aa change are the same for both NM_001128620.1 and NM_002576].

The 3 former variants located within the autoinhibitory domain while the latter in the protein kinase domain though - again - close to the autoinhibitory one (in tertiary structure). A gain of function effect by reduced ability of autoinhibition (leading to autophosphorylation) and activation of PAK1 is the suggested mechanism. Gain of function is also supported by the fact that Pak1-/- do not exhibit neurodevelopmental anomalies / abnormal head size. PAK1 is not particularly intolerant to LoF variants as suggested by its pLI of 0.67.

The corresponding phenotype in OMIM is Intellectual developmental disorder with macrocephaly, seizures, and speech delay (MIM 618158). The gene is part of the DD panel of G2P, associated with "Neurodevelopmental Disorder" (monoallelic, activating / disease confidence : probable).

PAK1 is included in the gene panel for ID offered by Radboudumc.

(Previous review below)
Intellectual disability v2.1021 PAK1 Konstantinos Varvagiannis edited their review of gene: PAK1: Added comment: Horn et al. (2019 - doi.org/10.1093/brain/awz264) report on 4 additional individuals with de novo missense PAK1 pathogenic variants. ID, seizures and macrocephaly and walking difficulties were observed in all (4/4). ASD was reported in 3 (but was not among the features in the study by Harms et al).

PAK1 encodes p21 protein-activated kinase 1. The protein has 2 major domains, an autoregulatory and a protein kinase domain. Homodimerization masks the active site of the kinase, leading to autoinhibition (inactive form). PAK1 is activated by dissociation into monomers upon binding of the GTP-bound forms of the Rho GTPases CDC42 and RAC1. TRIO and HACE1 are indirect regulators of PAK1, via RAC1. PAK1 in turn, activates LIMK1 which plays a critical role in dendritic spine morphogenesis and brain function.

CDC42, RAC1, TRIO, HACE1 are all associated with neurodevelopmental disorders. Activation of RAC-PAK1-LIMK1 pathway has been demonstrated for Fragile-X syndrome (sharing ID, macrocephaly and seizures).

Mutations in PAK3, another member of the group I PAK subfamily with similar activation mechanism to PAK1 (by CDC42 / RAC1), cause Mental retardation, X-linked 30/47 (MIM 300558) (Green rating in the current panel).

4 additional missense variants - further to the 2 previously described ones - were found, all as de novo events:
c.397T>C (p.Ser133Pro) / c.361C>T p.(Pro121Ser) / c.328T>A p.(Ser110Thr) / c.1409T>G (p.Leu470Arg) [For the specific variants, cDNA and aa change are the same for both NM_001128620.1 and NM_002576].

The 3 former variants located within the autoinhibitory domain while the latter in the protein kinase domain though - again - close to the autoinhibitory one (in tertiary structure). A gain of function effect by reduced ability of autoinhibition (leading to autophosphorylation) and activation of PAK1 is the suggested mechanism. Gain of function is also supported by the fact that Pak1-/- do not exhibit neurodevelopmental anomalies / abnormal head size. PAK1 is not particularly intolerant to LoF variants as suggested by its pLI of 0.67.

The corresponding phenotype in OMIM is Intellectual developmental disorder with macrocephaly, seizures, and speech delay (MIM 618158). The gene is part of the DD panel of G2P, associated with "Neurodevelopmental Disorder" (monoallelic, activating / disease confidence : probable).

PAK1 is included in the gene panel for ID offered by Radboudumc.; Changed rating: GREEN; Changed publications: 30290153, doi.org/10.1093/brain/awz264; Set current diagnostic: yes
Intellectual disability v2.1021 GABBR2 Rebecca Foulger commented on gene: GABBR2: Added missense tag: only missense variants (A707T and A567T) reported so far in the literature.
Intellectual disability v2.1021 GABBR2 Rebecca Foulger Added comment: Comment on list classification: Updated gene from Amber to Green: As noted by Konstantinos Varvagiannis, an additional 2018 study has been published associating a new GABBR2 variant (A707T) with a RETT-like phenotype including intellectual impairment (PMID:29369404). This adds to the previous papers documenting the recurring p.Ala567Thr variant in RETT-like patients from Portugal (PMID:26740508) and Korea (PMID:28856709). Plus OMIM has been updated since the Dec 2017 curation to include neurodevelopmental disorder MIM:617904. Thirdly, email correspondence from J. Evans notes a patient with a relevant phenotype and a previously-published pathogenic variant in GABBR2. Therefore sufficient unrelated cases to support a Green rating.
Intellectual disability v2.1020 GABBR2 Rebecca Foulger Phenotypes for gene: GABBR2 were changed from EPILEPTIC ENCEPHALOPATHY; Rett syndrome to EPILEPTIC ENCEPHALOPATHY; Rett syndrome; Neurodevelopmental disorder with poor language and loss of hand skills, 617903
Intellectual disability v2.1017 GOT2 Catherine Snow reviewed gene: GOT2: Rating: AMBER; Mode of pathogenicity: None; Publications: 31422819; Phenotypes: Global developmental delay, Intellectual disability, Seizures; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v2.1017 GEMIN4 Ivone Leong Added comment: Comment on list classification: Promoted from red to amber based on new evidence. PMID: 27878435 reported on different variant found in a patient with cataracts, global developmental delay and ataxia.
Intellectual disability v2.1015 HNRNPR Konstantinos Varvagiannis changed review comment from: Duijkers et al. (2019 - PMID: 31079900) report on the phenotype of 4 individuals with de novo HNRNPR variants and provide additional information on a previously published case (Helbig et al, 2016 - PMID: 26795593). All 5 were unrelated.

The phenotype consisted of DD (5/5 - moderate to severe in 4 for which this has been commented on), postnatal microcephaly, seizures, brachydactyly, with additional (cardiac, urogenital, etc) anomalies observed in few. Some partially overlapping facial features were also noted.

3 truncating variants as well as a missense one, all localizing within the last exon of the gene (NM_001102398.2 used as ref. although this exon is shared by all transcripts).

HNRNPR encodes heterogeneous nuclear ribonucleoprotein R, which is part of the spliceosome C. The latter functions in the nucleus to process and transport mRNA. Apart from splicing hnRNPs are also involved in other levels of gene regulation (PMID: 27215579). Some hnRNPs have been found in the cytoplasm in stress granules, aggregations of protein, RNAs and stalled initiation complexes that are formed as stress response upon oxidative insult and dissipate upon cessation of this insult.

Western blot in LCLs from affected individuals demonstrated the presence of the truncated protein as well as the full-length and short isoform (as expected by the variant localization).
As the C-terminal part has features of a "prion-like domain" (PrLD), critical for the formation of stress granules in the case of hnRNP-related disorders, comparison of fibroblasts from affected and healthy individuals revealed abnormal persistence of these granules in affected individuals following a recovery period, despite similar formation either at basal levels or under conditions of stress.

In line with a role of hnRNPs in splicing and gene regulation, RNA-Sequencing in fibroblasts from 2 affected individuals revealed abnormal splicing of some genes (eg. HOXA5, HOXB3, LHX9) and significant dysregulation of genes important for the development (upregulation of FOXG1, TBX1, several members of the HOX family and downregulation of LHX9, IRX3, etc) possibly contributing to the patient features.

Helbig et al. provide details on animal studies incl.expression in neural tissues (cerebrum and cerebellum), higher levels of expression early in the development (of both R1/R2 isoforms), etc (extensive discussion in the supplement with several articles cited).

HNRNPR is not associated with any phenotype in OMIM/G2P.

As a result this gene can be considered for inclusion as amber (developmental outcome not commented on sufficiently despite moderate/severe DD in most).
Sources: Literature; to: Duijkers et al. (2019 - PMID: 31079900) report on the phenotype of 4 individuals with de novo HNRNPR variants and provide additional information on a previously published case (Helbig et al, 2016 - PMID: 26795593). All 5 were unrelated.

The phenotype consisted of DD (5/5 - moderate to severe in 4 for which this has been commented on), postnatal microcephaly, seizures, brachydactyly, with additional (cardiac, urogenital, etc) anomalies observed in few. Some partially overlapping facial features were also noted.

3 truncating variants as well as a missense one, all localizing within the last exon of the gene (NM_001102398.2 used as ref. although this exon is shared by all transcripts).

HNRNPR encodes heterogeneous nuclear ribonucleoprotein R, which is part of the spliceosome C. The latter functions in the nucleus to process and transport mRNA. Apart from splicing hnRNPs are also involved in other levels of gene regulation (PMID: 27215579). Some hnRNPs have been found in the cytoplasm in stress granules, aggregations of protein, RNAs and stalled initiation complexes that are formed as stress response upon oxidative insult and dissipate upon cessation of this insult.

Western blot in LCLs from affected individuals demonstrated the presence of the truncated protein as well as the full-length and short isoform (as expected by the variant localization).
As the C-terminal part has features of a "prion-like domain" (PrLD), critical for the formation of stress granules in the case of hnRNP-related disorders, comparison of fibroblasts from affected and healthy individuals revealed abnormal persistence of these granules in affected individuals following a recovery period, despite similar formation either at basal levels or under conditions of stress.

In line with a role of hnRNPs in splicing and gene regulation, RNA-Sequencing in fibroblasts from 2 affected individuals revealed abnormal splicing of some genes (eg. HOXA5, HOXB3, LHX9) and significant dysregulation of genes important for the development (upregulation of FOXG1, TBX1, several members of the HOX family and downregulation of LHX9, IRX3, etc) possibly contributing to the patient features.

Helbig et al. provide details on animal studies incl.expression in neural tissues (cerebrum and cerebellum), higher levels of expression early in the development (of both R1/R2 isoforms), etc (extensive discussion in the supplement with several articles cited).

HNRNPR is not associated with any phenotype in OMIM/G2P.

As a result this gene can be considered for inclusion as amber (developmental outcome not commented on sufficiently despite moderate/severe DD in most) or green.
Sources: Literature
Intellectual disability v2.1015 HNRNPR Konstantinos Varvagiannis gene: HNRNPR was added
gene: HNRNPR was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: HNRNPR was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: HNRNPR were set to 31079900; 26795593
Phenotypes for gene: HNRNPR were set to Global developmental delay; Intellectual disability; Seizures; Postnatal microcephaly; Short digit
Penetrance for gene: HNRNPR were set to unknown
Review for gene: HNRNPR was set to GREEN
Added comment: Duijkers et al. (2019 - PMID: 31079900) report on the phenotype of 4 individuals with de novo HNRNPR variants and provide additional information on a previously published case (Helbig et al, 2016 - PMID: 26795593). All 5 were unrelated.

The phenotype consisted of DD (5/5 - moderate to severe in 4 for which this has been commented on), postnatal microcephaly, seizures, brachydactyly, with additional (cardiac, urogenital, etc) anomalies observed in few. Some partially overlapping facial features were also noted.

3 truncating variants as well as a missense one, all localizing within the last exon of the gene (NM_001102398.2 used as ref. although this exon is shared by all transcripts).

HNRNPR encodes heterogeneous nuclear ribonucleoprotein R, which is part of the spliceosome C. The latter functions in the nucleus to process and transport mRNA. Apart from splicing hnRNPs are also involved in other levels of gene regulation (PMID: 27215579). Some hnRNPs have been found in the cytoplasm in stress granules, aggregations of protein, RNAs and stalled initiation complexes that are formed as stress response upon oxidative insult and dissipate upon cessation of this insult.

Western blot in LCLs from affected individuals demonstrated the presence of the truncated protein as well as the full-length and short isoform (as expected by the variant localization).
As the C-terminal part has features of a "prion-like domain" (PrLD), critical for the formation of stress granules in the case of hnRNP-related disorders, comparison of fibroblasts from affected and healthy individuals revealed abnormal persistence of these granules in affected individuals following a recovery period, despite similar formation either at basal levels or under conditions of stress.

In line with a role of hnRNPs in splicing and gene regulation, RNA-Sequencing in fibroblasts from 2 affected individuals revealed abnormal splicing of some genes (eg. HOXA5, HOXB3, LHX9) and significant dysregulation of genes important for the development (upregulation of FOXG1, TBX1, several members of the HOX family and downregulation of LHX9, IRX3, etc) possibly contributing to the patient features.

Helbig et al. provide details on animal studies incl.expression in neural tissues (cerebrum and cerebellum), higher levels of expression early in the development (of both R1/R2 isoforms), etc (extensive discussion in the supplement with several articles cited).

HNRNPR is not associated with any phenotype in OMIM/G2P.

As a result this gene can be considered for inclusion as amber (developmental outcome not commented on sufficiently despite moderate/severe DD in most).
Sources: Literature
Intellectual disability v2.1015 FBXW11 Konstantinos Varvagiannis gene: FBXW11 was added
gene: FBXW11 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: FBXW11 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: FBXW11 were set to 31402090
Phenotypes for gene: FBXW11 were set to Global developmental delay; Intellectual disability; Abnormality of the eye; Abnormality of the head; Abnormality of digit
Penetrance for gene: FBXW11 were set to unknown
Review for gene: FBXW11 was set to GREEN
Added comment: Holt et al. (2019 - PMID: 31402090) report on 7 unrelated individuals with de novo FBXW11 variants.

Features included DD (6/7), ID (6/7 - severity relevant to the current panel in most cases), eye, digital, jaw anomalies, etc. There was some overlap with the phenotype of a 1.24-Mb 5q35.1 microduplication spanning FBXW11 and 6 additional genes (Koolen et al, 2006 - PMID: 16865294).

FBXW11 encodes an F-box protein part of the Skp1-cullin-F-box (SCF) ubiquitin ligase complex, involved in ubiquitination and proteasomal degratation. The SCF complex functions as a regulator of Wnt/β-catenin, Hh (and possibly RAS) signalling pathways.

Each individual harbored a private missense variant as a de novo event. Alternative diagnoses (eg. Noonan syndrome in the case of a suggestive phenotype) were ruled out to the extent possible.

All 7 variants localized in regions depleted for nonsynonymous variation (constrained coding regions) at the tips of loops of the WD repeat domains and were presumed to lead to destabilization of the protein and/or its interactions. Given the clustering a gain-of-function or dominant-negative effect of these variants might be suggested. [In gnomAD FBXW11 has a Z score = 3.96 for missense variants / pLI = 0.98].

In situ hybridization on human embryo sections demonstrated expression in the developping eye, hand, brain and mandibular process.

Relevant expression patterns were also observed for the 2 zebrafish orthologs of FBXW11, fbxw11a/b. Generated zebrafish homozygous for a frameshift fbxw11b frameshift variant demonstrated relevant phenotypes upon additional injection of a fbxw11a morpholino (abnormal pectoral fins, heart edema, smaller eyes, abnormal jaw development).

FBXW11 is not associated with any phenotype in OMIM/G2P.

As a result, this gene can be considered for inclusion in the ID panel as green (sufficient cases, expression, phenotype in zebrafish model, etc.) or amber.
Sources: Literature
Intellectual disability v2.1015 GOT2 Konstantinos Varvagiannis gene: GOT2 was added
gene: GOT2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: GOT2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GOT2 were set to 31422819
Phenotypes for gene: GOT2 were set to Global developmental delay; Intellectual disability; Seizures; Increased serum lactate; Hyperammonemia; Microcephaly; Failure to thrive; Feeding difficulties; Abnormality of nervous system morphology
Penetrance for gene: GOT2 were set to Complete
Review for gene: GOT2 was set to GREEN
Added comment: van Karnebeek et al. (2019 - PMID: 31422819) report on 4 individuals from 3 families, with biallelic GOT2 pathogenic variants (3 missense SNVs and 1 in-frame deletion).

The phenotype corresponded to a metabolic encephalopathy with onset of epilepsy in the first year of life (4/4) with DD and ID (4/4). Additional features included postnatal microcephaly, failure to thrive/feeding difficulties and cerebral anomalies (atrophy and white matter). All subjects had high blood lactate and hyperammonemia. Plasma serine was low in one case (alternative causes were ruled out).

Administration of serine and pyridoxine led to clinical improvement (cessation / better control of seizures) in 2 subjects suggesting that GOT2 deficiency may be amenable to therapeutic intervention. [Treatment could not be started in the 2 further affected individuals].

GOT2 encodes the mitochondrial glutamate oxaloacetate transaminase, a component of the malate-aspartate shuttle (MAS). The latter is important for intracellular NAD(H) redox homeostasis.

The authors provide several lines of evidence that GOT2 deficiency explains the patients' phenotype and metabolic defects incl. :
- Reduced GOT2 protein levels (due to lower expression/impaired stability) and diminished activity in patient fibroblasts (lower activity was also shown for carriers). Rescue of the GOT enzymatic activity was observed upon transduction of patient fibroblasts using lentiviral particles with wt GOT2.
- Impairment of de novo serine biosynthesis in patient (and to a lesser extent in carrier) fibroblasts compared to controls. This was similar in GOT2-knockout HEK293 cells. Serine biosynthesis in these cells was restored by pyruvate supplementation.
- CRISPR/Cas9 Got2-knockout mice resulted in early lethality (during pregnancy). Heterozygous mice were viable and healthy.
- Morpholino knockdown of got2a in zebrafish was shown to perturb embryonic development (smaller head, slow circulation, bend body, brain developmental defects, etc). Pyridoxine and serine in embryo water resulted in milder phenotypes/improved morphant survival. Zebrafish got2a morphants had seizure-like spikes upon EEG that were rescued by treatment with pyridoxine.

GOT2 is not associated with any phenotype in OMIM/G2P.

As a result, this gene can be considered for inclusion in both epilepsy and ID gene panels probably as green (3 families, relevant phenotypes and severity, evidence from cell and animal studies) or amber.

[Please consider inclusion in other relevant panels eg. mitochondrial disorders, metabolic disorders and/or addition of the 'treatable' tag].
Sources: Literature
Intellectual disability v2.1015 DDX6 Konstantinos Varvagiannis gene: DDX6 was added
gene: DDX6 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: DDX6 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: DDX6 were set to 31422817
Phenotypes for gene: DDX6 were set to Generalized hypotonia; Global developmental delay; Intellectual disability; Unsteady gait; Abnormality of the cardiovascular system; Abnormality of the genitourinary system; Abnormality of limbs
Penetrance for gene: DDX6 were set to unknown
Review for gene: DDX6 was set to GREEN
Added comment: Balak et al. (2019 - PMID: 31422817) report on 5 individuals with de novo likely pathogenic DDX6 variants.

Clinical details are provided for 4. Frequent features included hypotonia, DD, ID (4/4), gait instability, cardiac, genitourinary as well anomalies of the extremities.

DDX6 belongs to the DEAD box family of RNA helicases. This helicase is an essential component of processing bodies (P-bodies / PBs), which are mebrane-less organelles involved in storage of mRNAs and proteins related to mRNA decay thus playing an important role in translational repression/post-transcriptional regulation (PMID: 29381060).

All 5 variants had occurred as de novo events, clustered in exon 11 (NM_004397.5) and affected residues 372-373 of the QxxR motif (c.1115A>G or p.His372Arg / c.1118G>A or p.Arg373Gln) or 390-391 of the V motif (c.1168T>C or p.Cys390Arg / c.1171A>C or p.Thr391Pro / c.1172C>T or p.Thr391Ile). The specific motifs (and RecA-2 domain) are involved in RNA binding, helicase activity and protein-partner binding.

Fibroblasts from 2 individuals were studied. Patient cells contained fewer PBs compared to cells from relatives/control-subjects, despite similar amounts of DDX6 protein upon immunobloting. Additional studies suggested that DDX6 variants caused impaired binding of other DDX6 protein partners involved in PB formation / translation repression (eg. LSM14A, 4E-T, etc) thus resulting in defective PB assembly.

Transcriptome analysis in fibroblasts from one affected individual revealed (significant) differential expression of >1000 genes, enriched for genes related to protein translation, ribosome and RNA processing.

As the authors discuss, given the residual PB assembly, haploinsufficiency is favored over a dominant-negative effect which would result in complete suppression of PBs (as sugested by a previous study of a dominant-negative DDX6 variant - PMID cited: 19297524). [In gnomAD, DDX6 has a Z-score for missense variants of 3.78 and a pLI of 1].

DDX6 is not associated with any phenotype in OMIM.
In G2P it is associated with ID (disease confidence : probable / mutations : all missense/in frame).

As a result, this gene can be considered for inclusion in the ID panel as green (sufficient cases, relevant phenotype, functional studies) or amber.
Sources: Literature
Intellectual disability v2.1015 TRAPPC6B Konstantinos Varvagiannis reviewed gene: TRAPPC6B: Rating: GREEN; Mode of pathogenicity: None; Publications: 28626029, 28397838, DOI 10.1055/s-0039-1693664; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability v2.1015 KCNMA1 Konstantinos Varvagiannis reviewed gene: KCNMA1: Rating: AMBER; Mode of pathogenicity: None; Publications: 31427379, 31152168, 27567911; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes
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 v2.1013 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 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 v2.1008 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 v2.1007 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 v2.1004 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 v2.1001 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 v2.1000 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 v2.998 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: 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 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 v2.997 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.
----
In G2P, AFF3 is associated with Skeletal dysplasia with severe neurological disease (disease confidence : probable / ID and seizures among the assigned phenotypes). There is no associated phenotype in OMIM.
Some diagnostic laboratories include AFF3 in their ID panel (eg. among the many co-authors' affiliations GeneDx and Victorian Clinical Genetics - which was already listed as source for AFF3 in the current panel).
----
As a result this gene can be considered for upgrade to green (relevant phenotype and severity, sufficient cases, evidence for accumulation similar to AFF4, animal models, etc) or amber (pending publication of the article).; 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.
----
Shimizu et al. (8/2019 - PMID: 31388108) describe an additional individual with de novo AFF3 missense variant. The phenotype overlaps with that summarized by Voisin et al. incl. mesomelic dysplasia with additional skeletal anomalies, bilateral kidney hypoplasia and severe DD at the age of 2.5 years. Seizures and pulmonary problems were not observed. Although a different RefSeq is used the variant is among those also reported by Voisin et al. [NM_002285.2:c.697G>A (p.Ala233Thr) corresponding to NM_001025108.1:c.772G>A (p.Ala258Thr)].
----
In G2P, AFF3 is associated with Skeletal dysplasia with severe neurological disease (disease confidence : probable / ID and seizures among the assigned phenotypes). There is no associated phenotype in OMIM.
Some diagnostic laboratories include AFF3 in their ID panel (eg. among the many co-authors' affiliations GeneDx and Victorian Clinical Genetics - which was already listed as source for AFF3 in the current panel).
----
As a result this gene can be considered for upgrade to green (relevant phenotype and severity, sufficient cases, evidence for accumulation similar to AFF4, animal models, etc) or amber (pending publication of the article).

[Review modified to add additional reference/case report]
Intellectual disability v2.996 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 v2.995 POU3F3 Catherine Snow reviewed gene: POU3F3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
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 v2.992 PIGB Catherine Snow reviewed gene: PIGB: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
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 v2.990 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 v2.989 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 v2.982 MTO1 Catherine Snow reviewed gene: MTO1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 v2.977 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 v2.975 DLG4 Catherine Snow reviewed gene: DLG4: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
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 v2.970 CYP27A1 Catherine Snow reviewed gene: CYP27A1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
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 v2.968 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 v2.966 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 v2.965 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 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 v2.963 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 v2.961 ATN1 Catherine Snow reviewed gene: ATN1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
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 v2.957 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 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 v2.954 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).
----
The respective OMIM entry is Leukodystrophy, hypomyelinating, 18 (#618404). DEGS1 is not associated with any phenotype in G2P.
----
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 v2.952 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.
---
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).
---
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).
---
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 v2.950 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 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 v2.948 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 v2.945 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 v2.944 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 v2.942 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 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 v2.938 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.; 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 v2.937 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 v2.935 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 v2.933 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 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 v2.931 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 v2.930 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 PIGC Rebecca Foulger Phenotypes for gene: PIGC were changed from Glycosylphosphatidylinositol biosynthesis defect 16 to Glycosylphosphatidylinositol biosynthesis defect 16, 617816
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 v2.926 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 v2.925 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 v2.924 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 v2.923 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 Phenotypes for gene: TRAPPC12 were changed from to Encephalopathy, progressive, early-onset, with brain atrophy and spasticity, 617669
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 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 v2.919 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 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 v2.915 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 v2.914 PIGW Ivone Leong Phenotypes for gene: PIGW were changed from Glycosylphosphatidylinositol biosynthesis defect 11 to Glycosylphosphatidylinositol biosynthesis defect 11, 616025
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 v2.904 CSNK2B Rebecca Foulger Deleted their comment
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 v2.903 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 v2.901 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 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 v2.898 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 v2.894 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 v2.893 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 v2.890 ITPA Ivone Leong Phenotypes for gene: ITPA were changed from Epileptic encephalopathy, early infantile, 35 to Epileptic encephalopathy, early infantile, 35, 616647
Intellectual disability v2.886 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 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 v2.883 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 v2.881 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 v2.880 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 v2.878 SETD1B Ivone Leong reviewed gene: SETD1B: Rating: GREEN; Mode of pathogenicity: None; Publications: 31110234; Phenotypes: ; Mode of inheritance: None
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 v2.875 KMT5B Eleanor Williams Deleted their comment
Intellectual disability v2.875 KMT5B Eleanor Williams Deleted their comment
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 v2.873 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 Added comment: Comment on list classification: Sufficient cases of patients with ID to rate green
Intellectual disability v2.871 KMT5B Eleanor Williams Added comment: Comment on list classification: Sufficient cases of patients with ID to rate green
Intellectual disability v2.869 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 v2.867 KMT2E Eleanor Williams Added comment: Comment on list classification: Sufficient cases with ID to rate green.
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 v2.859 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 v2.857 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 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 v2.854 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 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 v2.851 CHD8 Louise Daugherty Phenotypes for gene: CHD8 were changed from AUTISM to Overgrowth with Intellectual disability
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 v2.847 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 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 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 v2.845 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 v2.844 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 v2.841 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 v2.839 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 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 v2.837 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 v2.836 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 v2.834 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 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 v2.833 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 v2.831 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 v2.828 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 v2.824 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 v2.822 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 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 v2.817 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 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 v2.815 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 v2.813 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 v2.811 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 v2.808 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 v2.807 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 v2.803 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 v2.800 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 v2.797 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 v2.794 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 v2.789 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 v2.788 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 v2.787 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 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 v2.786 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 v2.785 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 v2.784 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 v2.783 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).
-----------
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 v2.782 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 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 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 v2.780 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 v2.778 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 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 v2.775 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 v2.774 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 v2.773 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 v2.771 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 v2.769 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 v2.768 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 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 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 v2.763 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 v2.762 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 v2.761 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 v2.758 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 v2.757 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 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 v2.754 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 v2.753 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 v2.752 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 v2.751 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 v2.748 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 v2.744 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 v2.743 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 v2.742 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.
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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 v2.740 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 v2.739 ITCH Ivone Leong Phenotypes for gene: ITCH were changed from to Autoimmune disease, multisystem, with facial dysmorphism, 613385
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 v2.736 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 v2.735 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 v2.733 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 v2.732 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 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 v2.730 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 v2.727 FRMPD4 Louise Daugherty Added comment: Comment on publications: Added PMID: 29267967 from external review, to support this gene being upgraded to Green
Intellectual disability v2.725 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 v2.722 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 v2.720 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 v2.718 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 v2.717 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 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 v2.715 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 v2.714 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 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 v2.712 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 v2.708 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 v2.706 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 v2.705 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 v2.703 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 v2.700 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 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 v2.698 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 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 v2.696 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 v2.695 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 v2.694 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 v2.693 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 v2.692 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 v2.690 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 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 v2.687 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 v2.685 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 v2.682 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 v2.678 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 v2.675 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 v2.674 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 v2.672 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 v2.670 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 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 v2.665 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 v2.663 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 v2.660 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 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 v2.657 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 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 v2.655 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 v2.652 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 v2.651 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 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 v2.650 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 v2.649 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 v2.648 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 v2.647 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 v2.646 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 v2.645 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 v2.644 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 v2.643 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 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 v2.641 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 v2.638 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 v2.637 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 v2.634 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 v2.632 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 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 v2.625 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 v2.622 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 v2.618 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 v2.617 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 v2.614 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 v2.611 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 v2.603 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.
-------
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.
-------
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.
-------
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).
---------
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.
---------
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.
--------------
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 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 v2.595 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 v2.590 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 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 v2.588 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.
------------
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).
---------
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).
--------
In ClinVar additional variants have been submitted as pathogenic/likely pathogenic (although a phenotype is not specified for all).
--------
CWF19L1 is not associated with any phenotype in G2P.
This gene is included in gene panels for ID offered by diagnostic laboratories (incl. Radboudumc).
--------
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.
---------
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.
---------
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.
-----------
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.
---------
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 v2.587 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 v2.584 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 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 v2.582 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 v2.577 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 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 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 v2.571 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 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 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 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 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 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 v2.563 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 v2.562 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 v2.559 SCAPER Louise Daugherty edited their review of gene: SCAPER: Changed rating: GREEN
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 v2.556 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 v2.555 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 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 v2.554 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 v2.552 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 v2.551 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 v2.550 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 v2.549 CSNK2B Rebecca Foulger Phenotypes for gene: CSNK2B were changed from to Intellectual disability with or without myoclonic epilepsy
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 v2.545 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 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 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 v2.543 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 v2.541 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 v2.540 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 v2.538 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 v2.537 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 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 v2.535 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 v2.532 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 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 v2.530 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 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 v2.529 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 v2.528 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 v2.527 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 v2.526 CUX2 Louise Daugherty Phenotypes for gene: CUX2 were changed from to Epileptic encephalopathy, early infantile, 67, 618141; Seizures; Intellectual disability; Autistic behavior
Intellectual disability v2.524 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 v2.523 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 v2.521 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 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 v2.519 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 v2.518 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 v2.517 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 v2.516 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 v2.513 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 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 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 v2.510 PCGF2 Louise Daugherty Deleted their comment
Intellectual disability v2.510 REEP1 Eleanor Williams Deleted their review
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

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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 Deleted their review
Intellectual disability v2.510 ZNF81 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 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 v2.507 FBXO11 Helen Brittain Added comment: Comment on list classification: Sufficient cases with appropriate phenotype
Intellectual disability v2.507 FBXO11 Helen Brittain Added comment: Comment on list classification: Sufficient cases with appropriate phenotype
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 v2.504 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 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 v2.503 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 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 v2.501 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 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 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 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 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 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 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 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 v2.498 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 v2.497 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 v2.496 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 v2.495 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 v2.494 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 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 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 v2.493 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 v2.492 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 v2.491 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 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 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 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 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 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 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 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 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 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 v2.485 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 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 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 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 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 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 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 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 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 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 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 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 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 AHI1 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 v2.478 ACTL6A 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 v2.477 TTC37 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 v2.476 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 v2.476 TBCK 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 v2.475 SIN3A 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 v2.474 RERE 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 v2.474 PRMT7 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 v2.473 PIK3CA 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 v2.472 PDHX 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 v2.471 DIS3L2 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 v2.470 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 v2.470 DIS3L2 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 v2.469 CCDC88C 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 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 v2.469 AMER1 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 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 v2.468 THRB Louise Daugherty Source Victorian Clinical Genetics Services was added to THRB.
Intellectual disability v2.468 THOC6 Louise Daugherty Source Victorian Clinical Genetics Services was added to THOC6.
Intellectual disability v2.468 TH Louise Daugherty Source Victorian Clinical Genetics Services was added to TH.
Intellectual disability v2.468 MTHFR Louise Daugherty Source Victorian Clinical Genetics Services was added to MTHFR.
Intellectual disability v2.468 ETHE1 Louise Daugherty Source Victorian Clinical Genetics Services was added to ETHE1.
Intellectual disability v2.467 GRIA4 Louise Daugherty Added comment: Comment on list classification: Changed Amber to Green from external review comment and further publications to support gene-disease association
Intellectual disability v2.466 GRIA4 Louise Daugherty Phenotypes for gene: GRIA4 were changed from Neurodevelopmental disorder with or without seizures and gait abnormalities to Neurodevelopmental disorder with or without seizures and gait abnormalities, 617864
Intellectual disability v2.465 IBA57 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 v2.464 KDM1A Louise Daugherty Deleted their comment
Intellectual disability v2.464 IBA57 Louise Daugherty gene: IBA57 was added
gene: IBA57 was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: IBA57 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: IBA57 were set to 28671726; 23462291; 25971455; 28913435; 27785568
Phenotypes for gene: IBA57 were set to Multiple mitochondrial dysfunctions syndrome 3, 615330; intellectual disability, seizures, loss of milestones
Review for gene: IBA57 was set to GREEN
Added comment: New gene suggested 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
Sources: Expert list
Intellectual disability v2.462 KDM1A Louise Daugherty Added comment: Comment on list classification: Changed from Red to Green. Publications support gene-disease association and rating of this gene to Green on the ID panel
Intellectual disability v2.461 KDM1A Louise Daugherty Added comment: Comment on list classification: Changed from Red to Green. Publications support gene-disease association and rating of this gene to Green on the ID panel
Intellectual disability v2.460 KDM1A Louise Daugherty Added comment: Comment on list classification: Changed from Red to Green. Publications support gene-disease association and rating of this gene to Green on the ID panel
Intellectual disability v2.458 KDM1A Louise Daugherty edited their review of gene: KDM1A: Added comment: Recommendation that this gene should be Green. Three patients https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4902791/, there is functional characterisation of the three described mutations https://www.ncbi.nlm.nih.gov/pubmed/27094131?dopt=Abstract and the patients seem to share a similar phenotype, which recapitulates features of other deleterious mutations in better-characterised lysine demethylase and chromatin remodelling genes. There is also a recurrent de novo variant p.Tyr831Cys which has been reported in two separate "autism spectrum" patients in large cohort studies. The gene is also extensively constrained against both missense and LOF variation in humans http://exac.broadinstitute.org/gene/ENSG00000004487. I think what's been reported so far is probably robust enough to use the gene clinically.Pers comm. Ian Berry (NHS Leeds Genetics Laboratory); Changed rating: GREEN
Intellectual disability v2.458 PHIP Louise Daugherty Added comment: Comment on list classification: Changed rating from Red to Green. Publications now support gene-disease association and rating of this gene to Green on the ID panel.
Intellectual disability v2.457 PHIP Louise Daugherty Added comment: Comment on phenotypes: updated with OMIN and MIMid
Intellectual disability v2.455 PHIP Louise Daugherty edited their review of gene: PHIP: Added comment: Recommendation that this gene should be Green based on recent publication PMID:29209020, more than 20 unrelated cases Pers comm. Ian Berry (NHS Leeds Genetics Laboratory); Changed rating: GREEN; Changed publications: 29209020, 23033978, 27900362; Changed phenotypes: Developmental delay, intellectual disability, obesity, and dysmorphic features, 617991; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v2.455 PACS2 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 v2.455 PACS2 Louise Daugherty Phenotypes for gene: PACS2 were changed from Epileptic encephalopathy, early infantile, 66, 618067 to Epileptic encephalopathy, early infantile, 66, 618067; Global developmental delay; Intellectual disability; Seizures; Abnormality of the cerebellum
Intellectual disability v2.452 FBXO11 Sarah Leigh Phenotypes for gene: FBXO11 were changed from Intellectual developmental disorder with dysmorphic facies and behavioral abnormalities 618089 to Intellectual developmental disorder with dysmorphic facies and behavioral abnormalities 618089
Intellectual disability v2.451 FBXO11 Sarah Leigh Phenotypes for gene: FBXO11 were changed from Intellectual developmental disorder with dysmorphic facies and behavioral abnormalities 618089 to Intellectual developmental disorder with dysmorphic facies and behavioral abnormalities 618089
Intellectual disability v2.450 FBXO11 Sarah Leigh Phenotypes for gene: FBXO11 were changed from Intellectual developmental disorder with dysmorphic facies and behavioral abnormalities 618089 to Intellectual developmental disorder with dysmorphic facies and behavioral abnormalities 618089
Intellectual disability v2.449 FBXO11 Sarah Leigh Phenotypes for gene: FBXO11 were changed from Generalized hypotonia; Global developmental delay; Intellectual disability; Seizures to Intellectual developmental disorder with dysmorphic facies and behavioral abnormalities 618089
Intellectual disability v2.447 CDC42 Louise Daugherty Added comment: Comment on list classification: New gene added by external expert review, who notes that there are 17 unrelated individuals with de novo variants in this gene reported in the literature to date, ID is part of the phenotype. There are enough publications support gene-disease association and rating of this gene to Green.
Intellectual disability v2.444 DCHS1 Rebecca Foulger Source Other was added to DCHS1.
Phenotypes for gene: DCHS1 were changed from PERIVENTRICULAR NEURONAL HETEROTOPIA to PERIVENTRICULAR NEURONAL HETEROTOPIA; Van Maldergem syndrome 1, 601390
Intellectual disability v2.443 ISCA-46290-Gain Louise Daugherty Region: ISCA-46290-Gain was added
Region: ISCA-46290-Gain was added to Intellectual disability. Sources: ClinGen,Expert Review Green
Mode of inheritance for Region: ISCA-46290-Gain was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for Region: ISCA-46290-Gain were set to 25425167; 19716111; 21418194
Phenotypes for Region: ISCA-46290-Gain were set to Idiopathic mental retardation, speech delay, and a peculiar electroencephalographic (EEG) pattern in childhood. Autism and epilepsy, severe intellectual disability and dysmorphic facial features. Moderate to severe intellectual disability, early onset of puberty, language impairment, and age related epileptic syndromes such as West syndrome and focal epilepsy with activation during sleep evolving in some patients to continuous spikes-and-waves during slow sleep; 300801
Intellectual disability v2.443 ISCA-37431-Loss Louise Daugherty Region: ISCA-37431-Loss was added
Region: ISCA-37431-Loss was added to Intellectual disability. Sources: ClinGen,Expert Review Green
Mode of inheritance for Region: ISCA-37431-Loss was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for Region: ISCA-37431-Loss were set to dysmorphic features, cardiac anomalies and mental retardation; 613675; variable facial dysmorphism, cafe-au-lait spots, neurofibromas and Lisch nodules in the iris, mental retardation, developmental delay, an excessive number of early-onset neurofibromas and an increased risk for malignant peripheral nerve sheath tumors; NEUROFIBROMATOSIS 1 MICRODELETION SYNDROME; NF1 MICRODELETION SYNDROME; Chromosome 17q11.2 deletion syndrome, 1.4Mb
Intellectual disability v2.442 PACS2 Sarah Leigh Added comment: Comment when marking as ready: Associated with relevant phenotype in OMIM and as possible Gen2Phen gene. Single de novo variant reported in at least 14 unrelated cases variants (PMID 29656858), together with previous reports of haploinsufficiency encompassing the PACS2 gene
Intellectual disability v2.442 C12orf4 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 v2.441 PACS2 Sarah Leigh Added comment: Comment when marking as ready: Associated with relevant phenotype in OMIM and as possible Gen2Phen gene. Single de novo variant reported in at least 14 unrelated cases variants (PMID 29656858), together with previous reports of haploinsufficiency encompassing the PACS2 gene.
Intellectual disability v2.441 C12orf4 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 v2.437 PACS2 Sarah Leigh Phenotypes for gene: PACS2 were changed from Epileptic encephalopathy, early infantile, 66, 618067; Global developmental delay; Intellectual disability; Seizures; Abnormality of the cerebellum to Epileptic encephalopathy, early infantile, 66, 618067
Intellectual disability v2.431 BRF1 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 v2.430 BRF1 Louise Daugherty edited their review of gene: BRF1: Added comment: New gene added by external expert review, who notes that there are 3 unrelated individuals reported in the literature, ID is part of the phenotype.; Changed rating: GREEN
Intellectual disability v2.429 BPTF 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 v2.428 BPTF Louise Daugherty edited their review of gene: BPTF: Added comment: New gene added by external expert. From OMIM; Stankiewicz et al. 2017 (PMID: 28942966) reported 10 unrelated patients, ranging from 2 to 13 years of age, with a similar neurodevelopmental disorder. All patients had delayed psychomotor development and intellectual disability with delayed speech.; Changed rating: GREEN
Intellectual disability v2.428 BPTF Louise Daugherty Phenotypes for gene: BPTF were changed from Neurodevelopmental disorder with dysmorphic facies and distal limb anomalies to Neurodevelopmental disorder with dysmorphic facies and distal limb anomalies, 617755; intellectual disability
Intellectual disability v2.427 BCKDK 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 gene Green.
Intellectual disability v2.426 BCKDK Louise Daugherty edited their review of gene: BCKDK: Added comment: New gene added by external expert review, who notes that there are multiple unrelated individuals reported in the literature, ID is part of the phenotype. Publications support gene-disease association and rating of this gene to Green.; Changed rating: GREEN
Intellectual disability v2.424 ARCN1 Louise Daugherty Added comment: Comment on list classification: New gene added by External review and reviewed by curation team, enough evidence to support gene-disease association and rating of this gene to Green.
Intellectual disability v2.423 ARCN1 Louise Daugherty edited their review of gene: ARCN1: Added comment: New gene added by external expert review, who notes that there are 3 unrelated families reported in the literature (From OMIM based on report of 4 patients from 3 families- single report PMID:27476655, ID is part of the phenotype. Publication supports gene-disease association and rating of this gene to Green.; Changed rating: GREEN
Intellectual disability v2.423 ARCN1 Louise Daugherty Phenotypes for gene: ARCN1 were changed from Short stature, rhizomelic, with microcephaly, micrognathia, and developmental delay to Short stature, rhizomelic, with microcephaly, micrognathia, and developmental delay, 617164
Intellectual disability v2.422 AP1S1 Louise Daugherty Phenotypes for gene: AP1S1 were changed from MEDNIK syndrome to MEDNIK syndrome, 609313; MEDNIK syndrome; mental retardation, enteropathy, deafness, peripheral neuropathy, ichthyosis and keratoderma syndrome
Intellectual disability v2.421 AP1S1 Louise Daugherty Added comment: Comment on list classification: New gene added by external reviewer. Rated green based on external review comment, internal assessment (supportive functional data) and further publications to support gene-disease association.
Intellectual disability v2.420 AP1S1 Louise Daugherty edited their review of gene: AP1S1: Added comment: New gene added by external expert review, who notes French Canadian (founder effect); however, Sephardic Jewish family also reported with a different variant. ID is part of the phenotype, added publication to support gene-disease association.
The patients cases described in the literature to date are likely to be linked to a founder effect. 5 children from 3 families all from Quebec, Canada (with the same mutation) and 1 patient from a consanguineous Sephardic-Jewish background has been described (a different mutation in AP1S1).
However, this gene was rated Green on the Vici Syndrome and other autophagy disorders panel for MEDNIK syndrome after discussion with Emma Baple (South West GMC and Genomics England); as there is a second, independent case with a different variant, plus functional data, so this gene can be green on the ID panel, since intellectual disability is part of the phenotype; Changed rating: GREEN
Intellectual disability v2.420 AP1S1 Louise Daugherty Added comment: Comment on publications: Additional publications to support upgrading of the gene to Green
Intellectual disability v2.418 LYST Louise Daugherty Deleted their comment
Intellectual disability v2.418 KIF5A Louise Daugherty edited their review of gene: KIF5A: Changed rating: GREEN
Intellectual disability v2.418 KIF5A Louise Daugherty Added comment: Comment on publications: Added publications suggested from external expert review to support upgrading of the gene to Green
Intellectual disability v2.417 KIF5A Louise Daugherty Added comment: Comment on phenotypes: removed Spastic paraplegia 10, autosomal dominant, 604187, this is not a relevant phenotype on this panel.
Intellectual disability v2.414 PIGH Louise Daugherty Added comment: Comment on list classification: Changed from Red to Amber, recent publications support gene-disease association three affecteds (2 unrelated) cases
Intellectual disability v2.413 PIGH Louise Daugherty Added comment: Comment on publications: Added publications suggested from external expert review to support upgrading of the gene
Intellectual disability v2.412 PIGH Louise Daugherty Phenotypes for gene: PIGH were changed from hypotonia, moderate developmental delay, and autism, two episodes of febrile seizures to Glycosylphosphatidylinositol biosynthesis defect, 17; 618010; Hypotonia, moderate developmental delay, and autism, two episodes of febrile seizures
Intellectual disability v2.411 ALX4 Louise Daugherty edited their review of gene: ALX4: Added comment: In view of external Green review and after internal review it was decided to keep this gene Amber on the ID panel, as it does not seem to be a consistently predominant feature. ALX4 is noted as having significant findings wrt PMID 29215649 but phenotypically supports inclusion on the craniosynostosis panel, where this gene is rated as Green; Changed rating: AMBER
Intellectual disability v2.411 CCDC8 Louise Daugherty Added comment: Comment on list classification: After internal and external review, it was agreed this gene should be demoted from Green to Red
Intellectual disability v2.410 CISD2 Louise Daugherty Added comment: Comment on list classification: After internal and external review, it was agreed this gene should be demoted from Green to Red
Intellectual disability v2.409 CISD2 Louise Daugherty reviewed gene: CISD2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v2.409 EDNRB Louise Daugherty Added comment: Comment on list classification: After internal and external review, it was agreed this gene should be demoted from Green to Red
Intellectual disability v2.408 EDNRB Louise Daugherty edited their review of gene: EDNRB: Changed rating: RED
Intellectual disability v2.408 FGFR1 Louise Daugherty reviewed gene: FGFR1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v2.408 GBA Louise Daugherty commented on gene: GBA: In view of an external green review, this gene was reviewed again internally and with out internal clinical team. it was decided his gene should remain Amber. It was noted that the commonest type is type 1, where ID is not a clear feature, and that there are sufficient other features to suggest a metabolic / storage dysfunction in all types of Gaucher disease to prompt diagnosis via the undiagnosed metabolic route. So we have decided to leave this gene as amber on ID panel in view of the likely low yield and the complication of the later incidental neurological risks.
Intellectual disability v2.407 ORC1 Louise Daugherty Added comment: Comment on list classification: Although variants of ORC1 can result in microcephaly phenotype, there is no strong evidence for ID. single patient with ORC1 variants was described in this paper HERE, they had mild intellectual disability.
Intellectual disability v2.406 CDT1 Louise Daugherty Added comment: Comment on list classification: After internal and external review, it was agreed this gene should be demoted to Red
Intellectual disability v2.405 ORC6 Louise Daugherty Added comment: Comment on list classification: After internal and external review, it was agreed this gene should be demoted to Amber. There are some reports of ID but mild ID only.
Intellectual disability v2.404 ORC4 Louise Daugherty Added comment: Comment on list classification: After internal and external review, it was agreed this gene should be demoted to Red
Intellectual disability v2.403 GSPT2 Louise Daugherty Added comment: Comment on list classification: After internal and external review, it was agreed this gene should be demoted from Green to Red
Intellectual disability v2.402 ISCA-37433-Gain Louise Daugherty 22q11.2 recurrent (DGS/VCFS) region (proximal region, LCR22-A to -B) Gain was changed to 22q11.2 recurrent (DGS/VCFS) region (proximal, A-B) (includes TBX1) Gain
Added phenotypes 608363; Chromosome 22q11.2 microduplication syndrome; dysmorphic facial features, cognitive deficits, velopharyngeal insufficiency, congenital heart defects and immunologic derangement; delayed psychomotor development, growth retardation, and/or hypotonia for Region: ISCA-37433-Gain
Intellectual disability v2.402 ISCA-37433-Loss Louise Daugherty 22q11.2 recurrent (DGS/VCFS) region (proximal region, LCR22-A to -B) Loss was changed to 22q11.2 recurrent (DGS/VCFS) region (proximal, A-B) (includes TBX1) Loss
Added phenotypes 188400; immune deficiency; renal anomalies; 22q11.2 deletion syndrome; 192430; facial dysmorphic features, high frequency of cardiac defects, including conotruncal defects, prematurity, growth restriction, microcephaly, and mild developmental delay; polyhydramnios; Velocardiofacial syndrome; Learning difficulties; diaphragmatic hernia; DiGeorge syndrome; congenital heart disease; cleft palate, polydactyly for Region: ISCA-37433-Loss
Publications for Region: ISCA-37433-Loss were changed from 15545748; 15889418; 20301696 to 15889418; 20301696; 15545748
Intellectual disability v2.402 ISCA-37446-Gain Louise Daugherty 22q11.2 recurrent (DGS/VCFS) region (proximal region, LCR22-A to -D) Gain was changed to 22q11.2 recurrent (DGS/VCFS) region (proximal, A-D) (includes TBX1) Gain
Added phenotypes intellectual disability and congenital abnormalities,Autism; chromosome 22q11.2 microduplication; 608363; heart defects, urogenital abnormalities, velopharyngeal insufficiency with or without cleft palate, and ranging from multiple defects to mild learning difficulties with some individuals being essentially normal for Region: ISCA-37446-Gain
Intellectual disability v2.402 ISCA-37446-Loss Louise Daugherty 22q11.2 recurrent (DGS/VCFS) region (proximal region, LCR22-A to -D) Loss was changed to 22q11.2 recurrent (DGS/VCFS) region (proximal, A-D) (includes TBX1) Loss
Added phenotypes neonatal hypocalcemia, which may present as tetany or seizures, due to hypoplasia of the parathyroid glands, and susceptibility to infection due to a deficit of T cells; micrognathia; clefting; Hearing deficits; Velocardiofacial syndrome; cardiac malformations; DiGeorge syndrome for Region: ISCA-37446-Loss
Intellectual disability v2.401 ISCA-37404-Gain Louise Daugherty Phenotypes for Region: ISCA-37404-Gain were changed from chromosome 15q11-q13 duplication syndrome; include autism, mental retardation, ataxia, seizures, developmental delays, and behavioral problems; 608636; elayed development and intellectual disability associated with abnormal behavior and dysmorphic facial features. Additional variable features may include thin corpus callosum on brain imaging and sleep disturbances. Carrier females may be mildly affected to chromosome 15q11-q13 duplication syndrome; include autism, mental retardation, ataxia, seizures, developmental delays, and behavioral problems; 608636; delayed development and intellectual disability associated with abnormal behavior and dysmorphic facial features. Additional variable features may include thin corpus callosum on brain imaging and sleep disturbances. Carrier females may be mildly affected
Intellectual disability v2.399 ISCA-37478-Gain Louise Daugherty GRCh38 position for ISCA-37478-Gain was changed from - to 23513243-28312040.
Haploinsufficiency Score for ISCA-37478-Gain was changed from to None.
Source ClinGen was removed from Region: ISCA-37478-Gain.
Source Other was added to Region: ISCA-37478-Gain.
Intellectual disability v2.398 ISCA-37404-Gain Louise Daugherty Region: ISCA-37404-Gain was added
Region: ISCA-37404-Gain was added to Intellectual disability. Sources: ClinGen,Expert Review Green
Mode of inheritance for Region: ISCA-37404-Gain was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for Region: ISCA-37404-Gain were set to 18374305; 16840569; 9106540
Phenotypes for Region: ISCA-37404-Gain were set to chromosome 15q11-q13 duplication syndrome; include autism, mental retardation, ataxia, seizures, developmental delays, and behavioral problems; 608636; elayed development and intellectual disability associated with abnormal behavior and dysmorphic facial features. Additional variable features may include thin corpus callosum on brain imaging and sleep disturbances. Carrier females may be mildly affected
Intellectual disability v2.398 ISCA-37418-Gain Louise Daugherty Region: ISCA-37418-Gain was added
Region: ISCA-37418-Gain was added to Intellectual disability. Sources: ClinGen,Expert Review Green
Mode of inheritance for Region: ISCA-37418-Gain was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for Region: ISCA-37418-Gain were set to infantile hypotonia, failure to thrive, mental retardation, autistic features, sleep apnea, and structural cardiovascular anomalies; 610883; characterized by hypotonia, poor feeding, failure to thrive, developmental delay, mild-moderate intellectual deficit, and neuropsychiatric disorders. Structural cardiovascular anomalies (dilated aortic root, bicommissural aortic valve, atrial/ventricular and septal defects) and sleep disturbance (obstructive and central sleep apnea) are also frequently associated
Intellectual disability v2.398 ISCA-37418-Loss Louise Daugherty Region: ISCA-37418-Loss was added
Region: ISCA-37418-Loss was added to Intellectual disability. Sources: ClinGen,Expert Review Green
Mode of inheritance for Region: ISCA-37418-Loss was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for Region: ISCA-37418-Loss were set to Potocki-Lupski syndrome; hypotonia, poor feeding, failure to thrive, developmental delay particularly cognitive and language deficity, mild-moderate intellectual deficit, and neuropsychiatric disorders; Smith-Magenis syndrome; Structural cardiovascular anomalies (dilated aortic root, bicommissural aortic valve, atrial/ventricular and septal defects) and sleep disturbance; 182290; moderate intellectual disability, delayed speech and language skills, distinctive facial features, sleep disturbances, and behavioral problems; hypotonia, failure to thrive, mental retardation, pervasive developmental disorders, congenital anomalies; Dental abnormalities
Intellectual disability v2.398 ISCA-37421-Gain Louise Daugherty Region: ISCA-37421-Gain was added
Region: ISCA-37421-Gain was added to Intellectual disability. Sources: ClinGen,Expert Review Green
Mode of inheritance for Region: ISCA-37421-Gain was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for Region: ISCA-37421-Gain were set to 3298277; 3817079
Phenotypes for Region: ISCA-37421-Gain were set to Chromosome 1q21.1 duplication syndrome; ncomplete penetrance and variable expression characterized by macrocephaly, developmental delay, intellectual disability, psychiatric disturbances (autism spectrum disorder, attention deficit hyperactivity disorder, schizophrenia, mood disorders) and mild facial dysmorphism (high forehead, hypertelorism). Other associated features include congenital heart defects, hypotonia, short stature, scoliosis; 612475; 1q21.1 microduplication syndrome
Intellectual disability v2.398 ISCA-37423-Gain Louise Daugherty Region: ISCA-37423-Gain was added
Region: ISCA-37423-Gain was added to Intellectual disability. Sources: ClinGen,Expert Review Green
Mode of inheritance for Region: ISCA-37423-Gain was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for Region: ISCA-37423-Gain were set to 21933911; 23345203
Phenotypes for Region: ISCA-37423-Gain were set to Behavioral problems, cleft lip and/or palate, macrocephaly, and seizures were confirmed as additional features among the new patients, and novel features included neonatal respiratory distress, attention deficit hyperactivity disorder (ADHD), ocular anomalies, balance problems, hypotonia, and hydrocele.; mild to moderate developmental delay, intellectual disability, mild facial dysmorphism (incl. prominent forehead, arched eyebrows, broad nasal bridge, upturned nares, cleft lip and/or palate) and congenital cardiac anomalies (e.g., atrioventricular septal defect). Other reported features include macrocephaly, behavioral abnormalities (e.g., attention deficit disorder), seizures, hypotonia and ocular and digital anomalies (poly/syndactyly); congenital heart disease; 8p23.1 duplication syndrome
Intellectual disability v2.398 ISCA-37423-Loss Louise Daugherty Region: ISCA-37423-Loss was added
Region: ISCA-37423-Loss was added to Intellectual disability. Sources: ClinGen,Expert Review Green
Mode of inheritance for Region: ISCA-37423-Loss was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for Region: ISCA-37423-Loss were set to 23239632; 20969981
Phenotypes for Region: ISCA-37423-Loss were set to prenatal and postnatal growth retardation, low birth weight, mild to moderate intellectual deficit, psychomotor retardation, poor speech, seizures, behavioral problems such as hyperactivity and impulsiveness. Frequent craniofacial abnormalities include microcephaly, high and narrow forehead, broad nasal bridge, epicanthic folds, high arched palate, short neck and low set unusually shaped ears. Furthermore congenital heart defects (atrioventricular, septal defects, pulmonary stenosis), congenital diaphragmatic hernia and in boys cryptorchidism and hypospadias have been frequently reported.; congenital heart defects, microcephaly, psychomotor delay and behavioural problems; hyperactivity, craniofacial abnormalities; 8p23.1 microdeletion syndrome; moderate intellectual disability
Intellectual disability v2.398 ISCA-37425-Gain Louise Daugherty Region: ISCA-37425-Gain was added
Region: ISCA-37425-Gain was added to Intellectual disability. Sources: ClinGen,Expert Review Green
Mode of inheritance for Region: ISCA-37425-Gain was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for Region: ISCA-37425-Gain were set to 23913520; 23599694
Phenotypes for Region: ISCA-37425-Gain were set to Microcephaly, short stature and developmental delay; short stature, microcephaly, learning disability or mild to moderate ID, and distinctive facial features comprising periorbital fullness, short palpebral fissures, a long nose with broad or long nasal tip, a smooth philtrum and a thin upper lip vermilion. Behavioral problems, ocular and minor hand anomalies may be associated.
Intellectual disability v2.398 ISCA-37430-Loss Louise Daugherty Region: ISCA-37430-Loss was added
Region: ISCA-37430-Loss was added to Intellectual disability. Sources: ClinGen,Expert Review Green
Mode of inheritance for Region: ISCA-37430-Loss was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for Region: ISCA-37430-Loss were set to microcephaly, dysgenesis of the corpus callosum, and cerebellar atrophy, as well as neurobehavioral disorders, including delayed development, mental retardation, and attention deficit-hyperactivity disorder. Patients with duplications of YWHAE tended to have macrosomia, facial dysmorphism, and mild developmental delay; growth restriction, craniofacial dysmorphisms, structural abnormalities of brain and cognitive impairment; Chromosome 17p13.3 duplication syndrome; prominent forehead, bitemporal hollowing, short nose with upturned nares, protuberant upper lip, thin vermilion border, and small jaw; Characteristic facies, pre- and post-natal growth retardation; 247200; classic lissencephaly (pachygyria, incomplete or absent gyration of the cerebrum), microcephaly, wrinkled skin over the glabella and frontal suture, prominent occiput, narrow forehead, downward slanting palpebral fissures, small nose and chin, cardiac malformations, hypoplastic male extrenal genitalia, growth retardation, and mental deficiency with seizures and EEG abnormalities; Miller-Dieker lissencephaly syndrome
Intellectual disability v2.398 ISCA-37432-Gain Louise Daugherty Region: ISCA-37432-Gain was added
Region: ISCA-37432-Gain was added to Intellectual disability. Sources: ClinGen,Expert Review Green
Mode of inheritance for Region: ISCA-37432-Gain was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for Region: ISCA-37432-Gain were set to developmental delay, mild to severe intellectual disability, speech delay, seizures, microcephaly, behavioral abnormalities, autism spectrum disorder, eye or vision defects (such as strabismus, astigmatism, amblyopia, cataract, coloboma, and microphthalmia), non-specific dysmorphic features, hypotonia, cardiac and renal anomalies, schizophrenia; Speech and language delay; Seizures (not all); Chromosome 17q12 duplication syndrome; 614526; Behavioural difficulties
Intellectual disability v2.398 ISCA-37433-Gain Louise Daugherty Region: ISCA-37433-Gain was added
Region: ISCA-37433-Gain was added to Intellectual disability. Sources: ClinGen,Expert Review Green
Mode of inheritance for Region: ISCA-37433-Gain was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for Region: ISCA-37433-Gain were set to 17250668; 20301749; 18414210
Phenotypes for Region: ISCA-37433-Gain were set to delayed psychomotor development, growth retardation, and/or hypotonia; dysmorphic facial features, cognitive deficits, velopharyngeal insufficiency, congenital heart defects and immunologic derangement; Chromosome 22q11.2 microduplication syndrome; 608363
Intellectual disability v2.398 ISCA-37433-Loss Louise Daugherty Region: ISCA-37433-Loss was added
Region: ISCA-37433-Loss was added to Intellectual disability. Sources: ClinGen,Expert Review Green
Mode of inheritance for Region: ISCA-37433-Loss was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for Region: ISCA-37433-Loss were set to 15545748; 15889418; 20301696
Phenotypes for Region: ISCA-37433-Loss were set to facial dysmorphic features, high frequency of cardiac defects, including conotruncal defects, prematurity, growth restriction, microcephaly, and mild developmental delay; diaphragmatic hernia; Learning difficulties; 192430; immune deficiency; congenital heart disease; 22q11.2 deletion syndrome; Velocardiofacial syndrome; DiGeorge syndrome; cleft palate, polydactyly; polyhydramnios; 188400; renal anomalies
Intellectual disability v2.398 ISCA-37446-Gain Louise Daugherty Region: ISCA-37446-Gain was added
Region: ISCA-37446-Gain was added to Intellectual disability. Sources: ClinGen,Expert Review Green
Mode of inheritance for Region: ISCA-37446-Gain was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for Region: ISCA-37446-Gain were set to 23044707; 22970919
Phenotypes for Region: ISCA-37446-Gain were set to chromosome 22q11.2 microduplication; heart defects, urogenital abnormalities, velopharyngeal insufficiency with or without cleft palate, and ranging from multiple defects to mild learning difficulties with some individuals being essentially normal; 608363; intellectual disability and congenital abnormalities,Autism
Intellectual disability v2.398 ISCA-37446-Loss Louise Daugherty Region: ISCA-37446-Loss was added
Region: ISCA-37446-Loss was added to Intellectual disability. Sources: ClinGen,Expert Review Green
Mode of inheritance for Region: ISCA-37446-Loss was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for Region: ISCA-37446-Loss were set to cardiac malformations; clefting; neonatal hypocalcemia, which may present as tetany or seizures, due to hypoplasia of the parathyroid glands, and susceptibility to infection due to a deficit of T cells; Velocardiofacial syndrome; DiGeorge syndrome; micrognathia; Hearing deficits
Intellectual disability v2.398 ISCA-37434-Loss Louise Daugherty Region: ISCA-37434-Loss was added
Region: ISCA-37434-Loss was added to Intellectual disability. Sources: ClinGen,Expert Review Green
Mode of inheritance for Region: ISCA-37434-Loss was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for Region: ISCA-37434-Loss were set to 17918734; 22766398; 18245432
Phenotypes for Region: ISCA-37434-Loss were set to posteriorly rotated, low-set, abnormal ears; brachycephaly; epicanthus; heart defects; pointed chin; deep-set eyes; microcephaly; hypotonia; seizures; poor/absent speech; central nervous system anomalies; large anterior fontanels; microbrachycephaly; mental retardation; growth impairment; large, late-closing anterior fontanel; flat nose; nasal bridge; developmental delay; hearing impairment; distinct dysmorphic features; 1p36 deletion syndrome; 607872
Intellectual disability v2.398 ISCA-37440-Loss Louise Daugherty Region: ISCA-37440-Loss was added
Region: ISCA-37440-Loss was added to Intellectual disability. Sources: ClinGen,Expert Review Green
Mode of inheritance for Region: ISCA-37440-Loss was set to BIALLELIC, autosomal or pseudoautosomal
Publications for Region: ISCA-37440-Loss were set to 11524703; 18234729; 16385448
Phenotypes for Region: ISCA-37440-Loss were set to mild/moderate mental retardation; facial dysmorphism; Hypotonia-cystinuria syndrome (HCS); 2p21 deletion syndrome; rapid weight gain in late childhood; failure to thrive; growth hormone deficiency; 606407; lactic acidemia; respiratory chain complex IV deficiency; hyperphagia; minor facial dysmorphism; severe somatic and developmental delay; nephrolithiasis; cystinuria; neonatal seizures; hypotonia
Intellectual disability v2.398 ISCA-37441-Loss Louise Daugherty Region: ISCA-37441-Loss was added
Region: ISCA-37441-Loss was added to Intellectual disability. Sources: ClinGen,Expert Review Green
Mode of inheritance for Region: ISCA-37441-Loss was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for Region: ISCA-37441-Loss were set to 15852040; 16319823; 20140962
Phenotypes for Region: ISCA-37441-Loss were set to Potocki-Shaffer syndrome; multiple exostoses; biparietal foramina; intellectual disability; strabismus; minor craniofacial anomalies; myopia; ophthalmologic anomalies; 601224; mental retardation; enlarged anterior fontanel; genital abnormalities in males; parietal foramina; developmental delay
Intellectual disability v2.398 ISCA-37443-Loss Louise Daugherty Region: ISCA-37443-Loss was added
Region: ISCA-37443-Loss was added to Intellectual disability. Sources: ClinGen,Expert Review Green
Mode of inheritance for Region: ISCA-37443-Loss was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for Region: ISCA-37443-Loss were set to . mild to moderate mental retardation, with only slightly dysmorphic facial features that were similar in most patients: long and narrow face, short philtrum, and high nasal bridge. Autism, gait ataxia, chest wall deformity, and long and tapering fingers were noted in at least 2 of the 6 patients. delayed psychomotor development with mild to moderate mental retardation and/or learning disabilities with speech delay. All had low birth weight, microcephaly, high nasal bridge, and short philtrum, and 3 had clinodactyly of the toes. primary pulmonary hypertension, patent ductus arteriosus (PDA), subvalvular aortic stenosis, and gastroesophageal reflux, and required neonatal intensive care for 57 days after birth due to complications of meconium aspiration. He had mild dysmorphic features, including posteriorly rotated ears, shallow orbits, frontal bossing, prominent nose, long thin lip, and broad face. He also had bilateral sandal gap toes, single palmar creases, and bilateral inguinal hernia. However, he was developmentally normal at age 6 months. delayed psychomotor development with delayed waking and poor motor skills, autism with speech delay, mental retardation, and psychiatric disturbances, including aggression, anxiety, hyperactivity, and bipolar disorder with psychosis in 1. Both had dysmorphic features, including high nasal bridge, asymmetric face, and crowded/dysplastic teeth; 1 had micrognathia and epicanthal folds. Both had tapered fingers. 609425; Chromosome 3q29 microdeletion syndrome
Intellectual disability v2.398 ISCA-37397-Gain Louise Daugherty Region: ISCA-37397-Gain was added
Region: ISCA-37397-Gain was added to Intellectual disability. Sources: ClinGen,Expert Review Green
Mode of inheritance for Region: ISCA-37397-Gain was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for Region: ISCA-37397-Gain were set to 18414210; 22140377; 19193630
Phenotypes for Region: ISCA-37397-Gain were set to seizures; failure to thrive; ADHD; heart defects; speech disturbances; hypernasal speech; hearing impariment; abnormal behaviour; developmental delay; hypotonia; micro- or macrocephaly
Intellectual disability v2.398 ISCA-37397-Loss Louise Daugherty Region: ISCA-37397-Loss was added
Region: ISCA-37397-Loss was added to Intellectual disability. Sources: ClinGen,Expert Review Green
Mode of inheritance for Region: ISCA-37397-Loss was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for Region: ISCA-37397-Loss were set to 21671380; 23765049; 18179902
Phenotypes for Region: ISCA-37397-Loss were set to diaphragmatic hernia; mild skeletal abnormalities; uterine didelphys; 611867; DiGeorge syndrome (DGS); clinodactyly; velocardiofacial syndrome; ADHD; Goldenhar syndrome; prematurity; developmental delay; micropephaly; cardiovascular defects; Seizures; global developmental delay; language delay; prenatal and postnatal growth delay; Hyptonia
Intellectual disability v2.398 ISCA-37393-Gain Louise Daugherty Region: ISCA-37393-Gain was added
Region: ISCA-37393-Gain was added to Intellectual disability. Sources: ClinGen,Expert Review Green
Mode of inheritance for Region: ISCA-37393-Gain was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for Region: ISCA-37393-Gain were set to 11693792; 22890013; 22495764
Phenotypes for Region: ISCA-37393-Gain were set to PMID 22890013: variable phenotype including developmental delay, ocular coloboma, preauricular tags/pits, cleft palate, skeletal defects, heart defects, urogenital defect, anal defect, hearing loss, clinodactyly of fifth fingers, umbilical hernia, accessory spleen, strabismus, shortening of the fifth finger. PMID 22495764: Inter and intra individual variability of phenotype, mosaic. PMID 11693792: preauricular skin tags and pits, downslanting palpebral fissures, hypertelorism, ectopic anus, hypospadias, and hypoplastic left heart syndrome; 115470
Intellectual disability v2.398 ISCA-37439-Gain Louise Daugherty Region: ISCA-37439-Gain was added
Region: ISCA-37439-Gain was added to Intellectual disability. Sources: ClinGen,Expert Review Green
Mode of inheritance for Region: ISCA-37439-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-37439-Gain were set to 17546640; 20004760; 18047645
Phenotypes for Region: ISCA-37439-Gain were set to 28300815; Chromosome Xq duplication syndrome
Intellectual disability v2.398 ISCA-37390-Loss Louise Daugherty Region: ISCA-37390-Loss was added
Region: ISCA-37390-Loss was added to Intellectual disability. Sources: ClinGen,Expert Review Green
Mode of inheritance for Region: ISCA-37390-Loss was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for Region: ISCA-37390-Loss were set to 11238681; 15635506
Phenotypes for Region: ISCA-37390-Loss were set to 123450; PMID 15635506: characteristic cry, speech delay, facial dysmorphology, and level of mental retardation. PMID 11238681: interstitial deletions and one with a small terminal deletion confirmed the existence of two critical regions, one for dysmorphism and mental retardation in p15.2 and the other for the cat cry in p15.3. Results from one patient permitted the cat cry region to be distally narrowed from D5S13 to D5S731, study supports hypothesis of a separate region in p15.3 for the speech delay
Intellectual disability v2.398 ISCA-37394-Loss Louise Daugherty Region: ISCA-37394-Loss was added
Region: ISCA-37394-Loss was added to Intellectual disability. Sources: ClinGen,Expert Review Green
Mode of inheritance for Region: ISCA-37394-Loss was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for Region: ISCA-37394-Loss were set to 25402011; 23188045
Phenotypes for Region: ISCA-37394-Loss were set to 2q37 deletion syndrome is a condition that can affect many parts of the body. This condition is characterized by weak muscle tone (hypotonia) in infancy, mild to severe intellectual disability and developmental delay, behavioral problems, characteristic facial features, and other physical abnormalities. PMID 23188045 brachydactyly-mental retardation syndrome, Albright hereditary osteodystrophy-like syndrome, developmental delay and behavioural abnormalities in combination; 600430
Intellectual disability v2.398 ISCA-37405-Loss Louise Daugherty Region: ISCA-37405-Loss was added
Region: ISCA-37405-Loss was added to Intellectual disability. Sources: ClinGen,Expert Review Green
Mode of inheritance for Region: ISCA-37405-Loss was set to BIALLELIC, autosomal or pseudoautosomal
Publications for Region: ISCA-37405-Loss were set to 9856524; 15138899; 8852662
Phenotypes for Region: ISCA-37405-Loss were set to juvenile nephronophthisis 1: including growth retardation. Joubert syndrome: multisystem disease characterized by cerebellar vermis hypoplasia with prominent superior cerebellar peduncles (resulting in the 'molar tooth sign,' or MTS, on axial MRI), mental retardation, hypotonia, irregular breathing pattern, and eye movement abnormalities; 266900; 609583
Intellectual disability v2.398 ISCA-37406-Loss Louise Daugherty Region: ISCA-37406-Loss was added
Region: ISCA-37406-Loss was added to Intellectual disability. Sources: ClinGen,Expert Review Green
Mode of inheritance for Region: ISCA-37406-Loss was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for Region: ISCA-37406-Loss were set to 10573006; 16783566
Phenotypes for Region: ISCA-37406-Loss were set to PMID: 10573006 death in infancy, accessory spleens, hypoplastic left heart, abnormal pulmonary lobulation, renal agenesis (patient 1), severe neonatal seizures (patient 2). PMID 16783566: failure to thrive, life-threatening malformations, and/or critical infections, and all died in infancy (5 weeks, 7 months, and 9 months, respectivelyFrom Genetics Home Reference: short stature, moderate to severe intellectual disability, distinctive facial features, and broad thumbs and first toes; 610543
Intellectual disability v2.398 ISCA-37408-Loss Louise Daugherty Region: ISCA-37408-Loss was added
Region: ISCA-37408-Loss was added to Intellectual disability. Sources: ClinGen,Expert Review Green
Mode of inheritance for Region: ISCA-37408-Loss was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for Region: ISCA-37408-Loss were set to 16963482; 22579565; 18245392
Phenotypes for Region: ISCA-37408-Loss were set to PMID: 16963482 idiopathic intellectual disability including moderate to severe intellectual disability, autism/autistic features, microcephaly, structural brain anomalies including cortical dysplasia/pachygyria, renal anomalies (multicystic kidney, hydronephrosis), digital camptodactyly, visual impairment, strabismus, neuromotor deficits, communication and attention impairments, and a distinctive pattern of craniofacial features. Dysmorphic craniofacial features include progressive microcephaly, flat occiput, widened inner canthal distance, small palpebral fissures, ptosis, long and straight eyelashes, broad and high nasal root extending to a widened, prominent nasal tip with elongated, smooth philtrum, rounding of the upper vermillion border and everted lower lips. PMID: 18245392 A 32-year-old, mentally retarded male was referred to our centre for further clinical genetic analysis. He was born to non-consanguineous parents after 42 weeks gestation with a birth weight of 3500 g. He had a healthy older brother. In the neonatal period he was hypotonic and at 8 weeks of age he underwent surgery because of an inguinal hernia with removal of an atrophic right testis. His motor development was severely delayed with sitting at 3.5 years and walking at 5 years of age. Speech was poorly developed, characterised by the usage of only a few words. During infancy an optic nerve hypoplasia was diagnosed, and during childhood he frequently suffered from luxations of the patellae, which required surgery. At the age of 32 years his height is 163 cm (_3 SDS) and head circumference 52.5 cm (_2.5 SDS). He has a narrow receding forehead, widened inner canthal distance of 3.5 cm (90th centile), normal outer canthal distance of 8.5 cm (25th centile), telecanthus, short and down slanting palpebral fissures, epicanthal folds, ptosis, long, straight eyelashes, high nasal bridge, low set large ears, flat philtrum, small mouth with high, narrow palate and retrognathia. The thorax is broad with increased internipple distance and slight gynaecomastia. A recent renal ultrasound revealed multiple cysts in the left, dystrophic kidney and two uncomplicated cysts in the enlarged, right kidney. The patient has a normally sized phallus with absent right testis and small left testis. His hands show a simian crease right and tapering fingers with broad proximal interphalangeal joints. He shows sandal gaps on both flat feet with clinodactyly of the fourth and fifth toes (and more); 612513; PMID: 22579565 severe developmental delay, congenital microcephaly, intractable epilepsy, and renal anomalies, as well as a congenital choledochal cyst which has not been previously reported in other patients with this cytogenetic defect
Intellectual disability v2.398 ISCA-37411-Loss Louise Daugherty Region: ISCA-37411-Loss was added
Region: ISCA-37411-Loss was added to Intellectual disability. Sources: ClinGen,Expert Review Green
Mode of inheritance for Region: ISCA-37411-Loss was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for Region: ISCA-37411-Loss were set to 19289393; 19136953; 18278044
Phenotypes for Region: ISCA-37411-Loss were set to PMID: 19289393 incomplete penetrance for developmental delay, mental retardation, or borderline IQ in most and autistic spectrum disorder (6/14), speech delay, aggressiveness, attention deficit hyperactivity disorder, and other behavioural problems; 612001; PMID: 18278044 mental retardation, epilepsy and variable facial and digital dysmorphisms; PMID: 19136953 idiopathic generalized epilepsy without other features previously associated with 15q13.3 microdeletions, such as intellectual disability, autism or schizophrenia
Intellectual disability v2.398 ISCA-37415-Loss Louise Daugherty Region: ISCA-37415-Loss was added
Region: ISCA-37415-Loss was added to Intellectual disability. Sources: ClinGen,Expert Review Green
Mode of inheritance for Region: ISCA-37415-Loss was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for Region: ISCA-37415-Loss were set to 19843651; 18550696; 24246141
Phenotypes for Region: ISCA-37415-Loss were set to PMID: 18550696 Phenotypic variability, common features were identified: mental retardation, microcephaly and epilepsy in three patients, two of these had also short stature, and two other deletion carriers ascertained prenatally presented with cleft lip and midline defects
Intellectual disability v2.398 ISCA-37420-Loss Louise Daugherty Region: ISCA-37420-Loss was added
Region: ISCA-37420-Loss was added to Intellectual disability. Sources: ClinGen,Expert Review Green
Mode of inheritance for Region: ISCA-37420-Loss was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for Region: ISCA-37420-Loss were set to 25217958; 18628315
Phenotypes for Region: ISCA-37420-Loss were set to PMID: 18628315 developmental delay, hypotonia, facial dysmorphisms including a long face, a tubular or pear-shaped nose and a bulbous nasal tip, and a friendly/amiable behaviour, other clinically important features include epilepsy, heart defects and kidney/urologic anomalies; 610443; PMID: 25217958; Koolen-De Vries syndrome 610443
Intellectual disability v2.398 ISCA-37424-Loss Louise Daugherty Region: ISCA-37424-Loss was added
Region: ISCA-37424-Loss was added to Intellectual disability. Sources: ClinGen,Expert Review Green
Mode of inheritance for Region: ISCA-37424-Loss was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for Region: ISCA-37424-Loss were set to 25217958; 20345475; 21248748; 24550761
Phenotypes for Region: ISCA-37424-Loss were set to PMID 20345475 macrocephaly, hypertelorism, and arachnodactyly, and neurodevelopmental delay that includes failure to thrive, hypotonia, and feeding difficulties in the neonatal period, and receptive and expressive language delay with global neurodevelopmental delay after the neonatal period. PMID: 21248748 developmental delay, mainly affecting speech. In addition, macrocephaly, mild facial dysmorphisms, cerebellar anomalies, cardiac defects and congenital breast aplasia; PMID: 25217958 none specified; PMID: 24550761 age-appropriate language development evaluated by a standardized test at an age of 2 years and 3 months. The boy was born with a cleft palate - a feature not present in any of the patients described before, phenotype of patients with an LCR3/4-flanked 10q22.3q23.2 deletion can be rather variable
Intellectual disability v2.398 ISCA-37425-Loss Louise Daugherty Region: ISCA-37425-Loss was added
Region: ISCA-37425-Loss was added to Intellectual disability. Sources: ClinGen,Expert Review Green
Mode of inheritance for Region: ISCA-37425-Loss was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for Region: ISCA-37425-Loss were set to macrocephaly, overgrowth and advanced bone age; colpocephaly; Sotos syndrome; macrocephaly; 117550; rapid growth, acromegalic features, and a nonprogressive cerebral disorder with mental retardation. High-arched palate and prominent jaw
Intellectual disability v2.398 ISCA-37493-Loss Louise Daugherty Region: ISCA-37493-Loss was added
Region: ISCA-37493-Loss was added to Intellectual disability. Sources: ClinGen,Expert Review Green
Mode of inheritance for Region: ISCA-37493-Loss was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for Region: ISCA-37493-Loss were set to 21800092; 17603806; 22678713
Phenotypes for Region: ISCA-37493-Loss were set to microcephaly; seizures; agenesis of the corpus callosum; intellectual disability; hand and foot anomalies; 612337; non-specific craniofacial anomalies; hypoplasia; psychomotor retardation; hypogenesis of the corpus callosum
Intellectual disability v2.398 ISCA-46295-Loss Louise Daugherty Region: ISCA-46295-Loss was added
Region: ISCA-46295-Loss was added to Intellectual disability. Sources: ClinGen,Expert Review Green
Mode of inheritance for Region: ISCA-46295-Loss was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for Region: ISCA-46295-Loss were set to 19898479; 20236110; 22775350
Phenotypes for Region: ISCA-46295-Loss were set to seizures; 20236110; mental retardation; 22775350; dysmorphic features; developmental delay; severe epileptic encephalopathy
Intellectual disability IRF2BPL Konstantinos Varvagiannis edited their review of gene: IRF2BPL
Intellectual disability SYT1 Louise Daugherty edited their review of gene: SYT1
Intellectual disability CDKN1C Louise Daugherty edited their review of gene: CDKN1C
Intellectual disability TBC1D7 Konstantinos Varvagiannis edited their review of gene: TBC1D7
Intellectual disability ALX4 Louise Daugherty edited their review of gene: ALX4
Intellectual disability CA2 Louise Daugherty edited their review of gene: CA2
Intellectual disability COQ5 Louise Daugherty edited their review of gene: COQ5
Intellectual disability GBA Louise Daugherty edited their review of gene: GBA
Intellectual disability GSPT2 Louise Daugherty edited their review of gene: GSPT2
Intellectual disability HNRNPK Louise Daugherty edited their review of gene: HNRNPK
Intellectual disability IGF1R Louise Daugherty edited their review of gene: IGF1R
Intellectual disability IGF1R Louise Daugherty edited their review of gene: IGF1R
Intellectual disability NRXN2 Louise Daugherty edited their review of gene: NRXN2
Intellectual disability ALS2 Louise Daugherty edited their review of gene: ALS2
Intellectual disability MSL3 Louise Daugherty edited their review of gene: MSL3
Intellectual disability ORC4 Louise Daugherty edited their review of gene: ORC4
Intellectual disability PDGFRB Louise Daugherty edited their review of gene: PDGFRB
Intellectual disability PDGFRB Louise Daugherty edited their review of gene: PDGFRB
Intellectual disability NAA15 Louise Daugherty edited their review of gene: NAA15
Intellectual disability RBBP8 Louise Daugherty edited their review of gene: RBBP8
Intellectual disability RANBP2 Louise Daugherty edited their review of gene: RANBP2
Intellectual disability PRRT2 Louise Daugherty edited their review of gene: PRRT2
Intellectual disability PRRT2 Louise Daugherty edited their review of gene: PRRT2
Intellectual disability PRRT2 Louise Daugherty edited their review of gene: PRRT2
Intellectual disability PRRT2 Louise Daugherty edited their review of gene: PRRT2
Intellectual disability ARV1 Louise Daugherty edited their review of gene: ARV1
Intellectual disability LYST Louise Daugherty edited their review of gene: LYST
Intellectual disability SETD1B Louise Daugherty edited their review of gene: SETD1B
Intellectual disability LYST Louise Daugherty edited their review of gene: LYST
Intellectual disability SLC22A5 Louise Daugherty edited their review of gene: SLC22A5
Intellectual disability SLC25A20 Louise Daugherty edited their review of gene: SLC25A20
Intellectual disability THAP1 Louise Daugherty classified THAP1 as Red List (low evidence)
Intellectual disability THAP1 Louise Daugherty commented on gene: THAP1
Intellectual disability TIMM8A Louise Daugherty edited their review of gene: TIMM8A
Intellectual disability TRIM37 Louise Daugherty edited their review of gene: TRIM37
Intellectual disability SLC35A1 Louise Daugherty edited their review of gene: SLC35A1
Intellectual disability SRPX2 Louise Daugherty edited their review of gene: SRPX2
Intellectual disability TCF20 Louise Daugherty edited their review of gene: TCF20
Intellectual disability TGDS Louise Daugherty edited their review of gene: TGDS
Intellectual disability THAP1 Louise Daugherty reviewed gene: THAP1
Intellectual disability THAP1 Zornitza Stark reviewed gene: THAP1
Intellectual disability C9orf72 Ellen McDonagh edited their review of STR: C9orf72_GGGGCC
Intellectual disability WDR4 Ellen McDonagh edited their review of WDR4
Intellectual disability RUBCN Olivia Niblock edited their review of RUBCN
Intellectual disability NDN Sarah Leigh edited their review of NDN
Intellectual disability AKAP6 Louise Daugherty edited their review of AKAP6
Intellectual disability SETD1A Louise Daugherty edited their review of SETD1A
Intellectual disability GRIN1 Louise Daugherty edited their review of GRIN1
Intellectual disability A2ML1 Louise Daugherty edited their review of A2ML1
Intellectual disability PIK3CA Louise Daugherty edited their review of PIK3CA
Intellectual disability AMER1 Helen Brittain edited their review of AMER1
Intellectual disability PIK3CA Louise Daugherty edited their review of PIK3CA
Intellectual disability PCDH12 Ellen McDonagh edited their review of PCDH12
Intellectual disability OR5M1 Louise Daugherty edited their review of OR5M1
Intellectual disability PCDH19 Louise Daugherty edited their review of PCDH19
Intellectual disability FAM58A Louise Daugherty edited their review of FAM58A
Intellectual disability HTT Ellen McDonagh edited their review of HTT
Intellectual disability C4orf26 Louise Daugherty edited their review of C4orf26
Intellectual disability YY1 Sarah Leigh edited their review of YY1
Intellectual disability YY1 Sarah Leigh edited their review of YY1
Intellectual disability MEF2C Louise Daugherty edited their review of MEF2C
Intellectual disability OTUD6B Louise Daugherty edited their review of OTUD6B
Intellectual disability PPM1D Louise Daugherty edited their review of PPM1D
Intellectual disability LGI4 Louise Daugherty edited their review of LGI4
Intellectual disability PLAA Rebecca Foulger edited their review of PLAA
Intellectual disability RNU4ATAC Louise Daugherty edited their review of RNU4ATAC
Intellectual disability ZNF711 BRIDGE consortium edited their review of ZNF711
Intellectual disability ZNF148 BRIDGE consortium edited their review of ZNF148
Intellectual disability ZMPSTE24 BRIDGE consortium edited their review of ZMPSTE24
Intellectual disability ZIC3 BRIDGE consortium edited their review of ZIC3
Intellectual disability ZIC2 BRIDGE consortium edited their review of ZIC2
Intellectual disability ZIC1 BRIDGE consortium edited their review of ZIC1
Intellectual disability ZFYVE26 BRIDGE consortium edited their review of ZFYVE26
Intellectual disability ZFP57 BRIDGE consortium edited their review of ZFP57
Intellectual disability ZEB2 BRIDGE consortium edited their review of ZEB2
Intellectual disability ZDHHC9 BRIDGE consortium edited their review of ZDHHC9
Intellectual disability ZC4H2 BRIDGE consortium edited their review of ZC4H2
Intellectual disability ZBTB20 BRIDGE consortium edited their review of ZBTB20
Intellectual disability ZBTB18 BRIDGE consortium edited their review of ZBTB18
Intellectual disability XYLT1 BRIDGE consortium edited their review of XYLT1
Intellectual disability XRCC4 BRIDGE consortium edited their review of XRCC4
Intellectual disability XPC BRIDGE consortium edited their review of XPC
Intellectual disability XPA BRIDGE consortium edited their review of XPA
Intellectual disability WWOX BRIDGE consortium edited their review of WWOX
Intellectual disability WT1 BRIDGE consortium edited their review of WT1
Intellectual disability WRAP53 BRIDGE consortium edited their review of WRAP53
Intellectual disability WNT7A BRIDGE consortium edited their review of WNT7A
Intellectual disability WNT5A BRIDGE consortium edited their review of WNT5A
Intellectual disability WNT3 BRIDGE consortium edited their review of WNT3
Intellectual disability WNT10B BRIDGE consortium edited their review of WNT10B
Intellectual disability WNT1 BRIDGE consortium edited their review of WNT1
Intellectual disability WDR62 BRIDGE consortium edited their review of WDR62
Intellectual disability WDR60 BRIDGE consortium edited their review of WDR60
Intellectual disability WDR45 BRIDGE consortium edited their review of WDR45
Intellectual disability WDR35 BRIDGE consortium edited their review of WDR35
Intellectual disability WDR34 BRIDGE consortium edited their review of WDR34
Intellectual disability WDR19 BRIDGE consortium edited their review of WDR19
Intellectual disability WDR11 BRIDGE consortium edited their review of WDR11
Intellectual disability WDPCP BRIDGE consortium edited their review of WDPCP
Intellectual disability WAC BRIDGE consortium edited their review of WAC
Intellectual disability VSX2 BRIDGE consortium edited their review of VSX2
Intellectual disability VPS35 BRIDGE consortium edited their review of VPS35
Intellectual disability VPS33B BRIDGE consortium edited their review of VPS33B
Intellectual disability VPS13B BRIDGE consortium edited their review of VPS13B
Intellectual disability VLDLR BRIDGE consortium edited their review of VLDLR
Intellectual disability VIPAS39 BRIDGE consortium edited their review of VIPAS39
Intellectual disability VDR BRIDGE consortium edited their review of VDR
Intellectual disability VAMP1 BRIDGE consortium edited their review of VAMP1
Intellectual disability UVSSA BRIDGE consortium edited their review of UVSSA
Intellectual disability USB1 BRIDGE consortium edited their review of USB1
Intellectual disability UROS BRIDGE consortium edited their review of UROS
Intellectual disability UROC1 BRIDGE consortium edited their review of UROC1
Intellectual disability UPF3B BRIDGE consortium edited their review of UPF3B
Intellectual disability UNC80 BRIDGE consortium edited their review of UNC80
Intellectual disability UMPS BRIDGE consortium edited their review of UMPS
Intellectual disability UGT1A1 BRIDGE consortium edited their review of UGT1A1
Intellectual disability UBR1 BRIDGE consortium edited their review of UBR1
Intellectual disability UBE3B BRIDGE consortium edited their review of UBE3B
Intellectual disability UBE3A BRIDGE consortium edited their review of UBE3A
Intellectual disability UBE2A BRIDGE consortium edited their review of UBE2A
Intellectual disability UBA5 BRIDGE consortium edited their review of UBA5
Intellectual disability TYRP1 BRIDGE consortium edited their review of TYRP1
Intellectual disability TYR BRIDGE consortium edited their review of TYR
Intellectual disability TXNL4A BRIDGE consortium edited their review of TXNL4A
Intellectual disability TWIST2 BRIDGE consortium edited their review of TWIST2
Intellectual disability TWIST1 BRIDGE consortium edited their review of TWIST1
Intellectual disability TUSC3 BRIDGE consortium edited their review of TUSC3
Intellectual disability TUBGCP6 BRIDGE consortium edited their review of TUBGCP6
Intellectual disability TUBB4A BRIDGE consortium edited their review of TUBB4A
Intellectual disability TUBB2B BRIDGE consortium edited their review of TUBB2B
Intellectual disability TUBB2A BRIDGE consortium edited their review of TUBB2A
Intellectual disability TUBB BRIDGE consortium edited their review of TUBB
Intellectual disability TUBA8 BRIDGE consortium edited their review of TUBA8
Intellectual disability TUBA1A BRIDGE consortium edited their review of TUBA1A
Intellectual disability TTPA BRIDGE consortium edited their review of TTPA
Intellectual disability TTC8 BRIDGE consortium edited their review of TTC8
Intellectual disability TTC7A BRIDGE consortium edited their review of TTC7A
Intellectual disability TTC37 BRIDGE consortium edited their review of TTC37
Intellectual disability TTC19 BRIDGE consortium edited their review of TTC19
Intellectual disability TTBK2 BRIDGE consortium edited their review of TTBK2
Intellectual disability TSPAN7 BRIDGE consortium edited their review of TSPAN7
Intellectual disability TSHR BRIDGE consortium edited their review of TSHR
Intellectual disability TSHB BRIDGE consortium edited their review of TSHB
Intellectual disability TSEN54 BRIDGE consortium edited their review of TSEN54
Intellectual disability TSC2 BRIDGE consortium edited their review of TSC2
Intellectual disability TSC1 BRIDGE consortium edited their review of TSC1
Intellectual disability TRPV4 BRIDGE consortium edited their review of TRPV4
Intellectual disability TRPS1 BRIDGE consortium edited their review of TRPS1
Intellectual disability TRPM1 BRIDGE consortium edited their review of TRPM1
Intellectual disability TRMT10A BRIDGE consortium edited their review of TRMT10A
Intellectual disability TRIP12 BRIDGE consortium edited their review of TRIP12
Intellectual disability TRIP11 BRIDGE consortium edited their review of TRIP11
Intellectual disability TRIO BRIDGE consortium edited their review of TRIO
Intellectual disability TRIM37 BRIDGE consortium edited their review of TRIM37
Intellectual disability TRIM32 BRIDGE consortium edited their review of TRIM32
Intellectual disability TREX1 BRIDGE consortium edited their review of TREX1
Intellectual disability TRAPPC9 BRIDGE consortium edited their review of TRAPPC9
Intellectual disability TRAPPC2 BRIDGE consortium edited their review of TRAPPC2
Intellectual disability TPP1 BRIDGE consortium edited their review of TPP1
Intellectual disability TP63 BRIDGE consortium edited their review of TP63
Intellectual disability TOR1A BRIDGE consortium edited their review of TOR1A
Intellectual disability TOE1 BRIDGE consortium edited their review of TOE1
Intellectual disability TMPRSS6 BRIDGE consortium edited their review of TMPRSS6
Intellectual disability TMEM70 BRIDGE consortium edited their review of TMEM70
Intellectual disability TMEM67 BRIDGE consortium edited their review of TMEM67
Intellectual disability TMEM5 BRIDGE consortium edited their review of TMEM5
Intellectual disability TMEM240 BRIDGE consortium edited their review of TMEM240
Intellectual disability TMEM237 BRIDGE consortium edited their review of TMEM237
Intellectual disability TMEM165 BRIDGE consortium edited their review of TMEM165
Intellectual disability TMEM126B BRIDGE consortium edited their review of TMEM126B
Intellectual disability TMCO1 BRIDGE consortium edited their review of TMCO1
Intellectual disability TK2 BRIDGE consortium edited their review of TK2
Intellectual disability TINF2 BRIDGE consortium edited their review of TINF2
Intellectual disability TIMM8A BRIDGE consortium edited their review of TIMM8A
Intellectual disability THRA BRIDGE consortium edited their review of THRA
Intellectual disability THAP1 BRIDGE consortium edited their review of THAP1
Intellectual disability TH BRIDGE consortium edited their review of TH
Intellectual disability TGM6 BRIDGE consortium edited their review of TGM6
Intellectual disability TGIF1 BRIDGE consortium edited their review of TGIF1
Intellectual disability TGFBR2 BRIDGE consortium edited their review of TGFBR2
Intellectual disability TGFBR1 BRIDGE consortium edited their review of TGFBR1
Intellectual disability TGFB3 BRIDGE consortium edited their review of TGFB3
Intellectual disability TGFB2 BRIDGE consortium edited their review of TGFB2
Intellectual disability TGFB1 BRIDGE consortium edited their review of TGFB1
Intellectual disability TGDS BRIDGE consortium edited their review of TGDS
Intellectual disability TFG BRIDGE consortium edited their review of TFG
Intellectual disability TFAP2B BRIDGE consortium edited their review of TFAP2B
Intellectual disability TFAP2A BRIDGE consortium edited their review of TFAP2A
Intellectual disability TERT BRIDGE consortium edited their review of TERT
Intellectual disability TEK BRIDGE consortium edited their review of TEK
Intellectual disability TECPR2 BRIDGE consortium edited their review of TECPR2
Intellectual disability TCTN3 BRIDGE consortium edited their review of TCTN3
Intellectual disability TCOF1 BRIDGE consortium edited their review of TCOF1
Intellectual disability TCN2 BRIDGE consortium edited their review of TCN2
Intellectual disability TCF4 BRIDGE consortium edited their review of TCF4
Intellectual disability TCF20 BRIDGE consortium edited their review of TCF20
Intellectual disability TCF12 BRIDGE consortium edited their review of TCF12
Intellectual disability TBXAS1 BRIDGE consortium edited their review of TBXAS1
Intellectual disability TBX5 BRIDGE consortium edited their review of TBX5
Intellectual disability TBX4 BRIDGE consortium edited their review of TBX4
Intellectual disability TBX3 BRIDGE consortium edited their review of TBX3
Intellectual disability TBX22 BRIDGE consortium edited their review of TBX22
Intellectual disability TBX20 BRIDGE consortium edited their review of TBX20
Intellectual disability TBX15 BRIDGE consortium edited their review of TBX15
Intellectual disability TBX1 BRIDGE consortium edited their review of TBX1
Intellectual disability TBP BRIDGE consortium edited their review of TBP
Intellectual disability TBCK BRIDGE consortium edited their review of TBCK
Intellectual disability TBCE BRIDGE consortium edited their review of TBCE
Intellectual disability TBCD BRIDGE consortium edited their review of TBCD
Intellectual disability TBC1D24 BRIDGE consortium edited their review of TBC1D24
Intellectual disability TAZ BRIDGE consortium edited their review of TAZ
Intellectual disability TAT BRIDGE consortium edited their review of TAT
Intellectual disability TARDBP BRIDGE consortium edited their review of TARDBP
Intellectual disability TANGO2 BRIDGE consortium edited their review of TANGO2
Intellectual disability TAF1 BRIDGE consortium edited their review of TAF1
Intellectual disability TAB2 BRIDGE consortium edited their review of TAB2
Intellectual disability SYP BRIDGE consortium edited their review of SYP
Intellectual disability SYNJ1 BRIDGE consortium edited their review of SYNJ1
Intellectual disability SYNGAP1 BRIDGE consortium edited their review of SYNGAP1
Intellectual disability SYNE1 BRIDGE consortium edited their review of SYNE1
Intellectual disability SURF1 BRIDGE consortium edited their review of SURF1
Intellectual disability SUMF1 BRIDGE consortium edited their review of SUMF1
Intellectual disability SUCLG1 BRIDGE consortium edited their review of SUCLG1
Intellectual disability STXBP1 BRIDGE consortium edited their review of STXBP1
Intellectual disability STX1B BRIDGE consortium edited their review of STX1B
Intellectual disability STUB1 BRIDGE consortium edited their review of STUB1
Intellectual disability STS BRIDGE consortium edited their review of STS
Intellectual disability STRADA BRIDGE consortium edited their review of STRADA
Intellectual disability STRA6 BRIDGE consortium edited their review of STRA6
Intellectual disability STIL BRIDGE consortium edited their review of STIL
Intellectual disability STAT1 BRIDGE consortium edited their review of STAT1
Intellectual disability STAR BRIDGE consortium edited their review of STAR
Intellectual disability STAMBP BRIDGE consortium edited their review of STAMBP
Intellectual disability STAG1 BRIDGE consortium edited their review of STAG1
Intellectual disability ST3GAL5 BRIDGE consortium edited their review of ST3GAL5
Intellectual disability ST3GAL3 BRIDGE consortium edited their review of ST3GAL3
Intellectual disability SRY BRIDGE consortium edited their review of SRY
Intellectual disability SRD5A3 BRIDGE consortium edited their review of SRD5A3
Intellectual disability SRCAP BRIDGE consortium edited their review of SRCAP
Intellectual disability SPTLC2 BRIDGE consortium edited their review of SPTLC2
Intellectual disability SPTBN2 BRIDGE consortium edited their review of SPTBN2
Intellectual disability SPTAN1 BRIDGE consortium edited their review of SPTAN1
Intellectual disability SPRED1 BRIDGE consortium edited their review of SPRED1
Intellectual disability SPR BRIDGE consortium edited their review of SPR
Intellectual disability SPG7 BRIDGE consortium edited their review of SPG7
Intellectual disability SPG21 BRIDGE consortium edited their review of SPG21
Intellectual disability SPG20 BRIDGE consortium edited their review of SPG20
Intellectual disability SPG11 BRIDGE consortium edited their review of SPG11
Intellectual disability SPEG BRIDGE consortium edited their review of SPEG
Intellectual disability SPATA5 BRIDGE consortium edited their review of SPATA5
Intellectual disability SPAST BRIDGE consortium edited their review of SPAST
Intellectual disability SPAG1 BRIDGE consortium edited their review of SPAG1
Intellectual disability SOX9 BRIDGE consortium edited their review of SOX9
Intellectual disability SOX3 BRIDGE consortium edited their review of SOX3
Intellectual disability SOX2 BRIDGE consortium edited their review of SOX2
Intellectual disability SOX17 BRIDGE consortium edited their review of SOX17
Intellectual disability SOX10 BRIDGE consortium edited their review of SOX10
Intellectual disability SOS1 BRIDGE consortium edited their review of SOS1
Intellectual disability SON BRIDGE consortium edited their review of SON
Intellectual disability SNX14 BRIDGE consortium edited their review of SNX14
Intellectual disability SNRPB BRIDGE consortium edited their review of SNRPB
Intellectual disability SNORD118 BRIDGE consortium edited their review of SNORD118
Intellectual disability SNCA BRIDGE consortium edited their review of SNCA
Intellectual disability SMPD1 BRIDGE consortium edited their review of SMPD1
Intellectual disability SMOC1 BRIDGE consortium edited their review of SMOC1
Intellectual disability SMO BRIDGE consortium edited their review of SMO
Intellectual disability SMCHD1 BRIDGE consortium edited their review of SMCHD1
Intellectual disability SMC3 BRIDGE consortium edited their review of SMC3
Intellectual disability SMC1A BRIDGE consortium edited their review of SMC1A
Intellectual disability SMARCB1 BRIDGE consortium edited their review of SMARCB1
Intellectual disability SMARCAL1 BRIDGE consortium edited their review of SMARCAL1
Intellectual disability SMARCA4 BRIDGE consortium edited their review of SMARCA4
Intellectual disability SMARCA2 BRIDGE consortium edited their review of SMARCA2
Intellectual disability SMAD4 BRIDGE consortium edited their review of SMAD4
Intellectual disability SMAD3 BRIDGE consortium edited their review of SMAD3
Intellectual disability SLX4 BRIDGE consortium edited their review of SLX4
Intellectual disability SLC9A6 BRIDGE consortium edited their review of SLC9A6
Intellectual disability SLC6A8 BRIDGE consortium edited their review of SLC6A8
Intellectual disability SLC6A5 BRIDGE consortium edited their review of SLC6A5
Intellectual disability SLC6A3 BRIDGE consortium edited their review of SLC6A3
Intellectual disability SLC6A19 BRIDGE consortium edited their review of SLC6A19
Intellectual disability SLC6A17 BRIDGE consortium edited their review of SLC6A17
Intellectual disability SLC6A1 BRIDGE consortium edited their review of SLC6A1
Intellectual disability SLC5A5 BRIDGE consortium edited their review of SLC5A5
Intellectual disability SLC52A3 BRIDGE consortium edited their review of SLC52A3
Intellectual disability SLC4A4 BRIDGE consortium edited their review of SLC4A4
Intellectual disability SLC4A11 BRIDGE consortium edited their review of SLC4A11
Intellectual disability SLC4A1 BRIDGE consortium edited their review of SLC4A1
Intellectual disability SLC46A1 BRIDGE consortium edited their review of SLC46A1
Intellectual disability SLC39A8 BRIDGE consortium edited their review of SLC39A8
Intellectual disability SLC39A13 BRIDGE consortium edited their review of SLC39A13
Intellectual disability SLC35D1 BRIDGE consortium edited their review of SLC35D1
Intellectual disability SLC35C1 BRIDGE consortium edited their review of SLC35C1
Intellectual disability SLC35A2 BRIDGE consortium edited their review of SLC35A2
Intellectual disability SLC33A1 BRIDGE consortium edited their review of SLC33A1
Intellectual disability SLC2A2 BRIDGE consortium edited their review of SLC2A2
Intellectual disability SLC2A10 BRIDGE consortium edited their review of SLC2A10
Intellectual disability SLC2A1 BRIDGE consortium edited their review of SLC2A1
Intellectual disability SLC27A4 BRIDGE consortium edited their review of SLC27A4
Intellectual disability SLC26A2 BRIDGE consortium edited their review of SLC26A2
Intellectual disability SLC25A38 BRIDGE consortium edited their review of SLC25A38
Intellectual disability SLC25A26 BRIDGE consortium edited their review of SLC25A26
Intellectual disability SLC25A22 BRIDGE consortium edited their review of SLC25A22
Intellectual disability SLC25A20 BRIDGE consortium edited their review of SLC25A20
Intellectual disability SLC25A15 BRIDGE consortium edited their review of SLC25A15
Intellectual disability SLC22A5 BRIDGE consortium edited their review of SLC22A5
Intellectual disability SLC20A2 BRIDGE consortium edited their review of SLC20A2
Intellectual disability SLC19A3 BRIDGE consortium edited their review of SLC19A3
Intellectual disability SLC17A5 BRIDGE consortium edited their review of SLC17A5
Intellectual disability SLC16A2 BRIDGE consortium edited their review of SLC16A2
Intellectual disability SLC13A5 BRIDGE consortium edited their review of SLC13A5
Intellectual disability SLC12A6 BRIDGE consortium edited their review of SLC12A6
Intellectual disability SKIV2L BRIDGE consortium edited their review of SKIV2L
Intellectual disability SKI BRIDGE consortium edited their review of SKI
Intellectual disability SIX5 BRIDGE consortium edited their review of SIX5
Intellectual disability SIX3 BRIDGE consortium edited their review of SIX3
Intellectual disability SIX1 BRIDGE consortium edited their review of SIX1
Intellectual disability SIN3A BRIDGE consortium edited their review of SIN3A
Intellectual disability SIL1 BRIDGE consortium edited their review of SIL1
Intellectual disability SIK1 BRIDGE consortium edited their review of SIK1
Intellectual disability SIGMAR1 BRIDGE consortium edited their review of SIGMAR1
Intellectual disability SHOX BRIDGE consortium edited their review of SHOX
Intellectual disability SHOC2 BRIDGE consortium edited their review of SHOC2
Intellectual disability SHH BRIDGE consortium edited their review of SHH
Intellectual disability SHANK3 BRIDGE consortium edited their review of SHANK3
Intellectual disability SH3TC2 BRIDGE consortium edited their review of SH3TC2
Intellectual disability SH3PXD2B BRIDGE consortium edited their review of SH3PXD2B
Intellectual disability SGSH BRIDGE consortium edited their review of SGSH
Intellectual disability SGCE BRIDGE consortium edited their review of SGCE
Intellectual disability SF3B4 BRIDGE consortium edited their review of SF3B4
Intellectual disability SETX BRIDGE consortium edited their review of SETX
Intellectual disability SETD5 BRIDGE consortium edited their review of SETD5
Intellectual disability SETBP1 BRIDGE consortium edited their review of SETBP1
Intellectual disability SET BRIDGE consortium edited their review of SET
Intellectual disability SEC23B BRIDGE consortium edited their review of SEC23B
Intellectual disability SDHAF1 BRIDGE consortium edited their review of SDHAF1
Intellectual disability SDHA BRIDGE consortium edited their review of SDHA
Intellectual disability SDCCAG8 BRIDGE consortium edited their review of SDCCAG8
Intellectual disability SCO2 BRIDGE consortium edited their review of SCO2
Intellectual disability SCO1 BRIDGE consortium edited their review of SCO1
Intellectual disability SCN9A BRIDGE consortium edited their review of SCN9A
Intellectual disability SCN8A BRIDGE consortium edited their review of SCN8A
Intellectual disability SCN4A BRIDGE consortium edited their review of SCN4A
Intellectual disability SCN2A BRIDGE consortium edited their review of SCN2A
Intellectual disability SCN1B BRIDGE consortium edited their review of SCN1B
Intellectual disability SCN1A BRIDGE consortium edited their review of SCN1A
Intellectual disability SCN11A BRIDGE consortium edited their review of SCN11A
Intellectual disability SCARF2 BRIDGE consortium edited their review of SCARF2
Intellectual disability SCARB2 BRIDGE consortium edited their review of SCARB2
Intellectual disability SC5D BRIDGE consortium edited their review of SC5D
Intellectual disability SBF2 BRIDGE consortium edited their review of SBF2
Intellectual disability SBDS BRIDGE consortium edited their review of SBDS
Intellectual disability SATB2 BRIDGE consortium edited their review of SATB2
Intellectual disability SAMHD1 BRIDGE consortium edited their review of SAMHD1
Intellectual disability SALL4 BRIDGE consortium edited their review of SALL4
Intellectual disability SALL1 BRIDGE consortium edited their review of SALL1
Intellectual disability SACS BRIDGE consortium edited their review of SACS
Intellectual disability RYR1 BRIDGE consortium edited their review of RYR1
Intellectual disability RUNX2 BRIDGE consortium edited their review of RUNX2